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Sample records for antiangiogenic drug assessed

  1. A novel assay to assess the effectiveness of antiangiogenic drugs in human breast cancer.

    Science.gov (United States)

    Many cytotoxic drugs maintain antiangiogenic properties, but there are no human, tumor-based assays to evaluate their antiangiogenic potential. We used a fibrin-thrombin clot-based angiogenesis model to evaluate the angiogenic response of human breast cancer to various cytotoxic agents commonly used...

  2. Antiangiogenic drugs and advanced proliferative diabetic retinopathy

    OpenAIRE

    Jefferson Augusto Santana Ribeiro; André Messias; Rodrigo Jorge

    2011-01-01

    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 disc...

  3. Antiangiogenic cancer drug using the zebrafish model.

    Science.gov (United States)

    Santoro, Massimo M

    2014-09-01

    The process of de novo vessel formation, called angiogenesis, is essential for tumor progression and spreading. Targeting of molecular pathways involved in such tumor angiogenetic processes by using specific drugs or inhibitors is important for developing new anticancer therapies. Drug discovery remains to be the main focus for biomedical research and represents the essence of antiangiogenesis cancer research. To pursue these molecular and pharmacological goals, researchers need to use animal models that facilitate the elucidation of tumor angiogenesis mechanisms and the testing of antiangiogenic therapies. The past few years have seen the zebrafish system emerge as a valid model organism to study developmental angiogenesis and, more recently, as an alternative vertebrate model for cancer research. In this review, we will discuss why the zebrafish model system has the advantage of being a vertebrate model equipped with easy and powerful transgenesis as well as imaging tools to investigate not only physiological angiogenesis but also tumor angiogenesis. We will also highlight the potential of zebrafish for identifying antitumor angiogenesis drugs to block tumor development and progression. We foresee the zebrafish model as an important system that can possibly complement well-established mouse models in cancer research to generate novel insights into the molecular mechanism of the tumor angiogenesis. PMID:24903092

  4. Latest Results for Anti-Angiogenic Drugs in Cancer Treatment

    DEFF Research Database (Denmark)

    Frandsen, Sofie; Kopp, Sascha; Wehland, Markus;

    2016-01-01

    and gastrointestinal cancers. Furthermore, there will be a discussion of unsolved problems, such as lack of biomarkers, drug resistance, and adverse events, for which a solution is necessary in order to improve the benefit of anti-angiogenic drugs in the future. RESULTS: Anti-angiogenic therapy is extensively used...... in the treatment of cancer. There is evidence that drug-induced hypertension serves as a biomarker for a good response to therapy. Currently several possible anti-angiogenic biomarkers are under discussion. Further examples are changes in VEGF or interleukin [IL]-8 polymorphisms, changed plasma levels of VEGF......, or tumor microvessel density. To overcome therapy-associated problems, more research for valid biomarkers is necessary. In addition, a strategy to overcome resistance problems and severe adverse events is desirable. CONCLUSIONS: Clinical trials evaluating targeted therapies with specificity for resistance...

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

    Directory of Open Access Journals (Sweden)

    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.

  6. Comparison of effects of anti-angiogenic agents in the zebrafish efficacy–toxicity model for translational anti-angiogenic drug discovery

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    Chimote G

    2014-08-01

    off-target effects. The predicted therapeutic window was translational with the clinical trial outcomes of the anti-angiogenic agents. The zebrafish efficacy–toxicity approach could stratify anti-angiogenic agents based on the mechanism of action and delineate chemical structure-driven biological activity of anti-angiogenic compounds. Conclusion: The zebrafish efficacy–toxicity approach can be used as a predictive model for translational anti-angiogenic drug discovery to streamline compound selection, resulting in safer and efficacious anti-angiogenic agents entering the clinics. Keywords: angiogenesis, therapeutic window, VEGFR inhibitors, zebrafish toxicity assay

  7. Anti-Angiogenic Drugs: Involvement in Cutaneous Side Effects and Wound-Healing Complication

    OpenAIRE

    Bodnar, Richard J.

    2014-01-01

    Significance: The uses of anti-angiogenic drugs have not only made an impact on the battle to eliminate cancer but are also responsible for a number of medical complications. The long-term use of these drugs has increased the spectrum and incidence of cutaneous side effects and wound-healing complications. It is, therefore, necessary to understand the overall impact that these drugs have on patient care.

  8. Antiangiogenic cancer drug sunitinib exhibits unexpected proangiogenic effects on endothelial cells

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    Norton KA

    2014-09-01

    Full Text Available Kerri-Ann Norton,1 Zheyi Han,1 Aleksander S Popel,1,2 Niranjan B Pandey11Department of Biomedical Engineering, 2Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD, USAAbstract: Angiogenesis, the formation of new blood vessels, is an essential step for cancer progression, but antiangiogenic therapies have shown limited success. Therefore, a better understanding of the effects of antiangiogenic treatments on endothelial cells is necessary. In this study, we evaluate the changes in cell surface vascular endothelial growth factor receptor (VEGFR expression on endothelial cells in culture treated with the antiangiogenic tyrosine kinase inhibitor drug sunitinib, using quantitative flow cytometry. We find that proangiogenic VEGFR2 cell surface receptor numbers are increased with sunitinib treatment. This proangiogenic effect might account for the limited effects of sunitinib as a cancer therapy. We also find that this increase is inhibited by brefeldin A, an inhibitor of protein transport from the endoplasmic reticulum to the Golgi apparatus. The complex dynamics of cell surface VEGFRs may be important for successful treatment of cancer with antiangiogenic therapeutics.Keywords: flow cytometry, VEGFRs, sunitinib, angiogenesis, VEGFA

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

    Science.gov (United States)

    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. PMID:27197162

  10. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance

    Science.gov (United States)

    Boehm, Thomas; Folkman, Judah; Browder, Timothy; O'Reilly, Michael S.

    1997-11-01

    Acquired drug resistance is a major problem in the treatment of cancer. Of the more than 500,000 annual deaths from cancer in the United States, many follow the development of resistance to chemotherapy. The emergence of resistance depends in part on the genetic instability, heterogeneity and high mutational rate of tumour cells. In contrast, endothelial cells are genetically stable, homogenous and have a low mutational rate. Therefore, antiangiogenic therapy directed against a tumour's endothelial cells should, in principle, induce little or no drug resistance. Endostatin, a potent angiogenesis inhibitor, was administered to mice bearing Lewis lung carcinoma, T241 fibrosarcoma or B16F10 melanoma. Treatment was stopped when tumours had regressed. Tumours were then allowed to re-grow and endostatin therapy was resumed. After 6, 4 or 2 treatment cycles, respectively, no tumours recurred after discontinuation of therapy. These experiments show that drug resistance does not develop in three tumour types treated with a potent angiogenesis inhibitor. An unexpected finding is that repeated cycles of antiangiogenic therapy are followed by prolonged tumour dormancy without further therapy.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  13. Alters Intratumoral Drug Distribution and Affects Therapeutic Synergy of Antiangiogenic Organoselenium Compound

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    Youcef M. Rustum

    2010-01-01

    Full Text Available Tumor differentiation enhances morphologic and microvascular heterogeneity fostering hypoxia that retards intratumoral drug delivery, distribution, and compromise therapeutic efficacy. In this study, the influence of tumor biologic heterogeneity on the interaction between cytotoxic chemotherapy and selenium was examined using a panel of human tumor xenografts representing cancers of the head and neck and lung along with tissue microarray analysis of human surgical samples. Tumor differentiation status, microvessel density, interstitial fluid pressure, vascular phenotype, and drug delivery were correlated with the degree of enhancement of chemotherapeutic efficacy by selenium. Marked potentiation of antitumor activity was observed in H69 tumors that exhibited a well-vascularized, poorly differentiated phenotype. In comparison, modulation of chemotherapeutic efficacy by antiangiogenic selenium was generally lower or absent in well-differentiated tumors with multiple avascular hypoxic, differentiated regions. Tumor histomorphologic heterogeneity was found prevalent in the clinical samples studied and represents a primary and critical physiological barrier to chemotherapy.

  14. 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.

  15. Combretastatin A-4 Conjugated Antiangiogenic Micellar Drug Delivery Systems Using Dendron-Polymer Conjugates.

    Science.gov (United States)

    Sumer Bolu, Burcu; Manavoglu Gecici, Ece; Sanyal, Rana

    2016-05-01

    Employment of polymeric nanomaterials in cancer therapeutics is actively pursued since they often enable drug administration with increased efficacy along with reduced toxic side effects. In this study, drug conjugated micellar constructs are fabricated using triblock dendron-linear polymer conjugates where a hydrophilic linear polyethylene glycol (PEG) chain is flanked by well-defined hydrophobic biodegradable polyester dendrons bearing an antiangiogenic drug, combretastatin-A4 (CA4). Variation in dendron generation is utilized to obtain a library of micellar constructs with varying sizes and drug loadings. In particular, a family of drug appended dendron-polymer conjugates based on polyester dendrons of generations ranging from G1 to G3 and 10 kDa linear PEG were obtained using [3 + 2] Huisgen type "click" chemistry. The final constructs benefit from PEG's hydrophilicity and antibiofouling character, as well as biodegradable nature of the hydrophobic polyester dendrons. The hydrophobic-hydrophilic-hydrophobic character of these constructs leads to the formation of flower-like micelles in aqueous media. In addition to generation-dependent subnanomolar range critical micelle concentrations, the resulting micelles possess hydrodynamic diameters suitable for passive tumor targeting through enhanced permeability and retention (EPR) effect; thereby they are suitable candidates as controlled drug delivery agents. For all constructs, in vitro cytotoxicities were investigated and inhibitory effect of Comb-G3-PEG on tube formation was shown on human umbilical vein endothelial cells (HUVECs). PMID:27019335

  16. Raman optical activity spectra and conformational elucidation of chiral drugs. The case of the antiangiogenic aeroplysinin-1.

    Science.gov (United States)

    Nieto-Ortega, Belén; Casado, Juan; Blanch, Ewan W; López Navarrete, Juan T; Quesada, Ana R; Ramírez, Francisco J

    2011-04-01

    We present the determination of the conformational properties of aeroplysinin-1 in aqueous solution by means of a combined experimental and theoretical Raman optical activity (ROA) and vibrational circular dichroism (VCD) study. Aeroplysinin-1 is an antiangiogenic drug extracted from the sponge Aplysina cavernicola which has been proved to be a valuable candidate for the treatment of cancer and other antiangiogenic diseases. Our study shows that this molecule possesses the 1S,6R absolute configuration in aqueous solution, where only two conformers are present to a significant level. We discuss in detail the relationships between the chiro-optical ROA and VCD features, and the structural properties of various energy accessible conformers are described. The present work is one of the first studies in which both ROA and VCD have been used as complementary tools for the determination of absolute configuration and dominant solution-state conformations of an unknown therapeutically significant molecule. PMID:21401047

  17. 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

    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 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...

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

    Science.gov (United States)

    Platania, Chiara B M; Di Paola, Luisa; Leggio, Gian M; Romano, Giovanni L; Drago, Filippo; Salomone, Salvatore; Bucolo, Claudio

    2015-01-01

    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. PMID:26578958

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

    Directory of Open Access Journals (Sweden)

    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.

  20. Response assessment of anti-angiogenic therapy in recurrent high grade gliomas by molecular MR- and Pet- imaging

    International Nuclear Information System (INIS)

    Bevacizumab, a humanized monoclonal antibody inhibiting the biological activity of VEGF, is successfully used as an anti-angiogenic agent in recurrent high grade glioma (rHGG) treatment. Anti-angiogenic therapy, however, causes difficulties in distinguishing between anti-vascular and true anti-tumor effects when using standard MRI criteria, a so-called “pseudo-response”. The aim of this PhD thesis was (1) to evaluate functional and molecular neuroimaging response parameters during anti-angiogenic therapy in rHGG patients and (2) to compare two PET tracers to identify the most promising tracer for further neuroimaging of rHGG with respect to future use during anti-angiogenic treatment. In two independent studies, ADC (apparent diffusion coefficient) maps derived from diffusion-weighted MR images as well as FET-PET (18F-fluoro-ethyl-tyrosine) scans were analysed in rHGG patients at onset of anti-angiogenic treatment and at eight weeks follow-up. ADC histograms demonstrated significant changes in skewness in relation to progression-free survival (PFS6) at six months. Patients with increasing skewness following anti-angiogenic therapy had significantly shorter PFS than did patients with decreasing or stable skewness values. In the second study, MR scans according to RANO criteria (Response assessment in neurooncology) and FET-PET scans independently were able to predict PFS6. In four patients FET-PET was able to detect tumor progression earlier than MRI. In a third study we compared FET and FLT-PET (18F-fluoro-deoxy-thymidine) intra-individually and found that the sensitivity for detecting a HGG was higher for FET than for FLT. FET detected biologically active tumor even beyond the borders of contrast enhancement (CE) in T1 and FLT uptake was absent in tumors with no or moderate CE. In rHGG patients undergoing anti-angiogenic treatment, ADC maps and FET-PET, are predictive of treatment response. They contribute important information to response assessment based

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

    International Nuclear Information System (INIS)

    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-1 100 g-1 at baseline, and decreased to 125.7 ± 86.3 (134.5 ± 150.9) ml min-1 100 g-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 β2-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. Early response assessment in patients with multiple myeloma during anti-angiogenic therapy using arterial spin labelling: first clinical results

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  3. Recent developments in antiangiogenic therapy.

    Science.gov (United States)

    Dredge, Keith; Dalgleish, Angus G; Marriott, J Blake

    2002-12-01

    The use of antiangiogenic therapy is gaining momentum as a novel treatment for a number of conditions, ranging from cancer to psoriasis. This has stemmed from research in the early 1970s showing that the formation of new blood vessels by pre-existing endothelial cells is essential in tumour growth and progression. However, although antiangiogenic therapy was hailed as a new avenue of treatment for cancer, initial clinical data have been disappointing. This has led to the reassessment of antiangiogenic therapy for cancer, and new strategies have been proposed to increase the efficacy of these agents in this setting. Angiogenesis has also been implicated in other conditions that are notoriously difficult to treat, such as arteriosclerosis, arthritis, psoriasis and diabetic retinopathy. Increased understanding of the angiogenic process, the diversity of its inducers and mediators, appropriate drug schedules and the use of these agents with other modalities may lead to radically new treatment regimens for many of these conditions. The role of angiogenesis in different pathological settings, and emerging antiangiogenic agents currently in preclinical and clinical studies are discussed in this review. However, while potential benefits are profound, limitations of antiangiogenic therapy have also been identified, suggesting that there is also a need for caution in applying these compounds to the clinical setting. PMID:12517273

  4. Broad spectrum antiangiogenic treatment for ocular neovascular diseases.

    Directory of Open Access Journals (Sweden)

    Ofra Benny

    Full Text Available UNLABELLED: 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. METHODS AND FINDINGS: 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. CONCLUSIONS: 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

  5. Clinical trials of antiangiogenic therapy for hepatocellular carcinoma.

    Science.gov (United States)

    Taketomi, Akinobu

    2016-04-01

    Angiogenesis is a promising therapeutic target to inhibit tumor growth. This review summarizes data from clinical trials of antiangiogenic agents in hepatocellular carcinoma. A systematic search of PubMed was performed to identify clinical trials of specific antiangiogenic agents in hepatocellular carcinoma treatment, particularly phase III trials involving treatment guidelines for advanced hepatocellular carcinoma. Sorafenib is the only systemic drug approved for the treatment of advanced hepatocellular carcinoma. Two large-scale, randomized phase III trials using sorafenib involving patients with unresectable HCC showed a significant survival benefit compared with placebo control groups. However, subsequent phase III trials of antiangiogenic agents in hepatocellular carcinoma have failed to improve survival compared with standard treatment protocols using sorafenib. The efficacy of antiangiogenic agents in combination with other drugs, transarterial chemoembolization, and surgical resection is currently being investigated. Future research is expected to optimize antiangiogenic therapies in combination with standard treatment with sorafenib. PMID:26899258

  6. Mechanistic Study of Antiangiogenic Agents in Cancer Therapy

    OpenAIRE

    Zhang, Yin

    2013-01-01

    Tumor growth and metastasis are dependent on angiogenesis that constantly alters the tumor microenvironment. Based on the antiangiogenic principle proposed more than 40 years ago by Dr. Judah Folkman, antiangiogenic drugs (ADs) are successfully developed and are routinely used in combination with chemotherapeutics for treatment of various cancers in human patients. However, nearly 10-year clinical experiences with these drugs have taught us some unexpected outcomes that are mec...

  7. Therapeutic application of anti-angiogenic nanomaterials in cancers

    Science.gov (United States)

    Mukherjee, Sudip; Patra, Chitta Ranjan

    2016-06-01

    Angiogenesis, the formation of new blood vessels from pre-existing vasculature, plays a vital role in physiological and pathological processes (embryonic development, wound healing, tumor growth and metastasis). The overall balance of angiogenesis inside the human body is maintained by pro- and anti-angiogenic signals. The processes by which drugs inhibit angiogenesis as well as tumor growth are called the anti-angiogenesis technique, a most promising cancer treatment strategy. Over the last couple of decades, scientists have been developing angiogenesis inhibitors for the treatment of cancers. However, conventional anti-angiogenic therapy has several limitations including drug resistance that can create problems for a successful therapeutic strategy. Therefore, a new comprehensive treatment strategy using antiangiogenic agents for the treatment of cancer is urgently needed. Recently researchers have been developing and designing several nanoparticles that show anti-angiogenic properties. These nanomedicines could be useful as an alternative strategy for the treatment of various cancers using anti-angiogenic therapy. In this review article, we critically focus on the potential application of anti-angiogenic nanomaterial and nanoparticle based drug/siRNA/peptide delivery systems in cancer therapeutics. We also discuss the basic and clinical perspectives of anti-angiogenesis therapy, highlighting its importance in tumor angiogenesis, current status and future prospects and challenges.Angiogenesis, the formation of new blood vessels from pre-existing vasculature, plays a vital role in physiological and pathological processes (embryonic development, wound healing, tumor growth and metastasis). The overall balance of angiogenesis inside the human body is maintained by pro- and anti-angiogenic signals. The processes by which drugs inhibit angiogenesis as well as tumor growth are called the anti-angiogenesis technique, a most promising cancer treatment strategy. Over the

  8. Antiangiogenic therapy for breast cancer

    DEFF Research Database (Denmark)

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

    2010-01-01

    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 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...

  9. Antiangiogenic therapy for breast cancer

    DEFF Research Database (Denmark)

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

    2010-01-01

    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 and...

  10. Imaging Tumor Vascularity and Response to Anti-Angiogenic Therapy Using Gaussia Luciferase.

    Science.gov (United States)

    Kantar, Rami S; Lashgari, Ghazal; Tabet, Elie I; Lewandrowski, Grant K; Carvalho, Litia A; Tannous, Bakhos A

    2016-01-01

    We developed a novel approach to assess tumor vascularity using recombinant Gaussia luciferase (rGluc) protein and bioluminescence imaging. Upon intravenous injection of rGluc followed by its substrate coelenterazine, non-invasive visualization of tumor vascularity by bioluminescence imaging was possible. We applied this method for longitudinal monitoring of tumor vascularity in response to the anti-angiogenic drug tivozanib. This simple and sensitive method could be extended to image blood vessels/vasculature in many different fields. PMID:27198044

  11. Drug assessment: UK style.

    Science.gov (United States)

    2013-12-01

    Before medicines can be marketed in the UK, they are subject to a system of licensing and the granting of a marketing authorisation that describes the conditions and patient groups for which the medicinal product can be used within the terms of its licence.(1) The licensing process involves an assessment of data relating to the efficacy, safety and quality of the product. However, the marketing authorisation does not determine whether, or how, it will be used in clinical practice. In the UK, the National Institute for Health and Care Excellence (NICE), the Scottish Medicines Consortium (SMC) and the All Wales Medicines Strategy Group (AWMSG) publish recommendations on the use of medicines for health services in the United Kingdom. In this article we review their remit, work processes and the status of guidance published in England, Scotland, Wales and Northern Ireland. PMID:24336496

  12. In vitro anti-proliferative and anti-angiogenic activities of thalidomide dithiocarbamate analogs.

    Science.gov (United States)

    El-Aarag, Bishoy Y A; Kasai, Tomonari; Zahran, Magdy A H; Zakhary, Nadia I; Shigehiro, Tsukasa; Sekhar, Sreeja C; Agwa, Hussein S; Mizutani, Akifumi; Murakami, Hiroshi; Kakuta, Hiroki; Seno, Masaharu

    2014-08-01

    Inhibition of angiogenesis is currently perceived as a promising strategy in the treatment of cancer. The anti-angiogenicity of thalidomide has inspired a second wave of research on this teratogenic drug. The present study aimed to investigate the anti-proliferative and anti-angiogenic activities of two thalidomide dithiocarbamate analogs by studying their anti-proliferative effects on human umbilical vein endothelial cells (HUVECs) and MDA-MB-231 human breast cancer cell lines. Their action on the expression levels of IL-6, IL-8, TNF-α, VEGF165, and MMP-2 was also assessed. Furthermore, their effect on angiogenesis was evaluated through wound healing, migration, tube formation, and nitric oxide (NO) assays. Results illustrated that the proliferation of HUVECs and MDA-MB-231 cells was not significantly affected by thalidomide at 6.25-100μM. Thalidomide failed to block angiogenesis at similar concentrations. By contrast, thalidomide dithiocarbamate analogs exhibited significant anti-proliferative action on HUVECs and MDA-MB-231 cells without causing cytotoxicity and also showed powerful anti-angiogenicity in wound healing, migration, tube formation, and NO assays. Thalidomide analogs 1 and 2 demonstrated more potent activity to suppress expression levels of IL-6, IL-8, TNF-α, VEGF165, and MMP-2 than thalidomide. Analog 1 consistently, showed the highest potency and efficacy in all the assays. Taken together, our results support further development and evaluation of novel thalidomide analogs as anti-tumor and anti-angiogenic agents. PMID:24859059

  13. Complementary information from magnetic resonance imaging and {sup 18}F-fluoromisonidazole positron emission tomography in the assessment of the response to an antiangiogenic treatment in a rat brain tumor model

    Energy Technology Data Exchange (ETDEWEB)

    Valable, Samuel, E-mail: valable@cyceron.fr [CERVOxy group, UMR 6232 CI-NAPS. CNRS, Universite de Caen Basse-Normandie, Universite Paris-Descartes, CEA. GIP CYCERON, Bd Henri Becquerel, BP5229, 14074 CAEN cedex (France); Petit, Edwige; Roussel, Simon; Marteau, Lena; Toutain, Jerome; Divoux, Didier [CERVOxy group, UMR 6232 CI-NAPS. CNRS, Universite de Caen Basse-Normandie, Universite Paris-Descartes, CEA. GIP CYCERON, Bd Henri Becquerel, BP5229, 14074 CAEN cedex (France); Sobrio, Franck; Delamare, Jerome; Barre, Louisa [GDM-TEP DSV/I2BM group, UMR 6232 CI-NAPS. CNRS, Universite de Caen Basse-Normandie, Universite Paris-Descartes, CEA. GIP CYCERON, Bd Henri Becquerel, BP5229, 14074 CAEN cedex (France); Bernaudin, Myriam [CERVOxy group, UMR 6232 CI-NAPS. CNRS, Universite de Caen Basse-Normandie, Universite Paris-Descartes, CEA. GIP CYCERON, Bd Henri Becquerel, BP5229, 14074 CAEN cedex (France)

    2011-08-15

    Introduction: No direct proof has been brought to light in a link between hypoxic changes in glioma models and the effects of antiangiogenic treatments. Here, we assessed the sensitivity of the detection of hypoxia through the use of {sup 18}F-fluoromisonidazole positron emission tomography ([{sup 18}F]-FMISO PET) in response to the evolution of the tumor and its vasculature. Methods: Orthotopic glioma tumors were induced in rats after implantation of C6 or 9L cells. Sunitinib was administered from day (D) 17 to D24. At D17 and D24, multiparametric magnetic resonance imaging was performed to characterize tumor growth and vasculature. Hypoxia was assessed by [{sup 18}F]-FMISO PET. Results: We showed that brain hypoxic volumes are related to glioma volume and its vasculature and that an antiangiogenic treatment, leading to an increase in cerebral blood volume and a decrease in vessel permeability, is accompanied by a decrease in the degree of hypoxia. Conclusions: We propose that [{sup 18}F]-FMISO PET and multiparametric magnetic resonance imaging are pertinent complementary tools in the evaluation of the effects of an antiangiogenic treatment in glioma.

  14. Complementary information from magnetic resonance imaging and 18F-fluoromisonidazole positron emission tomography in the assessment of the response to an antiangiogenic treatment in a rat brain tumor model

    International Nuclear Information System (INIS)

    Introduction: No direct proof has been brought to light in a link between hypoxic changes in glioma models and the effects of antiangiogenic treatments. Here, we assessed the sensitivity of the detection of hypoxia through the use of 18F-fluoromisonidazole positron emission tomography ([18F]-FMISO PET) in response to the evolution of the tumor and its vasculature. Methods: Orthotopic glioma tumors were induced in rats after implantation of C6 or 9L cells. Sunitinib was administered from day (D) 17 to D24. At D17 and D24, multiparametric magnetic resonance imaging was performed to characterize tumor growth and vasculature. Hypoxia was assessed by [18F]-FMISO PET. Results: We showed that brain hypoxic volumes are related to glioma volume and its vasculature and that an antiangiogenic treatment, leading to an increase in cerebral blood volume and a decrease in vessel permeability, is accompanied by a decrease in the degree of hypoxia. Conclusions: We propose that [18F]-FMISO PET and multiparametric magnetic resonance imaging are pertinent complementary tools in the evaluation of the effects of an antiangiogenic treatment in glioma.

  15. 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

    2016-07-01

    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. PMID:27264671

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

    International Nuclear Information System (INIS)

    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/m2) 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

  17. Issues on fit-for-purpose validation of a panel of ELISAs for application as biomarkers in clinical trials of anti-Angiogenic drugs

    OpenAIRE

    Brookes, K; Cummings, J; Backen, A; Greystoke, A; Ward, T.; Jayson, G C; Dive, C

    2010-01-01

    Background: Successful introduction of new anticancer agents into the clinic is often hampered by a lack of qualified biomarkers. Studies have been conducted of 17 ELISAs representing a potential panel of pharmacodynamic/predictive biomarkers for drugs targeted to tumour vasculature. Methods: The fit-for-purpose approach to method validation was used. Stability studies were performed using recombinant proteins in surrogate matrices, endogenous analytes in healthy volunteer and cancer patient ...

  18. Sharks: a potential source of antiangiogenic factors and tumor treatments.

    Science.gov (United States)

    Cho, Jung; Kim, Young

    2002-12-01

    Since angiogenesis is a key feature of tumor growth, inhibiting this process is one way to treat cancer. Cartilage is a natural source of material with strong antiangiogenic activity. This report reviews knowledge of the anticancer properties of shark cartilage and clinical information on drugs such as neovastat and squalamine. Because their entire endoskeleton is composed of cartilage, sharks are thought to be an ideal source of angiogenic and tumor growth inhibitors. Shark cartilage extract has shown antiangiogenic and antitumor activities in animals and humans. The oral administration of cartilage extract was efficacious in reducing angiogenesis. Purified antiangiogenic factors from shark cartilage, such as U-995 and neovastat (AE-941), also showed antiangiogenic and antitumor activity. AE-941 is under phase III clinical investigation. Squalamine, a low molecular weight aminosterol, showed strong antitumor activity when combined with chemotherapeutic materials. The angiogenic tissue inhibitor of metalloprotease 3 (TIMP-3) and tumor suppressor protein (snm23) genes from shark cartilage were cloned and characterized. PMID:14961226

  19. Angiogenesis and Anti-Angiogenic Treatments

    Directory of Open Access Journals (Sweden)

    Ersin Demirer

    2013-10-01

    Full Text Available Blood vessels in our body is developed by vasculogenesis and angiogenesis. There have been new advances in molecular pathology and tumor biology areas in recent years. Angiogenesis is modulated by the balance between angiogenic and anti-angiogenic factors. Angiogenesis plays a key role in tumor growth. Drugs inhibiting angiogenesis have been in use in various malign or non-malign diseases. Inhibition of angiogenesis in malign diseases is a very attractive subject in medicine and studies are going on about long term affects and toxicities. Inhibition of angiogenesis is not an only treatment choice alone. It is a supplemental treatment option applied with conventional chemotherapy, radiotherapy, surgery, immunotherapy and hormonal therapy. It has been used in colorectal carcinoma, renal cell carcinoma, non-small cell lung cancer, glioblastoma, heoatocellular carcinoma, pancreatic neuroendocrine tumor, tyroid medullary cancer.

  20. 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...... the technique. Furthermore, it has been indicated that cutaneous microdialysis in rats may be useful for prediction of dermal pharmacokinetic properties of novel drugs/topical formulations in man....

  1. 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...... normal human dermal fibroblasts. Interestingly, the cluster morphology caused by N-methyllevamisole was different than the clusters observed for levamisole, and a third "cord-like" morphology resembling that of the known drug suramin was observed for an aniline-containing derivative. New chemotypes...

  2. Antiangiogenic Effect of Oyster Polypeptide (OPP

    Directory of Open Access Journals (Sweden)

    Zhenhua WANG

    2009-08-01

    Full Text Available Background and objective Drugs which block tumor angiogenesis will be likely effective towards inhibiting tumor growth for angiogenesis being a prerequisite for tumor growth and metastasis. Therefore, antiangiogenesis has become a promising strategy for the treatment of cancer. Investigation on both antiangiogenic effect and mechanism(s of oyster polypeptide (OPP were performed via experiments of chicken embryos model in vivo and human umbilical vein endothelial cells (HUVECs in vitro. Methods The methods employed in experiment were chorioallantoic membrane (CAM angiogenesis in chicken embryos in vivo, MTT cell survival assay, flat plate scarification, transwell plates assay, matrigel-induced tube formation assay and transmission electron microscope et al. and the OPP’s effects on angiogenesis was observed. Results Study showed that treatment with OPP resulted in significant inhibition of chorioallantoic membrane (CAM angiogenesis in chicken embryos. MTT cell survival assay showed that treatment with OPP resulted in strong inhibition of HUVECs growth, with an IC50 of 400 μg/mL. Flat plate scarification suggested that OPP (200 μg/mL, 400 μg/mL and 800 μg/mL distinctly inhibited HUVECs’ migration (18.75%, 37.93%, 74.07% respectively, treatment for 12 h. Treatment with OPP of different concentrations (200 μg/mL, 400 μg/mL and 800 μg/mL significantly reduced the density of the migration cells by 15.5%, 37.2% and 67.24% (P<0.05 respectively. Matrigel-induced tube formation assay showed that OPP resulted in striking inhibition of tube formation of 52.43%, 84.47% and 96.12% (P<0.01 at 200 μg/mL, 400 μg/mL and 800 μg/mL (treatment for 10 h respectively. In addition, the apoptotic analysis by transmission electron microscope showed that OPP (400 μg/mL, treatment for 48 h distinctly induced HUVECs’ apoptosis. Conclusion This study strikingly showed that OPP could inhibit angiogenesis through its effects on vascular endothelial cells

  3. Assessing Specificity of Anticancer Drugs In Vitro.

    Science.gov (United States)

    Kluwe, Lan

    2016-01-01

    A procedure for assessing specificity of anticancer drugs in vitro using cultures containing both tumor and non-tumor cells is demonstrated. The key element is the quantitative determination of a tumor-specific genetic alteration in relation to a universal sequence using a dual-probe digital PCR assay and the subsequent calculation of the proportion of tumor cells. The assay is carried out on a culture containing tumor cells of an established line and spiked-in non-tumor cells. The mixed culture is treated with a test drug at various concentrations. After the treatment, DNA is prepared directly from the survived adhesive cells in wells of 96-well plates using a simple and inexpensive method, and subjected to a dual-probe digital PCR assay for measuring a tumor-specific genetic alteration and a reference universal sequence. In the present demonstration, a heterozygous deletion of the NF1 gene is used as the tumor-specific genetic alteration and a RPP30 gene as the reference gene. Using the ratio NF1/RPP30, the proportion of tumor cells was calculated. Since the dose-dependent change of the proportion of tumor cells provides an in vitro indication for specificity of the drug, this genetic and cell-based in vitro assay will likely have application potential in drug discovery. Furthermore, for personalized cancer-care, this genetic- and cell-based tool may contribute to optimizing adjuvant chemotherapy by means of testing efficacy and specificity of candidate drugs using primary cultures of individual tumors. PMID:27078035

  4. Preeclampsia and the Anti-Angiogenic State

    OpenAIRE

    Agarwal, Isha; Karumanchi, S. Ananth

    2011-01-01

    Preeclampsia is a major cause of maternal and fetal morbidity and mortality worldwide, however, its etiology remains unclear. Abnormal placental angiogenesis during pregnancy resulting from high levels of anti-angiogenic factors, soluble Flt1 (sFlt1) and soluble endoglin (sEng), has been implicated in preeclampsia pathogenesis. Accumulating evidence also points to a role for these anti-angiogenic proteins as serum biomarkers for the clinical diagnosis and prediction of preeclampsia. Uncoverin...

  5. Antiangiogenic gene therapy of cancer: recent developments

    OpenAIRE

    Libutti Steven K; Blazer Dan G; Tandle Anita

    2004-01-01

    Abstract With the role of angiogenesis in tumor growth and progression firmly established, considerable effort has been directed to antiangiogenic therapy as a new modality to treat human cancers. Antiangiogenic agents have recently received much widespread attention but strategies for their optimal use are still being developed. Gene therapy represents an attractive alternative to recombinant protein administration for several reasons. This review evaluates the potential advantages of gene t...

  6. Assessing the proarrhythmic potential of drugs

    DEFF Research Database (Denmark)

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

    2006-01-01

    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...... models is emphasised in the present paper. It is feasible for the pharmaceutical industry to establish one or more of these proarrhythmic animal models and large benefits are potentially available if pharmaceutical industries and patient-care authorities embraced these models. Furthermore, suggested...

  7. Potentiation of radiotherapy by a localized antiangiogenic gene therapy

    International Nuclear Information System (INIS)

    Background and purpose: We hypothesized that electrotransfer of a plasmid encoding an antiangiogenic factor, the recombinant disintegrin domain of ADAM-15, (pRDD) could modify the tumor microenvironment and radiosensitize tumor. Materials and methods: pRDD was injected in the TLT tumor or FSaII fibrosarcomas before electroporation. pO2 in tumors and oxygen consumption in vitro were measured by electronic paramagnetic resonance (EPR) oximetry. Tumor perfusion was assessed by laser doppler imaging and patent blue assay. Results: pRDD electrotransfer caused a significant delay in TLT growth and an anti-angiogenic effect. It significantly increased tumor pO2 in TLT and FSaII for at least 4 days. pRDD electrotransfer and radiotherapy were more effective than either treatment alone. Modifications of tumor microenvironment were evaluated: tumor perfusion and interstitial fluid pressure were not modified. Oxygen consumption by the cells was decreased resulting both from a decrease in oxygen consumption rate and from a decrease in cell viability. Conclusion: The combination of localized antiangiogenic gene therapy and radiotherapy applied in the time of maximal oxygenation could be a promising alternative for cancer treatment

  8. Antiangiogenic Steroids in Human Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Richard J. Pietras

    2005-01-01

    Full Text Available Despite advances in the early detection of tumors and in the use of chemotherapy, radiotherapy and surgery for disease management, the worldwide mortality from human cancer remains unacceptably high. The treatment of cancer may benefit from the introduction of novel therapies derived from natural products. Natural products have served to provide a basis for many of the pharmaceutical agents in current use in cancer therapy. Emerging research indicates that progressive growth and spread of many solid tumors depends, in part, on the formation of an adequate blood supply, and this process of tumor-associated angiogenesis is reported to have prognostic significance in several human cancers. This review focuses on the potential application in antitumor therapy of naturally-occurring steroids that target tumor-associated angiogenesis. Squalamine, a 7,24 dihydroxylated 24-sulfated cholestane steroid conjugated to a spermidine at position C-3, is known to have strong antiangiogenic activity in vitro, and it significantly disrupts tumor proliferation and progression in laboratory studies. Work on the interactions of squalamine with vascular endothelial cells indicate that it binds with cell membranes, inhibits the membrane Na+/H+ exchanger and may further function as a calmodulin chaperone. These primary actions appear to promote inhibition of several vital steps in angiogenesis, such as blockade of mitogen-induced actin polymerization, cell–cell adhesion and cell migration, leading to suppression of endothelial cell proliferation. Preclinical studies with squalamine have shown additive benefits in tumor growth delay when squalamine is combined with cisplatin, paclitaxel, cyclophosphamide, genistein or radiation therapy. This compound has also been assessed in early phase clinical trials in cancer; squalamine was found to exhibit little systemic toxicity and was generally well tolerated by treated patients with various solid tumor malignancies

  9. Antiangiogenic Steroids in Human Cancer Therapy.

    Science.gov (United States)

    Pietras, Richard J; Weinberg, Olga K

    2005-03-01

    Despite advances in the early detection of tumors and in the use of chemotherapy, radiotherapy and surgery for disease management, the worldwide mortality from human cancer remains unacceptably high. The treatment of cancer may benefit from the introduction of novel therapies derived from natural products. Natural products have served to provide a basis for many of the pharmaceutical agents in current use in cancer therapy. Emerging research indicates that progressive growth and spread of many solid tumors depends, in part, on the formation of an adequate blood supply, and this process of tumor-associated angiogenesis is reported to have prognostic significance in several human cancers. This review focuses on the potential application in antitumor therapy of naturally-occurring steroids that target tumor-associated angiogenesis. Squalamine, a 7,24 dihydroxylated 24-sulfated cholestane steroid conjugated to a spermidine at position C-3, is known to have strong antiangiogenic activity in vitro, and it significantly disrupts tumor proliferation and progression in laboratory studies. Work on the interactions of squalamine with vascular endothelial cells indicate that it binds with cell membranes, inhibits the membrane Na(+)/H(+) exchanger and may further function as a calmodulin chaperone. These primary actions appear to promote inhibition of several vital steps in angiogenesis, such as blockade of mitogen-induced actin polymerization, cell-cell adhesion and cell migration, leading to suppression of endothelial cell proliferation. Preclinical studies with squalamine have shown additive benefits in tumor growth delay when squalamine is combined with cisplatin, paclitaxel, cyclophosphamide, genistein or radiation therapy. This compound has also been assessed in early phase clinical trials in cancer; squalamine was found to exhibit little systemic toxicity and was generally well tolerated by treated patients with various solid tumor malignancies, including ovarian, non

  10. Antioxidant and antiangiogenic activities of the essential oils of Myristica fragrans and Morinda citrifolia

    Institute of Scientific and Technical Information of China (English)

    Suthagar Pillai Piaru; Roziahanim Mahmud; Amin Malik Shah Abdul Majid; Zeyad Daoud Mahmoud Nassar

    2012-01-01

    ABSTRACT Objective:Toinvestigate the anti-angiogenic activity and antioxidant properties ofMyristica fragrans (M. fragrans) (nutmeg) andMorinda citrifolia (M. citrifolia)(mengkudu) oils. Methods: The nutmeg and megkudu essential oils were obtained by steam distillation. The antioxidant activities of both essential oils were determined by beta-carotene/linoleic acid bleaching assay and reducing power while the anti-angiogenic activity was investigated using rat aortic ring assay using various concentrations.Results:The results showed that nutmeg oil has higher antioxidant activity than mengkudu oil. The nutmeg oil effectively inhibited the oxidation of linoleic acid with (88.68±0.1)% while the inhibition percentage of oxidation of linoleic acid of the mengkudu oil is (69.44±0.4)%. The nutmeg oil and mengkudu oil showed reducing power with anEC50 value of 181.4 μg/mL and 3 043.0μg/mL, respectively. The antiangiogenic activity of nutmeg oil showed significant antiangiogenic activity withIC50 of77.64μg/mL comparing to mengkudu oil which exhibits IC50 of109.30 μg/mL.Conclusion: Bioactive compound(s) will be isolated from the nutmeg essential oil to be developed as antiangiogenic drugs.

  11. Assessment of the consistency among three drug compendia in listing and ranking of drug-drug interactions

    Science.gov (United States)

    Nikolić, Božana S.; Ilić, Maja S.

    2013-01-01

    Inconsistent information about drug-drug interactions can cause variations in prescribing, and possibly increase the incidence of morbidity and mortality. The aim of this study was to assess whether there is an inconsistency in drug-drug interaction listing and ranking in three authoritative, freely accessible online drug information sources: The British National Formulary; The Compendium about Drugs Licensed for Use in the United Kingdom (the Electronic Medicines Compendium) and the Compendium about Drugs Licensed for Use in the United States (the DailyMed). Information on drug-drug interactions for thirty drugs which have a high or medium potential for interactions have been selected for analysis. In total, 1971 drug-drug interactions were listed in all three drug information sources, of these 992 were ranked as the interactions with the potential of clinical significance. Comparative analysis identified that 63.98% of interactions were listed in only one drug information source, and 66.63% of interactions were ranked in only one drug information source. Only 15.12% listed and 11.19% ranked interactions were identified in all three information sources. Intraclass correlation coefficient indicated a weak correlation among the three drug information sources in listing (0.366), as well as in ranking drug interactions (0.467). This study showed inconsistency of information on drug-drug interaction for the selected drugs in three authoritative, freely accessible online drug information sources. The application of a uniform methodology in assessment of information, and then the presentation of information in a standardized format is required to prevent and adequately manage drug-drug interactions. PMID:24289762

  12. Concerns about anti-angiogenic treatment in patients with glioblastoma multiforme

    International Nuclear Information System (INIS)

    The relevance of angiogenesis inhibition in the treatment of glioblastoma multiforme (GBM) should be considered in the unique context of malignant brain tumours. Although patients benefit greatly from reduced cerebral oedema and intracranial pressure, this important clinical improvement on its own may not be considered as an anti-tumour effect. GBM can be roughly separated into an angiogenic component, and an invasive or migratory component. Although this latter component seems inert to anti-angiogenic therapy, it is of major importance for disease progression and survival. We reviewed all relevant literature. Published data support that clinical symptoms are tempered by anti-angiogenic treatment, but that tumour invasion continues. Unfortunately, current imaging modalities are affected by anti-angiogenic treatment too, making it even harder to define tumour margins. To illustrate this we present MRI, biopsy and autopsy specimens from bevacizumab-treated patients. Moreover, while treatment of other tumour types may be improved by combining chemotherapy with anti-angiogenic drugs, inhibiting angiogenesis in GBM may antagonise the efficacy of chemotherapeutic drugs by normalising the blood-brain barrier function. Although angiogenesis inhibition is of considerable value for symptom reduction in GBM patients, lack of proof of a true anti-tumour effect raises concerns about the place of this type of therapy in the treatment of GBM

  13. Post-authorisation assessment of orphan drugs

    NARCIS (Netherlands)

    C.E.M. Hollak; M. Biegstraaten; M. Levi; R. Hagendijk

    2015-01-01

    The EU regulation of orphan drugs has promoted the development of new treatments for rare disorders.1 However, the high cost of most orphan drugs threatens the sustainability of public health care. Unfortunately, the effectiveness of treatment is often unclear for part, if not all, of the patient po

  14. Adeno-associated virus-mediated delivery of antiangiogenic factors as an antitumor strategy.

    Science.gov (United States)

    Nguyen, J T; Wu, P; Clouse, M E; Hlatky, L; Terwilliger, E F

    1998-12-15

    Antiangiogenic tumor therapies have recently attracted intense interest for their broad-spectrum action, low toxicity, and, in the case of direct endothelial targeting, an absence of drug resistance. To promote tumor regression and to maintain dormancy, antiangiogenic agents need to be chronically administered. Gene therapy offers a potential way to achieve sustained therapeutic release of potent antiangiogenic substances. As a step toward this goal, we have generated recombinant adeno-associated virus (rAAV) vectors that carry genes coding for angiostatin, endostatin, and an antisense mRNA species against vascular endothelial growth factor (VEGF). These rAAVs efficiently transduced three human tumor cell lines tested. Transduction with an rAAV-encoding antisense VEGF mRNA inhibited the production of endogenous tumor cell VEGF. Conditioned media from cells transduced with this rAAV or with rAAV-expressing endostatin or angiostatin inhibited capillary endothelial cell proliferation in vitro. Antiangiogenic rAAVs may offer a novel gene therapy approach to undermining tumor neovascularization and cancer progression. PMID:9865720

  15. Assessment and diffusion of biotechnology drugs

    NARCIS (Netherlands)

    Zwart-van Rijkom, J.E.F.

    2002-01-01

    Biotechnology, viewed as a young and innovative field, is associated with great possibilities and high expectation on patient benefits. But there are also public controversies on ethical, social and economic issues. Beginning with recombinant human insulin in 1982, more than 50 biotechnology drugs h

  16. 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.)

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

    International Nuclear Information System (INIS)

    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. Quantitative methods to support drug benefit-risk assessment

    OpenAIRE

    Caster, Ola

    2014-01-01

    Joint evaluation of drugs’ beneficial and adverse effects is required in many situations, in particular to inform decisions on initial or sustained marketing of drugs, or to guide the treatment of individual patients. This synthesis, known as benefit-risk assessment, is without doubt important: timely decisions supported by transparent and sound assessments can reduce mortality and morbidity in potentially large groups of patients. At the same time, it can be hugely complex: drug effects are ...

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

    OpenAIRE

    Mahender Kyadari; Tasneem Fatma; Rajvardhan Azad; Thirumurthy Velpandian

    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...

  20. Marine sponge as a source of antiangiogenic compounds. The case of aeroplysinin-1

    OpenAIRE

    Quesada, AR; Martínez-Poveda, B.; Rodríguez-Nieto, S; Medina, MA

    2014-01-01

    The vast majority of the natural compounds that have been previously described as inhibitors of angiogenesis have been isolated from plants and terrestrial microorganisms, mainly due to their higher availability and because their therapeutic effects had been previously known in folk traditional medicines. However, increasing attention is being paid to the development of marine-derived antiangiogenic agents, probably fuelled by the increase in the number of marine-derived anticancer drugs whic...

  1. Non-invasive imaging for studying anti-angiogenic therapy effects

    OpenAIRE

    Ehling, J.; Lammers, T.; Kiessling, F.

    2013-01-01

    Noninvasive imaging plays an emerging role in preclinical and clinical cancer research and has high potential to improve clinical translation of new drugs. This article summarises and discusses tools and methods to image tumour angiogenesis and monitor anti-angiogenic therapy effects. In this context, micro-computed tomography (µCT) is recommended to visualise and quantify the micro-architecture of functional tumour vessels. Contrast-enhanced ultrasound (US) and magnetic resonance imaging (MR...

  2. 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...

  3. 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

  4. 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.

  5. Anti-angiogenic therapy (bevacizumab) in the management of oral lichen planus.

    Science.gov (United States)

    Mahmoud, Maha M; Afifi, Marwa M

    2016-04-01

    Oral lichen planus (OLP), a mucocutaneous chronic inflammatory disease, is conventionally managed using topical corticosteroid therapy. Given the fact that OLP is strongly linked to angiogenesis, anti-angiogenic drugs, such as bevacizumab, might be introduced as an alternative treatment for contraindicated, non-responsive patients. The aim of the present study was to report the short-term effectiveness and safety of intralesional bevacizumab injection in the management of atrophic/erosive OLP. A case series study was conducted in patients with atrophic/erosive OLP in the buccal mucosa, assigned to receive either 2.5 mg of bevacizumab, by intralesional injection (n = 20, test), or topical 0.1% triamcinolone acetonide ointment (n = 20, control). The size, score, and pain intensity of the lesions were assessed pre- and post-treatment. Tissue biopsies were collected for histopathologic, immunohistochemical, and ultrastructural examination. After 1 wk, the test group had significant reductions both in lesion seize and in pain scores compared with controls. A marked decrease in vascular endothelial growth factor (VEGF) and interleukin-8 immunoexpression was noted in tissue biopsies from bevacizumab-treated lesions compared with control lesions. Furthermore, ultrastructural examination of OLP tissue specimens revealed significant healing signs associated with bevacizumab treatment. Short-term data suggest that intralesional bevacizumab injection effectively and safely achieved resolution of atrophic/erosive OLP lesions without disease exacerbations during a 3-month follow-up period. PMID:26892241

  6. Environmental risk assessment of pharmaceutical drug substances - conceptual considerations

    OpenAIRE

    Länge, Reinhard; Dietrich, Daniel R

    2002-01-01

    Drugs, i.e. active ingredients of human medicinal products, may be introduced into the environment after use in patients by sewage effluent pathways and consequently are detected at low concentrations in sewage effluents and in surface waters. Legal requirements in a number of geographical regions (Europe, US, and intended in Canada) demand environmental risk assessments (ERA) for new drug substances. Existing regulatory concepts of ERA are based initially on a set of short-term ecotoxicologi...

  7. Bioluminescence for Assessing Drug Potency against Nonreplicating Mycobacterium tuberculosis

    OpenAIRE

    Vocat, Anthony; Hartkoorn, Ruben C; Lechartier, Benoit; Zhang, Ming; Dhar, Neeraj; Cole, Stewart T.; Sala, Claudia

    2015-01-01

    Targeting dormant Mycobacterium tuberculosis represents a challenge to antituberculosis drug discovery programs. We previously reported and validated the use of the streptomycin (STR)-dependent M. tuberculosis 18b strain as a tool for assessing drug potency against nonreplicating bacteria both in vitro and in vivo. In this study, we generated a luminescent 18b strain, named 18b-Lux, by transforming the bacteria with a vector expressing the luxCDABE operon from Photorhabdus luminescens. Lucife...

  8. Physiologically based pharmacokinetic modeling for assessing the clinical drug-drug interaction of alisporivir.

    Science.gov (United States)

    Xia, Binfeng; Barve, Avantika; Heimbach, Tycho; Zhang, Tao; Gu, Helen; Wang, Lai; Einolf, Heidi; Alexander, Natalya; Hanna, Imad; Ke, June; Mangold, James B; He, Handan; Sunkara, Gangadhar

    2014-10-15

    Alisporivir is a novel cyclophilin-binding molecule with potent anti-hepatitis C virus (HCV) activity. In vitro data from human liver microsomes suggest that alisporivir is a substrate and a time-dependent inhibitor (TDI) of CYP3A4. The aim of the current work was to develop a novel physiologically based pharmacokinetic (PBPK) model to quantitatively assess the magnitude of CYP3A4 mediated drug-drug interactions with alisporivir as the substrate or victim drug. Towards that, a Simcyp PBPK model was developed by integrating in vitro data with in vivo clinical findings to characterize the clinical pharmacokinetics of alisporivir and further assess the magnitude of drug-drug interactions. Incorporated with absorption, distribution, elimination, and TDI data, the model accurately predicted AUC, Cmax, and tmax values after single or multiple doses of alisporivir with a prediction deviation within ± 32%. The model predicted an alisporivir AUC increase by 9.4-fold and a decrease by 86% when alisporivir was co-administrated with ketoconazole (CYP3A4 inhibitor) or rifampin (CYP3A4 inducer), respectively. Predictions were within ± 20% of the observed changes. In conclusion, the PBPK model successfully predicted the alisporivir PK and the magnitude of drug-drug interactions. PMID:25008118

  9. Anti-angiogenic activity of gecko aqueous extracts and its macromolecular components in CAM and HUVE-12 cells.

    Science.gov (United States)

    Tang, Zhen; Huang, Shu-Qiong; Liu, Jian-Ting; Jiang, Gui-Xiang; Wang, Chun-Mei

    2015-01-01

    Gecko is a kind of traditional Chinese medicine with remarkable antineoplastic activity. However, undefined mechanisms and ambiguity regarding active ingredients limit new drug development from gecko. This study was conducted to assess anti-angiogenic properties of the aqueous extracts of fresh gecko (AG) or macromolecular components separated from AG (M-AG). An enzyme-linked immunosorbent assay (ELISA) approach was applied to detect the vascular endothelial growth factor (VEGF) secretion of the tumor cells treated with AG or M-AG. The effect of AG or M-AG on vascular endothelial cell proliferation and migratory ability was analyzed by tetrazolium dye colorimetric method, transwell and wound-healing assays. Chick embryo chorioallantoic membrane (CAM) assays were used to ensure the anti-angiogenic activity of M-AG in vivo. The results showed that AG or M-AG inhibited the VEGF secretion of tumor cells, the relative inhibition rates of AG and M-AG being 27.2% and 53.2% respectively at a concentration of 20 μL/mL. AG and M-AG inhibited the vascular endothelial (VE) cell proliferation with IC50 values of 11.5 ± 0.5 μL/mL and 12.9 ± 0.4 μL/mL respectively. The VE cell migration potential was inhibited significantly (p<0.01) by the AG (≥ 24 μL/mL) or M-AG (≥ 12 μL/ mL) treatment. In vivo, neovascularization of CAM treated with M-AG was inhibited significantly (p<0.05) at a concentration of 0.4 μL/mL. This study provided evidence that anti-angiogenesis is one of the anti-tumor mechanisms of AG and M-AG, with the latter as a promising active component. PMID:25773854

  10. MO-G-BRF-05: Determining Response to Anti-Angiogenic Therapies with Monte Carlo Tumor Modeling

    Energy Technology Data Exchange (ETDEWEB)

    Valentinuzzi, D [Jozef Stefan Institute, Ljubljana (Slovenia); Simoncic, U; Jeraj, R [Jozef Stefan Institute, Ljubljana (Slovenia); University of Wisconsin, Madison, WI (United States); Titz, B [University of Wisconsin, Madison, WI (United States)

    2014-06-15

    Purpose: Patient response to anti-angiogenic therapies with vascular endothelial growth factor receptor - tyrosine kinase inhibitors (VEGFR TKIs) is heterogeneous. This study investigates key biological characteristics that drive differences in patient response via Monte Carlo computational modeling capable of simulating tumor response to therapy with VEGFR TKI. Methods: VEGFR TKIs potently block receptors, responsible for promoting angiogenesis in tumors. The model incorporates drug pharmacokinetic and pharmacodynamic properties, as well as patientspecific data of cellular proliferation derived from [18F]FLT-PET data. Sensitivity of tumor response was assessed for multiple parameters, including initial partial oxygen tension (pO{sub 2}), cell cycle time, daily vascular growth fraction, and daily vascular regression fraction. Results were benchmarked to clinical data (patient 2 weeks on VEGFR TKI, followed by 1-week drug holiday). The tumor pO{sub 2} was assumed to be uniform. Results: Among the investigated parameters, the simulated proliferation was most sensitive to the initial tumor pO{sub 2}. Initial change of 5 mmHg can already Result in significantly different levels of proliferation. The model reveals that hypoxic tumors (pO{sub 2} ≥ 20 mmHg) show the highest decrease of proliferation, experiencing mean FLT standardized uptake value (SUVmean) decrease for at least 50% at the end of the clinical trial (day 21). Oxygenated tumors (pO{sub 2} 20 mmHg) show a transient SUV decrease (30–50%) at the end of the treatment with VEGFR TKI (day 14) but experience a rapid SUV rebound close to the pre-treatment SUV levels (70–110%) at the time of a drug holiday (day 14–21) - the phenomenon known as a proliferative flare. Conclusion: Model's high sensitivity to initial pO{sub 2} clearly emphasizes the need for experimental assessment of the pretreatment tumor hypoxia status, as it might be predictive of response to antiangiogenic therapies and the occurrence

  11. MO-G-BRF-05: Determining Response to Anti-Angiogenic Therapies with Monte Carlo Tumor Modeling

    International Nuclear Information System (INIS)

    Purpose: Patient response to anti-angiogenic therapies with vascular endothelial growth factor receptor - tyrosine kinase inhibitors (VEGFR TKIs) is heterogeneous. This study investigates key biological characteristics that drive differences in patient response via Monte Carlo computational modeling capable of simulating tumor response to therapy with VEGFR TKI. Methods: VEGFR TKIs potently block receptors, responsible for promoting angiogenesis in tumors. The model incorporates drug pharmacokinetic and pharmacodynamic properties, as well as patientspecific data of cellular proliferation derived from [18F]FLT-PET data. Sensitivity of tumor response was assessed for multiple parameters, including initial partial oxygen tension (pO2), cell cycle time, daily vascular growth fraction, and daily vascular regression fraction. Results were benchmarked to clinical data (patient 2 weeks on VEGFR TKI, followed by 1-week drug holiday). The tumor pO2 was assumed to be uniform. Results: Among the investigated parameters, the simulated proliferation was most sensitive to the initial tumor pO2. Initial change of 5 mmHg can already Result in significantly different levels of proliferation. The model reveals that hypoxic tumors (pO2 ≥ 20 mmHg) show the highest decrease of proliferation, experiencing mean FLT standardized uptake value (SUVmean) decrease for at least 50% at the end of the clinical trial (day 21). Oxygenated tumors (pO2 20 mmHg) show a transient SUV decrease (30–50%) at the end of the treatment with VEGFR TKI (day 14) but experience a rapid SUV rebound close to the pre-treatment SUV levels (70–110%) at the time of a drug holiday (day 14–21) - the phenomenon known as a proliferative flare. Conclusion: Model's high sensitivity to initial pO2 clearly emphasizes the need for experimental assessment of the pretreatment tumor hypoxia status, as it might be predictive of response to antiangiogenic therapies and the occurrence of proliferative flare. Experimental

  12. Improved survival of mice bearing liver metastases of colon cancer cells treated with a combination of radioimmunotherapy and antiangiogenic therapy

    International Nuclear Information System (INIS)

    We attempted to determine whether the combined regimen of radioimmunotherapy (RIT) and antiangiogenic therapy would favorably affect the survival of animals bearing liver metastases of colon cancer cells. Daily antiangiogenic therapy with 2-methoxyestradiol (2-ME), 75 mg/kg, was initiated at 3 days following intrasplenic cell inoculation of LS180 colon cancer cells. RIT with 7 MBq of 131I-A7, an IgG1 anti-colorectal monoclonal antibody, or 131I-HPMS-1, an irrelevant IgG1, was conducted at 7 days. Production of vascular endothelial growth factor (VEGF) by LS180 cells was assessed in vitro. All nontreated mice died by 31 days following cell inoculation (n=5). Monotherapy comprising 2-ME treatment resulted in slightly better survival of mice (n=8) (P131I-A7 RIT displayed a marked therapeutic effect (n=8) (P131I-A7 RIT and antiangiogenic therapy demonstrated a superior therapeutic effect in comparison to monotherapy consisting of either RIT or antiangiogenic therapy (n=10) (P131I-HPMS-1 RIT failed to provide an appreciable benefit (n=5). Treatment with 2-ME decreased VEGF production by LS180 cells in a dose-dependent fashion. In conclusion, a combination regimen comprising RIT and antiangiogenic therapy initiated at the early stage of metastasis would be of great benefit in terms of improvement of the therapeutic efficacy with respect to liver metastases. (orig.)

  13. Assessment of potential drug-drug interactions and its associated factors in the hospitalized cardiac patients.

    Science.gov (United States)

    Murtaza, Ghulam; Khan, Muhammad Yasir Ghani; Azhar, Saira; Khan, Shujaat Ali; Khan, Tahir M

    2016-03-01

    Drug-drug interactions (DDIs) may result in the alteration of therapeutic response. Sometimes they may increase the untoward effects of many drugs. Hospitalized cardiac patients need more attention regarding drug-drug interactions due to complexity of their disease and therapeutic regimen. This research was performed to find out types, prevalence and association between various predictors of potential drug-drug interactions (pDDIs) in the Department of Cardiology and to report common interactions. This study was performed in the hospitalized cardiac patients at Ayub Teaching Hospital, Abbottabad, Pakistan. Patient charts of 2342 patients were assessed for pDDIs using Micromedex® Drug Information. Logistic regression was applied to find predictors of pDDIs. The main outcome measure in the study was the association of the potential drug-drug interactions with various factors such as age, gender, polypharmacy, and hospital stay of the patients. We identified 53 interacting-combinations that were present in total 5109 pDDIs with median number of 02 pDDIs per patient. Overall, 91.6% patients had at least one pDDI; 86.3% were having at least one major pDDI, and 84.5% patients had at least one moderate pDDI. Among 5109 identified pDDIs, most were of moderate (55%) or major severity (45%); established (24.2%), theoretical (18.8%) or probable (57%) type of scientific evidence. Top 10 common pDDIs included 3 major and 7 moderate interactions. Results obtained by multivariate logistic regression revealed a significant association of the occurrence of pDDIs in patient with age of 60 years or more (p Older patients, patients with longer hospital stay and with elevated number of prescribed drugs were at higher risk of pDDIs. PMID:27013915

  14. In vitro and in vivo study of hydralazine, a potential anti-angiogenic agent.

    Science.gov (United States)

    Zhang, Quanwei; Lin, Zhexuan; Yin, Xiukai; Tang, Lingzhi; Luo, Hongjun; Li, Hui; Zhang, Yuan; Luo, Wenhong

    2016-05-15

    Hydralazine (HYD), an old routine clinical anti-hypertension drug, is rarely used in clinic nowadays. Since the strategy of repositioning old drugs was put forward, HYD has been reported to possess various biological activities, including antitumor efficacy and reducing intra-tumor microvessel. Here, we investigated that whether HYD had the ability of anti-angiogeneis and its underlying mechanism. Cells proliferation, wound-healing, Transwell migration and invasion, tube formation and rat aortic ring assays in vitro and chicken chorioallantoic membrane (CAM) model in vivo were designed to investigated HYD's anti-angiogenic effect. Levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were assessed by enzyme-linked immune sorbent assay (ELISA). Hepatocellular carcinoma (HCC) mice model was used to evaluate HYD's effect on tumor growth and microvessel density. Our results showed that HYD not only inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, wound-healing, Transwell migration and invasion and tube formation, but also suppressed the microvessel outgrowth of rat aortic ring in vitro and the neovascularzation of CAM in vivo. Furthermore, we demonstrated that HYD attenuated tumor angiogenesis and tumor growth. In the co-culture system of Transwell migration, the secretion of VEGF and bFGF was reduced by HYD respectively. In sum, our data indicate that HYD has the pharmacological effect of ant-angiogenesis by interference with VEGF and bFGF signaling pathways in endothelial cells. These findings suggest that HYD might be a promising angiogenesis inhibitor and a potential effective therapeutic agent for cancer therapy. PMID:26968484

  15. New antiangiogenics in non-small cell lung cancer treatment: Vargatef™ (BIBF 1120 and beyond

    Directory of Open Access Journals (Sweden)

    Gori B

    2011-11-01

    Full Text Available Bruno Gori1, Serena Ricciardi1, Alberto Fulvi1, Salvatore Intagliata2, Ester Del Signore1, Filippo de Marinis11Oncological-Pulmonary Unit 1st, San Camillo Hospital, Rome, Italy; 2Department of Medical Oncology, University Campus Bio-Medico, Rome, ItalyAbstract: Lung cancer is the leading cause of mortality worldwide. Non-small cell lung cancer (NSCLC is a particularly aggressive cancer, the optimum management of which is still being determined. In the metastatic disease, the standard therapy is a platinum-based combination chemotherapy; however, in spite of available treatment options for patients who progress beyond first-line therapy, prognosis remains poor. Angiogenesis is a tightly regulated process which comprises a complex, complementary, and overlapping network. Inhibition of tumor-related angiogenesis has become an attractive target for anticancer therapy. Antiangiogenic strategy includes: monoclonal antibodies against vascular endothelial growth factor (VEGF and VEGF receptor (VEGFR, small molecule inhibitors of VEGF tyrosine kinase activity, VEGF Trap, and a new class named “vascular disrupting agents,” tested in ongoing clinical trials which will further define their role in the management of NSCLC. BIBF 1120 is an investigational orally administered receptor tyrosine kinase inhibitor that has shown antiangiogenic and antineoplastic activity, inhibiting VEGFR, platelet-derived growth factor receptor, and fibroblast growth factor receptor tyrosine kinases, preventing tumor growth and interfering with the angiogenesis-signaling cascade and overcoming drug resistances.Keywords: NSCLC, angiogenesis, oral antiangiogenic agents, VEGF, PDGF, FGF

  16. Sigma receptor-mediated targeted delivery of anti-angiogenic multifunctional nanodrugs for combination tumor therapy.

    Science.gov (United States)

    Li, Yuanke; Wu, Yuanyuan; Huang, Leaf; Miao, Lei; Zhou, Jianping; Satterlee, Andrew Benson; Yao, Jing

    2016-04-28

    The potential of low molecular weight heparin (LMWH) in anti-angiogenic therapy has been tempered by poor in vivo delivery to the tumor cell and potentially harmful side effects, such as the risk of bleeding due to heparin's anticoagulant activity. In order to overcome these limitations and further improve the therapeutic effect of LMWH, we designed a novel combination nanosystem of LMWH and ursolic acid (UA), which is also an angiogenesis inhibitor for tumor therapy. In this system, an amphiphilic LMWH-UA (LHU) conjugate was synthesized and self-assembled into core/shell nanodrugs with combined anti-angiogenic activity and significantly reduced anticoagulant activity. Furthermore, DSPE-PEG-AA-modified LHU nanodrugs (A-LHU) were developed to facilitate the delivery of nanodrugs to the tumor. The anti-angiogenic activity of A-LHU was investigated both in vitro and in vivo. It was found that A-LHU significantly inhibited the tubular formation of human umbilical vein endothelial cells (HUVECs) (pnanodrugs are a promising multifunctional antitumor drug delivery system. PMID:26941036

  17. 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.

  18. Anti-Angiogenic Activity of Ficus carica Latex Extract on Human Umbilical Vein Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Ali Mostafaie

    2011-01-01

    Full Text Available Angiogenesis, the formation of new blood vessels, is a key process in cancer developmentand metastasis. In this study, the anti-angiogenic and anti-proliferative potentials of Ficuscarica latex extract have been investigated using human umbilical vein endothelial cells(HUVECs.Different doses of latex extract were prepared and added to a three-dimensional culture ofHUVEC in a collagen matrix. After 3-5 days of treatment, the anti-angiogenic effects of theextracts were monitored microscopically. For the anti-proliferation assay, different dosesof the extracts were examined on HUVECs.The results clearly indicated that latex extract could inhibit proliferation and capillary tubeformation of HUVECs in a dose-dependent manner at the range of 100-400 μg/ml. In addition,the extract was not cytotoxic up to 450 μg/ml as assessed by trypan blue and lactatedehydrogenase (LDH cytotoxicity assays.It is concluded that latex extracts of F. carica contain strong anti-angiogenic andanti-proliferative activities. Our data indicates that latex extract could be a candidateas a potential agent for the prevention of angiogenesis in cancer and other chronicdisorders.

  19. Cytotoxicity assessment of porous silicon microparticles for ocular drug delivery.

    Science.gov (United States)

    Korhonen, Eveliina; Rönkkö, Seppo; Hillebrand, Satu; Riikonen, Joakim; Xu, Wujun; Järvinen, Kristiina; Lehto, Vesa-Pekka; Kauppinen, Anu

    2016-03-01

    Porous silicon (PSi) is a promising material for the delivery and sustained release of therapeutic molecules in various tissues. Due to the constant rinsing of cornea by tear solution as well as the short half-life of intravitreal drugs, the eye is an attractive target for controlled drug delivery systems, such as PSi microparticles. Inherent barriers ensure that PSi particles are retained in the eye, releasing drugs at the desired speed until they slowly break down into harmless silicic acid. Here, we have examined the in vitro cytotoxicity of positively and negatively charged thermally oxidized (TOPSi) and thermally carbonized (TCPSi) porous silicon microparticles on human corneal epithelial (HCE) and retinal pigment epithelial (ARPE-19) cells. In addition to ocular assessment under an inverted microscope, cellular viability was evaluated using the CellTiter Blue™, CellTiter Fluor™, and lactate dehydrogenase (LDH) assays. CellTiter Fluor proved to be a suitable assay but due to non-specific and interfering responses, neither CellTiter Blue nor LDH assays should be used when evaluating PSi particles. Our results suggest that the toxicity of PSi particles is concentration-dependent, but at least at concentrations less than 200μg/ml, both positively and negatively charged PSi particles are well tolerated by human corneal and retinal epithelial cells and therefore applicable for delivering drug molecules into ocular tissues. PMID:26686646

  20. Bioluminescence for assessing drug potency against nonreplicating Mycobacterium tuberculosis.

    Science.gov (United States)

    Vocat, Anthony; Hartkoorn, Ruben C; Lechartier, Benoit; Zhang, Ming; Dhar, Neeraj; Cole, Stewart T; Sala, Claudia

    2015-07-01

    Targeting dormant Mycobacterium tuberculosis represents a challenge to antituberculosis drug discovery programs. We previously reported and validated the use of the streptomycin (STR)-dependent M. tuberculosis 18b strain as a tool for assessing drug potency against nonreplicating bacteria both in vitro and in vivo. In this study, we generated a luminescent 18b strain, named 18b-Lux, by transforming the bacteria with a vector expressing the luxCDABE operon from Photorhabdus luminescens. Luciferase expression was demonstrated under replicating conditions, and, more importantly, luminescence levels significantly above background were detected following STR removal. The sensitivity of STR-starved 18b-Lux to approved and candidate antituberculosis therapeutic agents was evaluated by means of a luciferase assay in a 96-well format. Results mirrored the data obtained with the standard resazurin reduction microplate assay, and the luminescence readout allowed time course assessments of drug efficacy in vitro. Specifically, we proved that bedaquiline, the rifamycins, and sutezolid displayed time-dependent activity against dormant bacteria, while pyrazinamide and SQ109 showed bactericidal effects at the highest concentrations tested. Overall, we established the optimal conditions for an inexpensive, simple, and very sensitive assay with great potential for future applications. PMID:25896710

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

    OpenAIRE

    Giuseppe Privitera; Grazia Acquaviva; Giovanni Carlo Ettorre; Corrado Spatola

    2009-01-01

    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...

  2. 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

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

    International Nuclear Information System (INIS)

    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

  4. 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.

  5. 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.

  6. 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. PMID:27020471

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

    International Nuclear Information System (INIS)

    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

  8. 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.

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

    International Nuclear Information System (INIS)

    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.

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

    Directory of Open Access Journals (Sweden)

    Mahender Kyadari

    2013-01-01

    Full Text Available 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 IC 50 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

  11. Anti-angiogenic agents in ovarian cancer: past, present, and future.

    Science.gov (United States)

    Monk, B J; Minion, L E; Coleman, R L

    2016-04-01

    Angiogenesis plays a pivotal role in normal ovarian physiology as well as in the progression of ovarian cancer through ascites formation and metastatic spread. Bevacizumab (Avastin(®), Genentech; South San Francisco, CA, USA), a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, is the most widely studied anti-angiogenesis agent both across tumor types and specifically in epithelial ovarian cancer. In 2005, single-agent bevacizumab at 15 mg/kg (IV) every 3 weeks was first reported to be active in a case of recurrent high-grade serous ovarian cancer after failing 11th line cytotoxic treatment. Since then, many case series, phase II and phase III trials have confirmed these results leading to regulatory approval in most countries including the US Food and Drug Administration in 2014. Guidelines now give clear recommendations as to when and how bevacizumab should be integrated into the ovarian cancer treatment paradigm. Other anti-VEGF agents such as the VEGF receptor (VEGFR) tyrosine kinase inhibitors have not shown increased activity or reduced toxicity relative to bevacizumab. However, anti-angiogenics other than anti-VEGF/VEGFR agents such as those targeting Angiopoietin-1 and -2 are in development as well as novel combinations with vascular disrupting agents (VDAs), PARP inhibitors and immune checkpoint inhibitors. Clearly, the benefits of anti-angiogenic agents such as bevacizumab must be carefully weighed against the cost and associated toxicities. Although almost all patients with ovarian cancer will receive an anti-angiogenic compound, cures are not increased. Predictive biomarkers are an urgent unmet need. PMID:27141068

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

    International Nuclear Information System (INIS)

    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

  13. Assessment of potential drug-drug interactions among outpatients receiving cardiovascular medications at Jimma University specialized hospital, South West Ethiopia

    Directory of Open Access Journals (Sweden)

    Legese Chelkeba

    2013-04-01

    Full Text Available Background: The quality of pharmacotherapy is highly dependent on the process of choosing a drug in relation to nature of the disease. Several factors should be considered in choosing optimal pharmacotherapeutics strategy including efficacy, safety, availability and cost of the drugs. The objective of this study was to assess potential drug-drug interactions and risk factors in outpatients taking cardiovascular drugs at Jimma University specialized hospital. Methods: A cross-sectional study was conducted from Feb. to April, 2011on patients visiting the cardiac clinic of Jimma University Specialized hospital. A sample of 332 outpatients who were taking cardiovascular medications at study clinic was studied. MicroMedex software was used to screen drug-drug interactions and SPSS for windows software versions-16.0 was used for data analysis. Results: A total of 1249 drugs with average of 3.76 drugs per prescription were prescribed for the 332 patients. The frequency of potential DDIs was found to be 241 (72.6%. Among these 200 (67.3% were of "moderate" severity and 164 (55.2% were delayed in onset. The most common potential DDI observed was between Enalapril and Furosemide (20%. Patients who prescribed many drugs (AOR=4.09; P=0.00 by medical intern had a higher risk of developing potential DDIs (AOR=4.6; P=0.00. Conclusions: Patients with cardiovascular disorders are subjected to high risk of potential drug-drug interactions and the number of drugs prescribed and educational level of the prescribers has a high significantly associated with the occurrence of potential drug-drug interactions. Therefore, it is imperative that further studies need to be conducted to identify reasons for and tackle the problem and provide appropriate mechanisms for management. [Int J Basic Clin Pharmacol 2013; 2(2.000: 144-152

  14. 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....

  15. Development of lentiviral vectors for antiangiogenic gene delivery.

    Science.gov (United States)

    Shichinohe, T; Bochner, B H; Mizutani, K; Nishida, M; Hegerich-Gilliam, S; Naldini, L; Kasahara, N

    2001-11-01

    Growth and metastasis of malignant tumors requires angiogenesis. Inhibition of tumor-induced angiogenesis may represent an effective cytostatic strategy. We have constructed recombinant self-inactivating lentiviral vectors expressing angiostatin and endostatin, and have tested their antiangiogenic activities. As VSV-G-pseudotyped lentiviral vectors showed low relative transduction titers on bovine aortic and human umbilical vein endothelial cells, it was difficult to achieve significant inhibition of endothelial cell growth by lentivirus-mediated antiangiogenic gene transfer directly to endothelial cells without concomitant vector-associated cytotoxicity. However, lentivirus vectors could efficiently and stably transduce T24 human bladder cancer cells that are relatively resistant to adenovirus infection due to loss of coxsackievirus-adenovirus receptor expression. Long-term expression and secretion of angiostatin and endostatin from lentivirus-transduced T24 cells resulted in significant inhibition of cellular proliferation on coculture with endothelial cells. This report represents the first use of lentivirus-based vectors to deliver the antiangiogenic factors, angiostatin and endostatin, and suggests the potential utility of antiangiogenic gene therapy with lentiviral vectors for the treatment of cancer. PMID:11773978

  16. Assessment of indicators for hospital drug formulary non-adherence

    NARCIS (Netherlands)

    Fijn, R; Lenderink, AW; Egberts, ACG; Brouwers, JRBJ; De Jong-Van DenBerg, LTW

    2001-01-01

    Background: Translation of rational drug therapy into practice remains an international problem. Although pharmacotherapeutic treatment guidelines (PTGs) as managerial tools are favoured over hospital drug formularies (HDFs), the latter are still applied in most hospitals. HDF enforcement often lead

  17. 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.

  18. 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 marke

  19. Vascular phenotype identification and anti-angiogenic treatment recommendation: A pseudo-multiscale mathematical model of angiogenesis.

    Science.gov (United States)

    Hutchinson, L G; Gaffney, E A; Maini, P K; Wagg, J; Phipps, A; Byrne, H M

    2016-06-01

    The development of anti-angiogenic drugs for cancer therapy has yielded some promising candidates, but novel approaches for interventions to angiogenesis have led to disappointing results. In addition, there is a shortage of biomarkers that are predictive of response to anti-angiogenic treatments. Consequently, the complex biochemical and physiological basis for tumour angiogenesis remains incompletely understood. We have adopted a mathematical approach to address these issues, formulating a spatially averaged multiscale model that couples the dynamics of VEGF, Ang1, Ang2 and PDGF, with those of mature and immature endothelial cells and pericyte cells. The model reproduces qualitative experimental results regarding pericyte coverage of vessels after treatment by anti-Ang2, anti-VEGF and combination anti-VEGF/anti-Ang2 antibodies. We used the steady state behaviours of the model to characterise angiogenic and non-angiogenic vascular phenotypes, and used mechanistic perturbations representing hypothetical anti-angiogenic treatments to generate testable hypotheses regarding transitions to non-angiogenic phenotypes that depend on the pre-treatment vascular phenotype. Additionally, we predicted a synergistic effect between anti-VEGF and anti-Ang2 treatments when applied to an immature pre-treatment vascular phenotype, but not when applied to a normalised angiogenic pre-treatment phenotype. Based on these findings, we conclude that changes in vascular phenotype are predicted to be useful as an experimental biomarker of response to treatment. Further, our analysis illustrates the potential value of non-spatial mathematical models for generating tractable predictions regarding the action of anti-angiogenic therapies. PMID:26987523

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

    International Nuclear Information System (INIS)

    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

  1. Evaluation of a procedure to assess the adverse effects of illicit drugs.

    NARCIS (Netherlands)

    Amsterdam, J G C van; Best, W; Opperhuizen, A; Wolff, F A de

    2004-01-01

    The assessment procedure of new synthetic illicit drugs that are not documented in the UN treaty on psychotropic drugs was evaluated using a modified Electre model. Drugs were evaluated by an expert panel via the open Delphi approach, where the written score was discussed on 16 items, covering medic

  2. 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.

  3. [Assessment of the legal awareness regarding drug consumption].

    Science.gov (United States)

    Morawska, Jowanka; Satora, Leszek

    2004-01-01

    The latest legislation against drug addiction has changed the approach of Pursuing Organs in Poland to the problem of taking and distribution of drugs. Many tests have been carried out in order to evaluate the extent of legal regulations as the appropriate instrument in the struggle against drug addiction. The survey and interview were introduced during the research. The results make it possible to form the following conclusions. Law, only as a supplementary means supporting other methods may help prevent and counteract the addictions. Legal regulation on drug addiction which are based on compulsion and punishment should be widely taken into account. PMID:15521595

  4. Adverse cutaneous drug reactions: Eight year assessment in hospitalized patients

    Directory of Open Access Journals (Sweden)

    Fatemeh Mokhtari

    2014-01-01

    Full Text Available Background: Adverse cutaneous drug reactions (ACDRs are the most commonly reported adverse drug events. The causative drugs and clinical patterns of ACDRs are different in various populations. This study was conducted to identify the clinical patterns, causative drugs and reasons for drug administration in patients hospitalized due to ACDR. Materials and Methods: This retrospective study was carried out in a referral university hospital, Isfahan, Iran. The medical records of all patients who were hospitalized in the Dermatology Department due to ACDRs were reviewed covering an 8-year period between December 2006 and August 2013. Results: A total number of 282 patients with the mean age of 29.48 ± 21.18 years were hospitalized in this time period, of which 61% were females. The most common clinical patterns regarding the final diagnosis were Stevens-Johnson syndrome (SJS (32%, exanthematous drug eruptions (24.5% and toxic epidermal necrolysis (TEN (11%. Anticonvulsants were the most frequently implicated drug group (51.8% followed by antibiotics (33.7% and analgesics and non-steroidal anti-inflammatory drugs (5.7%. The most common cause of drug administration was seizure (30% and then upper respiratory tract infections (12%. The frequency distribution of clinical types of reactions was different between age groups (P < 0.001. The severe types (SJS, TEN, drug rash with eosinophilia and systemic symptoms and overlap syndrome were more frequent in the patients aged ≤50 years old (55.2% compare to those aged ≤50 years (28% (P = 0.001. Conclusion: The main causative drugs of ACDRs were anticonvulsants and antibiotics. However, the sever types of reactions were more prevalent.

  5. Anti-angiogenic effect of high doses of ascorbic acid

    OpenAIRE

    Ichim Thomas E; Mikirova Nina A; Riordan Neil H

    2008-01-01

    Abstract Pharmaceutical doses of ascorbic acid (AA, vitamin C, or its salts) have been reported to exert anticancer activity in vitro and in vivo. One proposed mechanism involves direct cytotoxicity mediated by accumulation of ascorbic acid radicals and hydrogen peroxide in the extracellular environment of tumor cells. However, therapeutic effects have been reported at concentrations insufficient to induce direct tumor cell death. We hypothesized that AA may exert anti-angiogenic effects. To ...

  6. Evaluation of Antioxidant and Antiangiogenic Properties of Caesalpinia Echinata Extracts

    OpenAIRE

    da Silva Gomes, Elisangela Christhianne Barbosa; Jimenez, George Chaves; da Silva, Luis Claudio Nascimento; Sá, Fabrício Bezerra; de Souza, Karen Pena Cavalcanti; Paiva, Gerson S.; de Souza, Ivone Antônia

    2014-01-01

    Natural products contain important combinations of ingredients, which may to some extent help to modulate the effects produced by oxidation substrates in biological systems. It is known that substances capable of modulating the action of these oxidants on tissue may be important allies in the control of neovascularization in pathological processes. The aim of this study was to evaluate the antioxidant and antiangiogenic properties of an ethanol extract of Caesalpinia echinata. The evaluation ...

  7. Antiangiogenic and anticancer activity of saponins of Momordica cymbalaria

    OpenAIRE

    Raju Koneri; Nagarathna P. K. M.; Mubasheera M. G.; M. Madhu Mohan

    2014-01-01

    Background: The aim of the current study was to evaluate invitro anticancer activity of saponins of MC on EAC cells by using cytotoxicity (MTT) assay. To evaluate in vivo antiangiogenic potential of saponins of MC on rat air sac angiogenesis, EAC induced peritoneal angiogenesis, CAM angiogenesis. Methods: MTT assay was carried out at different concentrations of saponins of MC in 12 microliter plates containing media with EAC cells. In rat air sac angiogenesis, carrageenin was injected (s.c...

  8. A gene transfer comparative study of HSA-conjugated antiangiogenic factors in a transgenic mouse model of metastatic ocular cancer.

    Science.gov (United States)

    Frau, E; Magnon, C; Opolon, P; Connault, E; Opolon, D; Beermann, F; Beerman, F; Abitbol, M; Perricaudet, M; Bouquet, C

    2007-03-01

    Different antiangiogenic and antimetastatic recombinant adenoviruses were tested in a transgenic mouse model of metastatic ocular cancer (TRP1/SV40 Tag transgenic mice), which is a highly aggressive tumor, developed from the pigmented epithelium of the retina. These vectors, encoding amino-terminal fragments of urokinase plasminogen activator (ATF), angiostatin Kringles (K1-3), endostatin (ES) and canstatin (Can) coupled to human serum albumin (HSA) were injected to assess their metastatic and antiangiogenic activities in our model. Compared to AdCO1 control group, AdATF-HSA did not significantly reduce metastatic growth. In contrast, mice treated with AdK1-3-HSA, AdES-HSA and AdCan-HSA displayed significantly smaller metastases (1.19+/-1.19, 0.87+/-1.5, 0.43+/-0.56 vs controls 4.04+/-5.12 mm3). Moreover, a stronger inhibition of metastatic growth was obtained with AdCan-HSA than with AdK1-3-HSA (P=0.04). Median survival was improved by 4 weeks. A close correlation was observed between the effects of these viruses on metastatic growth and their capacity to inhibit tumor angiogenesis. Our study indicates that systemic antiangiogenic factors production by recombinant adenoviruses, particularly Can, might represent an effective way of delaying metastatic growth via inhibition of angiogenesis. PMID:17082795

  9. Anti-angiogenic peptides identified in thrombospondin type I domains

    International Nuclear Information System (INIS)

    Thrombospondin 1, the prototypical protein of the thrombospondin protein family, is a potent endogenous inhibitor of angiogenesis. Although the effects of the thrombospondin 1 on neovascularization have been well studied, little is known about the anti-angiogenic potency of other proteins or peptide fragments derived from the proteins in this family. Here we identify a set of 18 novel, anti-angiogenic 17- to 20-amino acid peptides that are derived from proteins containing type I thrombospondin motifs. We have named these peptides adamtsostatin-4, adamtsostatin-16, adamtsostatin-18, cartilostatin-1, cartilostatin-2, fibulostatin-6.2, fibulostatin-6.3, papilostatin-1, papilostatin-2, properdistatin, scospondistatin, semastatin-5A.1, semastatin-5A.2, semastatin-5B, thrombostatin containing-1, thrombostatin contaning-3, thrombostatin contaning-6, and wispostatin-1 to reflect their origin. We further demonstrate that these peptides inhibit the proliferation and migration of human umbilical vein endothelial cells in vitro. The anti-proliferative and anti-migratory properties of the identified peptides may be important in maintaining angiogenic homeostasis in vivo and make these peptides suitable candidates for use as anti-angiogenic pharmaceutical agents in numerous therapeutic applications

  10. 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. PMID:26399633

  11. Assessment of Club Patrons’ Alcohol and Drug Use

    Science.gov (United States)

    Miller, Brenda A.; Byrnes, Hilary F.; Branner, Amy C.; Voas, Robert; B. Johnson, Mark

    2014-01-01

    Background 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. Purpose 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. Methods 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. Results 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. Conclusions 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 harms is indicated by the findings. PMID:24139778

  12. Comprehensive Evaluation of the Anti-Angiogenic and Anti-Neoplastic Effects of Endostar on Liver Cancer through Optical Molecular Imaging

    OpenAIRE

    Qian ZHANG; Du, Yang; Xue, Zhenwen; Chi, Chongwei; Jia, Xiaohua; Tian, Jie

    2014-01-01

    Molecular imaging enables non-invasive monitoring of tumor growth, progression, and drug treatment response, and it has become an important tool to promote biological studies in recent years. In this study, we comprehensively evaluated the in vivo anti-angiogenic and anti-neoplastic effects of Endostar on liver cancer based on the optical molecular imaging systems including micro-computer tomography (Micro-CT), bioluminescence molecular imaging (BLI) and fluorescence molecular tomography (FMT...

  13. Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia

    OpenAIRE

    Conley, Sarah J.; Gheordunescu, Elizabeth; Kakarala, Pramod; Newman, Bryan; Korkaya, Hasan; Heath, Amber N.; Clouthier, Shawn G.; Wicha, Max S.

    2012-01-01

    Antiangiogenic therapy has been thought to hold significant potential for the treatment of cancer. However, the efficacy of such treatments, especially in breast cancer patients, has been called into question, as recent clinical trials reveal only limited effectiveness of antiangiogenic agents in prolonging patient survival. New research using preclinical models further suggests that antiangiogenic agents actually increase invasive and metastatic properties of breast cancer cells. We demonstr...

  14. Challenges in the clinical assessment of novel tuberculosis drugs.

    Science.gov (United States)

    Dooley, Kelly E; Phillips, Patrick P J; Nahid, Payam; Hoelscher, Michael

    2016-07-01

    To tackle the global TB epidemic effectively, novel treatment strategies are critically needed to shorten the duration of TB therapy and treat drug-resistant TB. Drug development for TB, stymied for decades, has enjoyed a renaissance over the past several years. However, the development of new TB regimens is hindered by the limitations in our understanding and use of preclinical models; the paucity of accurate, early surrogate markers of cure, and challenges in untangling the individual contributions of drugs to multidrug regimens in a complex, multi-compartment disease. Lack of profit motive, advocacy, and imagination has contributed mightily to the dearth of drugs we have on the shelf to treat this ancient disease. Areas that will speed the development of new regimens for TB include novel murine and in vitro pharmacodynamics models, clinical endpoints that are not culture-based, innovative clinical trial designs, and an infusion of much-needed funding. PMID:26827911

  15. Targeting CD9 produces stimulus-independent antiangiogenic effects predominantly in activated endothelial cells during angiogenesis: A novel antiangiogenic therapy

    International Nuclear Information System (INIS)

    Highlights: → CD9 plays stimulus-independent roles in angiogenesis in vitro and in vivo. → Targeting CD9 expression is effective in an angiogenic disease model. → Targeting CD9 expression predominantly affects activated endothelial cells. → CD9 is involved in endothelial cell proliferation, but not survival. → CD9 is part of angiogenic machinery in endothelial cells during angiogenesis. -- Abstract: The precise roles of tetraspanin CD9 are unclear. Here we show that CD9 plays a stimulus-independent role in angiogenesis and that inhibiting CD9 expression or function is a potential antiangiogenic therapy. Knocking down CD9 expression significantly inhibited in vitro endothelial cell migration and invasion induced by vascular endothelial growth factor (VEGF) or hepatocyte growth factor (HGF). Injecting CD9-specific small interfering RNA (siRNA-CD9) markedly inhibited HGF- or VEGF-induced subconjunctival angiogenesis in vivo. Both results revealed potent and stimulus-independent antiangiogenic effects of targeting CD9. Furthermore, intravitreous injections of siRNA-CD9 or anti-CD9 antibodies were therapeutically effective for laser-induced retinal and choroidal neovascularization in mice, a representative ocular angiogenic disease model. In terms of the mechanism, growth factor receptor and downstream signaling activation were not affected, whereas abnormal localization of integrins and membrane type-1 matrix metalloproteinase was observed during angiogenesis, by knocking down CD9 expression. Notably, knocking down CD9 expression did not induce death and mildly inhibited proliferation of quiescent endothelial cells under conditions without an angiogenic stimulus. Thus, CD9 does not directly affect growth factor-induced signal transduction, which is required in angiogenesis and normal vasculature, but is part of the angiogenesis machinery in endothelial cells during angiogenesis. In conclusion, targeting CD9 produced stimulus-independent antiangiogenic effects

  16. Impact of biomarker development on drug safety assessment

    International Nuclear Information System (INIS)

    Drug safety has always been a key aspect of drug development. Recently, the Vioxx case and several cases of serious adverse events being linked to high-profile products have increased the importance of drug safety, especially in the eyes of drug development companies and global regulatory agencies. Safety biomarkers are increasingly being seen as helping to provide the clarity, predictability, and certainty needed to gain confidence in decision making: early-stage projects can be stopped quicker, late-stage projects become less risky. Public and private organizations are investing heavily in terms of time, money and manpower on safety biomarker development. An illustrative and 'door opening' safety biomarker success story is the recent recognition of kidney safety biomarkers for pre-clinical and limited translational contexts by FDA and EMEA. This milestone achieved for kidney biomarkers and the 'know how' acquired is being transferred to other organ toxicities, namely liver, heart, vascular system. New technologies and molecular-based approaches, i.e., molecular pathology as a complement to the classical toolbox, allow promising discoveries in the safety biomarker field. This review will focus on the utility and use of safety biomarkers all along drug development, highlighting the present gaps and opportunities identified in organ toxicity monitoring. A last part will be dedicated to safety biomarker development in general, from identification to diagnostic tests, using the kidney safety biomarkers success as an illustrative example.

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

    OpenAIRE

    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 channe...

  18. Early detection of antiangiogenic treatment responses in a mouse xenograft tumor model using quantitative perfusion MRI

    International Nuclear Information System (INIS)

    Angiogenesis plays a major role in tumor growth and metastasis, with tumor perfusion regarded as a marker for angiogenesis. To evaluate antiangiogenic treatment response in vivo, we investigated arterial spin labeling (ASL) magnetic resonance imaging (MRI) to measure tumor perfusion quantitatively. Chronic and 24-h acute treatment responses to bevacizumab were assessed by ASL and dynamic-contrast-enhanced (DCE) MRI in the A498 xenograft mouse model. After the MRI, tumor vasculature was assessed by CD34 staining. After 39 days of chronic treatment, tumor perfusion decreased to 44.8 ± 16.1 mL/100 g/min (P < 0.05), compared to 92.6 ± 42.9 mL/100 g/min in the control group. In the acute treatment study, tumor perfusion in the treated group decreased from 107.2 ± 32.7 to 73.7 ± 27.8 mL/100 g/min (P < 0.01; two-way analysis of variance), as well as compared with control group post dosing. A significant reduction in vessel density and vessel size was observed after the chronic treatment, while only vessel size was reduced 24 h after acute treatment. The tumor perfusion correlated with vessel size (r = 0.66; P < 0.005) after chronic, but not after acute treatment. The results from DCE-MRI also detected a significant change between treated and control groups in both chronic and acute treatment studies, but not between 0 and 24 h in the acute treatment group. These results indicate that tumor perfusion measured by MRI can detect early vascular responses to antiangiogenic treatment. With its noninvasive and quantitative nature, ASL MRI would be valuable for longitudinal assessment of tumor perfusion and in translation from animal models to human

  19. 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.

  20. An R Package for Assessing Drug Synergism/Antagonism

    Directory of Open Access Journals (Sweden)

    John C. Boik

    2010-10-01

    Full Text Available Synergistic and antagonistic drug interactions are important to consider when developing mixtures of anticancer or other types of drugs. Boik, Newman, and Boik (2008 proposed the MixLow method as an alternative to the Median-Effect method of Chou and Talalay (1984 for estimating drug interaction indices. One advantage of the MixLow method is that the nonlinear mixed-effects model used to estimate parameters of concentration-response curves can provide more accurate parameter estimates than the log linearization and least-squares analysis used in the Median-Effect method. This paper introduces the mixlow package in R, an implementation of the MixLow method. Results are reported for a small simulation study.

  1. A new approach to assess drug development performance.

    Science.gov (United States)

    Rosiello, Alessandro; Dimitri, Nicola; Fiorini, Filippo

    2013-05-01

    This article suggests that successful innovation in biopharmaceuticals is strongly related to the ability of firms to move compounds forward along the drug pipeline, relatively to other companies, within the same therapeutic area. We used this intuition to build indicators of performance at the firm-level and use them to conduct empirical analysis that relies upon a comprehensive database. We consider the effect of various factors on drug development performance, including R&D funds allocation across therapeutic areas and the proportion of biological molecules in the drug development portfolio. Subsequently, we show that a correlation exists between our performance variables and the per-capita growth of biopharmaceutical firms' revenues. PMID:23337387

  2. Assessing dietary intake of drug abusing Hispanic adults with and without HIV infection

    Science.gov (United States)

    Drug abuse is an important risk factor for Human Immunodeficiency Virus (HIV) among Hispanics in the Northeastern United States and both drug abuse and HIV are associated with nutritional deficiencies. The selection of a dietary assessment method most appropriate for Hispanic adults with/without HIV...

  3. 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…

  4. Evaluation of a procedure to assess the adverse effects of illicit drugs.

    Science.gov (United States)

    van Amsterdam, J G C; Best, W; Opperhuizen, A; de Wolff, F A

    2004-02-01

    The assessment procedure of new synthetic illicit drugs that are not documented in the UN treaty on psychotropic drugs was evaluated using a modified Electre model. Drugs were evaluated by an expert panel via the open Delphi approach, where the written score was discussed on 16 items, covering medical, health, legal, and criminalistic issues of the drugs. After this face-to-face discussion the drugs were scored again. Taking the assessment of ketamine as an example, it appeared that each expert used its own scale to score, and that policymakers do not score deviant from experts trained in the medical-biological field. Of the five drugs evaluated by the panel, p-methoxy-metamphetamine (PMMA), gamma-hydroxybutyric acid (GHB), and 4-methylthio-amphetamine (MTA) were assessed as more adverse than ketamine and psilocine and psilocybine-containing mushrooms. Whereas some experts slightly adjusted during the assessment procedure their opinion on ketamine and PMMA, the opinion on mushrooms was not affected by the discussion held between the two scoring rounds. All experts rank the five drugs in a similar way on the adverse effect scale i.e., concordance scale of the Electre model, indicating unanimity in the expert panel with respect to the risk classification of these abused drugs. PMID:14746774

  5. A Choice Procedure to Assess the Aversive Effects of Drugs in Rodents

    Science.gov (United States)

    Podlesnik, Christopher A.; Jimenez-Gomez, Corina; Woods, James H.

    2010-01-01

    The goal of this series of experiments was to develop an operant choice procedure to examine rapidly the punishing effects of intravenous drugs in rats. First, the cardiovascular effects of experimenter-administered intravenous histamine, a known aversive drug, were assessed to determine a biologically active dose range. Next, rats responded on…

  6. Vessel Architectural Imaging Identifies Cancer Patient Responders to Anti-angiogenic Therapy

    Science.gov (United States)

    Emblem, Kyrre E.; Mouridsen, Kim; Bjornerud, Atle; Farrar, Christian T.; Jennings, Dominique; Borra, Ronald J. H.; Wen, Patrick Y.; Ivy, Percy; Batchelor, Tracy T.; Rosen, Bruce R.; Jain, Rakesh K.; Sorensen, A. Gregory

    2013-01-01

    Measurement of vessel caliber by Magnetic Resonance Imaging (MRI) is a valuable technique for in vivo monitoring of hemodynamic status and vascular development, especially in the brain. Here, we introduce a new paradigm in MRI coined as Vessel Architectural Imaging (VAI) that exploits an intriguing and overlooked temporal shift in the MR signal forming the basis for vessel caliber estimation and show how this phenomenon can reveal new information on vessel type and function not assessed by any other non-invasive imaging technique. We also show how this biomarker can provide novel biological insights into the treatment of cancer patients. As an example, we demonstrate using VAI that anti-angiogenic therapy can improve microcirculation and oxygen saturation levels and reduce vessel calibers in patients with recurrent glioblastomas, and more crucially, that patients with these responses have prolonged survival. Thus, VAI has the potential to identify patients who would benefit from therapies. PMID:23955713

  7. Assessment of cytochrome p450 enzyme inhibition and inactivation in drug discovery and development.

    Science.gov (United States)

    Nettleton, David O; Einolf, Heidi J

    2011-01-01

    Evaluation of the potential of a drug candidate to inhibit or inactivate cytochrome P450 (CYP) enzymes remains an important part of pharmaceutical drug Discovery and Development programs. CYP enzymes are considered to be one of the most important enzyme families involved in the metabolic clearance of the vast majority of prescribed drugs. Clinical drug-drug interactions (DDI) involving inhibition or time-dependent inactivation of these enzymes can result in dangerous side effects resulting from reduced clearance/increased exposure of the drug being affected (the 'victim' drug). In this regard, pharmaceutical companies have become quite vigilant in mitigating CYP inhibition/inactivation liabilities of drug candidates early in Discovery including continued risk assessment throughout Development. In this review, common strategies and decision making processes for the assessment of DDI risk in the different stages of pharmaceutical development are discussed. In addition, in vitro study designs, analysis, and interpretation of CYP inhibition and inactivation data are described in stage appropriate context. The in vitro tools and knowledge available now enable the Discovery Chemist to place the potential CYP DDI liability of a drug candidate into perspective and to aid in the optimization of chemical drug design to further mitigate this risk. PMID:21320066

  8. Multi-gene targeted antiangiogenic therapies for experimental corneal neovascularization

    OpenAIRE

    Chen, Peng; Yin, Hongmei; Wang, Yao; Mi, Jing; He, Wenxiao; Xie, Lixin; Wang, Yiqiang

    2010-01-01

    Purpose To determine the effectiveness of multigene-based anti-angiogenic gene therapies for experimental murine corneal neovascularization (corneal NV). Methods Recombinant retroviral vectors encoding murine endostatin (mEndo), murine-soluble vascular endothelial growth factor receptor-2 (msFlk-1), or murine-soluble Tie2 (msTie2) were constructed and packaged in PT67 cells. Viral titers were determined by infection of NIH3T3 cells. Expressions of mEndo, msFlk-1, and msTie2 were confirmed by ...

  9. Treating Women Drug Abusers: Action Therapy and Trauma Assessment

    OpenAIRE

    Uhler, Ann S.; Parker, Olga V.

    2002-01-01

    The authors suggest that action therapy, a group of techniques including psychodrama, drama therapy, and role training, warrants research attention to determine whether it is well suited to the special characteristics and needs of women clients. In addition, the authors call on researchers to develop a new standardized tool for counselors to use during initial interviews to determine whether women presenting for drug abuse treatment also have significant issues related to trauma. The authors ...

  10. Gene electrotransfer of plasmid antiangiogenic metargidin peptide (AMEP) in disseminated melanoma

    DEFF Research Database (Denmark)

    Spanggaard, Iben; Snoj, Marko; Cavalcanti, Andrea;

    2013-01-01

    Antiangiogenic metargidin peptide (AMEP) is a novel anticancer agent exerting antiproliferative and antiangiogenic effects by binding to αvβ3 and α5β1 integrins. Electrotransfer designates the use of electric pulses (electroporation) to transfer plasmid DNA into tissues. This first-in-man phase I...

  11. Anti-angiogenic therapies for advanced esophago-gastric cancer

    Directory of Open Access Journals (Sweden)

    Elisa Fontana

    2014-01-01

    Full Text Available Neo-vascularization is a vital process for tumor growth and development which involves the interaction between tumor cells and stromal endothelial cells through several growth factors and membranous receptors which ultimately activate pro-angiogenic intracellular signaling pathways. Inhibition of angiogenesis has become a standard treatment option for several tumor types including colorectal cancer, glioblastoma and ovarian cancer. In gastric cancer, the therapeutic role of anti-angiogenic agents is more controversial. Bevacizumab and ramucirumab, two monoclonal antibodies, which target vascular endothelial growth factor-A and vascular endothelial growth factor receptor-2, respectively, have been demonstrated antitumor activity in patients with tumors of the stomach or esophagogastric junction. However, especially for bevacizumab, this antitumor activity has not consistently translated into a survival advantage over standard treatment in randomized trials. In this article, we provide an overview of the role of angiogenesis in gastric cancer and discuss the results of clinical trials that investigated safety and effectiveness of antiangiogenic therapies in this disease. A review of the literature has been done using PubMed, ClinicalTrials.gov website and the ASCO Annual Meeting Library.

  12. Antioxidant and antiangiogenic activity of Astronium graveolens Jacq. leaves.

    Science.gov (United States)

    Hernández, Vanessa; Malafronte, Nicola; Mora, Flor; Pesca, Maria S; Aquino, Rita P; Mencherini, Teresa

    2014-01-01

    Angiogenesis is involved in many physiological and pathological conditions. Natural compounds with antioxidant activity have also been reported to possess potent antiangiogenic properties by regulating angiogenesis modulators such as vascular endothelial growth factor (VEGF). Based on this, we screened the antioxidant and antiangiogenic activities of Astronium graveolens leaf extracts by a DPPH test and a competitive enzyme-linked immunosorbent assay, respectively. MeOH extract expressed a significant free radical-scavenging activity (EC₅₀ = 37.65 μg/mL) and it was able to inhibit the interaction between placental growth factor (PlGF) (placental growth factor), a VEGF family member, and its receptor Flt-1 by more than 50% at 1 mg/mL. 1,2,3,4,6-Penta-O-galloyl-d-glucopyranose, 6 is the most active compound of the extract. It exhibited a high potency in scavenging DPPH (EC₅₀ = 2.16 μg/mL) and reduced by 58% the PlGF/Flt-1 interaction at a concentration of 50 μM. Moreover, the known compounds (1-6) have been isolated for the first time in A. graveolens. PMID:24588321

  13. In vitro assessment of drug-drug interaction potential of boceprevir associated with drug metabolizing enzymes and transporters.

    Science.gov (United States)

    Chu, Xiaoyan; Cai, Xiaoxin; Cui, Donghui; Tang, Cuyue; Ghosal, Anima; Chan, Grace; Green, Mitchell D; Kuo, Yuhsin; Liang, Yuexia; Maciolek, Cheri M; Palamanda, Jairam; Evers, Raymond; Prueksaritanont, Thomayant

    2013-03-01

    The inhibitory effect of boceprevir (BOC), an inhibitor of hepatitis C virus nonstructural protein 3 protease was evaluated in vitro against a panel of drug-metabolizing enzymes and transporters. BOC, a known substrate for cytochrome P450 (P450) CYP3A and aldo-ketoreductases, was a reversible time-dependent inhibitor (k(inact) = 0.12 minute(-1), K(I) = 6.1 µM) of CYP3A4/5 but not an inhibitor of other major P450s, nor of UDP-glucuronosyltransferases 1A1 and 2B7. BOC showed weak to no inhibition of breast cancer resistance protein (BCRP), P-glycoprotein (Pgp), or multidrug resistance protein 2. It was a moderate inhibitor of organic anion transporting polypeptide (OATP) 1B1 and 1B3, with an IC(50) of 18 and 4.9 µM, respectively. In human hepatocytes, BOC inhibited CYP3A-mediated metabolism of midazolam, OATP1B-mediated hepatic uptake of pitavastatin, and both the uptake and metabolism of atorvastatin. The inhibitory potency of BOC was lower than known inhibitors of CYP3A (ketoconazole), OATP1B (rifampin), or both (telaprevir). BOC was a substrate for Pgp and BCRP but not for OATP1B1, OATP1B3, OATP2B1, organic cation transporter, or sodium/taurocholate cotransporting peptide. Overall, our data suggest that BOC has the potential to cause pharmacokinetic interactions via inhibition of CYP3A and CYP3A/OATP1B interplay, with the interaction magnitude lower than those observed with known potent inhibitors. Conversely, pharmacokinetic interactions of BOC, either as a perpetrator or victim, via other major P450s and transporters tested are less likely to be of clinical significance. The results from clinical drug-drug interaction studies conducted thus far are generally supportive of these conclusions. PMID:23293300

  14. 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

  15. Antiangiogenic treatment delays chondrocyte maturation and bone formation during limb skeletogenesis.

    Science.gov (United States)

    Yin, Melinda; Gentili, Chiara; Koyama, Eiki; Zasloff, Michael; Pacifici, Maurizio

    2002-01-01

    Hypertrophic chondrocytes have important roles in promoting invasion of cartilage by blood vessels and its replacement with bone. However, it is unclear whether blood vessels exert reciprocal positive influences on chondrocyte maturation and function. Therefore, we implanted beads containing the antiangiogenic molecule squalamine around humeral anlagen in chick embryo wing buds and monitored the effects over time. Fluorescence microscopy showed that the drug diffused from the beads and accumulated in humeral perichondrial tissues, indicating that these tissues were the predominant targets of drug action. Diaphyseal chondrocyte maturation was indeed delayed in squalamine-treated humeri, as indicated by reduced cell hypertrophy and expression of type X collagen, transferrin, and Indian hedgehog (Ihh). Although reduced in amount, Ihh maintained a striking distribution in treated and control humeri, being associated with diaphyseal chondrocytes as well as inner perichondrial layer. These decreases were accompanied by lack of cartilage invasion and tartrate-resistant acid phosphatase-positive (TRAP+) cells and a significant longitudinal growth retardation. Recovery occurred at later developmental times, when in fact expression in treated humeri of markers such as matrix metalloproteinase 9 (MMP-9) and connective tissue growth factor (CTGF) appeared to exceed that in controls. Treating primary cultures of hypertrophic chondrocytes and osteoblasts with squalamine revealed no obvious changes in cell phenotype. These data provide evidence that perichondrial tissues and blood vessels in particular influence chondrocyte maturation in a positive manner and may cooperate with hypertrophic chondrocytes in dictating the normal pace and location of the transition from cartilage to bone. PMID:11771670

  16. 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. PMID:27137712

  17. Assessment of adverse drug reactions based on spontaneous signals at secondary care public hospital

    Directory of Open Access Journals (Sweden)

    S Ponnusankar

    2015-01-01

    Full Text Available 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.

  18. In vitro assessment of drug resistance in Plasmodium falciparum in five States of India

    OpenAIRE

    Anvikar, Anupkumar R.; Sharma, Bhawna; Sharma, S. K.; S.K. GHOSH; Bhatt, R. M.; Kumar, Ashwani; Mohanty, S.S.; Pillai, C. R.; A. P. Dash; Valecha, Neena

    2012-01-01

    Background & objectives: In vitro assays are an important tool to assess baseline sensitivity and monitor the drug response of Plasmodium falciparum over time and place and, therefore, can provide background information for the development and evaluation of drug policies. This study was aimed at determining the in vitro sensitivity of P. falciparum isolates to antimalarials. Methods: The in vitro activity of 108 P. falciparum isolates obtained from five States of India was evaluated using WHO...

  19. Transmission Assessment Surveys (TAS) to Define Endpoints for Lymphatic Filariasis Mass Drug Administration: A Multicenter Evaluation

    OpenAIRE

    Brian K Chu; Michael Deming; Nana-Kwadwo Biritwum; Bougma, Windtaré R.; Améyo M Dorkenoo; Maged El-Setouhy; Fischer, Peter U.; Katherine Gass; Manuel Gonzalez de Peña; Leda Mercado-Hernandez; Dominique Kyelem; Lammie, Patrick J; Rebecca M Flueckiger; Mwingira, Upendo J.; Rahmah Noordin

    2013-01-01

    BACKGROUND: 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 a level low enough that it cannot be sustained even in the absence of drug intervention. Guidelines advanced by WHO call for a transmission assessment survey (TAS) to determine if MDA can...

  20. Assessment of intestinal availability (FG) of substrate drugs of cytochrome p450s by analyzing changes in pharmacokinetic properties caused by drug-drug interactions.

    Science.gov (United States)

    Hisaka, Akihiro; Nakamura, Mikiko; Tsukihashi, Ayako; Koh, Saori; Suzuki, Hiroshi

    2014-10-01

    In this study, we developed the drug-drug interaction (DDI) method as a new assessment technique of intestinal availability (F(G), the fraction of drug transferred from the intestinal enterocytes into the liver, escaping from intestinal metabolism) based on the clearance theory. This method evaluates F(G) from changes caused by DDIs in the area under the blood concentration-time curve and in the elimination half-life of victim drugs. Application of the DDI method to data from the literature revealed that the mean and S.D. of F(G) values for 20 substrate drugs of CYP3A was 0.56 ± 0.29, whereas that for 8 substrate drugs of CYP2C9, CYP2C19, and CYP2D6 was 0.86 ± 0.11. These results were consistent with the fact that intestinal metabolism is mediated predominantly by CYP3A. The DDI method showed reasonable correlations with the conventional i.v./p.o. method and the grape fruit juice (GFJ) method (coefficients of determination of 0.41 and 0.81, respectively). The i.v./p.o. method was more susceptible to fluctuations in the hepatic blood flow rate compared with the DDI and GFJ methods. The DDI method evaluates F(G) separating from the absorption ratio (F(A)) although it requires approximation of F(A). Since preciseness of approximation of F(A) does not greatly affect the evaluation of F(G) by the DDI method, we proposed a reasonable approximation method of F(A) for the evaluation of F(G) in the DDI method. The DDI method would be applicable to a broad range of situations in which various DDI data are utilizable. PMID:25061161

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

    International Nuclear Information System (INIS)

    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 1H-MR spectroscopic imaging (1H-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

  2. 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.

  3. [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. PMID:27003322

  4. Adeno-associated virus 2-mediated antiangiogenic cancer gene therapy: long-term efficacy of a vector encoding angiostatin and endostatin over vectors encoding a single factor.

    Science.gov (United States)

    Ponnazhagan, Selvarangan; Mahendra, Gandham; Kumar, Sanjay; Shaw, Denise R; Stockard, Cecil R; Grizzle, William E; Meleth, Sreelatha

    2004-03-01

    Angiogenesis is characteristic of solid tumor growth and a surrogate marker for metastasis in many human cancers. Inhibition of tumor angiogenesis using antiangiogenic drugs and gene transfer approaches has suggested the potential of this form of therapy in controlling tumor growth. However, for long-term tumor-free survival by antiangiogenic therapy, the factors controlling tumor neovasculature need to be systemically maintained at stable therapeutic levels. Here we show sustained expression of the antiangiogenic factors angiostatin and endostatin as secretory proteins by recombinant adeno-associated virus 2 (rAAV)-mediated gene transfer. Both vectors provided significant protective efficacy in a mouse tumor xenograft model. Stable transgene persistence and systemic levels of both angiostatin and endostatin were confirmed by in situ hybridization of the vector-injected tissues and by serum ELISA measurements, respectively. Whereas treatment with rAAV containing either endostatin or angiostatin alone resulted in moderate to significant protection, the combination of endostatin and angiostatin gene transfer from a single vector resulted in a complete protection. These data suggest that AAV-mediated long-term expression of both endostatin and angiostatin may have clinical utility against recurrence of cancers after primary therapies and may represent rational adjuvant therapies in combination with radiation or chemotherapy. PMID:14996740

  5. Gastrointestinal Toxicities With Combined Antiangiogenic and Stereotactic Body Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Pollom, Erqi L.; Deng, Lei [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Pai, Reetesh K. [Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (United States); Brown, J. Martin; Giaccia, Amato; Loo, Billy W.; Shultz, David B.; Le, Quynh Thu; Koong, Albert C. [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Chang, Daniel T., E-mail: dtchang@stanford.edu [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States)

    2015-07-01

    Combining the latest targeted biologic agents with the most advanced radiation technologies has been an exciting development in the treatment of cancer patients. Stereotactic body radiation therapy (SBRT) is an ablative radiation approach that has become established for the treatment of a variety of malignancies, and it has been increasingly used in combination with biologic agents, including those targeting angiogenesis-specific pathways. Multiple reports have emerged describing unanticipated toxicities arising from the combination of SBRT and angiogenesis-targeting agents, particularly of late luminal gastrointestinal toxicities. In this review, we summarize the literature describing these toxicities, explore the biological mechanism of action of toxicity with the combined use of antiangiogenic therapies, and discuss areas of future research, so that this combination of treatment modalities can continue to be used in broader clinical contexts.

  6. Anti-angiogenic agents in metastatic colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Colorectal cancer (CRC) is a major public health concernbeing the third leading cause of cancer mortality inthe United States. The availability of better therapeuticoptions has led to a decline in cancer mortality in thesepatients. Surgical resection should be considered in allstages of the disease. The use of conversion therapyhas made surgery a potentially curative option even inpatients with initially unresectable metastatic disease.In this review we discuss the role of various antiangiogenicagents in patients with metastatic CRC(mCRC). We describe the mechanism of action of theseagents, and the rationale for their use in combinationwith chemotherapy. We also review important clinicalstudies that have evaluated the safety and efficacy ofthese agents in mCRC patients. Despite the discoveryof several promising anti-angiogenic agents, mCRCremains an incurable disease with a median overallsurvival of just over 2 years in patients exposed to allavailable treatment regimens. Further insights intotumor biology and tumor microenvironment may helpimprove outcomes in these patients.

  7. Anti-angiogenic and cytotoxicity studies of some medicinal plants.

    Science.gov (United States)

    Ng, Kwok-Wen; Salhimi, Salizawati Muhamad; Majid, Amin Malik; Chan, Kit-Lam

    2010-06-01

    Angiogenesis plays an important role in tumor formation and proliferation. The development of anti-angiogenic agents to block new blood vessel growth will inhibit metastasis and induce apoptosis of the cancer cells. Nine medicinal plants, Strobilanthes crispus, Phyllanthus niruri, Phyllanthus pulcher, Phyllanthus urinaria, Ailanthus malabarica, Irvingia malayana, Smilax myosotiflora, Tinospora crispa and blumea balsamifera were screened for anti-angiogenic properties using the rat aortic ring assay. Of these, the methanol extracts of Phyllanthus species and Irvingia malayana exhibited the highest activity. At 100 microg/mL, P. pulcher, P. niruri, P. urinaria and I. malayana recorded an inhibition of 78.8 %, 59.5 %, 56.7 % and 46.4 %, respectively, against rat aortic vascular growth. Their activities were further investigated by the tube formation assay involving human umbilical vein endothelial cells (HUVEC) on Matrigel. I. malayana, P. niruri and P. urinaria showed a significant decrease of 45.5, 37.9 and 35.6 %, respectively, whilst P. pulcher showed a much lower decrease of 15.5 % when compared with that of the rat aortic ring assay. All the plant extracts were evaluated for cytotoxicity on a panel of human cancer cell lines using the MTT assay. None of them displayed acute cytotoxicity. The HPLC of P. niruri, P. urinaria and P. pulcher indicated the extracts contained some identical chromatographic peaks of lignans. Further fractionation of I. malayana yielded betulinic acid reported in this plant for the first time and at 100 microg/mL it exhibited a 67.3 % inhibition of vessel outgrowth and 46.5 % inhibition of tube formation. PMID:20112179

  8. ERK1/2 and HIF1α Are Involved in Antiangiogenic Effect of Polyphenols-Enriched Fraction from Chilean Propolis

    Directory of Open Access Journals (Sweden)

    Alejandro Cuevas

    2015-01-01

    Full Text Available Propolis has been shown to modulate the angiogenesis in both in vitro and in vivo models. Thus, we aimed to evaluate the antiangiogenic properties of an ethanolic extract of Chilean propolis (EEP and Pinocembrin (Pn. Migration, formation of capillary-like structures of endothelial cells, and sprouting from rat aortic rings were used to assess the antiangiogenic properties of EEP or Pn. In addition, microRNAs and VEGFA mRNA expression were studied by qPCR. ERK1/2 phosphorylation and HIF1α stabilization were assessed by western blot. EEP or Pn attenuated the migration, the capillary-like tube formation, and the sprouting in the in vitro assays. In addition, the activation of HIF1α and ERK1/2 and the VEGFA mRNA expression was significantly inhibited in a dose-dependent manner. In summary, these results suggest that HIF1α and ERK1/2 phosphorylation could be involved in the antiangiogenic effect of Chilean propolis, but more studies are needed to corroborate these findings.

  9. Biometrical issues in the analysis of adverse events within the benefit assessment of drugs.

    Science.gov (United States)

    Bender, Ralf; Beckmann, Lars; Lange, Stefan

    2016-07-01

    The analysis of adverse events plays an important role in the benefit assessment of drugs. Consequently, results on adverse events are an integral part of reimbursement dossiers submitted by pharmaceutical companies to health policy decision-makers. Methods applied in the analysis of adverse events commonly include simple standard methods for contingency tables. However, the results produced may be misleading if observations are censored at the time of discontinuation due to treatment switching or noncompliance, resulting in unequal follow-up periods. In this paper, we present examples to show that the application of inadequate methods for the analysis of adverse events in the reimbursement dossier can lead to a downgrading of the evidence on a drug's benefit in the subsequent assessment, as greater harm from the drug cannot be excluded with sufficient certainty. Legal regulations on the benefit assessment of drugs in Germany are presented, in particular, with regard to the analysis of adverse events. Differences in safety considerations between the drug approval process and the benefit assessment are discussed. We show that the naive application of simple proportions in reimbursement dossiers frequently leads to uninterpretable results if observations are censored and the average follow-up periods differ between treatment groups. Likewise, the application of incidence rates may be misleading in the case of recurrent events and unequal follow-up periods. To allow for an appropriate benefit assessment of drugs, adequate survival time methods accounting for time dependencies and duration of follow-up are required, not only for time-to-event efficacy endpoints but also for adverse events. © 2016 The Authors. Pharmaceutical Statistics published by John Wiley & Sons Ltd. PMID:26928768

  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. 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

  12. Update on World Health Organization HIV Drug Resistance Prevention and Assessment Strategy: 2004–2011

    OpenAIRE

    Jordan, M. R.; Bennett, D. E.; Wainberg, M A; Havlir, D; Hammer, S.; Yang, C.; Morris, L.; Peeters, M; Wensing, A. M.; Parkin, N; Nachega, J. B.; Phillips, A; De Luca, A.; Geng, E; A Calmy

    2012-01-01

    The HIV drug resistance (HIVDR) prevention and assessment strategy, developed by the World Health Organization (WHO) in partnership with HIVResNet, includes monitoring of HIVDR early warning indicators, surveys to assess acquired and transmitted HIVDR, and development of an accredited HIVDR genotyping laboratory network to support survey implementation in resource-limited settings. As of June 2011, 52 countries had implemented at least 1 element of the strategy, and 27 laboratories had been a...

  13. ASSESSMENT OF DRUG USE PRACTICES AND COMPLETENESS OF PRESCRIPTIONS IN GONDAR UNIVERSITY TEACHING REFERRAL HOSPITAL

    Directory of Open Access Journals (Sweden)

    Endalkachew Admassie*, Birhan Begashaw and Wubshet Hailu

    2013-01-01

    Full Text Available Background: Rational drug use is a tool through which safe, effective and economic medication is provided. Rational prescribing ensures adherence to treatment and protects drug consumers from unnecessary adverse drug reactions. Rational dispensing on the other hand, promotes the safe, effective and economic use of drugs.Objectives: The aim of this study was to assess drug use practices and completeness of information on prescriptions in Gondar University Hospital.Methodology: A combination of retrospective and cross sectional study was conducted in outpatient pharmacy in the facility. Of the total of 30,000, some 1145 prescriptions containing drugs prescribed during the month of May 1, 2010 to April 30, 2011 were reviewed for retrospective and 31 patients coming with their prescriptions to outpatient pharmacy were interviewed in the middle of the week on the day of January 25, 2012.Results: The mean number of drugs per prescriptions was 1.76, percentage of prescriptions containing < 2 drugs per prescription was 80.87%. The generic name of the medication was used in 99.16 % of the prescriptions. Antibiotics were prescribed in 29.14 % of prescriptions and injections were prescribed in 28.50% of prescriptions. The drugs prescribed in 98.89% of prescriptions were part of the hospital essential drug list indicating the acceptance of this list by health care professionals. Patients age, sex and card number were written 86.64%, 67.93% and 73.54% respectively. Address of the patient and diagnosis were omitted 97.29% and 99.99% respectively. The correct name and strength of the drug were clearly stated in 80% of the prescriptions whereas dose, frequency and durations were clearly indicated in 81.38%, 76.07% and 82.01% of the prescriptions respectively. 33.42%, 96.69%, 72.56% and 16.09% of the prescriptions contain the name, signature, date and qualification of the prescribers. 80% of patients interviewed had adequate knowledge of how to take the

  14. Acrolein: unwanted side product or contribution to antiangiogenic properties of metronomic cyclophosphamide therapy?

    OpenAIRE

    Günther, M; Wagner, E.; Ogris, M.

    2008-01-01

    Tumour therapy with cyclophosphamide (CPA), an alkylating chemotherapeutic agent, has been associated with reduced tumour blood supply and antiangiogenic effects when applied in a continuous, low-dose metronomic schedule. Compared to conventional high-dose scheduling, metronomic CPA therapy exhibits antitumoural activity with reduced side effects. We have studied potential antiangiogenic properties of acrolein which is released from CPA after hydroxylation. Acrolein adducts were found in tumo...

  15. Antiangiogenic Gene Therapy of Cancer Utilizing a Recombinant Adenovirus to Elevate Systemic Endostatin Levels in Mice

    OpenAIRE

    Feldman, Andrew L.; Restifo, Nicholas P; Alexander, H. Richard; Bartlett, David L.; Hwu, Patrick; Seth, Prem; Libutti, Steven K.

    2000-01-01

    Gene therapy represents a possible alternative to the chronic delivery of recombinant antiangiogenic proteins to cancer patients. Inducing normal host tissues to produce high circulating levels of these proteins may be more effective than targeting antiangiogenic genes to tumor tissue specifically. Previously reported gene therapy approaches in mice have achieved peak circulating endostatin levels of 8–33 ng/ml. Here we report plasma endostatin levels of 1770 ng/ml after administration of a r...

  16. FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal.

    Science.gov (United States)

    Haemmerle, Monika; Bottsford-Miller, Justin; Pradeep, Sunila; Taylor, Morgan L; Choi, Hyun-Jin; Hansen, Jean M; Dalton, Heather J; Stone, Rebecca L; Cho, Min Soon; Nick, Alpa M; Nagaraja, Archana S; Gutschner, Tony; Gharpure, Kshipra M; Mangala, Lingegowda S; Rupaimoole, Rajesha; Han, Hee Dong; Zand, Behrouz; Armaiz-Pena, Guillermo N; Wu, Sherry Y; Pecot, Chad V; Burns, Alan R; Lopez-Berestein, Gabriel; Afshar-Kharghan, Vahid; Sood, Anil K

    2016-05-01

    Recent studies in patients with ovarian cancer suggest that tumor growth may be accelerated following cessation of antiangiogenesis therapy; however, the underlying mechanisms are not well understood. In this study, we aimed to compare the effects of therapy withdrawal to those of continuous treatment with various antiangiogenic agents. Cessation of therapy with pazopanib, bevacizumab, and the human and murine anti-VEGF antibody B20 was associated with substantial tumor growth in mouse models of ovarian cancer. Increased tumor growth was accompanied by tumor hypoxia, increased tumor angiogenesis, and vascular leakage. Moreover, we found hypoxia-induced ADP production and platelet infiltration into tumors after withdrawal of antiangiogenic therapy, and lowering platelet counts markedly inhibited tumor rebound after withdrawal of antiangiogenic therapy. Focal adhesion kinase (FAK) in platelets regulated their migration into the tumor microenvironment, and FAK-deficient platelets completely prevented the rebound tumor growth. Additionally, combined therapy with a FAK inhibitor and the antiangiogenic agents pazopanib and bevacizumab reduced tumor growth and inhibited negative effects following withdrawal of antiangiogenic therapy. In summary, these results suggest that FAK may be a unique target in situations in which antiangiogenic agents are withdrawn, and dual targeting of FAK and VEGF could have therapeutic implications for ovarian cancer management. PMID:27064283

  17. Dynamic contrast-enhanced ultrasonography (DCE-US) and anti-angiogenic treatments.

    Science.gov (United States)

    Lassau, Nathalie; Chami, Linda; Chebil, Mohamed; Benatsou, Baya; Bidault, Sophie; Girard, Elizabeth; Abboud, Ghassen; Roche, Alain

    2011-01-01

    Dynamic contrast-enhanced ultrasonography (DCE-US) is a current functional imaging technique enabling a quantitative assessment of tumor perfusion using raw linear data. DCE-US allows calculating several parameters as slope of wash-in or area under the curve representing, respectively, blood flow or blood volume. Decrease of vascularization can easily be detected in responders after 1 or 2 weeks of anti-angiogenic treatment for gastrointestinal stromal tumors (GIST), renal cell carcinoma (RCC), and hepatocellular carcinoma (HCC) and is correlated with progression-free survival and overall survival in RCC or HCC. DCE-US is supported by the French National Cancer Institute (INCa), which is currently studying the technique in metastatic breast cancer, melanoma, colon cancer, gastrointestinal stromal tumors and renal cell carcinoma, as well as in primary hepatocellular carcinoma, to establish the optimal perfusion parameters and timing for quantitative anticancer efficacy assessments. Currently 479 patients are included in 19 centers and the preliminary results on 400 patients with 1096 DCE-US demonstrated that the area under the curve (AUC) quantified at 1 month could be a robust parameter to predict response at 6 months. PMID:21276407

  18. Regulatory perspective on the importance of ADME assessment of nanoscale material containing drugs.

    Science.gov (United States)

    Zolnik, Banu S; Sadrieh, Nakissa

    2009-06-21

    The promise of nanoscale material containing drug products to treat complex diseases is mounting. According to the literature, in addition to the liposomes, micelles, emulsions, there are novel drug delivery systems such as dendrimers and metal colloids at different stages of pre-clinical and clinical development. With the anticipation that more nanoscale material containing drug products will be submitted to the Food and Drug Administration (FDA) for approval in the future, FDA formed a Nanotechnology Task Force in 2006 to determine the critical regulatory issues regarding nanomaterials. As a result, all centers within the FDA are considering the development of guidance documents to address nanomaterial specific issues. It is well established in the literature that physico-chemical characterization (PCC) studies are crucial for nanomaterial containing drug products. However, this paper addresses the equally important topic of Absorption, Distribution, Metabolism and Excretion (ADME) studies for nanomaterials and provides examples of how physical properties affect biodistribution (i.e. the state of agglomeration, or aggregation, surface characteristics, stability of PEG). This paper also attempts to highlight some of the ADME study design issues related to nanomaterials such as the need for conducting biodistribution studies on each moiety of the multifunctional nanoparticles, dual labeled pharmacokinetic (PK) studies, and comparative PK studies on the free versus encapsulated drugs. In addition, this paper underlines the importance of long-term biodistribution and mass balance studies to understand the nanoparticle accumulation profile which may help to assess the safety and efficacy of the nanomaterial containing drug products. This review also lists some of the pre-clinical guidance documents that may help sponsors get started in developing data for inclusion in an initial investigational new drug application package for nanoscale material containing drug

  19. 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

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

    International Nuclear Information System (INIS)

    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 1mm3. 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 1mm3. 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 obtained

  1. Cytokines, angiogenic, and antiangiogenic factors and bioactive lipids in preeclampsia.

    Science.gov (United States)

    Das, Undurti N

    2015-09-01

    Preeclampsia is a low-grade systemic inflammatory condition in which oxidative stress and endothelial dysfunction occurs. Plasma levels of soluble receptor for vascular endothelial growth factor (VEGFR)-1, also known as sFlt1 (soluble fms-like tyrosine kinase 1), an antiangiogenic factor have been reported to be elevated in preeclampsia. It was reported that pregnant mice deficient in catechol-O-methyltransferase (COMT) activity show a preeclampsia-like phenotype due to a deficiency or absence of 2-methoxyoestradiol (2-ME), a natural metabolite of estradiol that is elevated during the third trimester of normal human pregnancy. Additionally, autoantibodies (AT1-AAs) that bind and activate the angiotensin II receptor type 1 a (AT1 receptor) also have a role in preeclampsia. None of these abnormalities are consistently seen in all the patients with preeclampsia and some of them are not specific to pregnancy. Preeclampsia could occur due to an imbalance between pro- and antiangiogenic factors. VEGF, an angiogenic factor, is necessary for the transport of polyunsaturated fatty acids (PUFAs) to endothelial cells. Hence reduced VEGF levels decrease the availability of PUFAs to endothelial cells. This leads to a decrease in the formation of anti-inflammatory and angiogenic factors: lipoxins, resolvins, protectins, and maresins from PUFAs. Lipoxins, resolvins, protectins, maresins, and PUFAs suppress insulin resistance; activation of leukocytes, platelets, and macrophages; production of interleukin-6 and tumor necrosis factor-α; and oxidative stress and endothelial dysfunction; and enhance production of prostacyclin and nitric oxide (NO). Estrogen enhances the formation of lipoxin A4 and NO. PUFAs also augment the production of NO and inhibit the activity of angiotensin-converting enzyme and antagonize the actions of angiotensin II. Thus, PUFAs can prevent activation of angiotensin II receptor type 1 a (AT1 receptor). Patients with preeclampsia have decreased plasma

  2. Assessing Natural Product-Drug Interactions: An End-to-End Safety Framework.

    Science.gov (United States)

    Roe, Amy L; Paine, Mary F; Gurley, Bill J; Brouwer, Kenneth R; Jordan, Scott; Griffiths, James C

    2016-04-01

    The use of natural products (NPs), including herbal medicines and other dietary supplements, by North Americans continues to increase across all age groups. This population has access to conventional medications, with significant polypharmacy observed in older adults. Thus, the safety of the interactions between multi-ingredient NPs and drugs is a topic of paramount importance. Considerations such as history of safe use, literature data from animal toxicity and human clinical studies, and NP constituent characterization would provide guidance on whether to assess NP-drug interactions experimentally. The literature is replete with reports of various NP extracts and constituents as potent inhibitors of drug metabolizing enzymes, and transporters. However, without standard methods for NP characterization or in vitro testing, extrapolating these reports to clinically-relevant NP-drug interactions is difficult. This lack of a clear definition of risk precludes clinicians and consumers from making informed decisions about the safety of taking NPs with conventional medications. A framework is needed that describes an integrated robust approach for assessing NP-drug interactions; and, translation of the data into formulation alterations, dose adjustment, labelling, and/or post-marketing surveillance strategies. A session was held at the 41st Annual Summer Meeting of the Toxicology Forum in Colorado Springs, CO, to highlight the challenges and critical components that should be included in a framework approach. PMID:26776752

  3. 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.

  4. Assessment of Alcohol and Other Drug Use by Runaway Youths: A Test-Retest Study of the Form 90

    OpenAIRE

    SLESNICK, NATASHA; Tonigan, J. Scott

    2004-01-01

    While excellent adolescent alcohol and drug screening tools are available, there are relatively few, if any, psychometrically validated measures to use in the assessment of adolescent treatment outcome. This study conducted a test-retest exercise of the Form 90 Drug and Alcohol (Form 90 DnA) to determine the stability of adolescent responses when administering the day-by-day calendar/grid approach. Homeless youth (N = 37) with alcohol, drug, or alcohol and drug abuse/dependence combined were ...

  5. Comparison of Individual and Pooled Stool Samples for the Assessment of Soil-Transmitted Helminth Infection Intensity and Drug Efficacy

    OpenAIRE

    Zeleke Mekonnen; Selima Meka; Mio Ayana; Johannes Bogers; Jozef Vercruysse; Bruno Levecke

    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 fro...

  6. 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.

  7. A review of quality of life in Alzheimer's disease. Part 2: Issues in assessing drug effects.

    Science.gov (United States)

    Salek, S S; Walker, M D; Bayer, A J

    1998-12-01

    There are numerous methods available for assessing patients with Alzheimer's disease (AD) or other forms of dementia. Quality-of-life (QOL) assessment is unique among these methods. The subjective nature of quality of life provides healthcare professionals with the opportunity of incorporating the value systems of patients and their carers into their assessments. A systematic review was carried out to assess the published data (and some unpublished data) on QOL assessment tools and instruments that claim to measure quality of life in dementia. A number of measures or methods used in the literature for assessing the quality of life of patients with dementing illnesses were identified. It was decided to present the resultant review in 2 parts that correspond to the 2 main groups into which the instruments were categorised. The first (part 1), looked at measures used to assess the impact of disease as well as instruments at a developmental or testing stage. The second (part 2), includes instruments that claim to measure quality of life in studies documenting the impact of a drug in this therapeutic area. This second group consists mainly of instruments identified as being used to assess quality of life during clinical trials in dementia/AD. As in part 1, this part of the review was unable to identify any validated methods of assessing the quality of life of both patients with dementia and their carers at the same time. The ideal instrument must show that it can reliably, reproducibly and comprehensively assess quality of life for both patients with dementia and their carers. It should also demonstrate that it can measure quality of life effectively using a practical administration technique that does not place any unnecessary burden on either informal carers, other healthcare workers involved or the patient themselves. In addition, any measure intended for use in assessing the impact of drug treatment on quality of life must demonstrate sensitivity to change, also

  8. A study of pipeline drugs in neuroendocrine tumors

    Science.gov (United States)

    Inhibition of neovessel development can stabilize tumor growth. A rapid in vitro method that can evaluate the effectiveness of anti-angiogenic drugs would aid in drug development. We tested a series of investigational agents to determine their ability to inhibit angiogenesis in our in vitro human a...

  9. ASSESSMENT OF PRACTICE AT RETAIL PHARMACIES IN PAKISTAN: EXTENT OF COMPLIANCE WITH THE PREVAILING DRUG LAW OF PAKISTAN.

    Science.gov (United States)

    Ullah, Hanif; Zada, Wahid; Khan, Muhammad Sona; Iqbal, Muhammad; Chohan, Osaam; Raza, Naeem; Khawaja, Naeem Raza; Abid, Syed Mobasher Ali; Murtazai, Ghulam

    2016-01-01

    The main objective of this study was to assess the practice at retail pharmacies in Pakistan and to compare the same in rural and urban areas. The maintenance of pharmacy and drug inspectors' visit was also assessed. This cross sectional study was conducted in Abbottabad, Pakistan during October-November, 2012. A sample of 215 drug sellers or drug stores was selected by employing convenient sampling method. With a response rate of 91.6%, 197 drug sellers participated in this study. All the drug sellers were male. Overall, 35% (n = 197) of the drug sellers did not have any professional qualification. A majority of the drug sellers were involved in various malpractices like selling of medicines without prescription (80.7%), prescribing practice (60.9%), prescription intervention (62.4%) and selling of controlled substances (66%) without a license for selling it. These malpractices were significantly higher in rural area than that in urban area. PMID:27476300

  10. 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......; firstly, present methods suitable for assessing sensor accuracy, and secondly improve sensor performance by enhancing the preprocessing and feature extraction. Five different miniaturized sensors are presented. Naturally, each sensor require its own special preprocessing and feature extraction techniques...... emanated by explosives and drugs, similar to an electronic nose. To evaluate sensor responses a data processing and evaluation pipeline is required. The work presented herein focuses on the feature extraction, feature representation and sensor accuracy. Thus the primary aim of this thesis is twofold...

  11. Laser-evoked potentials as a tool for assessing the efficacy of antinociceptive drugs

    Science.gov (United States)

    Truini, A.; Panuccio, G.; Galeotti, F.; Maluccio, M.R.; Sartucci, F.; Avoli, M.; Cruccu, G.

    2016-01-01

    Laser-evoked potentials (LEPs) are brain responses to laser radiant heat pulses and reflect the activation of Aδ nociceptors. LEPs are to date the reference standard technique for studying nociceptive pathway function in patients with neuropathic pain. To find out whether LEPs also provide a useful neurophysiological tool for assessing antinociceptive drug efficacy, in this double-blind placebo-controlled study we measured changes induced by the analgesic tramadol on LEPs in 12 healthy subjects. We found that tramadol decreased the amplitude of LEPs, whereas placebo left LEPs unchanged. The opioid antagonist naloxone partially reversed the tramadol-induced LEP amplitude decrease. We conclude that LEPs may be reliably used in clinical practice and research for assessing the efficacy of antinociceptive drugs. PMID:19477145

  12. Assessment of Potential Herb-Drug Interactions among Nigerian Adults with Type-2 Diabetes

    Science.gov (United States)

    Ezuruike, Udoamaka; Prieto, Jose M.

    2016-01-01

    It is becoming increasingly evident that patients with diabetes do not rely only on prescription drugs for their disease management. The use of herbal medicines is one of the self-management practices adopted by these patients, often without the knowledge of their healthcare practitioners. This study assessed the potential for pharmacokinetic herb-drug interactions (HDIs) amongst Nigerian adult diabetic patients. This was done through a literature analysis of the pharmacokinetic profile of their herbal medicines and prescription drugs, based on information obtained from 112 patients with type-2 diabetes attending two secondary health care facilities in Nigeria. Fifty percent of the informants used herbal medicines alongside their prescription drugs. Worryingly, 60% of the patients taking herbal medicines did not know their identity, thus increasing the risk of unidentified HDIs. By comparing the pharmacokinetic profile of eight identified herbs taken by the patients for the management of diabetes against those of the prescription drugs, several scenarios of potential HDIs were identified and their clinical relevance is discussed. The lack of clinical predictors points toward cultural factors as the influence for herb use, making it more difficult to identify these patients and in turn monitor potential HDIs. In identifying these possible interactions, we have highlighted the need for healthcare professionals to promote a proactive monitoring of patients' use of herbal medicines. PMID:27559312

  13. Assessment of Potential Herb-Drug Interactions among Nigerian Adults with Type-2 Diabetes.

    Science.gov (United States)

    Ezuruike, Udoamaka; Prieto, Jose M

    2016-01-01

    It is becoming increasingly evident that patients with diabetes do not rely only on prescription drugs for their disease management. The use of herbal medicines is one of the self-management practices adopted by these patients, often without the knowledge of their healthcare practitioners. This study assessed the potential for pharmacokinetic herb-drug interactions (HDIs) amongst Nigerian adult diabetic patients. This was done through a literature analysis of the pharmacokinetic profile of their herbal medicines and prescription drugs, based on information obtained from 112 patients with type-2 diabetes attending two secondary health care facilities in Nigeria. Fifty percent of the informants used herbal medicines alongside their prescription drugs. Worryingly, 60% of the patients taking herbal medicines did not know their identity, thus increasing the risk of unidentified HDIs. By comparing the pharmacokinetic profile of eight identified herbs taken by the patients for the management of diabetes against those of the prescription drugs, several scenarios of potential HDIs were identified and their clinical relevance is discussed. The lack of clinical predictors points toward cultural factors as the influence for herb use, making it more difficult to identify these patients and in turn monitor potential HDIs. In identifying these possible interactions, we have highlighted the need for healthcare professionals to promote a proactive monitoring of patients' use of herbal medicines. PMID:27559312

  14. Thallium-199 myocardial scintigraphy for assessing the efficacy of drug and surgical treatment of coronary disease

    International Nuclear Information System (INIS)

    Potentialities of thallium-199 myocardial scintigraphy in evaluation of the effects of surgical and drug treatment of myocardial perfusion in coronary patients are studied. It is shown that thallium-199 myocardial scintigraphy helps assess the effect of treatment on myocardial perfusion. Positive effect of treatment manifests by decrease of myocardial perfusion defects. The method permits imaging the coronary microcirculation over the course of treatment and predicting a further course of disease

  15. Assessing directed evolution methods for the generation of biosynthetic enzymes with potential in drug biosynthesis

    OpenAIRE

    Nannemann, David P.; Birmingham, William R.; Scism, Robert A.; Bachmann, Brian O.

    2011-01-01

    To address the synthesis of increasingly structurally diverse small-molecule drugs, methods for the generation of efficient and selective biological catalysts are becoming increasingly important. ‘Directed evolution’ is an umbrella term referring to a variety of methods for improving or altering the function of enzymes using a nature-inspired twofold strategy of mutagenesis followed by selection. This article provides an objective assessment of the effectiveness of directed evolution campaign...

  16. Drug use during pregnancy in Sweden – assessed by the Prescribed Drug Register and the Medical Birth Register

    Directory of Open Access Journals (Sweden)

    Tobias Svensson

    2011-02-01

    Full Text Available Olof Stephansson, Fredrik Granath, Tobias Svensson, Bengt Haglund, Anders Ekbom, Helle KielerClinical Epidemiology Unit and Centre for Pharmacoepidemiology, Department of Medicine, Karolinska University Hospital and Institutet, Stockholm, SwedenPurpose: The purpose of this research is to study drug use during pregnancy in Sweden and agreement between use according to antenatal medical records and dispensed drugs from a pharmacy database.Patients and methods: From the Swedish Medical Birth Register (MBR, we established a population-based cohort of 102,995 women who gave birth in 2007. Using the unique personal registration number, information on dispensed drugs from the Prescribed Drug Register (PDR was obtained prior to, during, and after the pregnancies and compared with MBR information on drug use from standardized antenatal medical records.Results: According to the PDR, 57.6% of the 102,995 women filled a prescription with at least one drug during pregnancy and 50.9% during the lactating period (until 3 months after delivery. The most dispensed drugs during pregnancy were B-lactam antibacterials and penicillins. Agreement between drugs recorded in antenatal medical records and dispensed drugs was highest for drugs used for chronic conditions. The agreement was particularly high for thyroid therapy (85.3%, anti-intestinal inflammatory drugs (80.3%, antiepileptics (69.2%, immunosuppressants (67.4%, and insulin (63.8%. Agreement for drugs used for occasional use was generally lower, ranging between 42.5% for antihistamines and 0.8% for gynecological anti-infectives.Conclusions: A large proportion of women filled a prescription during pregnancy or the lactating period. Agreement between drug use in medical antenatal records and register information from a national pharmacy database was high for drugs used for chronic conditions but low for occasional use. For occasionally used drugs, medical record and register-based data may provide incomplete

  17. Combined immunotherapy and antiangiogenic therapy of cancer with microencapsulated cells.

    Science.gov (United States)

    Cirone, Pasquale; Bourgeois, Jacqueline M; Shen, Feng; Chang, Patricia L

    2004-10-01

    An alternative form of gene therapy involves immunoisolation of a nonautologous cell line engineered to secrete a therapeutic product. Encapsulation of these cells in a biocompatible polymer serves to protect these allogeneic cells from host-versus-graft rejection while recombinant products and nutrients are able to pass by diffusion. This strategy was applied to the treatment of cancer with some success by delivering either interleukin 2 or angiostatin. However, as cancer is a complex, multifactorial disease, a multipronged approach is now being developed to attack tumorigenesis via multiple pathways in order to improve treatment efficacy. A combination of immunotherapy with angiostatic therapy was investigated by treating B16-F0/neu melanoma-bearing mice with intraperitoneally implanted, microencapsulated mouse myoblasts (C2C12) genetically modified to deliver angiostatin and an interleukin 2 fusion protein (sFvIL-2). The combination treatment resulted in improved survival, delayed tumor growth, and increased histological indices of antitumor activity (apoptosis and necrosis). In addition to improved efficacy, the combination treatment also ameliorated some of the undesirable side effects from the individual treatments that have led to the previous failure of the single treatments, for example, inflammatory response to IL-2 or vascular mimicry due to angiostatin. In conclusion, the combination of immuno- and antiangiogenic therapies delivered by immunoisolated cells was superior to individual treatments for antitumorigenesis activity, not only because of their known mechanisms of action but also because of unexpected protection against the adverse side effects of the single treatments. Thus, the concept of a "cocktail" strategy, with microencapsulation delivering multiple antitumor recombinant molecules to improve efficacy, is validated. PMID:15585110

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

    Directory of Open Access Journals (Sweden)

    Jaime R Merchan

    Full Text Available BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: 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.

  19. 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 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...

  20. 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.)

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

    International Nuclear Information System (INIS)

    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. 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. PMID:23331218

  3. Statistical and regulatory considerations in assessments of interchangeability of biological drug products.

    Science.gov (United States)

    Tóthfalusi, Lászlo; Endrényi, László; Chow, Shein-Chung

    2014-05-01

    When the patent of a brand-name, marketed drug expires, new, generic products are usually offered. Small-molecule generic and originator drug products are expected to be chemically identical. Their pharmaceutical similarity can be typically assessed by simple regulatory criteria such as the expectation that the 90% confidence interval for the ratio of geometric means of some pharmacokinetic parameters be between 0.80 and 1.25. When such criteria are satisfied, the drug products are generally considered to exhibit therapeutic equivalence. They are then usually interchanged freely within individual patients. Biological drugs are complex proteins, for instance, because of their large size, intricate structure, sensitivity to environmental conditions, difficult manufacturing procedures, and the possibility of immunogenicity. Generic and brand-name biologic products can be expected to show only similarity but not identity in their various features and clinical effects. Consequently, the determination of biosimilarity is also a complicated process which involves assessment of the totality of the evidence for the close similarity of the two products. Moreover, even when biosimilarity has been established, it may not be assumed that the two biosimilar products can be automatically substituted by pharmacists. This generally requires additional, careful considerations. Without declaring interchangeability, a new product could be prescribed, i.e. it is prescribable. However, two products can be automatically substituted only if they are interchangeable. Interchangeability is a statistical term and it means that products can be used in any order in the same patient without considering the treatment history. The concepts of interchangeability and prescribability have been widely discussed in the past but only in relation to small molecule generics. In this paper we apply these concepts to biosimilars and we discuss: definitions of prescribability and interchangeability and

  4. Antiangiogenic agents combined with chemotherapy in non-small cell lung cancer

    Institute of Scientific and Technical Information of China (English)

    Shanshan Chen; Shun Lu 

    2015-01-01

    As a targeted therapy, antiangiogenic treatment has been increasingly studied for advanced non-smal cel lung cancer (NSCLC) and has proven ef ective for the treatment of advanced NSCLC. Bevacizumab, a monoclonal antibody targeting angiogenesis, is the only antiangiogenic agent approved for use in com-bination with first-line chemotherapy for non-squamous NSCLC. Smal-molecule inhibitors targeting the tyrosine kinase receptor have also shown promise when combined with standard chemotherapeutic agents in patients with advanced NSCLC. However, unlike bevacizumab, not al other antiangiogenic agents show significant benefits when combined with chemotherapy. As for the failures of most other combinations, the combination schedule may be an important reason that has so far been overlooked in clinical trials. This article reviews the combination of angiogenic agents with chemotherapy in the treatment of NSCLC.

  5. The role of validated analytical methods in JECFA drug assessments and evaluation for recommending MRLs.

    Science.gov (United States)

    Boison, Joe O

    2016-05-01

    The Joint Food and Agriculture Organization and World Health Organization (FAO/WHO) Expert Committee on Food Additives (JECFA) is one of three Codex committees tasked with applying risk analysis and relying on independent scientific advice provided by expert bodies organized by FAO/WHO when developing standards. While not officially part of the Codex Alimentarius Commission structure, JECFA provides independent scientific advice to the Commission and its specialist committees such as the Codex Committee on Residues of Veterinary Drugs in Foods (CCRVDF) in setting maximum residue limits (MRLs) for veterinary drugs. Codex methods of analysis (Types I, II, III, and IV) are defined in the Codex Procedural Manual as are criteria to be used for selecting methods of analysis. However, if a method is to be used under a single laboratory condition to support regulatory work, it must be validated according to an internationally recognized protocol and the use of the method must be embedded in a quality assurance system in compliance with ISO/IEC 17025:2005. This paper examines the attributes of the methods used to generate residue depletion data for drug registration and/or licensing and for supporting regulatory enforcement initiatives that experts consider to be useful and appropriate in their assessment of methods of analysis. Copyright © 2016 Her Majesty the Queen in Right of Canada. Drug Testing and Analysis © 2016 John Wiley & Sons, Ltd. PMID:27443214

  6. Assessment of Binding Affinity between Drugs and Human Serum Albumin Using Nanoporous Anodic Alumina Photonic Crystals.

    Science.gov (United States)

    Nemati, Mahdieh; Santos, Abel; Law, Cheryl Suwen; Losic, Dusan

    2016-06-01

    In this study, we report an innovative approach aiming to assess the binding affinity between drug molecules and human serum albumin by combining nanoporous anodic alumina rugate filters (NAA-RFs) modified with human serum albumin (HSA) and reflectometric interference spectroscopy (RIfS). NAA-RFs are photonic crystal structures produced by sinusoidal pulse anodization of aluminum that present two characteristic optical parameters, the characteristic reflection peak (λPeak), and the effective optical thickness of the film (OTeff), which can be readily used as sensing parameters. A design of experiments strategy and an ANOVA analysis are used to establish the effect of the anodization parameters (i.e., anodization period and anodization offset) on the sensitivity of HSA-modified NAA-RFs toward indomethacin, a model drug. To this end, two sensing parameters are used, that is, shifts in the characteristic reflection peak (ΔλPeak) and changes in the effective optical thickness of the film (ΔOTeff). Subsequently, optimized NAA-RFs are used as sensing platforms to determine the binding affinity between a set of drugs (i.e., indomethacin, coumarin, sulfadymethoxine, warfarin, and salicylic acid) and HSA molecules. Our results verify that the combination of HSA-modified NAA-RFs with RIfS can be used as a portable, low-cost, and simple system for establishing the binding affinity between drugs and plasma proteins, which is a critical factor to develop efficient medicines for treating a broad range of diseases and medical conditions. PMID:27128744

  7. Real-time assessment of alcohol drinking and drug use in opioid-dependent polydrug users.

    Science.gov (United States)

    Preston, Kenzie L; Jobes, Michelle L; Phillips, Karran A; Epstein, David H

    2016-10-01

    We investigated relationships between drinking, other drug use, and drug craving, using ecological momentary assessment (EMA), in a sample of polydrug users who were not heavy drinkers. In a prospective longitudinal cohort study, 114 heroin and cocaine users on methadone-maintenance treatment carried handheld electronic diaries during waking hours and were screened for drug and alcohol use for up to 25 weeks. Individuals who fulfilled the Diagnostic and Statistical Manual of Mental Disorders criteria for alcohol abuse or dependence were excluded. Participants responded to 2-5 random prompts per day to report on their moods, cravings, and activities and initiated entries when they used or acutely craved heroin or cocaine. Drinking alcohol was assessed in both types of entries. Breath alcohol was measured three times weekly. Participants reported drinking alcohol in 1.6% of random-prompt entries, 3.7% of event-contingent entries when craving cocaine and/or heroin, and 11.6% of event-contingent entries when using cocaine and/or heroin. Alcohol drinking was also associated with higher craving ratings and prestudy alcohol use. More drinking was detected by ambulatory self-report than by in-clinic breath testing. Even though we had screened out heavy drinkers from our sample of polydrug users, drinking was associated with heroin and cocaine craving and actual use. PMID:27579810

  8. Antibiotic use and resistance : Assessing and improving utilisation and provision of antibiotics and other drugs in Vietnam

    OpenAIRE

    Larsson, Mattias

    2003-01-01

    Background: In Vietnam there were shortages of drugs until the end of the 1980's. In 1986 the "Doi Moi" economic reforms towards market economy were initiated. An expanding private health care sector emerged and the per capita drug consumption has increased dramatically. Aim: To assess drug provision in the public and private sectors, antibiotic use and resistance in the community, as well as the effect of an intervention package aimed at improving case management in private...

  9. Assessment of potential drug–drug interactions and its associated factors in the hospitalized cardiac patients

    Directory of Open Access Journals (Sweden)

    Ghulam Murtaza

    2016-03-01

    Full Text Available Drug–drug interactions (DDIs may result in the alteration of therapeutic response. Sometimes they may increase the untoward effects of many drugs. Hospitalized cardiac patients need more attention regarding drug–drug interactions due to complexity of their disease and therapeutic regimen. This research was performed to find out types, prevalence and association between various predictors of potential drug–drug interactions (pDDIs in the Department of Cardiology and to report common interactions. This study was performed in the hospitalized cardiac patients at Ayub Teaching Hospital, Abbottabad, Pakistan. Patient charts of 2342 patients were assessed for pDDIs using Micromedex® Drug Information. Logistic regression was applied to find predictors of pDDIs. The main outcome measure in the study was the association of the potential drug–drug interactions with various factors such as age, gender, polypharmacy, and hospital stay of the patients. We identified 53 interacting-combinations that were present in total 5109 pDDIs with median number of 02 pDDIs per patient. Overall, 91.6% patients had at least one pDDI; 86.3% were having at least one major pDDI, and 84.5% patients had at least one moderate pDDI. Among 5109 identified pDDIs, most were of moderate (55% or major severity (45%; established (24.2%, theoretical (18.8% or probable (57% type of scientific evidence. Top 10 common pDDIs included 3 major and 7 moderate interactions. Results obtained by multivariate logistic regression revealed a significant association of the occurrence of pDDIs in patient with age of 60 years or more (p < 0.001, hospital stay of 7 days or longer (p < 0.001 and taking 7 or more drugs (p < 0.001. We found a high prevalence for pDDIs in the Department of Cardiology, most of which were of moderate severity. Older patients, patients with longer hospital stay and with elevated number of prescribed drugs were at higher risk of pDDIs.

  10. Biomarkers for metabolic drug activation : towards an integrated risk assessment for drug-induced liver injury (DILI)

    OpenAIRE

    Teppner, Marieke

    2014-01-01

    The term drug-induced liver injury (DILI) describes adverse effects upon therapeutic drug treatment. They are relatively rare, affecting only 1 of 10000 - 1000000 patients, and remain mostly unpredictable. Due to development of severe hepatotoxicity or death, drugs causing DILI display a high risk for patients and have been withdrawn from the market or severely restricted in use. For the pharmaceutical industry late stage attrition due to DILI represents a big burden stretching development ti...

  11. Pharmacokinetic/Pharmacodynamic Assessment of irrelevant drug concentrations in horse plasma or urine for a selection of drugs

    OpenAIRE

    Toutain, Pierre-Louis; Lassourd, V

    2002-01-01

    The lower limits of detection of the analytical techniques currently used for drug testing in horses result in the dilemma of whether or not to report trace levels of drugs legitimately used for therapeutic medication. A non-experimental pharmacokinetic/pharmacodynamic approach for the determination of irrelevant drug plasma concentrations (IPC) and irrelevant urine concentrations (IUC) has been put forward by Toutain and Lassourd (2002). The published plasma clearance is used to transfor...

  12. Identification of treatment response predictors and potential molecular targets for chemo preventive and antiangiogenic therapies

    International Nuclear Information System (INIS)

    The aims of the project were: To evaluate the cellular responses to anti-inflammatory and anti-angiogenic natural or synthetic compounds (chemo preventives, inhibitors of cell survival and inflammation related signal transduction). To identify bio markers for treatment response through the selection of targets that are common to or specific for anti-inflammatory and anti-angiogenic activities. To analyze the regulation of the key tumor-promotion pathways Akt, HIF1α, NFκB. We focused our studies on the antiapoptotic role of the AKT survival pathway, which is involved in prostate tumor progression to an androgen-independent phenotype

  13. An assessment of quality of sleep and the use of drugs with sedating properties in hospitalized adult patients

    OpenAIRE

    Naumann Terryn; Wilbur Kerry; Bandali Shakeel; Marra Carlo; Frighetto Luciana; Jewesson Peter

    2004-01-01

    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...

  14. 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.

  15. 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?

    Science.gov (United States)

    Lim, Roxanne; Choudry, Hassan; Conner, Kim; Karnsakul, Wikrom

    2014-01-01

    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. PMID:25506455

  16. 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

  17. Assessment of drug metabolism enzyme and transporter pharmacogenetics in drug discovery and early development: perspectives of the I-PWG.

    Science.gov (United States)

    Brian, William; Tremaine, Larry M; Arefayene, Million; de Kanter, Ruben; Evers, Raymond; Guo, Yingying; Kalabus, James; Lin, Wen; Loi, Cho-Ming; Xiao, Guangqing

    2016-04-01

    Genetic variants of drug metabolism enzymes and transporters can result in high pharmacokinetic and pharmacodynamic variability, unwanted characteristics of efficacious and safe drugs. Ideally, the contributions of these enzymes and transporters to drug disposition can be predicted from in vitro experiments and in silico modeling in discovery or early development, and then be utilized during clinical development. Recently, regulatory agencies have provided guidance on the preclinical investigation of pharmacogenetics, for application to clinical drug development. This white paper summarizes the results of an industry survey conducted by the Industry Pharmacogenomics Working Group on current practice and challenges with using in vitro systems and in silico models to understand pharmacogenetic causes of variability in drug disposition. PMID:27045656

  18. Assessment of drug-drug interactions among renal failure patients of nephrology ward in a south Indian tertiary care hospital

    Directory of Open Access Journals (Sweden)

    Mylapuram Rama

    2012-01-01

    Full Text Available Polypharmacy is common in drug prescriptions of chronic kidney disease patients. A study of the prescription patterns of drugs with potential interactions would be of interest to prevent drug related adverse events. A prospective observational study of six months (Dec 2009-May 2010 was carried out among the chronic kidney disease patients admitted to the nephrology ward of a South Indian tertiary care hospital. The pattern and rates of drug-drug interactions seen in the prescriptions of these patients was studied. Among the 205 prescriptions included, a total of 474 interactions were reported, making 2.7 interactions per prescription with incidence rates of 76.09%. Around 19.62% of interactions were of major severity. Most common interactions were found between ascorbic acid and cyanocobalamine (12.45%, clonidine and metoprolol (3.80% respectively. Hypo or hypertension (31.65%, decreased drug efficacy (29.11% and hypo or hyperglycemia (14.14%, were the most commonly reported clinical outcomes of the drug interactions. Cardiovascular drugs (calcium channel blockers and beta blockers; 52% constitute the major class of drugs involved in interactions. As most of the interactions had a delayed onset, long term follow-up is essential to predict the clinically significant outcomes of these interactions. Hence, drug interactions are commonly seen in the prescriptions of chronic kidney disease patients which can lead to serious adverse events if not detected early. Need for collaboration with a clinical pharmacist and electronic surveillance, which are absent in developing countries like India, is emphatic.

  19. The Use of Transporter Probe Drug Cocktails for the Assessment of Transporter-Based Drug-Drug Interactions in a Clinical Setting-Proposal of a Four Component Transporter Cocktail.

    Science.gov (United States)

    Ebner, Thomas; Ishiguro, Naoki; Taub, Mitchell E

    2015-09-01

    Probe drug cocktails are used clinically to assess the potential for drug-drug interactions (DDIs), and in particular, DDIs resulting from coadministration of substrates and inhibitors of cytochrome P450 enzymes. However, a probe drug cocktail has not been identified to assess DDIs involving inhibition of drug transporters. We propose a cocktail consisting of the following substrates to explore the potential for DDIs caused by inhibition of key transporters: digoxin (P-glycoprotein, P-gp), rosuvastatin (breast cancer resistance protein, BCRP; organic anion transporting polypeptides, OATP), metformin (organic cation transporter, OCT; multidrug and toxin extrusion transporters, MATE), and furosemide (organic anion transporter, OAT). Furosemide was evaluated in vitro, and is a substrate of OAT1 and OAT3, with Km values of 38.9 and 21.5 μM, respectively. Furosemide was also identified as a substrate of BCRP, OATP1B1, and OATP1B3. Furosemide inhibited BCRP (50% inhibition of drug transport: 170 μM), but did not inhibit OATP1B1, OATP1B3, OCT2, MATE1, and MATE2-K at concentrations below 300 μM, and P-gp at concentrations below 2000 μM. Conservative approaches for the estimation of the likelihood of in vivo DDIs indicate a remote chance of in vivo transporter inhibition by these probe drugs when administered at low single oral doses. This four component probe drug cocktail is therefore proposed for clinical evaluation. PMID:25981193

  20. [Patient-relevant outcomes and surrogates in the early benefit assessment of drugs: first experiences].

    Science.gov (United States)

    Kvitkina, Tatjana; ten Haaf, Anette; Reken, Stefanie; McGauran, Natalie; Wieseler, Beate

    2014-01-01

    The Act on the Reform of the Market for Medicinal Products (AMNOG) became effective in Germany on January 1, 2011. Since then, the assessment of the added benefit of new drugs versus a therapeutic standard on the basis of dossiers submitted by pharmaceutical companies has been required by law. The Federal Joint Committee (G-BA) generally commissions the Institute for Quality and Efficiency in Health Care (IQWiG) with this task. The added benefit is primarily to be demonstrated on the basis of patient-relevant outcomes. The aim of this paper is to describe the feasibility of the early benefit assessment on the basis of patient-relevant outcomes by systematically characterising the outcomes available in company dossiers and comparing the companies' and IQWiG's evaluations regarding patient relevance and surrogate validity. Dossier assessments published between October 2011 and June 2012 were used for this purpose. The outcomes available and the respective evaluations were extracted and compared. 12 out of 22 submitted dossiers contained sufficient data to assess outcomes; all 12 assessable dossiers provided data on patient-relevant outcomes. Data on mortality and adverse events were available in all dossiers, except that one dossier did not contain adverse event data on the relevant subpopulation. In contrast, data on morbidity and health-related quality of life were available in 8 and 7 dossiers, respectively. Of a total of 214 outcomes extracted by IQWiG, 124 patient-relevant and 3 surrogate outcomes were included in IQWiG's assessment (companies: a total of 183 outcomes included, of which 172 were patient-relevant and 11 were surrogates). The first experiences with AMNOG have shown that in principle an early benefit assessment of drugs based on patient-relevant outcomes is feasible. The companies' and IQWiG's evaluations regarding patient relevance and surrogate validity of outcomes partly deviated from each other. By increasingly considering patient

  1. Bone marrow derived myeloid cells orchestrate antiangiogenic resistance in glioblastoma through coordinated molecular networks.

    Science.gov (United States)

    Achyut, B R; Shankar, Adarsh; Iskander, A S M; Ara, Roxan; Angara, Kartik; Zeng, Peng; Knight, Robert A; Scicli, Alfonso G; Arbab, Ali S

    2015-12-28

    Glioblastoma (GBM) is a hypervascular and malignant form of brain tumors. Anti-angiogenic therapies (AAT) were used as an adjuvant against VEGF-VEGFR pathway to normalize blood vessels in clinical and preclinical studies, which resulted into marked hypoxia and recruited bone marrow derived cells (BMDCs) to the tumor microenvironment (TME). In vivo animal models to track BMDCs and investigate molecular mechanisms in AAT resistance are rare. We exploited recently established chimeric mouse to develop orthotopic U251 tumor, which uses as low as 5 × 10(6) GFP+ BM cells in athymic nude mice and engrafted >70% GFP+ cells within 14 days. Our unpublished data and published studies have indicated the involvement of immunosuppressive myeloid cells in therapeutic resistance in glioma. Similarly, in the present study, vatalanib significantly increased CD68+ myeloid cells, and CD133+, CD34+ and Tie2+ endothelial cell signatures. Therefore, we tested inhibition of CSF1R+ myeloid cells using GW2580 that reduced tumor growth by decreasing myeloid (Gr1+ CD11b+ and F4/80+) and angiogenic (CD202b+ and VEGFR2+) cell signatures in TME. CSF1R blockade significantly decreased inflammatory, proangiogenic and immunosuppressive molecular signatures compared to vehicle, vatalanib or combination. TCK1 or CXCL7, a potent chemoattractant and activator of neutrophils, was observed as most significantly decreased cytokine in CSF1R blockade. ERK MAPK pathway was involved in cytokine network regulation. In conclusion, present study confirmed the contribution of myeloid cells in GBM development and therapeutic resistance using chimeric mouse model. We identified novel molecular networks including CXCL7 chemokine as a promising target for future studies. Nonetheless, survival studies are required to assess the beneficial effect of CSF1R blockade. PMID:26404753

  2. 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...... phase. The proposed benefit-risk assessment method involves eight successive steps: (1) establishment of the decision context, (2) identification of benefit and risk criteria, (3) weighting, (4) scoring, (5) evaluation of uncertainty, (6) calculation of weighted scores, (7) visualization, and (8...

  3. A review on pro- and anti-angiogenic factors as targets of clinical intervention

    NARCIS (Netherlands)

    Bouis, D; Kusumanto, Y; Meijer, C; Mulder, NH; Hospers, GAP

    2006-01-01

    Angiogenesis plays an important role in physiology and pathology. It is a tightly regulated process, influenced by the microenvironment and modulated by a multitude of pro- and anti-angiogenic factors. A thorough understanding of the angiogenic process may lead to novel therapies to target ischemic

  4. Drug-induced QT interval prolongation and torsades de pointes: Role of the pharmacist in risk assessment, prevention and management.

    Science.gov (United States)

    Tisdale, James E

    2016-05-01

    Torsades de pointes (TdP) is a life-threatening arrhythmia associated with prolongation of the corrected QT (QTc) interval on the electrocardiogram. More than 100 drugs available in Canada, including widely used antibiotics, antidepressants, cardiovascular drugs and many others, may cause QTc interval prolongation and TdP. Risk factors for TdP include QTc interval >500 ms, increase in QTc interval ≥60 ms from the pretreatment value, advanced age, female sex, acute myocardial infarction, heart failure with reduced ejection fraction, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, treatment with diuretics and elevated plasma concentrations of QTc interval-prolonging drugs due to drug interactions, inadequate dose adjustment of renally eliminated drugs in patients with kidney disease and rapid intravenous administration. Pharmacokinetic drug interactions associated with the highest risk of TdP include antifungal agents, macrolide antibiotics (except azithromycin) and drugs to treat human immunodeficiency virus interacting with amiodarone, disopyramide, dofetilide or pimozide. Other important pharmacokinetic interactions include antidepressants (bupropion, duloxetine, fluoxetine, paroxetine) interacting with flecainide, quinidine or thioridazine. Pharmacists play an important role in minimizing the risk of drug-induced QTc interval prolongation and TdP through knowledge of drugs that are associated with a known or possible risk of TdP, individualized assessment of risk of drug-induced QTc interval prolongation, awareness of drug interactions most likely to result in TdP and attention to dose reduction of renally eliminated QTc interval-prolonging drugs in patients with kidney disease. Treatment of hemodynamically stable TdP consists of discontinuation of the offending drug(s), correction of electrolyte abnormalities and administration of intravenous magnesium sulfate 1 to 2 g. PMID:27212965

  5. 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.

  6. Using ICR and SCID mice as animal models for smallpox to assess antiviral drug efficacy.

    Science.gov (United States)

    Titova, Ksenya A; Sergeev, Alexander A; Zamedyanskaya, Alena S; Galahova, Darya O; Kabanov, Alexey S; Morozova, Anastasia A; Bulychev, Leonid E; Sergeev, Artemiy A; Glotova, Tanyana I; Shishkina, Larisa N; Taranov, Oleg S; Omigov, Vladimir V; Zavjalov, Evgenii L; Agafonov, Alexander P; Sergeev, Alexander N

    2015-09-01

    The possibility of using immunocompetent ICR mice and immunodeficient SCID mice as model animals for smallpox to assess antiviral drug efficacy was investigated. Clinical signs of the disease did not appear following intranasal (i.n.) challenge of mice with strain Ind-3a of variola virus (VARV), even when using the highest possible dose of the virus (5.2 log10 p.f.u.). The 50 % infective doses (ID50) of VARV, estimated by the virus presence or absence in the lungs 3 and 4 days post-infection, were 2.7 ± 0.4 log10 p.f.u. for ICR mice and 3.5 ± 0.7 log10 p.f.u. for SCID mice. After i.n. challenge of ICR and SCID mice with VARV 30 and 50 ID50, respectively, steady reproduction of the virus occurred only in the respiratory tract (lungs and nose). Pathological inflammatory destructive changes were revealed in the respiratory tract and the primary target cells for VARV (macrophages and epithelial cells) in mice, similar to those in humans and cynomolgus macaques. The use of mice to assess antiviral efficacies of NIOCH-14 and ST-246 demonstrated the compliance of results with those described in scientific literature, which opens up the prospect of their use as an animal model for smallpox to develop anti-smallpox drugs intended for humans. PMID:26067292

  7. Prediction and assessment of ecogenotoxicity of antineoplastic drugs in binary mixtures.

    Science.gov (United States)

    Kundi, Michael; Parrella, Alfredo; Lavorgna, Margherita; Criscuolo, Emma; Russo, Chiara; Isidori, Marina

    2016-08-01

    The combined genotoxic effects of four anticancer drugs (5-fluorouracil [5-FU], cisplatin [CDDP], etoposide [ET], and imatinib mesylate [IM]) were studied testing their binary mixtures in two crustaceans that are part of the freshwater food chain, namely Daphnia magna and Ceriodaphnia dubia. Genotoxicity was assessed using the in vivo comet assay. Assessment was based on two distinct effect sizes determined from dose-response experiments. Doses for single and combined exposures expected to result in these effect sizes were computed based on Bliss independence as reference model. Statistical comparison by analysis of variance of single and combined toxicities allowed accepting or rejecting the independency hypothesis. The results obtained for D. magna showed independent action for all mixtures except for IM+5-FU that showed an antagonistic interaction. In C. dubia, most mixtures had antagonist interactions except IM+5-FU and IM+CDDP that showed Bliss independence. Despite the antagonistic interactions, our results demonstrated that combinations of anticancer drugs could be of environmental concern because effects occur at very low concentrations that are in the range of concentrations encountered in aquatic systems. PMID:26139396

  8. Assessing Drug Efficacy in a Miniaturized Pancreatic Cancer In Vitro 3D Cell Culture Model.

    Science.gov (United States)

    Shelper, Todd B; Lovitt, Carrie J; Avery, Vicky M

    2016-09-01

    Pancreatic cancer continues to have one of the poorest prognoses among all cancers. The drug discovery efforts for this disease have largely failed, with no significant improvement in survival outcomes for advanced pancreatic cancer patients over the past 20 years. Traditional in vitro cell culture techniques have been used extensively in both basic and early drug discovery; however, these systems offer poor models to assess emerging therapeutics. More predictive cell-based models, which better capture the cellular heterogeneity and complexities of solid pancreatic tumors, are urgently needed not only to improve drug discovery success but also to provide insight into the tumor biology. Pancreatic tumors are characterized by a unique micro-environment that is surrounded by a dense stroma. A complex network of interactions between extracellular matrix (ECM) components and the effects of cell-to-cell contacts may enhance survival pathways within in vivo tumors. This biological and physical complexity is lost in traditional cell monolayer models. To explore the predictive potential of a more complex cellular system, a three-dimensional (3D) micro-tumor assay was evaluated. Efficacy of six current chemotherapeutics was determined against a panel of primary and metastatic pancreatic tumor cell lines in a miniaturized ECM-based 3D cell culture system. Suitability for potential use in high-throughput screening applications was assessed, including ascertaining the effects that miniaturization and automation had on assay robustness. Cellular health was determined by utilizing an indirect population-based metabolic activity assay and a direct imaging-based cell viability assay. PMID:27552143

  9. Anti-angiogenic Activity and Mechanism of Sesquiterpene Lactones from Centipeda minima.

    Science.gov (United States)

    Huang, Weihuan; Yu, Xiaobin; Liang, Ning; Ge, Wei; Kwok, Hin Fai; Lau, Clara Bik-San; Li, Yaolan; Chung, Hau Yin

    2016-04-01

    Centipeda minima is a Chinese herbal medicine used in the treatment of various diseases including cancer. An ethanol extract of the herb, its four fractions with different polarities, and two volatile oils prepared by steam distillation (SD) and supercritical fluid extraction (SFE) were investigated for their anti-angiogenic activity in a wild-type zebrafish model using a quantitative endogenous alkaline phosphatase (EAP) assay. The SFE oil displayed potent anti-angiogenic activity. Fifteen sesquiterpene lactones (SLs; compounds 1-15) isolated from the SFE oil were evaluated for their anti-angiogenic effect. Results revealed that pseudoguaianolide type SLs (1-8) inhibited vessel formation in the zebrafish embryos while guaianolide type SLs (9-15) showed little effect. Among the active ones, 6-O-angeloylenolin (1), a major component of SFE oil, possessed the strongest effect by reducing vessel formation in zebrafish embryos to 40% of the control value at 29.7 µM. Further study using the Tg (fli1a:EGFP) y1-type zebrafish model revealed that it blocked both intersegmental blood vessels (ISVs) and subintestinal vessels plexus (SIVs) formation in zebrafish embryos. Real-time polymerase chain reaction assay on the wild-type zebrafish embryos suggested that 6-O-angeloylenolin affected multiple molecular targets related to angiogenesis including VEGF receptor, angiopoietin, and its receptors. Taken together, our findings demonstrate that C. minima possesses anti-angiogenic activity, and 6-O-angeloylenolin is a promising candidate for the development of an anti-angiogenic agent. PMID:27396185

  10. The anti-angiogenic and antibacterial effect ofTinomiscium philippinense Miers. (Menispermaceae) leaf extract

    Institute of Scientific and Technical Information of China (English)

    Sheryl Rena-Aguila; Mario A Tan; Oliver B Villaflores

    2016-01-01

    Objective:To determine the toxicity profile, anti-angiogenic and antibacterial activity of the crude and semi-crude leaf extracts ofTinomiscium philippinense (T. philippinense). Methods:The leaves ofT. philippinense were extracted with methanol and partitioned with solvents of different polarities, namely, hexane, dichloromethane and butanol. The extracts were subjected to duck chorioallantoic membrane assay to establish its anti-angiogenic property. Microwell assay was utilized to determine the minimum inhibitory concentration and minimum bactericidal concentration of the different extracts of the plant. Results:The dichloromethane leaf extract ofT. philippinense at 1 000µg/disc showed the highest anti-angiogenic activity with 37.46% inhibition. All the fractions exhibited a bacteriostatic and bactericidal effect on the three bacterial strains withPseudomonas aeruginosa, a Gram negative lactose fermenter exhibiting a higher sensitivity to dichloromethane semi-crude extract among the treatment groups. For the toxicity test, no mortality and no change in behavior were observed in the Sprague-Dawley rats 14 days after the oral administration of the plant extracts. The methanolic leaf extract ofT. philippinense is non-toxic at a maximum dose of 5 000 mg/kg. Conclusions: The dichloromethane leaf extract ofT. philippinense is a potential anti-angiogenic endemic plant species. This plant extract is also a potential antibacterial candidate as determined by microwell assay. The anti-angiogenic and antibacterial activity of the plant may be attributed to the essential oil, steroid, flavonoid, sterol and triterpene content of the plant.

  11. Literature based drug interaction prediction with clinical assessment using electronic medical records: novel myopathy associated drug interactions.

    Directory of Open Access Journals (Sweden)

    Jon D Duke

    Full Text Available Drug-drug interactions (DDIs are a common cause of adverse drug events. In this paper, we combined a literature discovery approach with analysis of a large electronic medical record database method to predict and evaluate novel DDIs. We predicted an initial set of 13197 potential DDIs based on substrates and inhibitors of cytochrome P450 (CYP metabolism enzymes identified from published in vitro pharmacology experiments. Using a clinical repository of over 800,000 patients, we narrowed this theoretical set of DDIs to 3670 drug pairs actually taken by patients. Finally, we sought to identify novel combinations that synergistically increased the risk of myopathy. Five pairs were identified with their p-values less than 1E-06: loratadine and simvastatin (relative risk or RR = 1.69; loratadine and alprazolam (RR = 1.86; loratadine and duloxetine (RR = 1.94; loratadine and ropinirole (RR = 3.21; and promethazine and tegaserod (RR = 3.00. When taken together, each drug pair showed a significantly increased risk of myopathy when compared to the expected additive myopathy risk from taking either of the drugs alone. Based on additional literature data on in vitro drug metabolism and inhibition potency, loratadine and simvastatin and tegaserod and promethazine were predicted to have a strong DDI through the CYP3A4 and CYP2D6 enzymes, respectively. This new translational biomedical informatics approach supports not only detection of new clinically significant DDI signals, but also evaluation of their potential molecular mechanisms.

  12. Assessing drug distribution in tissues expressing P-glycoprotein through physiologically based pharmacokinetic modeling: model structure and parameters determination

    Directory of Open Access Journals (Sweden)

    Li Jun

    2009-01-01

    Full Text Available Abstract Background The expression and activity of P-glycoproteins due to genetic or environmental factors may have a significant impact on drug disposition, drug effectiveness or drug toxicity. Hence, characterization of drug disposition over a wide range of conditions of these membrane transporters activities is required to better characterize drug pharmacokinetics and pharmacodynamics. This work aims to improve our understanding of the impact of P-gp activity modulation on tissue distribution of P-gp substrate. Methods A PBPK model was developed in order to examine activity and expression of P-gp transporters in mouse brain and heart. Drug distribution in these tissues was first represented by a well-stirred (WS model and then refined by a mechanistic transport-based (MTB model that includes P-gp mediated transport of the drug. To estimate transport-related parameters, we developed an original three-step procedure that allowed extrapolation of in vitro measurements of drug permeability to the in vivo situation. The model simulations were compared to a limited set of data in order to assess the model ability to reproduce the important information of drug distributions in the considered tissues. Results This PBPK model brings insights into the mechanism of drug distribution in non eliminating tissues expressing P-gp. The MTB model accounts for the main transport mechanisms involved in drug distribution in heart and brain. It points out to the protective role of P-gp at the blood-brain barrier and represents thus a noticeable improvement over the WS model. Conclusion Being built prior to in vivo data, this approach brings an interesting alternative to fitting procedures, and could be adapted to different drugs and transporters. The physiological based model is novel and unique and brought effective information on drug transporters.

  13. Phospholipid vesicle-based permeation assay and EpiSkin® in assessment of drug therapies destined for skin administration.

    Science.gov (United States)

    Engesland, André; Škalko-Basnet, Nataša; Flaten, Gøril Eide

    2015-03-01

    Cost-effective and efficient methods for permeability screening are crucial during early development of drugs, drug formulations, and cosmeceuticals. Alternatives to animal experiments are impelled for both economical and ethical reasons. The aim of this study was to determine the ability of the phospholipid vesicle-based permeation assay (PVPA) to assess the effect of different formulations on drug permeability and thus establish its utility in formulation development. Three model drugs were tested in solutions and as liposomal formulations. The permeability results for the PVPA models were compared with the results for the reconstructed human skin model, EpiSkin(®). The drugs were ranked based on their estimated penetration potentials, and the results were in accordance with what was expected considering the physicochemical properties of the drugs. PVPAs (E-80, ceramide, cholesterol, cholesteryl sulfate, and palmitic acid) was able to distinguish between drug solutions and liposomal formulations; however, EpiSkin(®) detected only small differences between the drugs in solution and formulations. In contrast with EpiSkin(®), which is limited by a 3-day testing window, PVPA barriers can be stored frozen for up to 2 weeks or even up to 16 months, depending on their compositions. The PVPA models are thus more cost effective and efficient than the EpiSkin(®) model for permeability screening during early drug development. PMID:25558045

  14. The NIfETy Method for Environmental Assessment of Neighborhood-level Indicators of Violence, Alcohol, and Other Drug Exposure

    OpenAIRE

    Furr-Holden, C. D. M.; Smart, M. J.; Pokorni, J. L.; Ialongo, N. S.; Leaf, P. J.; Holder, H D; Anthony, J. C.

    2008-01-01

    There are limited validated quantitative assessment methods to measure features of the built and social environment that might form the basis for environmental preventive interventions. This study describes a model approach for epidemiologic assessment of suspected environmental determinants of violence, alcohol and other drug (VAOD) exposure and fills this gap in current research. The investigation sought to test the feasibility of a systematic and longitudinal assessment of residential bloc...

  15. Identifying and assessing highly hazardous drugs within quality risk management programs.

    Science.gov (United States)

    Sussman, Robert G; Schatz, Anthony R; Kimmel, Tracy A; Ader, Allan; Naumann, Bruce D; Weideman, Patricia A

    2016-08-01

    Historically, pharmaceutical industry regulatory guidelines have assigned certain active pharmaceutical ingredients (APIs) to various categories of concern, such as "cytotoxic", "hormones", and "steroids". These categories have been used to identify APIs requiring segregation or dedication in order to prevent cross-contamination and protect the quality and safety of drug products. Since these terms were never defined by regulatory authorities, and many novel pharmacological mechanisms challenge these categories, there is a recognized need to modify the historical use of these terms. The application of a risk-based approach using a health-based limit, such as an acceptable daily exposure (ADE), is more appropriate for the development of a Quality Risk Management Program (QRMP) than the use of categories of concern. The toxicological and pharmacological characteristics of these categories are discussed to help identify and prioritize compounds requiring special attention. Controlling airborne concentrations and the contamination of product contact surfaces in accordance with values derived from quantitative risk assessments can prevent adverse effects in workers and patients, regardless of specific categorical designations to which these APIs have been assigned. The authors acknowledge the movement away from placing compounds into categories and, while not yet universal, the importance of basing QRMPs on compound-specific ADEs and risk assessments. Based on the results of a risk assessment, segregation and dedication may also be required for some compounds to prevent cross contamination during manufacture of APIs. PMID:27267171

  16. Assess the frequency and severity of adverse drug reactions due to errors in drug intake at a tertiary care hospital

    Directory of Open Access Journals (Sweden)

    G. Shivaprakash

    2015-10-01

    Conclusion: Proper education about the importance of compliance and damaging consequences of self-modification of drug dosage in patients who are on treatment for chronic disorders like diabetes and hypertension will be an effective strategy to prevent many of these ADRs. [Int J Basic Clin Pharmacol 2015; 4(5.000: 931-935

  17. Property profiling of biosimilar mucus in a novel mucus-containing in vitro model for assessment of intestinal drug absorption

    DEFF Research Database (Denmark)

    Bøgh, Marie; Baldursdóttir, Stefania G; Müllertz, Anette; Nielsen, Hanne M

    2014-01-01

    Oral delivery of drugs, including peptide and protein therapeutics, can be impeded by the presence of the mucus surface-lining the intestinal epithelium. The aim of the present project was to design and characterize biosimilar mucus compatible with Caco-2 cell monolayers cultured in vitro to esta...... of the biorelevance of the Caco-2 cell culture model by application of mucus, resulting in an in vitro model of oral mucosa suitable for future assessment of innovative drug delivery approaches....

  18. Risk Assessment of Drug Management Process in Women Surgery Department of Qaem Educational Hospital (QEH) Using HFMEA Method (2013)

    OpenAIRE

    khani-Jazani, Reza; Molavi-Taleghani, Yasamin; Seyedin, Hesam; Vafaee-Najar, Ali; Ebrahimipour, Hossein; Pourtaleb, Arefeh

    2015-01-01

    Evaluation and improvement of drug management process are essential for patient safety. The present study was performed whit the aim of assessing risk of drug management process in Women Surgery Department of QEH using HFMEA method in 2013. A mixed method was used to analyze failure modes and their effects with HFMEA. To classify failure modes; nursing errors in clinical management model, for classifying factors affecting error; approved model by the UK National Health System, and for determi...

  19. 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.

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

    Science.gov (United States)

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

    2013-12-01

    The plant alkaloid ibogaine has promising anti-addictive properties. Albeit not licensed 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 Nav1.5 sodium and Cav1.2 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. PMID:23707769

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

    Science.gov (United States)

    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 Nav1.5 sodium and Cav1.2 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. PMID:23707769

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

    Directory of Open Access Journals (Sweden)

    G. RIGOS

    2012-12-01

    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.

  3. 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.

  4. Uterotonic drug quality: an assessment of the potency of injectable uterotonic drugs purchased by simulated clients in three districts in Ghana

    OpenAIRE

    Stanton, Cynthia; Koski, Alissa; Cofie, Patience; Mirzabagi, Ellie; Grady, Breanne L; Brooke, Steve

    2012-01-01

    Article summary Article focus The need for high-quality uterotonic drugs for the prevention and treatment of maternal mortality and morbidity in poor countries is indisputable. Best practice for long-term storage for all injectable uterotonics is refrigeration, which is a key logistical constraint for scale up of postpartum haemorrhage reduction strategies and is a general challenge for maternity services without consistent electricity. The objectives of the study were to assess the populatio...

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

    International Nuclear Information System (INIS)

    Background: Drugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (INa) may carry pro-arrhythmic risks. Due to the frequency-dependent block of INa, 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 (Emax 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

  6. 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

  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. 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)

    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 Nav1.5 sodium and Cav1.2 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

  9. 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.

  10. Stress ventricular function test in conscious, nonthoracotomised dogs to assess cardiac drug efficacy.

    Science.gov (United States)

    French, W J; Averill, W; Ung, S; Laks, M M

    1985-01-01

    The measurement of left ventricular (LV) function is frequently performed in unconscious or thoracotomised animals in the resting state; these conditions may seriously affect the basal haemodynamic state. To assess myocardial function in conscious animals, a technique was developed to place a catheter across the atrial septum into the left ventricle without a thoracotomy. A stress ventricular function test (SVFT) was performed by raising the systemic blood pressure with methoxamine in the conscious dog. In order to demonstrate the effectiveness of the SVFT in the detection of a decrease in ventricular function, a SVFT was performed before and after the acute infusion of verapamil to determine resting and reserve LV function. A slope relating systolic aortic pressure to the LV end-diastolic pressure was obtained in 10 dogs using a low dose (0.005) and in four dogs a high dose (0.01 microgram X kg-1 X min-1) verapamil (V). The mean slope before V was 3.6 +/- 1.2 and after 2.0 +/- 0.92 (p less than 0.001). The day-to-day variability of the SVFT was less than 22% (coefficient of variability). The SVFT is a sensitive, reproducible method to assess resting and increased or decreased myocardial contractility and is useful in selecting appropriate doses of cardiac drugs to determine their effect on the myocardium during acute and chronic infusion studies in the conscious, nonthoracotomised dog. PMID:3986853

  11. Development and validation of an instrument to assess treatment adherence for each individual drug taken by a patient

    Science.gov (United States)

    Sidorkiewicz, Stéphanie; Tran, Viet-Thi; Cousyn, Cécile; Perrodeau, Elodie; Ravaud, Philippe

    2016-01-01

    Objective To develop and validate an instrument to assess adherence to each individual drug taken by patients undergoing long-term treatment. Design Multicentre prospective observational validation study. Setting Six general practitioners' clinics and 6 university hospitals in Paris, France. Participants Patients 18 years and older receiving at least one long-term treatment. Methods The instrument was developed from a literature search and interviews with experts. Clarity and wording were assessed during pilot testing with 51 patients. The tool was validated in a sample of consecutive patients. We assessed agreement between adherence measured with our tool and drug diaries and compared measurements from our instrument with (1) the Lu instrument; (2) the Adherence Estimator (AE); (3) patient's adherence assessed by physicians; (4) the Morisky Medication Adherence Scale-4 items (MMAS-4); and (5) the Treatment Burden Questionnaire (TBQ). Reliability was assessed by a test–retest method. Results A total of 243 patients taking 961 drugs were recruited in 2014. We found good agreement between adherence measured by our tool and drug diaries (intraclass correlation coefficient (ICC) 0.69, 95% CI 0.34 to 0.91) and a linear relationship between measurement with our tool and (1) the Lu instrument (p<0.01); (2) 2 items of the AE (perceived need for medication (p<0.01) and concerns about medication (p<0.01)); (3) patients' adherence assessed by their physicians (p<0.01); (4) the MMAS-4 (p<0.01) and (5) the TBQ (p<0.01). Reliability of the retest was good (ICC 0.67, 95% CI 0.42 to 0.85). Conclusions We developed an instrument with acceptable validity and reliability to assess adherence for each drug taken by patients, usable in hospital and primary care settings. PMID:27165645

  12. ASSESSMENT OF ATTITUDE AND BEHAVIOR OF HEALTH PROFESSIONALS TOWARDS PROVISION OF DRUG INFORMATION SERVICES IN ENUGU STATE

    Directory of Open Access Journals (Sweden)

    Pharm. Adibe M.O

    2010-09-01

    Full Text Available Background: Access to authoritative and independent information is fundamental for the rational and effective use of drugs. In Nigeria, there is currently very few drug information centres or other source for problem oriented drug information. Purpose: To assess the attitude and behaviour of health professionals (physicians and pharmacists in Enugu State, Nigeria towards provision of drug information services in the state. Methods: A self-completion questionnaire was administered to 37 doctors and 41 pharmacists in the included hospitals and faculty of pharmacy. A twenty-item question was added to assess the attitude and behaviour of the respondents towards provision of drug information services. Respondents were requested to rate necessity of each item by selecting among ??Not Important at all?? to ??Very Important?? (lowest to highest. The instrument was prefaced: ??Very important??, ??Important??, ??Less important??, and ??Not important at all??. Their attitude and behaviour were expressed in term of item-performance. The percentage item-performance was calculated to reflect the level of necessity of each items; high percentage item-performance of an item correlates with high level of necessity of the item in provision of drug information services and vice versa. Results: Out of 78 questionnaires administered, 67 were retrieved given a response rate of 85.90%. The major sources of drug information currently in use were medical journals (79.1%, medical representatives of drug manufacturers and marketers (71.6%. The drug information areas mostly sought for by the respondent were indication (86.6%, use of drug in special group (77.6%. The attitude and behaviour of health professionals towards provision of drug information services in Enugu state were positive. This study identified three barriers and five facilitators as the major factors affecting provision of efficient and effective drug information services in Enugu state. The major

  13. The Antiangiogenic Compound Aeroplysinin-1 Induces Apoptosis in Endothelial Cells by Activating the Mitochondrial Pathway

    OpenAIRE

    Beatriz Martínez-Poveda; Salvador Rodríguez-Nieto; Melissa García-Caballero; Miguel-Ángel Medina; Quesada, Ana R.

    2012-01-01

    Aeroplysinin-1 is a brominated metabolite extracted from the marine sponge Aplysina aerophoba that has been previously characterized by our group as a potent antiangiogenic compound in vitro and in vivo. In this work, we provide evidence of a selective induction of apoptosis by aeroplysinin-1 in endothelial cells. Studies on the nuclear morphology of treated cells revealed that aeroplysinin-1 induces chromatin condensation and nuclear fragmentation, and it increases the percentage of cells wi...

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

    OpenAIRE

    SUNTORNSUK, Leena; Koizumi, Keiichi; Saitoh, Yurika; Nakamura, Eliane Shizuka; 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...

  15. Mathematical and numerical analysis of a model for anti-angiogenic therapy in metastatic cancers

    CERN Document Server

    Benzekry, Sebastien

    2010-01-01

    We introduce and analyze a phenomenological model for anti-angiogenic therapy in the treatment of metastatic cancers. It is a structured transport equation with a nonlocal boundary condition describing the evolution of the density of metastasis that we analyze first at the continuous level. We present the numerical analysis of a lagrangian scheme based on the characteristics whose convergence establishes existence of solutions. Then we prove an error estimate and use the model to perform interesting simulations in view of clinical applications.

  16. In Vitro and In Vivo Antiangiogenic Properties of the Serpin Protease Nexin-1

    OpenAIRE

    Selbonne, Sonia; Azibani, Feriel; Iatmanen, Soria; Boulaftali, Yacine; Richard, Benjamin; Jandrot-Perrus, Martine; Bouton, Marie-Christine; Arocas, Véronique

    2012-01-01

    The serpin protease nexin-1 (PN-1) is expressed by vascular cells and secreted by platelets upon activation, and it is known to interact with several modulators of angiogenesis, such as proteases, matrix proteins, and glycosaminoglycans. We therefore investigated the impact of PN-1 on endothelial cell angiogenic responses in vitro and ex vivo and in vivo in PN-1-deficient mice. We found that PN-1 is antiangiogenic in vitro: it inhibited vascular endothelial growth factor (VEGF)-induced endoth...

  17. Assessment of Disease-Related Therapeutic Protein Drug-Drug Interaction for Etrolizumab in Patients With Moderately to Severely Active Ulcerative Colitis.

    Science.gov (United States)

    Wei, Xiaohui; Kenny, Jane R; Dickmann, Leslie; Maciuca, Romeo; Looney, Caroline; Tang, Meina T

    2016-06-01

    The efficacy and safety of etrolizumab, a humanized IgG1 mAb, were evaluated in patients with ulcerative colitis (UC) in a phase 2 study (EUCALYPTUS). The current study assessed the risk of therapeutic protein drug-drug interaction (TP-DDI) of etrolizumab on CYP3A activity in patients with UC. Literature review was performed to compare serum proinflammatory cytokine levels and pharmacokinetic (PK) parameters of CYP3A substrate drugs between patients with inflammatory bowel disease (IBD) and healthy subjects. Treatment effect of etrolizumab on CYP3A activity was evaluated by measuring colonic CYP3A4 mRNA expression and serum C-reactive protein (CRP) in EUCALYPTUS patients. Literature data suggested similar levels between IBD patients and healthy subjects for serum proinflammatory cytokines and PK parameters of CYP3A substrate drugs. Additionally, treatment with etrolizumab did not change colonic CYP3A4 mRNA expression or serum CRP levels in UC patients. In conclusion, our results indicate a low TP-DDI risk for etrolizumab in UC patients, particularly on medications metabolized by CYP3A. PMID:26412221

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

    Science.gov (United States)

    Luan, Xin; Gao, Yun-Ge; Guan, Ying-Yun; Xu, Jian-Rong; Lu, Qin; Zhao, Mei; Liu, Ya-Rong; Liu, Hai-Jun; Fang, Chao; Chen, Hong-Zhuan

    2014-09-22

    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. PMID:25250884

  19. Antiangiogenic effects of pazopanib in xenograft hepatocellular carcinoma models: evaluation by quantitative contrast-enhanced ultrasonography

    International Nuclear Information System (INIS)

    Antiangiogenesis is a promising therapy for advanced hepatocellular carcinoma (HCC), but the effects are difficult to be evaluated. Pazopanib (GW786034B) is a pan-vascular endothelial growth factor receptor inhibitor, the antitumor effects or antiangiogenic effects haven't been investigated in HCC. In vitro direct effects of pazopanib on human HCC cell lines and endothelial cells were evaluated. In vivo antitumor effects were evaluated in three xenograft nude mice models. In the subcutaneous HCCLM3 model, intratumoral blood perfusion was detected by contrast-enhanced ultrasonography (CEUS), and serial quantitative parameters were profiled from the time-intensity curves of ultrasonograms. In vitro proliferation of various HCC cell lines were not inhibited by pazopanib. Pazopanib inhibited migration and invasion and induced apoptosis significantly in two HCC cell lines, HCCLM3 and PLC/PRF/5. Proliferation, migration, and tubule formation of human umbilical vein endothelial cells were inhibited by pazopanib in a dose-dependent manner. In vivo tumor growth was significantly inhibited by pazopanib in HCCLM3, HepG2, and PLC/PRF/5 xenograft models. Various intratumoral perfusion parameters changed over time, and the signal intensity was significantly impaired in the treated tumors before the treatment efficacy on tumor size could be observed. Mean transit time of the contrast media in hotspot areas of the tumors was reversely correlated with intratumoral microvessel density. Antitumor effects of pazopanib in HCC xenografts may owe to its antiangiogenic effects, and the in vivo antiangiogenic effects could be evaluated by quantitative CEUS

  20. Anti-angiogenic action of plasma hyaluronan binding protein in human umbilical vein endothelial cells.

    Science.gov (United States)

    Jeon, Ji Won; Song, Hyun Seok; Moon, Eun-Joung; Park, Shi-Young; Son, Myung Jin; Jung, Seung Youn; Kim, Ji Tae; Nam, Do-Hyun; Choi-Miura, Nam-Ho; Kim, Kyu-Won; Kim, Yung-Jin

    2006-07-01

    The kringle domain is a triple loop structure present in angiostatin and endostatin. The disulfide bond-linked kringle architectures have been known to be essential for anti-angiogenic activity. Plasma hyaluronan binding protein (PHBP) is a novel serine protease which consists of three epidermal growth factor (EGF) domains, a kringle domain, and a serine protease domain. PHBP can be cleaved autocatalytically to generate activity and is highly expressed in the human blood and liver. To determine the anti-angiogenic activities of PHBP, we purified recombinant mouse PHBP from stable cell line overexpressing PHBP and used protein in vivo and in vitro angiogenesis assays. We found that recombinant PHBP inhibits not only angiogenesis in vivo in chorioallantoic membrane (CAM) assay but also the basic fibroblast growth factor (bFGF)-induced proliferation, invasion and tube formation of human umbilical vein endothelial cells (HUVECs) in a dose-dependant manner. Moreover, we found that the kringle domain of PHBP was essential for the anti-angiogenic action of PHBP by the deletion mutants. These findings unravel a new function of PHBP as an inhibitor of the proangiogenic phenotype of vascular endothelial cells and demonstrate that the kringle domain of PHBP might be a potent novel inhibitor of activated endothelial cells in vitro and in vivo. PMID:16773202

  1. Antiangiogenic Activity and Pharmacogenomics of Medicinal Plants from Traditional Korean Medicine

    Directory of Open Access Journals (Sweden)

    Ean-Jeong Seo

    2013-01-01

    Full Text Available Aim. In the present study, we investigated the antiangiogenic properties of 59 plants used in traditional Korean medicine. Selected phytochemicals were investigated in more detail for their modes of action. Methods. A modified chicken-chorioallantoic-membrane (CAM assay using quail eggs was applied to test for antiangiogenic effects of plant extracts. A molecular docking in silico approached the binding of plant constituents to the vascular endothelial growth factor receptors 1 and 2 (VEGFR1, VEGFR2. Microarray-based mRNA expression profiling was employed to correlate the 50% inhibition concentrations (IC50 of a panel of 60 NCI cell lines to these phytochemicals. Results. Extracts from Acer mono leaves, Reynoutria sachalniensis fruits, Cinnamomum japonicum stems, Eurya japonica leaves, Adenophora racemosa whole plant, Caryopteris incana leaves-stems, and Schisandra chinensis stems inhibited angiogenesis more than 50% in quail eggs. Selected phytochemicals from Korean plants were analyzed in more detail using microarray-based mRNA expression profiles and molecular docking to VEGFR1 and VEGFR2. These results indicate multifactorial modes of action of these natural products. Conclusion. The antiangiogenic activity of plants used in traditional Korean medicine implicates their possible application for diseases where inhibition of blood vessel formation is desired, for example, cancer, macular degeneration, diabetic retinopathy and others.

  2. 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.

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

    International Nuclear Information System (INIS)

    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

  4. Transmission Assessment Surveys (TAS) to Define Endpoints for Lymphatic Filariasis Mass Drug Administration: A Multicenter Evaluation

    Science.gov (United States)

    Chu, Brian K.; Deming, Michael; Biritwum, Nana-Kwadwo; Bougma, Windtaré R.; Dorkenoo, Améyo M.; El-Setouhy, Maged; Fischer, Peter U.; Gass, Katherine; Gonzalez de Peña, Manuel; Mercado-Hernandez, Leda; Kyelem, Dominique; Lammie, Patrick J.; Flueckiger, Rebecca M.; Mwingira, Upendo J.; Noordin, Rahmah; Offei Owusu, Irene; Ottesen, Eric A.; Pavluck, Alexandre; Pilotte, Nils; Rao, Ramakrishna U.; Samarasekera, Dilhani; Schmaedick, Mark A.; Settinayake, Sunil; Simonsen, Paul E.; Supali, Taniawati; Taleo, Fasihah; Torres, Melissa; Weil, Gary J.; Won, Kimberly Y.

    2013-01-01

    Background 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 a level low enough that it cannot be sustained even in the absence of drug intervention. Guidelines advanced by WHO call for a transmission assessment survey (TAS) to determine if MDA can be stopped within an LF evaluation unit (EU) after at least five effective rounds of annual treatment. To test the value and practicality of these guidelines, a multicenter operational research trial was undertaken in 11 countries covering various geographic and epidemiological settings. Methodology The TAS was conducted twice in each EU with TAS-1 and TAS-2 approximately 24 months apart. Lot quality assurance sampling (LQAS) formed the basis of the TAS survey design but specific EU characteristics defined the survey site (school or community), eligible population (6–7 year olds or 1st–2nd graders), survey type (systematic or cluster-sampling), target sample size, and critical cutoff (a statistically powered threshold below which transmission is expected to be no longer sustainable). The primary diagnostic tools were the immunochromatographic (ICT) test for W. bancrofti EUs and the BmR1 test (Brugia Rapid or PanLF) for Brugia spp. EUs. Principal Findings/Conclusions In 10 of 11 EUs, the number of TAS-1 positive cases was below the critical cutoff, indicating that MDA could be stopped. The same results were found in the follow-up TAS-2, therefore, confirming the previous decision outcome. Sample sizes were highly sex and age-representative and closely matched the target value after factoring in estimates of non-participation. The TAS was determined to be a practical and effective evaluation tool for stopping MDA although its validity for longer-term post-MDA surveillance

  5. Development of an Adverse Drug Reaction Risk Assessment Score among Hospitalized Patients with Chronic Kidney Disease

    Science.gov (United States)

    Saheb Sharif-Askari, Fatemeh; Syed Sulaiman, Syed Azhar; Saheb Sharif-Askari, Narjes; Al Sayed Hussain, Ali

    2014-01-01

    Background Adverse drug reactions (ADRs) represent a major burden on the healthcare system. Chronic kidney disease (CKD) patients are particularly vulnerable to ADRs because they are usually on multiple drug regimens, have multiple comorbidities, and because of alteration in their pharmacokinetics and pharmacodynamic parameters. Therefore, one step towards reducing this burden is to identify patients who are at increased risk of an ADR. Objective To develop a method of identifying CKD patients who are at increased risk for experiencing ADRs during hospitalisation. Materials and Methods Factors associated with ADRs were identified by using demographic, clinical and laboratory variables of patients with CKD stages 3 to 5 (estimated glomerular filtration rate, 10–59 ml/min/1.73 m2) who were admitted between January 1, 2012, and December 31, 2012, to the renal unit of Dubai Hospital. An ADR risk score was developed by constructing a series of logistic regression models. The overall model performance for sequential models was evaluated using Akaike Information Criterion for goodness of fit. Odd ratios of the variables retained in the best model were used to compute the risk scores. Results Of 512 patients (mean [SD] age, 60 [16] years), 62 (12.1%) experienced an ADR during their hospitalisation. An ADR risk score included age 65 years or more, female sex, conservatively managed end-stage renal disease, vascular disease, serum level of C-reactive protein more than 10 mg/L, serum level of albumin less than 3.5 g/dL, and the use of 8 medications or more during hospitalization. The C statistic, which assesses the ability of the risk score to predict ADRs, was 0.838; 95% CI, 0.784–0.892). Conclusion A score using routinely available patient data can be used to identify CKD patients who are at increased risk of ADRs. PMID:24755778

  6. A Comprehensive Assessment of Lymphatic Filariasis in Sri Lanka Six Years after Cessation of Mass Drug Administration

    OpenAIRE

    Ramakrishna U Rao; Nagodavithana, Kumara C.; Sandhya D Samarasekera; Wijegunawardana, Asha D.; Welmillage D Y Premakumara; Samudrika N Perera; Settinayake, Sunil; Miller, J. Phillip; Weil, Gary J

    2014-01-01

    Background The Sri Lankan Anti-Filariasis Campaign conducted 5 rounds of mass drug administration (MDA) with diethycarbamazine plus albendazole between 2002 and 2006. We now report results of a comprehensive surveillance program that assessed the lymphatic filariasis (LF) situation in Sri Lanka 6 years after cessation of MDA. Methodology and Principal Findings Transmission assessment surveys (TAS) were performed per WHO guidelines in primary school children in 11 evaluation units (EUs) in all...

  7. Assessment of Quality of Sleep and Use of Drugs with Sedating Properties in Adult Patients Hospitalized in Hamadan Ekbatan Hospital

    OpenAIRE

    F. Zeraati; M.A. Seif Rabie; M. Araghchian; T. Sabouri

    2010-01-01

    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 admitte...

  8. 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

    Torsades de Pointes (TdP) is a potentially lethal cardiac arrhythmia and a known adverse effect of many drugs secondary to block of the rapidly activating delayed rectifier potassium current (IKr). In animal models antipsychotic drugs have shown reduced pro-arrhythmic potential compared to drugs...

  9. 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....

  10. 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

  11. 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

  12. Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment

    International Nuclear Information System (INIS)

    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

  13. ASSESSMENT AND EVALUATION OF DRUG INFORMATION SERVICE PROVIDED BY PHARMACY PRACTICE DEPARTMENT BASED ON ENQUIRER’S PERSPECTIVE

    Directory of Open Access Journals (Sweden)

    Jeevangi V M

    2012-10-01

    Full Text Available Drug information service refers to activities carried out by pharmacists in providing any drug related information to healthcare professionals to provide better patient care. Providing drug information is a clinical pharmacy service and delivered as part of the multidisciplinary approach to patient care. Accurate information about safety of drugs is very essential for health care professionals in identifying, preventing and managing Adverse Drug Reactions (ADRs, thereby ensuring safe use of medications. The aim of the study was to assess and evaluate the drug information service from enquirer’s perspective. The data was collected from drug information centre through drug information request forms and feedback questionnaires form. A nine months hospital based prospective study was carried out at Basaveshwar Teaching and General Hospital (BTGH, Gulbarga. A total number of 122 queries were received during the study period. Most of the queries were received from general medicine department 82(67.21% and least were from general surgery 2(1.64%. Most of the queries were for update of knowledge 69 (56.56% and time frame for reply was within a day 83 (68.03%, answers were given in printed format 77(63.11%. The majority of queries were regarding dose and administration of drug 49 (36.03% and most preferred resource was Micromedex 75 (52.45%. The quality of the services provided by the centre was appreciated by majority of its users. However there is a need to bring greater awareness about the service in the hospital and to encourage the healthcare professionals to utilize the services for better patient care.

  14. Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment

    Institute of Scientific and Technical Information of China (English)

    Rolf; Teschke; Albrecht; Wolff; Christian; Frenzel; Alexander; Schwarzenboeck; Johannes; Schulze; Axel; Eickhoff

    2014-01-01

    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. 2014 Baishideng Publishing Group Co., Limited. All rights

  15. Establishment of a Predictive In Vitro Assay for Assessment of the Hepatotoxic Potential of Oligonucleotide Drugs.

    Directory of Open Access Journals (Sweden)

    Sabine Sewing

    Full Text Available Single stranded oligonucleotides (SSO represent a novel therapeutic modality that opens new space to address previously undruggable targets. In spite of their proven efficacy, the development of promising SSO drug candidates has been limited by reported cases of SSO-associated hepatotoxicity. The mechanisms of SSO induced liver toxicity are poorly understood, and up to now no preclinical in vitro model has been established that allows prediction of the hepatotoxicity risk of a given SSO. Therefore, preclinical assessment of hepatic liability currently relies on rodent studies that require large cohorts of animals and lengthy protocols. Here, we describe the establishment and validation of an in vitro assay using primary hepatocytes that recapitulates the hepatotoxic profile of SSOs previously observed in rodents. In vitro cytotoxicity upon unassisted delivery was measured as an increase in extracellular lactate dehydrogenase (LDH levels and concomitant reduction in intracellular glutathione and ATP levels after 3 days of treatment. Furthermore, toxic, but not safe, SSOs led to an increase in miR-122 in cell culture supernatants after 2 days of exposure, revealing the potential use of miR122 as a selective translational biomarker for detection of SSO-induced hepatotoxicity. Overall, we have developed and validated for the first time a robust in vitro screening assay for SSO liver safety profiling which allows rapid prioritization of candidate molecules early on in development.

  16. Establishment of a Predictive In Vitro Assay for Assessment of the Hepatotoxic Potential of Oligonucleotide Drugs.

    Science.gov (United States)

    Sewing, Sabine; Boess, Franziska; Moisan, Annie; Bertinetti-Lapatki, Cristina; Minz, Tanja; Hedtjaern, Maj; Tessier, Yann; Schuler, Franz; Singer, Thomas; Roth, Adrian B

    2016-01-01

    Single stranded oligonucleotides (SSO) represent a novel therapeutic modality that opens new space to address previously undruggable targets. In spite of their proven efficacy, the development of promising SSO drug candidates has been limited by reported cases of SSO-associated hepatotoxicity. The mechanisms of SSO induced liver toxicity are poorly understood, and up to now no preclinical in vitro model has been established that allows prediction of the hepatotoxicity risk of a given SSO. Therefore, preclinical assessment of hepatic liability currently relies on rodent studies that require large cohorts of animals and lengthy protocols. Here, we describe the establishment and validation of an in vitro assay using primary hepatocytes that recapitulates the hepatotoxic profile of SSOs previously observed in rodents. In vitro cytotoxicity upon unassisted delivery was measured as an increase in extracellular lactate dehydrogenase (LDH) levels and concomitant reduction in intracellular glutathione and ATP levels after 3 days of treatment. Furthermore, toxic, but not safe, SSOs led to an increase in miR-122 in cell culture supernatants after 2 days of exposure, revealing the potential use of miR122 as a selective translational biomarker for detection of SSO-induced hepatotoxicity. Overall, we have developed and validated for the first time a robust in vitro screening assay for SSO liver safety profiling which allows rapid prioritization of candidate molecules early on in development. PMID:27442522

  17. Liver Status Assessment by Spectrally and Time Resolved IR Detection of Drug Induced Breath Gas Changes

    Directory of Open Access Journals (Sweden)

    Tom Rubin

    2016-05-01

    Full Text Available The actual metabolic capacity of the liver is crucial for disease identification, liver therapy, and liver tumor resection. By combining induced drug metabolism and high sensitivity IR spectroscopy of exhaled air, we provide a method for quantitative liver assessment at bedside within 20 to 60 min. Fast administration of 13C-labelled methacetin induces a fast response of liver metabolism and is tracked in real-time by the increase of 13CO2 in exhaled air. The 13CO2 concentration increase in exhaled air allows the determination of the metabolic liver capacity (LiMAx-test. Fluctuations in CO2 concentration, pressure and temperature are minimized by special gas handling, and tracking of several spectrally resolved CO2 absorption bands with a quantum cascade laser. Absorption measurement of different 12CO2 and 13CO2 rotation-vibration transitions in the same time window allows for multiple referencing and reduction of systematic errors. This FLIP (Fast liver investigation package setup is being successfully used to plan operations and determine the liver status of patients.

  18. Establishment of a Predictive In Vitro Assay for Assessment of the Hepatotoxic Potential of Oligonucleotide Drugs

    Science.gov (United States)

    Sewing, Sabine; Boess, Franziska; Moisan, Annie; Bertinetti-Lapatki, Cristina; Minz, Tanja; Hedtjaern, Maj; Tessier, Yann; Schuler, Franz; Singer, Thomas; Roth, Adrian B.

    2016-01-01

    Single stranded oligonucleotides (SSO) represent a novel therapeutic modality that opens new space to address previously undruggable targets. In spite of their proven efficacy, the development of promising SSO drug candidates has been limited by reported cases of SSO-associated hepatotoxicity. The mechanisms of SSO induced liver toxicity are poorly understood, and up to now no preclinical in vitro model has been established that allows prediction of the hepatotoxicity risk of a given SSO. Therefore, preclinical assessment of hepatic liability currently relies on rodent studies that require large cohorts of animals and lengthy protocols. Here, we describe the establishment and validation of an in vitro assay using primary hepatocytes that recapitulates the hepatotoxic profile of SSOs previously observed in rodents. In vitro cytotoxicity upon unassisted delivery was measured as an increase in extracellular lactate dehydrogenase (LDH) levels and concomitant reduction in intracellular glutathione and ATP levels after 3 days of treatment. Furthermore, toxic, but not safe, SSOs led to an increase in miR-122 in cell culture supernatants after 2 days of exposure, revealing the potential use of miR122 as a selective translational biomarker for detection of SSO-induced hepatotoxicity. Overall, we have developed and validated for the first time a robust in vitro screening assay for SSO liver safety profiling which allows rapid prioritization of candidate molecules early on in development. PMID:27442522

  19. Screening of antiangiogenic potential of twenty two marine invertebrate extracts of phylum Mollusca from South East Coast of India

    Institute of Scientific and Technical Information of China (English)

    Pankaj Gupta; Muthuvel Arumugam; Raj Vardhan Azad; Rohit Saxena; Supriyo Ghose; Nihar Ranjan Biswas; Thirumurthy Velpandian

    2014-01-01

    Objective: To evaluate the antiangiogenic potential of twenty two marine invertebrate species of Phylum Mollusca from south east coast of India.Methods:Live specimens of molluscan species were collected and their methanolic extracts were evaluated for preliminary antiangiogenic activity using the in ovo chick chorio-allantoic membrane assay. The extracts were further evaluated for in vivo antiangiogenic activity using chemical cautery induced corneal neovascularization assay in rats and oxygen induced retinopathy assay in rat pups.Results:In the chick chorio-allantoic membrane assay, four methanolic extracts of marine molluscan species viz. Meretrix meretrix, Meretrix casta, Telescopium telescopium and Bursacrumena methanolic extracts exhibited noticeable antiangiogenic activity at the tested concentration of 200 µg whereby they significantly inhibited the VEGF induced proliferation of new blood vessels. Among these four extracts, the methanolic extract of Meretrix casta exhibited relatively higher degree of antiangiogenic activity with an inhibitiory percentage (64.63%) of the VEGF induced neovascularization followed by the methanolic extracts of Telescopium telescopium (62.02%), Bursa crumena (60.48%) and Meretrix meretrix (47.01%). These four methanolic extracts were further evaluated for in vivo antiangiogenic activity whereby the methanolic extract of Telescopium telescopium exhibited most noticeable inhibition (42.58%) of the corneal neovascularization in rats in comparison to the sham treated group, and also exhibited most noticeable inhibition (31.31%) of the oxygen induced retinal neovascularization in rat pups in comparison to the hyperoxia group that was observed for considerable retinal neovascularization.Conclusions:The significant antiangiogenic activity evinced by the extract of Telescopium telescopium merits further investigation for ocular neovascular diseases.

  20. MID TERM ASSESSMENT OF MASS DRUG ADMINISTRATION IN LYMPHATIC FILARIASIS ENDEMIC AREA OF DAMOH AND SAGAR DISTRICT OF MADHYA PRADESH

    Directory of Open Access Journals (Sweden)

    Mohan

    2015-03-01

    Full Text Available BACKGROUND: Lymphatic filariasis caused by Wuchereria bancrofti and Brugia malayi is an important public health problem in India. Filariasis is a major social and the fourth most common cause of disability all over the globe. Filariasis is endemic in 17 States and six Union Territories, with about 553 million people at risk of infection. It has been a major public health problem in India. The Global Programme for Elimination of Lymphatic filariasis was launched by the WHO in 2000 with the goal of eliminating Lymphatic filariasis as a public health problem by the year 2020. For the effective control of filariasis >65% population of endemic areas should be covered by single dose of Diethylcarbamazine 6mg/kg (DEC. OBJECTIVES: To assess the coverage and compliance of mass drug administration in the selected District and to make independent assessment with respect to process and out - come indicators. MATERIAL AND METHODS : A community based cross sectional study through house to house survey method in selected clusters was adopted. An independent evaluation was done and the outcome was assessed as the coverage and compliance of mass drug administration. RESULTS: In both Damoh and Sagar Districts of Madhya Pradesh, the coverage level for DEC was > 80% in all the Blocks. CONCL USION: The mass drug administration was aimed only to distribute the drug and the issues related to compliance, proper health education and side effects management were not given enough attention. These issues are important to make programme effective.

  1. Assessment of cardiovascular risk of new drugs for the treatment of diabetes mellitus: risk assessment vs. risk aversion.

    Science.gov (United States)

    Zannad, Faiez; Stough, Wendy Gattis; Lipicky, Raymond J; Tamargo, Juan; Bakris, George L; Borer, Jeffrey S; Alonso García, Maria de Los Angeles; Hadjadj, Samy; Koenig, Wolfgang; Kupfer, Stuart; McCullough, Peter A; Mosenzon, Ofri; Pocock, Stuart; Scheen, André J; Sourij, Harald; Van der Schueren, Bart; Stahre, Christina; White, William B; Calvo, Gonzalo

    2016-07-01

    The Food and Drug Administration issued guidance for evaluating the cardiovascular risk of new diabetes mellitus drugs in 2008. Accumulating evidence from several completed trials conducted within this framework raises questions as to whether requiring safety outcome studies for all new diabetes mellitus therapies remains justified. Given the burden of cardiovascular disease in patients with diabetes, the focus should shift towards cardiovascular outcome studies designed to evaluate efficacy (i.e. to determine the efficacy of a drug over placebo or standard care) rather than demonstrating that risk is not increased by a pre-specified safety margin. All stakeholders are responsible for ensuring that new drug approvals occur under conditions of appropriate safety and effectiveness. It is also a shared responsibility to avoid unnecessary hurdles that may compromise access to useful drugs and threaten the sustainability of health systems. It is critical to renew this debate so that stakeholders can collectively determine the optimal approach for developing new drugs to treat type 2 diabetes mellitus. PMID:27418973

  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. PMID:24752638

  3. HVAC Modeling for Cost of Ownership Assessment in Biotechnology & Drugs Manufacturing

    OpenAIRE

    Broomes, Peter; Dornfeld, David A

    2003-01-01

    Heating, ventilation, and air conditioning (HVAC) systems used in the clean room environment of biotechnology and drug development and manufacturing, are extremely energy and water intensive and represent a significant operating cost for these facilities [1]. HVAC systems are also the primary source of environmental emissions for the majority of companies operating within the biotechnology and drugs sector. While the processes used in drug manufacture have negligible environmental impact...

  4. A hidden Markov model to assess drug-induced sleep fragmentation in the telemetered rat

    OpenAIRE

    Diack, C.; Ackaert, O.; Ploeger, B A; van der Graaf, P H; Gurrell, R.; Ivarsson, M.; Fairman, D.

    2011-01-01

    Drug-induced sleep fragmentation can cause sleep disturbances either via their intended pharmacological action or as a side effect. Examples of disturbances include excessive daytime sleepiness, insomnia and nightmares. Developing drugs without these side effects requires insight into the mechanisms leading to sleep disturbance. The characterization of the circadian sleep pattern by EEG following drug exposure has improved our understanding of these mechanisms and their translatability across...

  5. Pharmacokinetic drug-drug interaction assessment of LCZ696 (an angiotensin receptor neprilysin inhibitor) with omeprazole, metformin or levonorgestrel-ethinyl estradiol in healthy subjects.

    Science.gov (United States)

    Gan, Lu; Jiang, Xuemin; Mendonza, Anisha; Swan, Therese; Reynolds, Christine; Nguyen, Joanne; Pal, Parasar; Neelakantham, Srikanth; Dahlke, Marion; Langenickel, Thomas; Rajman, Iris; Akahori, Mizuki; Zhou, Wei; Rebello, Sam; Sunkara, Gangadhar

    2016-01-01

    LCZ696 is a novel angiotensin receptor neprilysin inhibitor in development for the treatment of cardiovascular diseases. Here, we assessed the potential for pharmacokinetic drug-drug interaction of LCZ696 (400 mg, single dose or once daily [q.d.]) when co-administered with omeprazole 40 mg q.d. (n = 28) or metformin 1000 mg q.d. (n = 27) or levonorgestrel-ethinyl estradiol 150/30 μg single dose (n = 24) in three separate open-label, single-sequence studies in healthy subjects. Pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan), metformin, and levonorgestrel-ethinyl estradiol were assessed. Omeprazole did not alter the AUCinf of sacubitril and pharmacokinetics of LBQ657; however, 7% decrease in the Cmax of sacubitril, and 11% and 13% decreases in AUCinf and Cmax of valsartan were observed. Co-administration of LCZ696 with metformin had no significant effect on the pharmacokinetics of LBQ657 and valsartan; however, AUCtau,ss and Cmax,ss of metformin were decreased by 23%. Co-administration of LCZ696 with levonorgestrel-ethinyl estradiol had no effect on the pharmacokinetics of ethinyl estradiol and LBQ657 or AUCinf of levonorgestrel. The Cmax of levonorgestrel decreased by 15%, and AUCtau,ss and Cmax,ss of valsartan decreased by 14% and 16%, respectively. Co-administration of LCZ696 with omeprazole, metformin, or levonorgestrel-ethinyl estradiol was not associated with any clinically relevant pharmacokinetic drug interactions. PMID:27119576

  6. 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. PMID:26134089

  7. 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. PMID:27388755

  8. Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro

    Science.gov (United States)

    Funk, Juergen; Robbins, Justin B.; Crogan-Grundy, Candace; Presnell, Sharon C.; Singer, Thomas; Roth, Adrian B.

    2016-01-01

    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. PMID:27387377

  9. Cytotoxicity, anti-angiogenic, apoptotic effects and transcript profiling of a naturally occurring naphthyl butenone, guieranone A

    Directory of Open Access Journals (Sweden)

    Kuete Victor

    2012-06-01

    Full Text Available Abstract Background Malignant diseases are responsible of approximately 13% of all deaths each year in the world. Natural products represent a valuable source for the development of novel anticancer drugs. The present study was aimed at evaluating the cytotoxicity of a naphtyl butanone isolated from the leaves of Guiera senegalensis, guieranone A (GA. Results The results indicated that GA was active on 91.67% of the 12 tested cancer cell lines, the IC50 values below 4 μg/ml being recorded on 83.33% of them. In addition, the IC50 values obtained on human lymphoblastic leukemia CCRF-CEM (0.73 μg/ml and its resistant subline CEM/ADR5000 (1.01 μg/ml and on lung adenocarcinoma A549 (0.72 μg/ml cell lines were closer or lower than that of doxorubicin. Interestingly, low cytotoxicity to normal hepatocyte, AML12 cell line was observed. GA showed anti-angiogenic activity with up to 51.9% inhibition of the growth of blood capillaries on the chorioallantoic membrane of quail embryo. Its also induced apotosis and cell cycle arrest. Ingenuity Pathway Analysis identified several pathways in CCRF-CEM cells and functional group of genes regulated upon GA treatment (P , the Cell Cycle: G2/M DNA Damage Checkpoint Regulation and ATM Signaling pathways being amongst the four most involved functional groups. Conclusion The overall results of this work provide evidence of the cytotoxic potential of GA and supportive data for its possible use in cancer chemotherapy.

  10. Assessment of prescribing information for generic drugs manufactured in the Middle East and marketed in Saudi Arabia

    International Nuclear Information System (INIS)

    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)

  11. Effects of sustained antiangiogenic therapy in multistage prostate cancer in TRAMP model.

    Science.gov (United States)

    Isayeva, Tatyana; Chanda, Diptiman; Kallman, Lisa; Eltoum, Isam-Eldin A; Ponnazhagan, Selvarangan

    2007-06-15

    Antiangiogenic therapy is a promising alternative for prostate cancer growth and metastasis and holds great promise as an adjuvant therapy. The present study evaluated the potential of stable expression of angiostatin and endostatin before the onset of neoplasia and during the early and late stages of prostate cancer progression in transgenic adenocarcinoma of mouse prostate (TRAMP) mice. Groups of 5-, 10-, and 18-week-old male TRAMP mice received recombinant adeno-associated virus-6 encoding mouse endostatin plus angiostatin (E+A) by i.m. injection. The effects of therapy were determined by sacrificing groups of treated mice at defined stages of tumor progression and following cohorts of similarly treated mice for long-term survival. Results indicated remarkable survival after recombinant adeno-associated virus-(E+A) therapy only when the treatment was given at an earlier time, before the onset of high-grade neoplasia, compared with treatment given for invasive cancer. Interestingly, early-stage antiangiogenic therapy arrested the progression of moderately differentiated carcinoma to poorly differentiated state and distant metastasis. Immunohistochemical analysis of the prostate from treated mice indicated significantly lower endothelial cell proliferation and increased tumor cell apoptosis. Vascular endothelial growth factor receptor (VEGFR)-2 expression was significantly down-regulated in tumor endothelium after treatment but not VEGFR-1. Analysis of the neuroendocrine marker synaptophysin expression indicated that antiangiogenic therapy given at an early-stage disease reduced neuroendocrine transition of the epithelial tumors. These studies indicate that stable endostatin and angiostatin gene therapy may be more effective for minimally invasive tumors rather than advanced-stage disease. PMID:17575146

  12. Soil transmitted helminths and scabies in Zanzibar, Tanzania following mass drug administration for lymphatic filariasis - a rapid assessment methodology to assess impact

    OpenAIRE

    Mohammed Khalfan A; Deb Rinki M; Stanton Michelle C; Molyneux David H

    2012-01-01

    Abstract Background Ivermectin and albendazole are used in annual mass drug administration (MDA) for the lymphatic filariasis elimination programmes in African countries co-endemic for onchocerciasis, but have additional impact on soil transmitted helminths and the ectoparasitic mite which causes scabies. Assessing these collateral impacts at scale is difficult due to the insensitivity of available parasite detection techniques. Methods The numbers of cases diagnosed with intestinal helminths...

  13. 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.

  14. Pitfalls in the Neuroimaging of Glioblastoma in the Era of Antiangiogenic and Immuno/Targeted Therapy - Detecting Illusive Disease, Defining Response

    Directory of Open Access Journals (Sweden)

    Raymond Yi-Kun Huang

    2015-02-01

    Full Text Available Glioblastoma, the most common malignant primary brain tumor in adults is a devastating diagnosis with an average survival of 14-16 months using the current standard of care treatment. The determination of treatment response and clinical decision making is based on the accuracy of radiographic assessment. Notwithstanding, challenges exist in the neuroimaging evaluation of patients undergoing treatment for malignant glioma.Differentiating treatment response from tumor progression is problematic and currently combines long-term follow-up using standard MRI, with clinical status and corticosteroid-dependency assessments. In the clinical trial setting, treatment with gene therapy, vaccines, immunotherapy, and targeted biologicals similarly produces MRI changes mimicking disease progression. A neuroimaging method to clearly distinguish between pseudoprogression and tumor progression has unfortunately not been found to date. With the incorporation of antiangiogenic therapies, a further pitfall in imaging interpretation is pseudoresponse. The Macdonald Criteria that correlate tumor burden with contrast enhanced imaging proved insufficient and misleading in the context of rapid blood brain barrier normalization following antiangiogenic treatment that is not accompanied by expected survival benefit. Even improved criteria, such as the RANO criteria, that incorporate non-enhancing disease, clinical status, and need for corticosteroid use, fall short of definitively distinguishing tumor progression, pseudoresponse, and pseudoprogression.This review focuses on advanced imaging techniques including perfusion MRI, diffusion MRI, MR spectroscopy, and new PET imaging tracers. The relevant image analysis algorithms and interpretation methods of these promising techniques are discussed in the context of determining response and progression during treatment of glioblastoma both in the standard of care as well as clinical trial context.

  15. Antitumor and anti-angiogenic activity of Ganoderma lucidum polysaccharides peptide

    Institute of Scientific and Technical Information of China (English)

    Qi-zhen CAO; Zhi-bin LIN

    2004-01-01

    AIM: To investigate the antitumor and anti-angiogenic activity of Ganoderma lucidum polysaccharides peptide (GLPP). METHODS: Antitumor effect of GLPP was observed in tumor-bearing mice in vivo. At the same time,the effects of GLPP on proliferation of tumor cells and human umbilical cord vascular endothelial cell (HUVEC)were detected by MTT assay in vitro. Subsequently, spleen lymphocytes proliferation of nude mice was stimulated by LPS or ConA. To investigate the anti-angiogenic effect of GLPP, GLPP 80 μg per disc and GLPP-treated serum 10 μL per disc were added to the chick chorioallantoic membrane (CAM) respectively in vivo. RESULTS: GLPP 50, 100, and 200 mg/kg inhibited growth of Sarcoma 180 in BALB/c mice markedly by 35.2 %, 45.2%, and 61.9%,respectively. GLPP which was directly added to the cultured medium did not inhibit PG cell proliferation in vitro;but GLPP-treated serum 50, 100, 200 mg/kg potently inhibited PG cell proliferation by 22.5%, 26.8%, and 30.3 %,respectively; and reduced the xenograft (human lung carcinoma cell PG) in BALB/c nude mice greatly in vivo by 55.5 %, 46.0 %, and 46.8 %, respectively. Lymphocytes proliferation of nude mice could be stimulated by LPS 5 mg/L but not by ConA 2.5 mg/L, indicating that GLPP could not promote the T lymphocyte proliferation and neutral red phagocytosis of peritoneal macrophages of nude mice. The CAM assay showed that GLPP and GLPP-treated serum had anti-angiogenic effect. GLPP (1, 10, and 100 mg/L) inhibited HUVEC proliferation in vitro with the inhibitory rate of 9.4 %, 15.6%, and 40.4%, respectively. CONCLUSION: GLPP has antitumor and antiangiogenic activity. The anti-angiogenesis of GLPP may be a new mechanism underlying its anti-tumor effects.

  16. A novel antiangiogenic peptide derived from hepatocyte growth factor inhibits neovascularization in vitro and in vivo

    OpenAIRE

    Xu, Yi; Zhao, Hui; Zheng, Ying; Gu, Qing; Ma, Jianxing; Xu, Xun

    2010-01-01

    Purpose To study the antiangiogenic activity of two small peptides (H-RN and H-FT) derived from the hepatocyte growth factor kringle 1 domain (HGF K1) using in vitro and in vivo assays. Methods RF/6A rhesus macaque choroid-retina endothelial cells were used for in vitro studies. The inhibiting effect of two peptides on a vascular endothelial growth factor (VEGF)-stimulated cell proliferation, cell migration, and endothelial cell tube formation were investigated. For in vivo assays, the antian...

  17. The prospects of treatment for highly malignant brain gliomas. Antiangiogenic therapy

    International Nuclear Information System (INIS)

    Treatment for malignant brain tumors is an urgent issue of modern oncology. The prognosis of these patients is unfavorable, with median survival of 9-12 months. New treatment methods capable of increasing the relapse-free period and general survival of the patients are searched for. Modern strategy of treatment of the patients with malignant gliomas is based on interdisciplinary approach including surgery, radiation and chemotherapy, symptomatic treatment. Variants of antiangiogenic therapy have been developed recently. The results it its application are equivocal and require further investigation.

  18. Natural phenolic metabolites with anti-angiogenic properties - a review from the chemical point of view.

    Science.gov (United States)

    Sun, Qiu; Heilmann, Jörg; König, Burkhard

    2015-01-01

    Considering the many secondary natural metabolites available from plants, phenolic compounds play a particularly important role in human health as they occur in significant amounts in many fruits, vegetables and medicinal plants. In this review natural phenolic compounds of plant origin with significant anti-angiogenic properties are discussed. Thirteen representatives from eight different natural or natural-like phenolic subclasses are presented with an emphasis on their synthesis and methods to modify the parent compounds. When available, the consequence of structural variation on the pharmacological activity of the molecules is described. PMID:25815077

  19. 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.

  20. Project Towards No Drug Abuse (TND): Needs Assessment of a Social Service Referral Telephone Program for High Risk Youth

    OpenAIRE

    Sussman, Steve; SKARA, SILVANA; Pumpuang, Patchareeya

    2008-01-01

    The purpose of this study was to conduct a needs assessment of a potential social service resource telephone program component among high risk youth who received the Project Towards No Drug Abuse (TND) classroom-based program (approximately 1 year earlier). Results supported youths’ overwhelming receptiveness of a social service referral program. The vast majority of respondents indicated a strong desire for resource and referral information on vocational, educational, recreational, transport...

  1. Comparative risk assessment of alcohol, tobacco, cannabis and other illicit drugs using the margin of exposure approach

    OpenAIRE

    Lachenmeier, Dirk W; Jürgen Rehm

    2015-01-01

    A comparative risk assessment of drugs including alcohol and tobacco using the margin of exposure (MOE) approach was conducted. The MOE is defined as ratio between toxicological threshold (benchmark dose) and estimated human intake. Median lethal dose values from animal experiments were used to derive the benchmark dose. The human intake was calculated for individual scenarios and population-based scenarios. The MOE was calculated using probabilistic Monte Carlo simulations. The benchmark dos...

  2. Therapeutic drug monitoring for triazoles: A needs assessment review and recommendations from a Canadian perspective

    Science.gov (United States)

    Laverdiere, Michel; Bow, Eric J; Rotstein, Coleman; Autmizguine, Julie; Broady, Raewyn; Garber, Gary; Haider, Shariq; Hussaini, Trana; Husain, Shahid; Ovetchkine, Philippe; Seki, Jack T; Théorêt, Yves

    2014-01-01

    Invasive fungal infections cause significant morbidity and mortality in patients with concomitant underlying immunosuppressive diseases. The recent addition of new triazoles to the antifungal armamentarium has allowed for extended-spectrum activity and flexibility of administration. Over the years, clinical use has raised concerns about the degree of drug exposure following standard approved drug dosing, questioning the need for therapeutic drug monitoring (TDM). Accordingly, the present guidelines focus on TDM of triazole antifungal agents. A review of the rationale for triazole TDM, the targeted patient populations and available laboratory methods, as well as practical recommendations based on current evidence from an extended literature review are provided in the present document. PMID:25587296

  3. Evaluation of the impact of transient interruption of antiangiogenic treatment using ultrasound-based techniques in a murine model of hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Development of escape pathways from antiangiogenic treatments was reported to be associated with enhanced tumor aggressiveness and rebound effect was suggested after treatment stop. Aim of the study was to evaluate tumor response simulating different conditions of administration of antiangiogenic treatment (transient or definitive treatment stop) in a mouse model of hepatocellular carcinoma. Subcutaneous tumors were created by inoculating 5×106 Huh7 cells into the right flank of 14 nude mice. When tumor size reached 5–10 mm, mice were divided in 3 groups: group 1 was treated with placebo, group 2 was treated with sorafenib (62 mg/kg via gavage) but temporarily suspended from day +5 to +9, whereas in group 3 sorafenib was definitively stopped at day +5. At day +13 all mice were sacrificed, collecting masses for Western-Blot analyses. Volume was calculated with B-mode ultrasonography at day 0, +5, +9, +11 and +13. VEGFR2-targeted contrast-enhanced ultrasound using BR55 (Bracco Imaging) was performed at day +5 and +13 and elastonosography (Esaote) at day +9 and +11 to assess tumor stiffness. Median growth percentage delta at day +13 versus day 0 was 197% (115–329) in group 1, 81% (48–144) in group 2 and 111% (27–167) in group 3. Median growth delta at day +13 with respect to day +5 was 79% (48–127), 37% (−14128) and 81% (15–87) in groups 1, 2 and 3, respectively. Quantification of targeted-CEUS at day +13 showed higher values in group 3 (509 Arbitrary Units AI, range 293–652) than group 1 (275 AI, range 191–494) and group 2 (181 AI, range 63–318) (p = 0.033). Western-Blot analysis demonstrated higher VEGFR2 expression in group 3 with respect to group 1 and 2. A transient interruption of antiangiogenic treatment does not impede restoration of tumor response, while a definitive interruption tends to stimulate a rebound of angiogenesis to higher level than without treatment

  4. 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

  5. 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

  6. Elderly drug utilization in the community assessed through pharmacy dispensing data

    OpenAIRE

    Martínez Sánchez, Alina de las Mercedes

    2013-01-01

    People of 65 years and above now comprise a greater share of the world's population than ever before, and this proportion will increase during the 21st century. In Spain, between 55 and 90% of the elderly consume a drug. This study characterizes the use of drugs by elderly through dispensing data at the community pharmacy. This study was conducted at a community pharmacy in Madrid, Spain in 2011. A retrospective and descriptive consumption study was conducted using computerized ph...

  7. Arrhythmic risk biomarkers for the assessment of drug cardiotoxicity: from experiments to computer simulations

    OpenAIRE

    Corrias, A.; Jie, X.; Romero, L.; Bishop, M. J.; Bernabeu, M.; Pueyo, E.; Rodriguez, B.

    2010-01-01

    In this paper, we illustrate how advanced computational modelling and simulation can be used to investigate drug-induced effects on cardiac electrophysiology and on specific biomarkers of pro-arrhythmic risk. To do so, we first perform a thorough literature review of proposed arrhythmic risk biomarkers from the ionic to the electrocardiogram levels. The review highlights the variety of proposed biomarkers, the complexity of the mechanisms of drug-induced pro-arrhythmia and the existence of si...

  8. PRECLINICAL DRUG TRIALS IN THE mdx MOUSE: ASSESSMENT OF RELIABLE AND SENSITIVE OUTCOME MEASURES

    OpenAIRE

    SPURNEY, CHRISTOPHER F.; Gordish-Dressman, Heather; Alfredo D Guerron; Sali, Arpana; Gouri S Pandey; Rawat, Rashmi; van der Meulen, Jack H; Cha, Hee-Jae; Pistilli, Emidio E.; Partridge, Terence A.; Hoffman, Eric P; Nagaraju, Kanneboyina

    2009-01-01

    The availability of animal models for Duchenne muscular dystrophy has led to extensive preclinical research on potential therapeutics. Few studies have focused on reliability and sensitivity of endpoints for mdx mouse drug trials. Therefore, we sought to compare a wide variety of reported and novel endpoint measures in exercised mdx and normal control mice at 10, 20, and 40 weeks of age. Statistical analysis as well as power calculations for expected effect sizes in mdx preclinical drug trial...

  9. Validation of radiolabeling of drug formulations for aerosol deposition assessment of orally inhaled products.

    Science.gov (United States)

    Devadason, Sunalene G; Chan, Hak-Kim; Haeussermann, Sabine; Kietzig, Claudius; Kuehl, Philip J; Newman, Stephen; Sommerer, Knut; Taylor, Glyn

    2012-12-01

    Radiolabeling of inhaler formulations for imaging studies is an indirect method of determining lung deposition and regional distribution of drug in human subjects. Hence, ensuring that the radiotracer and drug exhibit similar aerodynamic characteristics when aerosolized, and that addition of the radiotracer has not significantly altered the characteristics of the formulation, are critical steps in the development of a radiolabeling method. The validation phase should occur during development of the radiolabeling method, prior to commencement of in vivo studies. The validation process involves characterization of the aerodynamic particle size distribution (APSD) of drug in the reference formulation, and of both drug and radiotracer in the radiolabeled formulation, using multistage cascade impaction. We propose the adoption of acceptance criteria similar to those recommended by the EMA and ISAM/IPAC-RS for determination of therapeutic equivalence of orally inhaled products: (a) if only total lung deposition is being quantified, the fine particle fraction ratio of both radiolabeled drug and radiotracer to that of the reference drug should fall between 0.85 and 1.18, and (b) if regional lung deposition (e.g., outer and inner lung regions) is to be quantified, the ratio of both radiolabeled drug and radiotracer to reference drug on each impactor stage or group of stages should fall between 0.85 and 1.18. If impactor stages are grouped together, at least four separate groups should be provided. In addition, while conducting in vivo studies, measurement of the APSD of the inhaler used on each study day is recommended to check its suitability for use in man. PMID:23215848

  10. An analytical method for assessing stage-specific drug activity in Plasmodium vivax malaria: implications for ex vivo drug susceptibility testing.

    Directory of Open Access Journals (Sweden)

    Douglas H Kerlin

    Full Text Available The emergence of highly chloroquine (CQ resistant P. vivax in Southeast Asia has created an urgent need for an improved understanding of the mechanisms of drug resistance in these parasites, the development of robust tools for defining the spread of resistance, and the discovery of new antimalarial agents. The ex vivo Schizont Maturation Test (SMT, originally developed for the study of P. falciparum, has been modified for P. vivax. We retrospectively analysed the results from 760 parasite isolates assessed by the modified SMT to investigate the relationship between parasite growth dynamics and parasite susceptibility to antimalarial drugs. Previous observations of the stage-specific activity of CQ against P. vivax were confirmed, and shown to have profound consequences for interpretation of the assay. Using a nonlinear model we show increased duration of the assay and a higher proportion of ring stages in the initial blood sample were associated with decreased effective concentration (EC(50 values of CQ, and identify a threshold where these associations no longer hold. Thus, starting composition of parasites in the SMT and duration of the assay can have a profound effect on the calculated EC(50 for CQ. Our findings indicate that EC(50 values from assays with a duration less than 34 hours do not truly reflect the sensitivity of the parasite to CQ, nor an assay where the proportion of ring stage parasites at the start of the assay does not exceed 66%. Application of this threshold modelling approach suggests that similar issues may occur for susceptibility testing of amodiaquine and mefloquine. The statistical methodology which has been developed also provides a novel means of detecting stage-specific drug activity for new antimalarials.

  11. A Review of Quality of Life in Alzheimer's Disease: Part 2: Issues in Assessing Drug Effects

    OpenAIRE

    Sam S. Salek; Melvyn D. Walker; Antony J. Bayer

    1998-01-01

    There are numerous methods available for assessing patients with Alzheimer's disease (AD) or other forms of dementia. Quality-of-life (QOL) assessment is unique among these methods. The subjective nature of quality of life provides healthcare professionals with the opportunity of incorporating the value systems of patients and their carers into their assessments. A systematic review was carried out to assess the published data (and some unpublished data) on QOL assessment tools and instrument...

  12. Kinetic modeling of tricarboxylic acid cycle and glyoxylate bypass in Mycobacterium tuberculosis, and its application to assessment of drug targets

    Directory of Open Access Journals (Sweden)

    Ghosh Indira

    2006-08-01

    Full Text Available Abstract Background Targeting persistent tubercule bacilli has become an important challenge in the development of anti-tuberculous drugs. As the glyoxylate bypass is essential for persistent bacilli, interference with it holds the potential for designing new antibacterial drugs. We have developed kinetic models of the tricarboxylic acid cycle and glyoxylate bypass in Escherichia coli and Mycobacterium tuberculosis, and studied the effects of inhibition of various enzymes in the M. tuberculosis model. Results We used E. coli to validate the pathway-modeling protocol and showed that changes in metabolic flux can be estimated from gene expression data. The M. tuberculosis model reproduced the observation that deletion of one of the two isocitrate lyase genes has little effect on bacterial growth in macrophages, but deletion of both genes leads to the elimination of the bacilli from the lungs. It also substantiated the inhibition of isocitrate lyases by 3-nitropropionate. On the basis of our simulation studies, we propose that: (i fractional inactivation of both isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 is required for a flux through the glyoxylate bypass in persistent mycobacteria; and (ii increasing the amount of active isocitrate dehydrogenases can stop the flux through the glyoxylate bypass, so the kinase that inactivates isocitrate dehydrogenase 1 and/or the proposed inactivator of isocitrate dehydrogenase 2 is a potential target for drugs against persistent mycobacteria. In addition, competitive inhibition of isocitrate lyases along with a reduction in the inactivation of isocitrate dehydrogenases appears to be a feasible strategy for targeting persistent mycobacteria. Conclusion We used kinetic modeling of biochemical pathways to assess various potential anti-tuberculous drug targets that interfere with the glyoxylate bypass flux, and indicated the type of inhibition needed to eliminate the pathogen. The advantage of such an

  13. Antiangiogenic therapy enhances the efficacy of transcatheter arterial embolization for hepatocellular carcinomas.

    Science.gov (United States)

    Jiang, Hongchi; Meng, Qinghui; Tan, Hongtao; Pan, Shangha; Sun, Bei; Xu, Ruian; Sun, Xueying

    2007-07-15

    Transcatheter arterial embolization (TAE) is a well-established technique for unresectable hepatic malignancies. However, TAE can temporally halt the growth of hepatic tumors by blocking their arterial supply, but often tumors rapidly develop collateral blood vessels via angiogenesis. We have previously demonstrated that intraportal delivery of adeno-associated viral particles expressing angiostatin leads to long-term expression of angiostatin capable of inhibiting angiogenesis and suppressing the outgrowth of tumors in the liver. Thus, we hypothesize that adeno-associated virus (AAV)-mediated antiangiogenic therapy could enhance the efficacy of TAE to combat liver cancers. To achieve this objective, we engineered a recombinant AAV vector encoding rat angiostatin. Intraportal delivery of this vector led to long term and stable transgenic expression of angiostatin locally in rat hepatocytes and suppressed the growth of CBRH7919 hepatocellular carcinomas established in rat livers by inhibiting formation of neovessels. Although TAE therapy led to necrosis of liver tumors and suppressed their growth, the neovessels of tumors were rapidly reformed 3 weeks after TAE. However, intraportal injection of AAV-angiostatin inhibited the angiogenesis stimulated by TAE, synergized with TAE in suppressing growth of tumors established in livers and prolonged the survival of rats. In conclusion, these encouraging results warrant future investigation of the use of antiangiogenic therapy for enhancing the therapeutic efficacy of TAE to treat unresectable liver cancers. PMID:17330237

  14. Antiangiogenic immunotherapy targeting Flk-1, DNA vaccine and adoptive T cell transfer, inhibits ocular neovascularization

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Han [Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582 (Japan); Sonoda, Koh-Hei, E-mail: sonodak@med.kyushu-u.ac.jp [Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582 (Japan); Hijioka, Kuniaki; Qiao, Hong; Oshima, Yuji; Ishibashi, Tatsuro [Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582 (Japan)

    2009-04-17

    Ocular neovascularization (NV) is the primary cause of blindness in a wide range of ocular diseases. The exact mechanism underlying the pathogenesis of ocular NV is not yet well understood, and so there is no satisfactory therapy for ocular NV. Here, we describe a strategy targeting Flk-1, a self-antigen overexpressed on proliferating endothelial cells in ocular NV, by antiangiogenic immunotherapy-DNA vaccine and adoptive T cell therapy. An oral DNA vaccine encoding Flk-1 carried by attenuated Salmonella typhimurium markedly suppressed development of laser-induced choroidal NV. We further demonstrated that adoptive transfer of vaccine-induced CD8{sup +} T cells reduced pathological preretinal NV, with a concomitant facilitation of physiological revascularization after oxygen-induced retinal vessel obliteration. However, physiological retinal vascular development was unaffected in neonatal mice transferred with vaccine-induced CD8{sup +} T cells. These findings suggested that antiangiogenic immunotherapy targeting Flk-1 such as vaccination and adoptive immunotherapy may contribute to future therapies for ocular NV.

  15. Antiangiogenic immunotherapy targeting Flk-1, DNA vaccine and adoptive T cell transfer, inhibits ocular neovascularization

    International Nuclear Information System (INIS)

    Ocular neovascularization (NV) is the primary cause of blindness in a wide range of ocular diseases. The exact mechanism underlying the pathogenesis of ocular NV is not yet well understood, and so there is no satisfactory therapy for ocular NV. Here, we describe a strategy targeting Flk-1, a self-antigen overexpressed on proliferating endothelial cells in ocular NV, by antiangiogenic immunotherapy-DNA vaccine and adoptive T cell therapy. An oral DNA vaccine encoding Flk-1 carried by attenuated Salmonella typhimurium markedly suppressed development of laser-induced choroidal NV. We further demonstrated that adoptive transfer of vaccine-induced CD8+ T cells reduced pathological preretinal NV, with a concomitant facilitation of physiological revascularization after oxygen-induced retinal vessel obliteration. However, physiological retinal vascular development was unaffected in neonatal mice transferred with vaccine-induced CD8+ T cells. These findings suggested that antiangiogenic immunotherapy targeting Flk-1 such as vaccination and adoptive immunotherapy may contribute to future therapies for ocular NV.

  16. Apoptotic and anti-angiogenic effects of Salvia triloba extract in prostate cancer cell lines.

    Science.gov (United States)

    Atmaca, Harika; Bozkurt, Emir

    2016-03-01

    Plants, due to their remarkable composition, are considered as natural resources of bioactive compounds with specific biological activities. Salvia genus (Lamiaceae) has been used around the world in complementary medicine since ancient times. We investigated the cytotoxic, apoptotic and anti-angiogenic effects of methanolic Salvia triloba extract (STE) in prostate cancer cells. Cell viability was evaluated by XTT; apoptosis was investigated by DNA fragmentation and caspase 3/7 activity assays. Changes in the angiogenic cytokine levels were investigated by human angiogenesis antibody array. Scratch assay was used to determine the cell motility. STE induced cytotoxicity and apoptosis in a concentration-dependent manner in both cancer cells; however, it was not cytotoxic to normal cells. Cell motility was reduced in PC-3, DU-145 and HUVEC cells by STE treatment. ANG, ENA-78, bFGF, EGF, IGF-1 and VEGF-D levels were significantly decreased by -2.9, -3.7, -1.7, -1.7, -2.0 and -1.8 fold in STE-treated DU-145 cells, however, ANG, IL-8, LEP, RANTES, TIMP-1, TIMP-2 and VEGF levels were significantly decreased by -5.1, -2.0, -2.4, -3.1, -1.5, -2.0 and -2.5 fold in PC-3 cells. These data suggest that STE might be a promising candidate for anti-tumor and anti-angiogenic treatment of prostate cancer. PMID:26459311

  17. 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.

  18. Risk assessment of drug interaction potential and concomitant dosing pattern on targeted toxicities in pediatric cancer patients.

    Science.gov (United States)

    Barrett, Jeffrey S; Patel, Dimple; Dombrowsky, Erin; Bajaj, Gaurav; Skolnik, Jeffrey M

    2013-07-01

    This investigation evaluated the impact of potential drug interactions on the incidence of reported toxicities seen with common dosing patterns in children with cancer, with the intent of being able to screen and reduce the incidence of adverse drug reactions (ADRs) in the future. Toxicity reported in pediatric cancer patients treated at the Children's Hospital of Philadelphia from 2004 to 2010 were abstracted from a cancer tumor registry and merged with drug order profiles from the medical record system. Analysis datasets were created in SAS and permutation algorithms were used to identify pairwise drug combinations associated with specific toxicity occurrence. Relative risk of toxicity based on dosing pattern was assessed via comparison to control patients. A total of 326 of 1,713 patients (19%) had reportable toxicities. Neutrophil count decreases and alanine aminotransferase increases represented the highest occurring, corresponding to 28.8% and 31.9% prevalence among patients reporting toxicity, respectively. Of coadministered drug pairs, acetaminophen-diphenhydramine occurred most frequently; however, methotrexate-vincristine was the highest occurring pair linked to a single toxicity (hepatotoxicity). Toxicity was highly associated with the diagnoses of leukemia (52.1%) or neuroblastoma (28.5%). Comparison of the dosing interval (≤30 versus >30 min) suggested that risk of toxicity can be associated with the timing of coadministration, with ≤30 min increasing the risk of hepatotoxicity with fentanyl-midazolam and methotrexate-midazolam combinations. Knowledge of drug interactions in children with cancer may help reduce the incidence of ADRs by providing pharmacotherapy options that may reduce the likelihood of toxicity. PMID:23595361

  19. Assessing the viability of microsponges as gastro retentive drug delivery system of curcumin: optimization and pharmacokinetics.

    Science.gov (United States)

    Arya, Priyanka; Pathak, Kamla

    2014-01-01

    The work was aimed to validate the gastroretentive potential of microsponges via optimization of targeted floating curcumin microsponges for improved site specific absorption for gastric cancer Modified quasi emulsion solvent diffusion method was used to formulate microsponges using 3(2) full factorial design. The effect of different levels of ethyl cellulose and polyvinyl alcohol concentration, selected as independent variables was determined on the % entrapment efficiency, % buoyancy and % cumulative drug release. Modified rosette rise apparatus was used for in vitro release and the release data best fitted Higuchi's model and mechanism of drug release was diffusion (n). The optimized formulation (MS5) demonstrated favourable % entrapment efficiency (90.7 ± 1.7), % buoyancy (82.0 ± 2.0) and % cumulative drug release (85.2 ± 1.07) with maximum desirability factor of 0.816. SEM revealed spherical and porous microsponges. DSC confirmed molecular dispersion of the drug in the microsponges polymeric matrix. DRIFT revealed no chemical interaction between the drug and polymer used. The in vitro permeation of curcumin through gastric mucin gel layer affirmed the capability of microsponges to deliver drug across mucin r and reach the target site to treat gastric cancer. Anticancer oral dose of microsponges was calculated as 50mg by cytotoxicity assay in human cancer cell line KB. The pharmacokinetic evaluation of MS5 in rabbits revealed 10-fold increase in bioavailability as compared to native curcumin, demonstrated the superiority of microsponges over native curcumin as gastro retentive drug delivery system. This study presents a new approach based on floating ability of microsponges for treatment of gastric cancer. PMID:24184218

  20. 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. PMID:27341432

  1. Mechanisms of Very Late Drug-Eluting Stent Thrombosis Assessed by Optical Coherence Tomography

    DEFF Research Database (Denmark)

    Taniwaki, Masanori; Radu, Maria D; Zaugg, Serge; Amabile, Nicolas; Garcia-Garcia, Hector M; Yamaji, Kyohei; Jørgensen, Erik; Kelbæk, Henning; Pilgrim, Thomas; Caussin, Christophe; Zanchin, Thomas; Veugeois, Aurelie; Abildgaard, Ulrik; Jüni, Peter; Cook, Stephane; Koskinas, Konstantinos C; Windecker, Stephan; Räber, Lorenz

    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 December...... 2014, 64 patients were investigated at the time point of VLST as part of an international optical coherence tomography registry. Optical coherence tomography pullbacks were performed after restoration of flow and analyzed at 0.4 mm. A total of 38 early- and 20 newer-generation drug-eluting stents were...... malapposed struts with thrombus were consistent among early- and newer-generation drug-eluting stents. CONCLUSIONS: The leading associated findings in VLST patients in descending order were malapposition, neoatherosclerosis, uncovered struts, and stent underexpansion without differences between patients...

  2. Quantitative measurement of handwriting in the assessment of drug-induced parkinsonism.

    Science.gov (United States)

    Caligiuri, Michael P; Teulings, Hans-Leo; Filoteo, J Vincent; Song, David; Lohr, James B

    2006-10-01

    Monitoring drug-induced side effects is especially important for patients who undergo treatment with antipsychotic medications, as these drugs often produce extrapyramidal side effects (EPS) resulting in movement abnormalities similar to parkinsonism. Scientists have developed several objective laboratory tests to measure and research drug-induced movement disorders, but equipment and tests are complex and costly and have not become accepted in large-scale, multi-site clinical trials. The goals of this study were to test whether a simple handwriting measure can discriminate between individuals with psychotropic-induced parkinsonism, Parkinson's disease, and healthy individuals, and to examine some of the psychometric properties of the measure. We examined pen movement kinematics during cursive writing of a standard word in 13 patients with idiopathic Parkinson's disease (PD), 10 schizophrenia patients with drug-induced parkinsonism (SZ), and 12 normal healthy control participants (NC). Participants were instructed to write the word "hello" in cursive twice, at three vertical height scales. Software was used for data acquisition and analysis of vertical stroke velocities, velocity scaling, and smoothness. There were four important results from this study: (1) both SZ patients with drug-induced EPS and PD participants exhibited impaired movement velocities and velocity scaling; (2) performance on the velocity scaling measure distinguished drug-induced EPS from normal with 90% accuracy; (3) SZ, but not PD participants displayed abnormalities in movement smoothness; and (4) there was a positive correlation between age and magnitude of the velocity scaling deficit in PD participants. This study demonstrates that kinematic analyses of pen movements during handwriting may be useful in detecting and monitoring subtle changes in motor control related to the adverse effects of psychotropic medications. PMID:16647772

  3. Assessing Consumer Gains from a Drug Price Control Policy in the U.S.

    OpenAIRE

    Rexford Santerre; John A. Vernon

    2005-01-01

    This paper uses national data for the period 1960 to 2000 to estimate an aggregate private consumer demand for pharmaceuticals in the U.S. The estimated demand curve is then used to simulate the value of consumer surplus gains from a drug price control regime that holds drug price increases to the same rate of growth as the general consumer price level over the time period from 1981 to 2000. Based upon a 7 percent real interest rate, we find that the future value of consumer surplus gains fro...

  4. Synergistic Effect of Anti-Angiogenic and Radiation Therapy: Quantitative Evaluation with Dynamic Contrast Enhanced MR Imaging.

    Directory of Open Access Journals (Sweden)

    Hyun Jung Koo

    Full Text Available We assessed the effects of anti-angiogenic therapy (AAT on radiation therapy (RT, evaluating the tumor growth and perfusion patterns on dynamic contrast enhanced MR (DCE-MR images.Thirteen nude mice with heterotopic xenograft cancer of human lung cancer cell line were used. To observe the interval change of the tumor size and demonstrate the time-signal intensity enhancement curve of the tumor, the mice were subdivided into four groups: control (n = 2, AAT (n = 2, RT (n = 5, and combined therapy (AART, n = 4. DCE-MR images were taken four weeks after treatment. Perfusion parameters were obtained based on the Brix model. To compare the interval size changes in the RT group with those in the AART group, repeated measures ANOVA was used. Perfusion parameters in both the RT and AART groups were compared using a Mann-Whitney U test.Tumor growth was more suppressed in AART group than in the other groups. Control group showed the rapid wash-in and wash-out pattern on DCE-MR images. In contrast to RT group with delayed and prolonged enhancement, both AAT and AART groups showed the rapid wash-in and plateau pattern. The signal intensity in the plateau/time to peak enhancement (P<0.016 and the maximum enhancement ratio (P<0.016 of AART group were higher than those of RT group.AART showed synergistic effects in anticancer treatment. The pattern of the time-intensity curve on the DCE-MR images in each group implies that AAT might help maintain the perfusion in the cancer of AART group.

  5. Longitudinal monitoring of tumor antiangiogenic therapy with near-infrared fluorophore-labeled agents targeted to integrin α{sub v}β{sub 3} and vascular endothelial growth factor

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Xianlei; Ma, Teng; Liu, Hao; Yu, Xinhe; Wu, Yue; Jia, Bing; Wang, Fan; Liu, Zhaofei [Peking University, Medical Isotopes Research Center, Beijing (China); Peking University, Department of Radiation Medicine, School of Basic Medical Sciences, Beijing (China); Shi, Jiyun; Zhao, Huiyun [Peking University, Medical Isotopes Research Center, Beijing (China); Peking University, Medical and Healthy Analytical Center, Beijing (China)

    2014-07-15

    Optical imaging is emerging as a powerful tool for the noninvasive imaging of the biological processes in living subjects. This study aimed to investigate whether optical imaging of integrin α{sub v}β{sub 3} and vascular endothelial growth factor (VEGF) expression can serve as sensitive biomarkers for tumor early response to antiangiogenic therapy. We synthesized two near-infrared fluorescence (NIRF) imaging agents, CF680R-3PRGD2 and CF750-BevF(ab'){sub 2}, which were designed to specifically bind to integrin α{sub v}β{sub 3} and VEGF, respectively. The ability of optical imaging using the two imaging agents for early monitoring the antiangiogenic effect of sunitinib was evaluated. CF680R-3PRGD2 and CF750-BevF(ab'){sub 2} specifically bound to their respective targets in vitro and in HT-29 tumor-bearing nude mice. Sunitinib treatment led to significantly decreased tumor uptake of CF680R-3PRGD2 (e.g., 7.47 ± 1.62 % vs. 4.24 ± 0.16 % on day 4; P < 0.05) and CF750-BevF(ab'){sub 2} (e.g., 7.43 ± 2.43 % vs. 4.04 ± 1.39 % on day 2; P < 0.05) in vivo. Immunofluorescence staining and an enzyme-linked immunosorbent assay confirmed that sunitinib-induced changes in tumor uptake of CF680R-3PRGD2 and CF750-BevF(ab'){sub 2} were correlated with changes in the levels of integrin α{sub v}β{sub 3} and VEGF. Radiobiodistribution of {sup 99m}Tc-3PRGD2 and {sup 125}I-BevF(ab'){sub 2}, the radiocounterparts of CF680R-3PRGD2 and CF750-BevF(ab'){sub 2}, respectively, also validated optical imaging results. Longitudinal monitoring of tumor integrin α{sub v}β{sub 3} and VEGF expression could be used as early biomarkers for tumor response to antiangiogenic therapy. This strategy may facilitate the development of new antiangiogenic drugs, and be used for elucidation of the underlying mechanisms of therapies involving the integrin and the VEGF signaling pathway. (orig.)

  6. 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. PMID:24841527

  7. Assessment of mitochondrial dysfunction-related, drug-induced hepatotoxicity in primary rat hepatocytes.

    Science.gov (United States)

    Liu, Cong; Sekine, Shuichi; Ito, Kousei

    2016-07-01

    Evidence that mitochondrial dysfunction plays a central role in drug-induced liver injury is rapidly accumulating. In contrast to physiological conditions, in which almost all adenosine triphosphate (ATP) in hepatocytes is generated in mitochondria via aerobic respiration, the high glucose content and limited oxygen supply of conventional culture systems force primary hepatocytes to generate most ATP via cytosolic glycolysis. Thus, such anaerobically poised cells are resistant to xenobiotics that impair mitochondrial function, and are not suitable to identify drugs with mitochondrial liabilities. In this study, primary rat hepatocytes were cultured in galactose-based medium, instead of the conventional glucose-based medium, and in hyperoxia to improve the reliance of energy generation on aerobic respiration. Activation of mitochondria was verified by diminished cellular lactate release and increased oxygen consumption. These conditions improved sensitivity to the mitochondrial complex I inhibitor rotenone. Since oxidative stress is also a general cause of mitochondrial impairment, cells were exposed to test compounds in the presence of transferrin to increase the generation of reactive oxygen species via increased uptake of iron. Finally, 14 compounds with reported mitochondrial liabilities were tested to validate this new drug-induced mitochondrial toxicity assay. Overall, the culture of primary rat hepatocytes in galactose, hyperoxia and transferrin is a useful model for the identification of mitochondrial dysfunction-related drug-induced hepatotoxicity. PMID:27095095

  8. New drugs and indications in 2010: inadequate assessment; patients at risk.

    Science.gov (United States)

    2011-04-01

    In 2010, we rated 97 new drugs or new indications in our French edition la revue Prescrire, only 4 of which provided a therapeutic advantage. However, 19 others (1 in 5) were approved despite having more harms than benefits. More paediatric products were released in 2010 than in previous years, but few of them made any real difference and many had not been properly evaluated. Drug regulatory agencies can protect patients from exposure to dangerous drugs by refusing to grant market approval or by demanding their market withdrawal.Yet they are failing to fulfil this responsibility: so-called risk management plans and modifications to the wording in the SPC are only half-measures. Too often the authorities put companies' short-term financial interests above patients' well-being by granting premature marketing authorisation, by agreeing to high levels of reimbursement that fail to take added therapeutic value into account, and by allowing the development of "umbrella" ranges. The European authorities' questionable plans for pharmacovigilance and advertising of prescription-only drugs were restricted after public mobilisation, but they are still likely to undermine healthcare quality. Decision-makers must make patients' well-being their top priority. PMID:21648217

  9. 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 a...

  10. A hidden Markov model to assess drug-induced sleep fragmentation in the telemetered rat.

    Science.gov (United States)

    Diack, C; Ackaert, O; Ploeger, B A; van der Graaf, P H; Gurrell, R; Ivarsson, M; Fairman, D

    2011-12-01

    Drug-induced sleep fragmentation can cause sleep disturbances either via their intended pharmacological action or as a side effect. Examples of disturbances include excessive daytime sleepiness, insomnia and nightmares. Developing drugs without these side effects requires insight into the mechanisms leading to sleep disturbance. The characterization of the circadian sleep pattern by EEG following drug exposure has improved our understanding of these mechanisms and their translatability across species. The EEG shows frequent transitions between specific sleep states leading to multiple correlated sojourns in these states. We have developed a Markov model to consider the high correlation in the data and quantitatively compared sleep disturbance in telemetered rats induced by methylphenidate, which is known to disturb sleep, and of a new chemical entity (NCE). It was assumed that these drugs could either accelerate or decelerate the transitions between the sleep states. The difference in sleep disturbance of methylphenidate and the NCE were quantitated and different mechanisms of action on rebound sleep were identified. The estimated effect showed that both compounds induce sleep fragmentation with methylphenidate being fivefold more potent compared to the NCE. PMID:21909798

  11. A novel isothermal microcalorimetry tool to assess drug effects on Ancylostoma ceylanicum and Necator americanus.

    Science.gov (United States)

    Flores, Dayana; Panic, Gordana; Braissant, Olivier; Keiser, Jennifer

    2016-01-01

    Soil-transmitted helminths, which affect the poorest communities, worldwide cause a range of symptoms and morbidity, yet few treatment options are available and drug resistance is a concern. To improve and accelerate anthelminthic drug discovery, novel drug screening tools such as isothermal microcalorimetry (IMC) have been tested with great potential. In this study, we used a novel microcalorimeter, the calScreener™, to study the viability on the hookworms Necator americanus and Ancylostoma ceylanicum as well as the whipworm Trichuris muris. Significant heat flow signals could be obtained with already one adult worm per channel for all three species. High-amplitude oscillations were observed for the hookworms; however, adult T. muris showed a twofold heat flow decrease during the first 24 h. Antinematodal effects of ivermectin and levamisole at 1, 10, and 100 μg/ml were evaluated on adult N. americanus and A. ceylanicum. Levamisole-treated hookworms showed a decline in heat flow and oscillation amplitude in a dose-response manner. Heat flow for ivermectin-treated hookworms increased proportionally with increased concentrations of ivermectin, though the wavelet analysis showed an opposite trend as observed by flatter wavelets. In conclusion, the calScreener™ is an excellent tool to study drug effects on intestinal hookworms at the adult worm stage as it offers a lower detection limit than other IMC devices and the possibility to monitor worm viability online. PMID:26519051

  12. Cationic Albumin Nanoparticles for Enhanced Drug Delivery to Treat Breast Cancer: Preparation and In Vitro Assessment

    OpenAIRE

    Sana Abbasi; Arghya Paul; Wei Shao; Satya Prakash

    2012-01-01

    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 f...

  13. Assessing Coverage of Mass Drug Administration against Lymphatic Filariasis in Gulbarga District, Karnataka

    OpenAIRE

    Anil NS

    2012-01-01

    Background: Lymphatic filariasis is an important public health problem in India not only due to morbid condition but also due to social stigma, sexual incapacitation and considerable economic loss. The Government of India in 2004 began a nationwide mass drug administration (MDA) campaign in all the known Lymphatic filariasis endemic districts with an annual single dose of Diethylcarbamazine citrate with the aim of eliminating it as a public health problem by the year 2015. Inspite...

  14. AN ANALYSIS OF CRO SELECTION PROCESS &RISK ASSESSMENT FOR ASTRAZENECA GENERIC DRUG DEVELOPMENT PROJECT IN CHINA

    OpenAIRE

    Shetty, Shraddha

    2012-01-01

    The current challenging situation in the pharmaceutical industry has caused has many big pharmaceutical companies to move towards Generic drugs .As the markets in the western countries are nearing saturation emerging nations like India and China are attractive destinations for Pharma companies. The on-going healthcare reforms, rising economy, untapped rural market, improved infrastructure & population pool in China gives tremendous opportunities for pharmaceutical companies to grow their b...

  15. Are zebrafish larvae suitable for assessing the hepatotoxicity potential of drug candidates?

    OpenAIRE

    Mesens, Natalie; Crawford, Alexander D.; Menke, Aswin; Pham, Duc Hung; Van Goethem, Freddy; Nuyts, Rik; Hansen, Erik; Wolterbeek, Andre; Van Gompel, Jacky; de Witte, Peter; Esguerra, Camila 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 DILI; however, the possible occurrence of other organ toxicities and the immature larval stage of the zebrafish might complicate accurate and fast analysis. We investigated whether expression analys...

  16. Assessing the added value of wastewater-based epidemiology to monitor illicit drug use

    OpenAIRE

    Béen F.

    2015-01-01

    Wastewater-based epidemiology consists in acquiring relevant information about the lifestyle and health status of the population through the analysis of wastewater samples collected at the influent of a wastewater treatment plant. Whilst being a very young discipline, it has experienced an astonishing development since its firs application in 2005. The possibility to gather community-wide information about drug use has been among the major field of application. The wide resonance of the first...

  17. Assessment of Substances Abuse in Burn Patients by Using Drug Abuse Screening Test

    OpenAIRE

    Kobra Gaseminegad; Bita Kamranfar; Parviz Nemazi; Faride Ahrari; Jaber Musavi; Kamran As'adi; Seyed Hamid Salehi; Somaie Faramarzi; Saeed Shoar

    2012-01-01

    There has been an increase in the frequency of substance abuse among hospitalized burn injury patients. However, few studies have investigated substance abuse among burn patients. This study was aimed to identify the incidence of substance abuse in burn injury patients using the "Drug Abuse Screening Test" (DAST-20). We determined the validity of DAST-20 in spring 2010. Subsequently, this descriptive study was performed on 203 burn injury patients who fit the study's inclusion criteria. We ch...

  18. Assessment of the efficacy of drug transdermal delivery by electro-phonophoresis in treating tuberculous lymphadenitis.

    Science.gov (United States)

    Chen, Suting; Qin, Ming; Han, Yi; Zhao, Liping; Fu, Yuhong; Shang, Yuanyuan; Liu, Zhidong; Huang, Hairong

    2016-06-01

    Electro-phonophoresis (EP) has been used in various clinical fields. The objective of present study is to evaluate the skin permeability of isoniazid (INH) and rifampicin (RIF) in patients with tuberculous lymphadenitis with the aid of EP to validate the clinical applications of this transdermal delivery system for the treatment of superficial extrapulmonary tuberculosis. INH and RIF solutions were delivered transdermally, with or without EP, in the surrounding tissue of the lesion for 0.5 h. Local pyogenic fluids or necrotic tissue samples from the infection sites in patients were collected at 1 h after dosing. Drug concentrations in samples were evaluated by high performance liquid chromatography. The median INH and RIF intra-lesional concentrations were 0.365 (interquartile range [IQR] 0.185-1.775) μg/mL and 1.231 (IQR 0.304-1.836) μg/mL in oral group; 2.964 (IQR 0.193-7.325) μg/mL and 2.646 (IQR 1.211-3.753) μg/mL in INH- and RIF-transdermal plus EP group. Drug concentrations in the local sites of patients receiving INH or RIF through EP transdermal delivery were statistically higher than those observed in patients only taking INH and RIF orally. However, this enhancement was not observed in the transdermal delivery of INH or RIF without EP in contrast to the oral administrations of drugs. EP can effectively enhance the skin permeability of INH and RIF in patients with tuberculous lymphadenitis. The increase in drug concentrations in the lesions could help eradication of the germs; shorten the treatment course and increase the cure rate of patients with tuberculous lymphadenitis. PMID:26669820

  19. 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.

  20. Blood compatibility assessment of polymers used in drug eluting stent coatings.

    Science.gov (United States)

    Szott, Luisa Mayorga; Irvin, Colleen A; Trollsas, Mikael; Hossainy, Syed; Ratner, Buddy D

    2016-06-01

    Differences in thrombosis rates have been observed clinically between different drug eluting stents. Such differences have been attributed to numerous factors, including stent design, injury created by the catheter delivery system, coating application technologies, and the degree of thrombogenicity of the polymer. The relative contributions of these factors are generally unknown. This work focuses on understanding the thrombogenicity of the polymer by examining mechanistic interactions with proteins, human platelets, and human monocytes of a number of polymers used in drug eluting stent coatings, in vitro. The importance for blood interactions of adsorbed albumin and the retention of albumin was suggested by the data. Microscopic imaging and immunostaining enhanced the interpretation of results from the lactate dehydrogenase cell counting assay and provided insight into platelet interactions, total quantification, and morphometry. In particular, highly spread platelets may be surface-passivating, possibly inhibiting ongoing thrombotic events. In many of the assays used here, poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) showed a differentiated protein deposition pattern that may contribute to the explanation of the consistently thromboresistant blood-materials interaction for fluororpolymers cited in literature. These results are supportive of one of several possible factors contributing to the good thromboresistant clinical safety performance of PVDF-HFP coated drug eluting stents. PMID:27083991

  1. Assessment of antimicrobial drug residues in beef in Abuja, the Federal Capital Territory, Nigeria.

    Science.gov (United States)

    Omeiza, Gabriel K; Ajayi, Itopa E; Ode, Okwoche J

    2012-01-01

    Drugs administered to food-producing animals close to the time of slaughter often result in prohibited antimicrobial residues in the animal tissues at slaughter. Evidence based on the Premi® test confirmed the occurrence of antimicrobial drug residues in 89.3% of kidney and urine samples from cattle slaughtered within Abuja town where the residents rely heavily on beef as a source of protein. The administration of antibiotics close to the time of slaughter by marketers/herd owners and transporters was found to be significantly (p<0.05) higher when compared with butchers and abattoir workers. The practice of administering antibiotics to animals close to the time of slaughter was believed to be profit-motivated. The research suggests that awareness campaigns amongst the stakeholders, the enactment of appropriate laws for the control of antibiotic use and the empowerment of veterinary public health practitioners in food regulatory agencies as some of the strategies which may positively reduce the risk of antimicrobial drug residues in food animals in Nigeria. PMID:23038074

  2. 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

  3. 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.

  4. Structural characterization and effect on anti-angiogenic activity of a fucoidan from Sargassum fusiforme.

    Science.gov (United States)

    Cong, Qifei; Chen, Huanjun; Liao, Wenfeng; Xiao, Fei; Wang, Peipei; Qin, Yi; Dong, Qun; Ding, Kan

    2016-01-20

    A fucoidan FP08S2 was isolated from the boiling-water extract of Sargassum fusiforme, purified by CaCl2 precipitation and chromatography on DEAE-cellulose and Sephacryl S-300. FP08S2 contained fucose, xylose, galactose, mannose, glucuronic acid, and 20.8% sulfate. The sulfate groups were attached to diverse positions of fucose, xylose, mannose, and galactose residues. The backbone of FP08S2 consisted of alternate 1,2-linked α-D-Manp and 1,4-linked β-D-GlcpA. Sugar composition analysis and ESI-MS revealed that the oligosaccharides from branches contained fucose, xylose, galactose, glucuronic acid and sulfate. FP08S2 could significantly inhibit tube formation and migration of human microvascular endothelial cells (HMEC-1) dose-dependently. These results suggested that the fucoidan FP08S2 from brown seaweeds S. fusiforme could be a potent anti-angiogenic agent. PMID:26572427

  5. 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.

  6. Diterpenoids from the roots of Croton crassifolius and their anti-angiogenic activity.

    Science.gov (United States)

    Wang, Jia-Jian; Chung, Hau Yin; Zhang, Yu-Bo; Li, Guo-Qiang; Li, Yao-Lan; Huang, Wei-Huan; Wang, Guo-Cai

    2016-02-01

    Six diterpenoids [crassifolin J, K, L, M, N and O] along with eleven known ones were isolated from the supercritical fluid extract (SFE) of the roots of Croton crassifolius (Euphorbiaceae). Their structures were elucidated using spectroscopic methods (IR, UV, HRESIMS, 1D and 2D NMR). The structure and stereochemistry of crassifolin J was confirmed by single-crystal X-ray diffraction analysis, and the absolute configurations of crassifolin K-M were determined by CD spectra. Twenty-three diterpenoids from this plant were screened for their anti-angiogenic activity using a wild-type zebrafish in vivo model. Four of the known compounds were active, of which penduliflaworosin possessed the best activity relative to the positive control (SU5416). Further study demonstrated that penduliflaworosin could inhibit vessel formation on Tg(fli1a:EGFP)y1-type zebrafish embryos. PMID:26725185

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

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Shuaiyu [Food Biotechnology, University of Science and Technology, 113 Gwahangno, Yuseong-gu, Daejeon 305-333 (Korea, Republic of); Korea Food Research Institute, 516 Baekhyun-dong, Bundang-gu, Songnam, Kyungki-do 463-746 (Korea, Republic of); Yoon, Yeo Cho; Sung, Mi-Jeong; Hur, Haeng-Jeon [Korea Food Research Institute, 516 Baekhyun-dong, Bundang-gu, Songnam, Kyungki-do 463-746 (Korea, Republic of); Park, Jae-Ho, E-mail: jaehoparkmail@gmail.com [Korea Food Research Institute, 516 Baekhyun-dong, Bundang-gu, Songnam, Kyungki-do 463-746 (Korea, Republic of)

    2012-05-11

    Highlights: Black-Right-Pointing-Pointer Cafestol inhibits tube formation and migration of VEGF-stimulated HUVEC. Black-Right-Pointing-Pointer Cafestol inhibits phosphorylation of FAK and Akt. Black-Right-Pointing-Pointer 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.

  8. The AEROPATH project targeting Pseudomonas aeruginosa: crystallographic studies for assessment of potential targets in early-stage drug discovery

    International Nuclear Information System (INIS)

    A focused strategy has been directed towards the structural characterization of selected proteins from the bacterial pathogen P. aeruginosa. The objective is to exploit the resulting structural data, in combination with ligand-binding studies, and to assess the potential of these proteins for early-stage antimicrobial drug discovery. Bacterial infections are increasingly difficult to treat owing to the spread of antibiotic resistance. A major concern is Gram-negative bacteria, for which the discovery of new antimicrobial drugs has been particularly scarce. In an effort to accelerate early steps in drug discovery, the EU-funded AEROPATH project aims to identify novel targets in the opportunistic pathogen Pseudomonas aeruginosa by applying a multidisciplinary approach encompassing target validation, structural characterization, assay development and hit identification from small-molecule libraries. Here, the strategies used for target selection are described and progress in protein production and structure analysis is reported. Of the 102 selected targets, 84 could be produced in soluble form and the de novo structures of 39 proteins have been determined. The crystal structures of eight of these targets, ranging from hypothetical unknown proteins to metabolic enzymes from different functional classes (PA1645, PA1648, PA2169, PA3770, PA4098, PA4485, PA4992 and PA5259), are reported here. The structural information is expected to provide a firm basis for the improvement of hit compounds identified from fragment-based and high-throughput screening campaigns

  9. Assessment of drug hypersensitivity with non-irritating concentrations of antibacterial agents for allergic skin tests: a review

    Directory of Open Access Journals (Sweden)

    Pritam Biswas

    2014-08-01

    Full Text Available Hypersensitivity reactions to antibiotics are common with a prevalence of 6-10% of all adverse reactions. There is a lack of guidelines and standardization of skin tests for the screening of hypersensitivity to all antibiotics, in terms of the methodology, dose and time of evaluation of the tests. Literature from Europe and America suggests the use of non-irritating concentration (NIC of antibiotics for skin testing such as intra dermal test (IDT, skin prick test (SPT. These are concentrations at which the drug is unlikely to produce irritation by virtue of its chemical nature resulting in false positive reactions. These concentrations have been validated by trials in their populations. Due to the increase of antibiotic resistance in our country, declaring a patient allergic to a specific class of antibiotics based on positive skin tests can further narrow the therapeutic armory. These individuals have an increased incidence of infections with resistant organisms as well as increased cost of hospitalization. This is due to the use of alternative broad spectrum antibiotics. Therefore, there is a need for a standardized protocol for the use of skin tests in screening of hypersensitivity, with validated NIC of all antibacterial agents. The aim of this article is to review literature of protocols for assessment of drug hypersensitivity with NIC of antibacterial drugs for SPT, IDT and also establish the need for research in this area in our country. [Int J Basic Clin Pharmacol 2014; 3(4.000: 586-590

  10. Anti-angiogenic activities of Cnidium officinale Makino and Tabanus bovinus.

    Science.gov (United States)

    Kwak, Dong Hoon; Kim, Jin Kyeoung; Kim, Ji Yeoun; Jeong, Heun Young; Keum, Kyung Soo; Han, Sun Hee; Rho, Young Il; Woo, Won Hong; Jung, Kyu Yong; Choi, Bong Kyu; Choo, Young Kug

    2002-08-01

    This study investigated the anti-angiogenic activities of Cnidium officinale Makino and Tabanus bovinus by using cultured glomerular capillary endothelial cells (GECs), chorioallantoic membrane (CAM) and rat cornea. Treatment of GECs with several concentrations (5-50 microg/ml) of C. officinale Makino and T. bovinus extracts for 24 h inhibited angiotensin II (10(-8) M)-induced increases of [3H]thymidine uptake and cell numbers in a concentration-dependent manner. The extent of inhibitory rate of [3H]thymidine incorporation by C. officinale Makino and T. bovinus at 50 microg/ml was a similar to that by 10(-5) M of retinoic acid. Herbal extracts also conspicuously inhibited the neovascularization. In contrast to the normal branching of vascular vessels, blood vessel patterns in CAMs treated with extracts (50 microg per egg) of C. officinale Makino and T. bovinus were ran parallel to each other without much branching. Moreover, oral administration of herbal extracts (20 mg/kg per day) for 4 weeks significantly inhibited the rat corneal neovascularization induced by suture, and the length of blood vessels in herbal medicine-treated rat cornea was conspicuously lower than that in control animals. A similar inhibitory effect to these was also observed in the rat cornea treated with thalidomide (200 mg/kg per day). These findings indicate that the anti-angiogenic properties of C. officinale Makino and T. bovinus may be one of the pharmacological mechanisms underlying the anti-tumor and anti-metastatic activities of herbal extracts tested in this study. PMID:12127239

  11. Anti-angiogenic activities of CRBGP from buccal glands of lampreys (Lampetra japonica).

    Science.gov (United States)

    Jiang, Qi; Liu, Yu; Duan, Dandan; Gou, Meng; Wang, Hao; Wang, Jihong; Li, Qingwei; Xiao, Rong

    2016-04-01

    Cysteine-rich secretory proteins (CRISPs), characterized by 16 conserved cysteines, are distributed in a wide range of organisms, such as secernenteas, amphibians, reptiles and mammals. In the previous studies, a novel CRISP family member (cysteine-rich buccal gland protein, CRBGP) was separated from the buccal gland of lampreys (Lampetra japonica, L. japonica). Lamprey CRBGP could not only suppress depolarization-induced contraction of rat tail arterial smooth muscle, but also block voltage-gated sodium channels (VGSCs). In the present study, the anti-angiogenic activities of lamprey CRBGP were investigated using endothelial cells and chick chorioallantoic membrane (CAM) models. In vitro assays, lamprey CRBGP is able to induce human umbilical vein endothelial cells (HUVECs) apoptosis by disturbing the calcium homeostasis and mitochondria functions. In addition, lamprey CRBGP could inhibit proliferation, adhesion, migration, invasion and tube formation of HUVECs by affecting the organization of F-actin and expression level of matrix metallo-proteinase 2 (MMP-2), matrix metallo-proteinase 9 (MMP-9) and vascular endothelial growth factor A (VEGFA) which are related to angiogenesis. In vivo assays, lamprey CRBGP could suppress the blood vessel formation in CAM models. Therefore, lamprey CRBGP is an important protein present in the buccal gland of lampreys and might help lampreys suppress the contraction of blood vessels, nociceptive responses and wound healing of host fishes during their feeding time. In addition, lamprey CRBGP might have the potential to act as an effective anti-angiogenic factor for the treatment of abnormal angiogenesis induced diseases. PMID:26616010

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

    Institute of Scientific and Technical Information of China (English)

    Maushmi Shailesh Kumar; Sukanya Gopalkrishnan

    2014-01-01

    Objective: To test three marine sponges Halichondria glabrata Keller, 1891; Spirastrellapachyspira (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.

  13. Antitumor effect and antiangiogenic potential of the mTOR inhibitor temsirolimus against malignant pleural mesothelioma.

    Science.gov (United States)

    Moriya, Makio; Yamada, Tadaaki; Tamura, Masaya; Ishikawa, Daisuke; Hoda, Mir Alireza; Matsumoto, Isao; Klepetko, Walter; Oda, Makoto; Yano, Seiji; Watanabe, Go

    2014-03-01

    The mTOR inhibitor temsirolimus has antitumor and antiangiogenic activity against several carcinomas, yet few reports document the efficacy of temsirolimus against malignant pleural mesothelioma (MPM). Therefore, we evaluated the efficacy of temsirolimus and the antiangiogenic effect of temsirolimus in the treatment of MPM. We examined the efficacy of temsirolimus alone and the efficacy of the combination of temsirolimus and cisplatin or pemetrexed against four MPM cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The effect of temsirolimus on the production of proangiogenic cytokines by MPM cell lines was examined by enzyme-linked immunosorbent assay (ELISA). Expression of mTOR and proangiogenic cytokines in clinical specimens from MPM patients was determined by immunohistochemistry. Temsirolimus inhibited cell viability and suppressed cell proliferation of all MPM cell lines. Combined treatment with temsirolimus and cisplatin inhibited the viability of all MPM cell lines more effectively than temsirolimus alone. Temsirolimus strongly inhibited the phosphorylation of p70s6k, a downstream molecule of mTOR, in all MPM cell lines and led to an increase in the levels of cleaved caspase-3 in the H226 and Y-meso14 cells. Temsirolimus also inhibited the production of vascular endothelial growth factor (VEGF) and platelet-derived growth factor-AA (PDGF-AA). Phosphorylated mTOR and high expression of VEGF and PDGF were detected in 2 and 3, respectively, out of the 5 MPM specimens. These results suggest that temsirolimus has activity against MPM cells by inhibition of cell proliferation and angiogenesis, and may be beneficial for a subset of MPM patients with high mTOR expression. PMID:24378576

  14. 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.

  15. 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

  16. 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

  17. 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. PMID

  18. An integrated approach to improved toxicity prediction for the safety assessment during preclinical drug development using Hep G2 cells.

    Science.gov (United States)

    Noor, Fozia; Niklas, Jens; Müller-Vieira, Ursula; Heinzle, Elmar

    2009-06-01

    Efficient and accurate safety assessment of compounds is extremely important in the preclinical development of drugs especially when hepatotoxicity is in question. Multiparameter and time resolved assays are expected to greatly improve the prediction of toxicity by assessing complex mechanisms of toxicity. An integrated approach is presented in which Hep G2 cells and primary rat hepatocytes are compared in frequently used cytotoxicity assays for parent compound toxicity. The interassay variability was determined. The cytotoxicity assays were also compared with a reliable alternative time resolved respirometric assay. The set of training compounds consisted of well known hepatotoxins; amiodarone, carbamazepine, clozapine, diclofenac, tacrine, troglitazone and verapamil. The sensitivity of both cell systems in each tested assay was determined. Results show that careful selection of assay parameters and inclusion of a kinetic time resolved assay improves prediction for non-metabolism mediated toxicity using Hep G2 cells as indicated by a sensitivity ratio of 1. The drugs with EC(50) values 100 microM or lower were considered toxic. The difference in the sensitivity of the two cell systems to carbamazepine which causes toxicity via reactive metabolites emphasizes the importance of human cell based in-vitro assays. Using the described system, primary rat hepatocytes do not offer advantage over the Hep G2 cells in parent compound toxicity evaluation. Moreover, respiration method is non invasive, highly sensitive and allows following the time course of toxicity. Respiration assay could serve as early indicator of changes that subsequently lead to toxicity. PMID:19332084

  19. An integrated approach to improved toxicity prediction for the safety assessment during preclinical drug development using Hep G2 cells

    International Nuclear Information System (INIS)

    Efficient and accurate safety assessment of compounds is extremely important in the preclinical development of drugs especially when hepatotoxicty is in question. Multiparameter and time resolved assays are expected to greatly improve the prediction of toxicity by assessing complex mechanisms of toxicity. An integrated approach is presented in which Hep G2 cells and primary rat hepatocytes are compared in frequently used cytotoxicity assays for parent compound toxicity. The interassay variability was determined. The cytotoxicity assays were also compared with a reliable alternative time resolved respirometric assay. The set of training compounds consisted of well known hepatotoxins; amiodarone, carbamazepine, clozapine, diclofenac, tacrine, troglitazone and verapamil. The sensitivity of both cell systems in each tested assay was determined. Results show that careful selection of assay parameters and inclusion of a kinetic time resolved assay improves prediction for non-metabolism mediated toxicity using Hep G2 cells as indicated by a sensitivity ratio of 1. The drugs with EC50 values 100 μM or lower were considered toxic. The difference in the sensitivity of the two cell systems to carbamazepine which causes toxicity via reactive metabolites emphasizes the importance of human cell based in-vitro assays. Using the described system, primary rat hepatocytes do not offer advantage over the Hep G2 cells in parent compound toxicity evaluation. Moreover, respiration method is non invasive, highly sensitive and allows following the time course of toxicity. Respiration assay could serve as early indicator of changes that subsequently lead to toxicity.

  20. Bcl-2 Targeted Structural Based Computer Aided Drug Design (CAAD For Therapeutic Assessment of Ricin in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Meghraj Singh Baghel

    2015-03-01

    Full Text Available Cancer is referred as uncontrolled growth of abnormal cell mass. Out of the several types of cancer, prostate cancer (PC has become a major public health problem in men worldwide. Bcl-2 and p27 proteins are important regulatory molecules of cell cycle. Failure of cell cycle regulation leads to uncontrolled cell proliferation and causes cancer. For designing an effective structural based targeted drug, the assessment of protein-protein and protein-ligand interaction is indispensable. Therefore for treatment of PC, we selected a ribosome inactivating protein, Ricin, for assessment of its therapeutic nature. In the present work through CLUSTAL-W phylogenetic analysis, we found that Bcl-2 protein was found more conserved than p27. Further Bcl-2 was selected as target molecule for docking study with Ricin protein and other chemically synthetic inhibitor molecules i.e. 2-difluoromethylornithine (DFMO and Sarcosine, as lead molecule. Through HEX5.1 docking software docking was performed between targeted receptor and lead molecules. Energy maximum (Emax= -93.12 and energy minimum (Emin= -163.07 was observed for docking complex of optimised and energy minimised structure of Bcl-2 receptor with Ricin, which in turn shows that it is highly stable interaction. On the other hand, for synthetic inhibitors, we found energy maximum (DFMO; Emax= -77.17, Emin= -117.83 and Sarcosine; Emax= -72.23, Emin= -103.00 and energy minimum, which are significant more as compared to Ricin docking complex. Due to ricin docking complex having less energies shows stable interaction with Bcl-2. We also observed that Ricin is less toxic (lesser log P value as compared to other molecules by toxicity analysis by ADME/TOX server. These evidences show this Ricin could be better drug for PC. Further results are needed to validate by in vitro and in vivo study to make proper elucidation of drug for better PC treatment.

  1. Determination of anti-anxiety and anti-epileptic drugs in hospital effluent and a preliminary risk assessment.

    Science.gov (United States)

    de Almeida, Carlos Alberto A; Brenner, Carla G B; Minetto, Luciane; Mallmann, Carlos A; Martins, Ayrton F

    2013-11-01

    In this study, an analytical methodology was developed for the determination of psycho-active drugs in the treated effluent of the University Hospital at the Federal University of Santa Maria, RS - Brazil. Samples were collected from point A (Emergency) and point B (General effluent). The adopted methodology included a pre-concentration procedure involving the use of solid phase extraction and determination by liquid chromatography coupled to mass spectrometry. The limit of detection for bromazepam and lorazepam was 4.9 ± 1.0 ng L(-1) and, for carbamazepine, clonazepam and diazepam was 6.1 ± 1.5 ng L(-1). The limit of quantification was 30.0 ± 1.1 ng L(-1), for bromazepam, clonazepam and lorazepam; for carbamazepine was 50.0 ± 1.8 ng L(-1) and was 40.0 ± 1.0 ng L(-1) for diazepam. The mean concentrations in the Emergency and General effluent treated currents were as follows: for bromazepam, 195 ± 6 ng L(-1) and 137 ± 7 ng L(-1); for carbamazepine, 590 ± 6 ng L(-1) and 461 ± 10 ng L(-1); for diazepam, 645 ± 1 ng L(-1) and 571 ± 10 ng L(-1); for lorazepam, 96 ± 7 ng L(-1) and 42 ± 4 ng L(-1); and for clonazepam, 134 ± 10 ng L(-1) and 57 ± 10 ng L(-1). A preliminary risk assessment was conducted: carbamazepine and diazepam require considerable attention owing to their environmental toxicity. The occurrence of these psychoactive-drugs and the environmental risks that they pose demonstrated the need for a more efficient treatment system. As far we are aware, there have been no comparable studies to this on the hazards of hospital effluents in Brazil, and very few that have carried out a risk assessment of psycho-active drugs in hospital effluent in general. PMID:24034828

  2. Assessment of Free Drug Concentration in Cyclodextrin Formulations Is Essential to Determine Drug Potency in Functional In Vitro Assays.

    Science.gov (United States)

    Sjögren, Erik; Andersson, Sara; Sundgren-Andersson, Anna K; Halldin, Magnus M; Stålberg, Olle

    2016-09-01

    Cyclodextrins (CD) have the ability to form inclusion complexes with drugs and can be used as excipients to enhance solubility of poorly soluble drugs. To make accurate estimations of the potency of the drug, knowledge of the free drug concentration is important. The aim of this study was to evaluate the applicability of calculated free drug concentrations toward response measurements in a transient receptor potential vanilloid receptor-1 cell-based in vitro assay. This included accounting for potential competitive CD binding of 2 transient receptor potential vanilloid receptor-1 active entities: 1 antagonist, and 1 agonist (capsaicin). Solubility of the CD-drug complexes was measured, and the ligand to substrate affinity in CD formulations was determined according to the phase-solubility technique. The total concentration of antagonist, agonist, CD, and the binding constants between ligands and CD were used to calculate the free concentration of CD ligands. For capsaicin and 2 of the 3 investigated model drugs, the calculated free drug concentration was consistent with the experimental in vitro data while it was overestimated for one of the compounds. In conclusion, the suggested approach can be used to calculate free drug concentration and competitive binding in CD formulations for the application of cell-based drug functionality assays. PMID:27431012

  3. 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.

  4. 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.).

  5. Venous return curve and its application to assessment of the effect of cardiovascular drugs

    International Nuclear Information System (INIS)

    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.)

  6. Coadministration of pioglitazone or glyburide and alogliptin: pharmacokinetic drug interaction assessment in healthy participants.

    Science.gov (United States)

    Karim, Aziz; Laurent, Aziz; Munsaka, Melvin; Wann, Elisabeth; Fleck, Penny; Mekki, Qais

    2009-10-01

    Alogliptin is a dipeptidyl peptidase-4 inhibitor under investigation for treatment of patients with type 2 diabetes mellitus. Potential pharmacokinetic (PK) drug-drug interactions of alogliptin with pioglitazone or glyburide were evaluated in healthy adults. In a randomized, 6-sequence, 3-period crossover study (study I), participants (n = 30 enrolled; n = 27 completed) received monotherapy with pioglitazone 45 mg once daily (qd), alogliptin 25 mg qd, or coadministration of the 2 agents. The 12-day treatment periods were separated by a > or =10-day washout interval. In a nonrandomized, single-sequence study (study II), participants (n = 24 completed) received a single 5-mg dose of the sulfonylurea glyburide, alone and after 8 days of dosing with alogliptin 25 mg qd. Sequential samples of blood (both studies) and urine (first study) were obtained for determination of PK parameters for alogliptin, pioglitazone, their metabolites, and glyburide. Minor changes in PK parameters between combination therapy and monotherapy were obtained but not judged to be clinically relevant. The combination treatments were well tolerated, although glyburide frequently caused hypoglycemia. Most adverse events were of mild intensity and occurred with a frequency similar to that with monotherapy. It is concluded that pioglitazone or glyburide can be administered with alogliptin without dose adjustment to any component of the combination therapy. PMID:19622714

  7. Non-steroidal Anti-inflammatory Drugs Ranking by Nondeterministic Assessments of Probabilistic Type

    Directory of Open Access Journals (Sweden)

    Madalina luiza MOLDOVEANU

    2012-09-01

    Full Text Available With a number of common therapeutic prescriptions, common mechanisms, common pharmacological effects - analgesic, antipyretic and anti-inflammatory (acetaminophen excepted, common side effects (SE (platelet dysfunction, gastritis and peptic ulcers, renal insufficiency in susceptible patients, water and sodium retention, edemas, nephropathies, and only a few different characteristics – different chemical structures, pharmacokinetics and different therapeutic possibility, different selectivities according to cyclooxygenase pathway 1 and 2, non-steroidal anti-inflammatory drugs (NSAIDs similarities are more apparent than differences. Being known that in a correct treatment benefits would exceed risks, the question “Which anti-inflammatory drug presents the lowest risks for a patient?” is just natural. By the Global Risk Method (GRM and the Maximum Risk Method (MRM we have determined the ranking of fourteen NSAIDs considering the risks presented by each particular NSAID. Nimesulide, Etoricoxib and Celecoxib safety level came superior to the other NSAIDs, whereas Etodolac and Indomethacin present an increased side effects risk.

  8. Crushing oral solid drugs: Assessment of nursing practices in health-care facilities in Auvergne, France.

    Science.gov (United States)

    Clauson, Hélène; Rull, Françoise; Thibault, Magali; Ordekyan, Audrey; Tavernier, Jérôme

    2016-08-01

    Iatrogenic harm from crushing oral drugs, a common but hazardous practice, can be largely avoided by following recommendations for good practice. The aims of this study were to evaluate the frequency of tablet crushing and opening capsules in hospitals and to compare the nursing practices with national recommendations. From 46 health facilities in Auvergne, 1110 nurses answered an anonymous self-completed questionnaire between September and November 2014 regarding general medication issues, prescription, preparation and administration of crushed medications. Crushing tablets or opening capsules was reported as a daily practice for 28% (increasing to 67% in geriatric units). While most best practice recommendations were followed by most nurses, scope for improvement remained: pharmacists were rarely contacted, rationales for change of medication formulation were seldom recorded in patients' files and medications were often crushed and administered together, risking drug interactions. Study data were used to inform recommendations for practice improvement. As findings bear similarities to those from other countries, this may be a widespread issue and study recommendations may be widely relevant. Practice will be reviewed again once practice improvement has been completed. PMID:27287304

  9. Assessing the therapeutic efficacy of VEGFR-1-targeted polymer drug conjugates in mouse tumor models.

    Science.gov (United States)

    Shamay, Yosi; Golan, Moran; Tyomkin, Dalia; David, Ayelet

    2016-05-10

    Polymer-drug conjugates that can actively target the tumor vasculature have emerged as an attractive technology for improving the therapeutic efficacy of cytotoxic drugs. We have recently provided, for the first time, in vivo evidence showing the significant advantage of the E-selectin-targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin conjugate, P-(Esbp)-DOX, in inhibiting primary tumor growth and preventing the formation and development of cancer metastases. Here, we describe the design of a vascular endothelial growth factor receptor (VEGFR)-1-targeted HPMA copolymer-DOX conjugate (P-(F56)-DOX) that can actively and simultaneously target different cell types in the tumor microenvironment, such as endothelial cells (ECs), bone marrow-derived cells and many human cancer cells of diverse tumor origin. The VEGFR-1-targeted copolymer was tested for its binding, internalization and in vitro cytotoxicity in ECs (bEnd.3 and cEND cells) and cancer cells (B16-F10, 3LL and HT29). The in vivo anti-cancer activity of P-(F56)-DOX was then tested in two tumor-bearing mice (TBM) models (i.e., primary Lewis lung carcinoma (3LL) tumors and B16-F10 melanoma pulmonary metastases), relative to that of the E-selectin-targeted system (P-(Esbp)-DOX) that solely targets ECs. Our results indicate that the binding and internalization profiles of the VEGFR-1-targeted copolymer were superior towards ECs as compared to cancer cells and correlated well to the level of VEGFR-1 expression in cells. Accordingly, the VEGFR-1-targeted copolymer (P-(F56)-DOX) was more toxic towards bEnd.3 cells than to cancer cells, and exhibited significantly higher cytotoxicity than did the non-targeted control copolymer. P-(F56)-DOX inhibited 3LL tumor growth and significantly prolonged the survival of mice with B16-F10 pulmonary metastases. When compared to a system that actively targets only tumor vascular ECs, P-(F56)-DOX and P-(Esbp)-DOX exhibited comparable efficacy in slowing the

  10. Assessment of cytochrome P450-mediated drug-drug interaction potential of orteronel and exposure changes in patients with renal impairment using physiologically based pharmacokinetic modeling and simulation.

    Science.gov (United States)

    Lu, Chuang; Suri, Ajit; Shyu, Wen Chyi; Prakash, Shimoga

    2014-12-01

    Orteronel is a nonsteroidal, selective inhibitor of 17,20-lyase that was recently in phase 3 clinical development as a treatment for castration-resistant prostate cancer. In humans, the primary clearance route for orteronel is renal excretion. Human liver microsomal studies indicated that orteronel weakly inhibits CYP1A2, 2C8, 2C9 and 2C19, with IC50 values of 17.8, 27.7, 30.8 and 38.8 µm, respectively, whereas orteronel does not inhibit CYP2B6, 2D6 or 3A4/5 (IC50  > 100 µm). Orteronel also does not exhibit time-dependent inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4/5. The results of a static model indicated an [I]/Ki ratio >0.1 for CYP1A2, 2C8, 2C9 and 2C19. Therefore, a physiologically based pharmacokinetic (PBPK) model was developed to assess the potential for drug-drug interactions (DDIs) between orteronel and theophylline, repaglinide, (S)-warfarin and omeprazole, which are sensitive substrates of CYP1A2, 2C8, 2C9 and 2C19, respectively. Simulation of the area under the plasma concentration-time curve (AUC) of these four CYP substrates in the presence and absence of orteronel revealed geometric mean AUC ratios <1.25. Therefore, in accordance with the 2012 US FDA Draft Guidance on DDIs, orteronel can be labeled a 'non-inhibitor' and further clinical DDI evaluation is not required. In PBPK models of moderate and severe renal impairment, the AUC of orteronel was predicted to increase by 52% and 83%, respectively. These results are in agreement with those of a clinical trial in which AUC increases of 38% and 87% were observed in patients with moderate and severe renal impairment, respectively. PMID:25264242

  11. 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?

    OpenAIRE

    Roxanne Lim; Hassan Choudry; Kim Conner; Wikrom Karnsakul

    2014-01-01

    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 ...

  12. 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...... 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 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...

  13. 药品质量管理中风险评估的应用%Drug Quality Management in the Application of Risk Assessment

    Institute of Scientific and Technical Information of China (English)

    何莎

    2015-01-01

    在药品生产与管理工作中,药品质量管理是非常重要的一项管理内容,在开展药品质量管理过程中,进行药品质量管理的风险评估十分重要。目前,药品研发与生产过程中,还存在较多的药品质量管理风险,本文就药品质量管理风险评估的主要内容予以简要分析,对药品质量管理中的风险评估流程予以简单介绍。%In pharmaceutical production and management work,the drug quality management is a management content is very important,in the development of drug quality management process,a very important job is to conduct a risk assessment of drug quality management.The current drug development and production process,there are stil many drug quality risk management,the main content of this paper is the drug quality management risk assessment to the simple analysis,a brief description of the risk assessment process of drug quality management.

  14. Monitoring early tumor response to drug therapy with diffuse optical tomography

    OpenAIRE

    Flexman, Molly L.; Vlachos, Fotios; Kim, Hyun Keol; Sirsi, Shashank R.; Huang, Jianzhong; Hernandez, Sonia L; Johung, Tessa B.; Gander, Jeffrey W; Reichstein, Ari R.; Lampl, Brooke S.; Wang, Antai; Borden, Mark A.; Yamashiro, Darrell J.; Kandel, Jessica J; Hielscher, Andreas H.

    2012-01-01

    Although anti-angiogenic agents have shown promise as cancer therapeutics, their efficacy varies between tumor types and individual patients. Providing patient-specific metrics through rapid noninvasive imaging can help tailor drug treatment by optimizing dosages, timing of drug cycles, and duration of therapy—thereby reducing toxicity and cost and improving patient outcome. Diffuse optical tomography (DOT) is a noninvasive three-dimensional imaging modality that has been shown to capture phy...

  15. 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.

  16. Development and evaluation of an ITS1 "Touchdown" PCR for assessment of drug efficacy against animal African trypanosomosis.

    Science.gov (United States)

    Tran, Thao; Napier, Grant; Rowan, Tim; Cordel, Claudia; Labuschagne, Michel; Delespaux, Vincent; Van Reet, Nick; Erasmus, Heidi; Joubert, Annesca; Büscher, Philippe

    2014-05-28

    Animal African trypanosomoses (AAT) are caused by flagellated protozoa of the Trypanosoma genus and contribute to considerable losses in animal production in Africa, Latin America and South East Asia. Trypanosoma congolense is considered the economically most important species. Drug resistant T. congolense strains present a threat to the control of AAT and have triggered research into discovery of novel trypanocides. In vivo assessment of trypanocidal efficacy relies on monitoring of treated animals with microscopic parasite detection methods. Since these methods have poor sensitivity, follow-up for up to 100 days after treatment is recommended to increase the chance of detecting recurrent parasitaemia waves. Molecular techniques are more amendable to high throughput processing and are generally more sensitive than microscopic detection, thus bearing the potential of shortening the 100-day follow up period. The study presents a "Touchdown" PCR targeting the internal transcribed spacer 1 of the ribosomal DNA (ITS1 TD PCR) that enables detection and discrimination of different Trypanosoma taxa in a single run due to variations in PCR product sizes. The assay achieves analytical sensitivity of 10 parasites per ml of blood for detection of T. congolense savannah type and T. brucei, and 100 parasites per ml of blood for detection of T. vivax in infected mouse blood. The ITS1 TD PCR was evaluated on cattle experimentally infected with T. congolense during an investigational new veterinary trypanocide drug efficacy study. ITS1 TD PCR demonstrated comparable performance to microscopy in verifying trypanocide treatment success, in which parasite DNA became undetectable in cured animals within two days post-treatment. ITS1 TD PCR detected parasite recrudescence three days earlier than microscopy and had a higher positivity rate than microscopy (84.85% versus 57.58%) in 66 specimens of relapsing animals collected after treatments. Therefore, ITS1 TD PCR provides a useful tool

  17. Radioisotopic measurement of gastric emptying in man: a tool for assessing drug effect on gastric motility

    International Nuclear Information System (INIS)

    With the use of radiopharmaceutical preparation it is possible to label selectively the liquid or/and the solid component of the meal. This potentially allows to study the gastric emptying of liquids, of solids or of both simultaneously. However a severe limitation of all water soluble radiopharmaceuticals (usually markers of the liquid component of the meal) is their unpredictable intragastric dilution by secretion. Gastric emptying of solids is more reliably evaluated, because it appears to be largely independent of the volume of intragastric liquid. A radioisotopic technique for the study of gastric emptying of solid meals is described and validated. This technique is proved to be simple inexpensive and reproducible. It has been successfully used to study the effect of new drugs and gastrointestinal peptides on gastric motility in man

  18. Assessment on the prevalence and contributing factors of social drugs utilization among university of Gondar regular undergraduate students, maraki campus, 2013.

    Directory of Open Access Journals (Sweden)

    Desalegn Birara Mamo

    2014-08-01

    Full Text Available Introduction: According to WHO expert committee on drug dependence, drug abuse is persistent or sporadic excessive drug use in consistence with all unrelated to medical practice. Substances of abuse include controlled drugs (under international law and other substance with abuse potential but not subjected to international controls such as alcohol, khat, tobacco, and volatile substances. Social drug utilization has a negative impact on health and economic development of an individual and a country as a whole. Especially youngsters, who are the most productive section of the population, are suffering from the negative consequences of social drugs utilization. The objective of this study is to assess the prevalence and contributing factors of social drugs utilization in university of Gondar regular undergraduate students, Maraki campus, in 2013 academic year. The study design employed was mixed type where quantitative data was emphasized and the qualitative data was used to illustrate the quantitative data. Descriptive survey method using questionnaires, key informant interview and focus group discussion (FGD was conducted to collect the data. Utilization of social drugs among regular students of different departments of Maraki campus of University of Gondar was assessed using cross sectional study in 2013. Results: From a total of 682 respondents the majority 429(62.9% were found as utilizers and the rest 253(37.1% as non utilizers. Regarding contributing factors the result of this study showed that relaxation 125(29.1%, to increase performance 63(14.7%, and peer pressure 53(12.4% were the major contributing factors for students’ social drugs utilization. The prevalence of social drugs utilization was high (62.9%. Although the majority of utilizers started utilization before they join campus, peer pressure had a statistically significant association with social drugs utilization. All the concerned bodies should take part and work hand in hand

  19. Assessing Concordance of Drug-Induced Transcriptional Response in Rodent Liver and Cultured Hepatocytes.

    Science.gov (United States)

    Sutherland, Jeffrey J; Jolly, Robert A; Goldstein, Keith M; Stevens, James L

    2016-03-01

    The effect of drugs, disease and other perturbations on mRNA levels are studied using gene expression microarrays or RNA-seq, with the goal of understanding molecular effects arising from the perturbation. Previous comparisons of reproducibility across laboratories have been limited in scale and focused on a single model. The use of model systems, such as cultured primary cells or cancer cell lines, assumes that mechanistic insights derived from the models would have been observed via in vivo studies. We examined the concordance of compound-induced transcriptional changes using data from several sources: rat liver and rat primary hepatocytes (RPH) from Drug Matrix (DM) and open TG-GATEs (TG), human primary hepatocytes (HPH) from TG, and mouse liver/HepG2 results from the Gene Expression Omnibus (GEO) repository. Gene expression changes for treatments were normalized to controls and analyzed with three methods: 1) gene level for 9071 high expression genes in rat liver, 2) gene set analysis (GSA) using canonical pathways and gene ontology sets, 3) weighted gene co-expression network analysis (WGCNA). Co-expression networks performed better than genes or GSA when comparing treatment effects within rat liver and rat vs. mouse liver. Genes and modules performed similarly at Connectivity Map-style analyses, where success at identifying similar treatments among a collection of reference profiles is the goal. Comparisons between rat liver and RPH, and those between RPH, HPH and HepG2 cells reveal lower concordance for all methods. We observe that the baseline state of untreated cultured cells relative to untreated rat liver shows striking similarity with toxicant-exposed cells in vivo, indicating that gross systems level perturbation in the underlying networks in culture may contribute to the low concordance. PMID:27028627

  20. Assessing Concordance of Drug-Induced Transcriptional Response in Rodent Liver and Cultured Hepatocytes.

    Directory of Open Access Journals (Sweden)

    Jeffrey J Sutherland

    2016-03-01

    Full Text Available The effect of drugs, disease and other perturbations on mRNA levels are studied using gene expression microarrays or RNA-seq, with the goal of understanding molecular effects arising from the perturbation. Previous comparisons of reproducibility across laboratories have been limited in scale and focused on a single model. The use of model systems, such as cultured primary cells or cancer cell lines, assumes that mechanistic insights derived from the models would have been observed via in vivo studies. We examined the concordance of compound-induced transcriptional changes using data from several sources: rat liver and rat primary hepatocytes (RPH from Drug Matrix (DM and open TG-GATEs (TG, human primary hepatocytes (HPH from TG, and mouse liver / HepG2 results from the Gene Expression Omnibus (GEO repository. Gene expression changes for treatments were normalized to controls and analyzed with three methods: 1 gene level for 9071 high expression genes in rat liver, 2 gene set analysis (GSA using canonical pathways and gene ontology sets, 3 weighted gene co-expression network analysis (WGCNA. Co-expression networks performed better than genes or GSA when comparing treatment effects within rat liver and rat vs. mouse liver. Genes and modules performed similarly at Connectivity Map-style analyses, where success at identifying similar treatments among a collection of reference profiles is the goal. Comparisons between rat liver and RPH, and those between RPH, HPH and HepG2 cells reveal lower concordance for all methods. We observe that the baseline state of untreated cultured cells relative to untreated rat liver shows striking similarity with toxicant-exposed cells in vivo, indicating that gross systems level perturbation in the underlying networks in culture may contribute to the low concordance.

  1. Assessing the efficacy of melatonin to curtail benzodiazepine/Z drug abuse.

    Science.gov (United States)

    Cardinali, Daniel P; Golombek, Diego A; Rosenstein, Ruth E; Brusco, Luis I; Vigo, Daniel E

    2016-07-01

    The abuse of benzodiazepine (BZP) and Z drugs has become, due to the tolerance and dependence they produce, a serious public health problem. Thirty years ago, we demonstrated in experimental animals the interaction of melatonin with central BZD receptors, and in 1997 we published the first series of elderly patients who reduced BZP consumption after melatonin treatment. Almost every single neuron in the hypothalamic suprachiasmatic nuclei (SCN), the central pacemaker of the circadian system, contains γ-aminobutyric acid (GABA) and many results in animals point out to a melatonin interaction with GABA-containing neurons. In addition, central-type BZD antagonism, that obliterates GABAA receptor function, blunted most behavioral effects of melatonin including sleep. Melatonin is involved in the regulation of human sleep. This is supported by the temporal relationship between the rise of plasma melatonin levels and sleep propensity as well as by the sleep-promoting effects of exogenously administered melatonin. Both meta-analyses and consensus agreements give support to the therapeutic use of melatonin in sleep disorders. This action is attributed to MT1 and MT2 melatoninergic receptors localized in the SCN, as well as in other brain areas. This review discusses available data on the efficacy of melatonin to curtail chronic BZD/Z drug use in insomnia patients. A major advantage is that melatonin has a very safe profile, it is usually remarkably well tolerated and, in some studies, it has been administered to patients at very large doses and for long periods of time, without any potentiality of abuse. Further studies on this application of melatonin are warranted. PMID:26438969

  2. The anti-angiogenic factor PEDF is present in the human heart and is regulated by anoxia in cardiac myocytes and fibroblasts

    OpenAIRE

    Rychli, Kathrin; Kaun, Christoph; Hohensinner, Philipp J.; Dorfner, Adrian J; Pfaffenberger, Stefan; Niessner, Alexander; Bauer, Michael; Dietl, Wolfgang; Podesser, Bruno K.; Maurer, Gerald; Huber, Kurt; Wojta, Johann

    2009-01-01

    Abstract Cardiac diseases such as myocardial infarction and heart failure are among the leading causes of death in western societies. Therapeutic angiogenesis has been suggested as a concept to combat these diseases. The biology of angiogenic factors expressed in the heart such as vascular endothelial growth factor (VEGF) is well studied, whereas data on anti-angiogenic mediators in the heart are scarce. Here we study the expression of the anti-angiogenic factor pigment epithelium-derived fac...

  3. Epidemiological assessment of eight rounds of mass drug administration for lymphatic filariasis in India: implications for monitoring and evaluation.

    Directory of Open Access Journals (Sweden)

    Subramanian Swaminathan

    Full Text Available BACKGROUND: Monitoring and evaluation guidelines of the programme to eliminate lymphatic filariasis require impact assessments in at least one sentinel and one spot-check site in each implementation unit (IU. Transmission assessment surveys (TAS that assess antigenaemia (Ag in children in IUs that have completed at least five rounds of mass drug administration (MDA each with >65% coverage and with microfilaria (Mf levels 70% of 50,363 population. The corresponding values for Ag were 2.3% and 17.3 Ag-units respectively. Ag-prevalence ranged from 0.7 to 0.9%, in children (2-10 years and 2.7 to 3.0% in adults. Although the Mf-levels in the survey and the sentinel/spot check sites were <1% and Ag-level was <2% in children, we identified 7 "residual" (Mf-prevalence ≥ 1%, irrespective of Ag-status in children and 17 "transmission" (at least one Ag-positive child born during the MDA period hotspots. Antigenaemic persons were clustered both at household and site levels. We identified an Ag-prevalence of ~1% in children (equivalent to 0.4% community Mf-prevalence as a possible threshold value for stopping MDA. CONCLUSIONS/SIGNIFICANCE: Existence of 'hotspots' and spatial clustering of infections in the study area indicate the need for developing good surveillance strategies for detecting 'hotspots', adopting evidence-based sampling strategies and evaluation unit size for TAS.

  4. Counterfeit Drug Penetration into Global Legitimate Medicine Supply Chains: A Global Assessment

    OpenAIRE

    Mackey, Tim K.; Liang, Bryan A.; York, Peter; Kubic, Thomas

    2015-01-01

    Counterfeit medicines are a global public health risk. We assess counterfeit reports involving the legitimate supply chain using 2009–2011 data from the Pharmaceutical Security Institute Counterfeit Incident System (PSI CIS) database that uses both open and nonpublic data sources. Of the 1,510 identified CIS reports involving counterfeits, 27.6% reported China as the source country of the incident/detection. Further, 51.3% were reported as counterfeit but the specific counterfeit subcategory ...

  5. Assessing the performance, practices and roles of drug sellers/dispensers and mothers'/guardians' behaviour for common childhood conditions in Kibaha district, Tanzania.

    Science.gov (United States)

    Nsimba, S E D

    2007-10-01

    In most third world countries, self-medication is common and pharmacies, drug stores and drug shops are important providers of health advice and inexpensive medicines. We used exit interviews to assess drug sellers'/dispensers' roles and consumers' behaviour in Kibaha district, Coast region, Tanzania. Exit interviews with mothers/guardians reported the following childhood conditions treated with or without prescriptions at drug shops: respiratory infections (34%), fever (21%), a combination of diarrhoea, acute respiratory infection (ARI) and fever (14%), diarrhoea alone (13%) and other conditions (17%). The majority of drug sellers/dispensers prescribed or dispensed branded drugs (85%) for most mothers/guardians who visited these drug shops. In addition, antibiotics in total were prescribed for 31% of the mothers/guardians. Of the antibiotics dispensed, 38% were not prescribed by clinicians. In total, oral rehydration salts (ORSs) (3%), antimalarials (sulphadoxine/pyrimethamine) (24%) and antipyretics (11%), were prescribed in 20% but were bought by only 9%; multivitamins (6%), cough mixtures (4%) and other drugs (2%) (antihelminthics, benzylbenzoate emulsions, ear and eye drops) were also purchased from these facilities. Of the diarrhoea case histories presented by simulated clients at the drug shops, only 35% of the bloody diarrhoea scenarios were accurately diagnosed for getting antibiotics as compared with 44% for watery diarrhoea for which the use of antibiotics were wrongly advised (Pdispensers in these drug shops recommended use of ORS less frequently (3%) for a combination of diarrhoea, ARI and fever, and 2% for ARI alone than for watery (29%) and bloody diarrhoea (32%), respectively, for children under five years of age (Pdispense generic drugs so that it costs patients less when they buy drugs in shops. There is a need to increase awareness in recommending the use of ORS for clients to manage watery and bloody diarrhoea, and ARI in children under five

  6. Health technology assessment of cancer drugs in Canada, the United Kingdom and Australia: should the United States take notice?

    Science.gov (United States)

    Dranitsaris, George; Papadopoulos, George

    2015-06-01

    Cancer remains a global problem, with 7.5 million deaths annually, making it responsible for approximately 13% of deaths from all causes. Cancer also becomes more prevalent as the population ages, making it a major health policy challenge for many countries around the world. However, the encouraging news is that the number of cancer-related deaths has stabilized in many countries. At least part of this success may be attributed to improved diagnosis, early intervention strategies and the development of a newer class of anticancer agents, collectively called "targeted therapies", that are more specific in inhibiting key pathways in tumour genesis. However, these newer drugs are associated with a higher cost. As a result, expenditures for agents and cancer in general have been rising rapidly, far beyond the rate of inflation. Some view this as threatening the very health care systems themselves, which are integral to the modern social contract. Different countries have adopted unique mechanisms to facilitate patient access to these newer agents, with the intent of ensuring value for money and sustainability. In this review, cancer care policies and mechanisms for patient access to new drugs will be discussed and compared between select countries. Given its position as a country that allows free pharmaceutical pricing and multi-payer health insurance, the USA will be the reference country and will be compared with the UK, Canada and Australia, three countries with socialized health care systems and active health technology assessment programmes. PMID:25274258

  7. Analysis of drugs of abuse by online SPE-LC high resolution mass spectrometry: communal assessment of consumption.

    Science.gov (United States)

    Heuett, Nubia V; Ramirez, Cesar E; Fernandez, Adolfo; Gardinali, Piero R

    2015-04-01

    An online SPE-LC-HRMS method was developed to monitor the consumption of 18 drugs of abuse (DOAs) including amphetamines, opioids, cocainics, cannabinoids, lysergics, and their corresponding metabolites in a well characterized college campus setting via wastewater analysis. Filtered and diluted (10×) sewage water samples (5 mL inj.) were automatically pre-concentrated and analyzed in 15 min using a Thermo EQuan MAX online SPE system equipped with a HyperSep™ Retain PEP (20×2.1 mm×12 μm) SPE column and a Hypersil Gold™ aQ (150×2.1 mm×3 μm) analytical column. A Q Exactive™ Hybrid Quadrupole-Orbitrap HRMS was used in full scan mode (R=140,000) for positive identification, and quantitation of target compounds. Method detection limits for all analytes ranged between 0.6 and 1.7 ng/L in sewage. A total of 14 DOAs were detected from two different locations (dorms and main college campus) within a one-year period. Most frequently detected drugs throughout the entire study were amphetamine (>96%) and THC's metabolite 11-nor-9-carboxy-Δ-9-THC (>100%) with maximum concentrations of 5956 and 2413 ng/L respectively. Daily doses per 1000 people were determined in order to assess consumption of THC, amphetamine, heroin and cocaine, in both dorms and main campus. PMID:25553546

  8. Human CD34(+) progenitor hematopoiesis in liquid culture for in vitro assessment of drug-induced myelotoxicity.

    Science.gov (United States)

    Guo, Liang; Hamre, John; Davis, Myrtle; Parchment, Ralph E

    2016-03-01

    Utilization of validated CFU-GM assays for myelotoxicity screening is hampered by its labor-intensive and low-throughput nature. Herein, we transformed the defined CFU-GM assay conditions and IC90 endpoint into a higher throughput format. Human CD34(+) hematopoietic progenitors were cultured in a 96-well plate for 14 days with the same cytokine (rhGM-CSF) used in the CFU-GM assay. Expansion and differentiation toward myeloid lineages were manifested by characteristic changes in nuclear and cytoplasmic morphology and by temporal expression patterns of CD34, CD11b and CD13 markers. Inhibition of CD34(+) cell myelopoiesis by 12 anticancer drugs known to induce myelotoxicity in the clinic was quantifiable using either general cytotoxicity endpoints (cell growth area or total nucleus count) or lineage specific readouts (count of cells expressing CD11b and/or CD13). The IC50 and IC90 values derived from the concentration-response curves of 14-day drug exposure in CD34(+) cell culture were highly correlated with those from the international validation study of the CFU-GM assay, demonstrating capability to assess general cytotoxicity, cell proliferation and myelopoiesis simultaneously. These results suggest that this human CD34(+) hematopoietic progenitor cell assay can be used as a direct replacement for the validated, low throughput CFU-GM assay, and could expand application of in vitro myelotoxicity testing. PMID:26616282

  9. ECG in neonate mice with spinal muscular atrophy allows assessment of drug efficacy.

    Science.gov (United States)

    Heier, Christopher R; DiDonato, Christine J

    2015-01-01

    Molecular technologies have produced diverse arrays of animal models for studying genetic diseases and potential therapeutics. Many have neonatal phenotypes. Spinal muscular atrophy (SMA) is a neuromuscular disorder primarily affecting children, and is of great interest in translational medicine. The most widely used SMA mouse models require all phenotyping to be performed in neonates since they do not survive much past weaning. Pre-clinical studies in neonate mice can be hindered by toxicity and a lack of quality phenotyping assays, since many assays are invalid in pups or require subjective scoring with poor inter-rater variability. We find, however, that passive electrocardiography (ECG) recording in conscious 11-day old SMA mice provides sensitive outcome measures, detecting large differences in heart rate, cardiac conduction, and autonomic control resulting from disease. We find significant drug benefits upon treatment with G418, an aminoglycoside targeting the underlying protein deficiency, even in the absence of overt effects on growth and survival. These findings provide several quantitative physiological biomarkers for SMA preclinical studies, and will be of utility to diverse disease models featuring neonatal cardiac arrhythmias. PMID:25553367

  10. Assessment of Substances Abuse in Burn Patients by Using Drug Abuse Screening Test

    Directory of Open Access Journals (Sweden)

    Kobra Gaseminegad

    2012-04-01

    Full Text Available There has been an increase in the frequency of substance abuse among hospitalized burn injury patients. However, few studies have investigated substance abuse among burn patients. This study was aimed to identify the incidence of substance abuse in burn injury patients using the "Drug Abuse Screening Test" (DAST-20. We determined the validity of DAST-20 in spring 2010. Subsequently, this descriptive study was performed on 203 burn injury patients who fit the study's inclusion criteria. We chose a score of 6 as the cutoff and thus achieved a sensitivity of 89% and a specificity of 85% for the DAST-20. During the study, we gathered demographic data, burn features and DAST-20 results for all patients. Patients with scores of 6 or more were considered to be substances abusers. A statistical analysis was conducted using SPSS v16 software. According to the DAST-20 results, 33% of the patients were in the user group. The mean score of DAST-20 was significantly higher among users than it was among nonusers (P<0.05. The level of substance abuse was severe in 77% of users. No significant differences were found among the substances, with the exception of alcohol. Substance abuse is an important risk factor for burn patients. In addition, this study showed that DAST-20 is a valid screening measure for studies on burn patients.

  11. Photochemical fate and eco-genotoxicity assessment of the drug etodolac

    Energy Technology Data Exchange (ETDEWEB)

    Passananti, Monica [Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte S. Angelo, via Cintia, 4, 80126 Napoli (Italy); Clermont Université, Université Blaise Pascal, Institut de Chimie de Clermont-Ferrand (ICCF) UMR 6296, BP 10448, F-63000 Clermont-Ferrand (France); Lavorgna, Margherita [Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università di Napoli, Via Vivaldi 43, I-81100 Caserta (Italy); Iesce, Maria Rosaria, E-mail: iesce@unina.it [Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte S. Angelo, via Cintia, 4, 80126 Napoli (Italy); DellaGreca, Marina [Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte S. Angelo, via Cintia, 4, 80126 Napoli (Italy); Brigante, Marcello [Clermont Université, Université Blaise Pascal, Institut de Chimie de Clermont-Ferrand (ICCF) UMR 6296, BP 10448, F-63000 Clermont-Ferrand (France); Criscuolo, Emma [Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università di Napoli, Via Vivaldi 43, I-81100 Caserta (Italy); Cermola, Flavio [Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte S. Angelo, via Cintia, 4, 80126 Napoli (Italy); Isidori, Marina, E-mail: marina.isidori@unina2.it [Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università di Napoli, Via Vivaldi 43, I-81100 Caserta (Italy)

    2015-06-15

    The photochemical behavior of etodolac was investigated under various irradiation conditions. Kinetic data were obtained after irradiation of 10{sup −4} M aqueous solutions by UVB, UVA and direct exposure to sunlight. The Xenon lamp irradiation was used in order to determine the photodegradation quantum yield under sun-simulated condition (ϕ{sub sun}). The value was determined to be = 0.10 ± 0.01. In order to obtain photoproducts and for mechanistic purposes, experiments were carried out on more concentrated solutions by exposure to sunlight and to UVA and UVB lamps. The drug underwent photooxidative processes following an initial oxygen addition to the double bond of the five membered ring and was mainly converted into a spiro compound and a macrolactam. Ecotoxicity tests were performed on etodolac, its photostable spiro derivative and its sunlight irradiation mixture on two different aquatic trophic levels, plants (algae) and invertebrates (rotifers and crustaceans). Mutagenesis and genotoxicity were detected on bacterial strains. The results showed that only etodolac had long term effects on rotifers although at concentrations far from environmental detection values. A mutagenic and genotoxic potential was found for its derivative. - Highlights: • Photochemical transformation of etodolac occurs in the environment. • Etodolac was slightly toxic in the long term for some aquatic organisms. • A mutagenic and genotoxic potential was found for etodolac photostable derivative.

  12. Photochemical fate and eco-genotoxicity assessment of the drug etodolac

    International Nuclear Information System (INIS)

    The photochemical behavior of etodolac was investigated under various irradiation conditions. Kinetic data were obtained after irradiation of 10−4 M aqueous solutions by UVB, UVA and direct exposure to sunlight. The Xenon lamp irradiation was used in order to determine the photodegradation quantum yield under sun-simulated condition (ϕsun). The value was determined to be = 0.10 ± 0.01. In order to obtain photoproducts and for mechanistic purposes, experiments were carried out on more concentrated solutions by exposure to sunlight and to UVA and UVB lamps. The drug underwent photooxidative processes following an initial oxygen addition to the double bond of the five membered ring and was mainly converted into a spiro compound and a macrolactam. Ecotoxicity tests were performed on etodolac, its photostable spiro derivative and its sunlight irradiation mixture on two different aquatic trophic levels, plants (algae) and invertebrates (rotifers and crustaceans). Mutagenesis and genotoxicity were detected on bacterial strains. The results showed that only etodolac had long term effects on rotifers although at concentrations far from environmental detection values. A mutagenic and genotoxic potential was found for its derivative. - Highlights: • Photochemical transformation of etodolac occurs in the environment. • Etodolac was slightly toxic in the long term for some aquatic organisms. • A mutagenic and genotoxic potential was found for etodolac photostable derivative

  13. Squalamine: a polyvalent drug of the future?

    Science.gov (United States)

    Brunel, Jean Michel; Salmi, Chanaz; Loncle, Celine; Vidal, Nicolas; Letourneux, Yves

    2005-06-01

    The purpose of this mini-review is to summarize and highlight the different advances in our understanding of the antimicrobial and antiangiogenic activity of squalamine, a cationic steroid isolated in 1993 from the dogfish shark Squalus Acanthias. Indeed, squalamine has shown to be useful for the treatment of important diseases such as cancers (lung, ovarian, brain and others), age-related macular degeneration (AMD) and the control of body weight in man. All these results led to a question: could we consider squalamine as a polyvalent drug of the future? PMID:15975047

  14. Evaluación positiva de medicamentos: 1er trimestre 2012 Positive assessment of drugs: 1st trimester 2012

    Directory of Open Access Journals (Sweden)

    M. González Alfonso

    2012-06-01

    Full Text Available Se reseñan los medicamentos ya evaluados por la Agencia Española de Medicamentos y Productos Sanitarios hechos públicos en el 1er trimestre de 2012, y considerados de mayor interés para el profesional sanitario en el ámbito hospitalario. Se trata de opiniones técnicas positivas que son previas a la autorización y puesta en el mercado del medicamento.The drugs assessed by the Spanish Agency for Medicines and Health Products made public in the first trimester of 2012, and considered of interest in hospital healthcare professional, are reviewed. These are positive technical reports prior to the authorization and placing on the market of the product.

  15. Antitumor and anti-angiogenic potentials of isolated crude saponins and various fractions of Rumex hastatus D. Don.

    OpenAIRE

    Ahmad, Sajjad; Ullah, Farhat; Ayaz, Muhammad; Zeb, Anwar; Ullah, Farman; Sadiq, Abdul

    2016-01-01

    Background Cancer, being the foremost challenge of the modern era and the focus of world-class investigators, gargantuan research is in progress worldwide to explore novel therapeutic for its management. The exploitation of natural sources has been proven to be an excellent approach to treat or minify the excessive angiogenesis and proliferation of cells. Similarly, based the ethnomedicinal uses and literature survey, the current study is designed to explore the anti-tumor and anti-angiogenic...

  16. Natural phenolic metabolites with anti-angiogenic properties – a review from the chemical point of view

    OpenAIRE

    Qiu Sun; Jörg Heilmann; Burkhard König

    2015-01-01

    Considering the many secondary natural metabolites available from plants, phenolic compounds play a particularly important role in human health as they occur in significant amounts in many fruits, vegetables and medicinal plants. In this review natural phenolic compounds of plant origin with significant anti-angiogenic properties are discussed. Thirteen representatives from eight different natural or natural-like phenolic subclasses are presented with an emphasis on their synthesis and method...

  17. IGFBP-4 Anti-Angiogenic and Anti-Tumorigenic Effects Are Associated with Anti-Cathepsin B Activity

    OpenAIRE

    María J. Moreno; Marguerite Ball; Marina Rukhlova; Jacqueline Slinn; Denis L'Abbe; Umar Iqbal; Robert Monette; Martin Hagedorn; Maureen D O'Connor-McCourt; Yves Durocher; Stanimirovic, Danica B

    2013-01-01

    Insulin-like growth factor-binding protein 4 (IGFBP-4/IBP-4) has potent IGF-independent anti-angiogenic and antitumorigenic effects. In this study, we demonstrated that these activities are located in the IGFBP-4 C-terminal protein fragment (CIBP-4), a region containing a thyroglobulin type 1 (Tg1) domain. Proteins bearing Tg1 domains have been shown to inhibit cathepsins, lysosomal enzymes involved in basement membrane degradation and implicated in tumor invasion and angiogenesis. In our stu...

  18. IGFBP-4 Anti-Angiogenic and Anti-Tumorigenic Effects Are Associated with Anti-Cathepsin B Activity1

    OpenAIRE

    María J. Moreno; Ball, Marguerite; Rukhlova, Marina; Slinn, Jacqueline; L'Abbe, Denis; Iqbal, Umar; Monette, Robert; Hagedorn, Martin; O'Connor-McCourt, Maureen D.; Durocher, Yves; Stanimirovic, Danica B

    2013-01-01

    Insulin-like growth factor-binding protein 4 (IGFBP-4/IBP-4) has potent IGF-independent anti-angiogenic and antitumorigenic effects. In this study, we demonstrated that these activities are located in the IGFBP-4 C-terminal protein fragment (CIBP-4), a region containing a thyroglobulin type 1 (Tg1) domain. Proteins bearing Tg1 domains have been shown to inhibit cathepsins, lysosomal enzymes involved in basement membrane degradation and implicated in tumor invasion and angiogenesis. In our stu...

  19. Growth-Inhibitory and Antiangiogenic Activity of the MEK Inhibitor PD0325901 in Malignant Melanoma with or without BRAF Mutations

    OpenAIRE

    Ludovica Ciuffreda; Donatella Del Bufalo; Marianna Desideri; Cristina Di Sanza; Antonella Stoppacciaro; Maria Rosaria Ricciardi; Sabina Chiaretti; Simona Tavolaro; Barbara Benassi; Alfonso Bellacosa; Robin Foà; Agostino Tafuri; Francesco Cognetti; Andrea Anichini; Gabriella Zupi

    2009-01-01

    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 leas...

  20. 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

  1. The role of semaphorin 4D as a potential biomarker for antiangiogenic therapy in colorectal cancer

    Science.gov (United States)

    Ding, Xiaojie; Qiu, Lijuan; Zhang, Lijuan; Xi, Juemin; Li, Duo; Huang, Xinwei; Zhao, Yujiao; Wang, Xiaodang; Sun, Qiangming

    2016-01-01

    Background 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 anti-angiogenic 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 expression level varies among these cell lines. HCT-116 showed the lowest VEGF level, while Caco-2 showed the maximum VEGF level. In vitro migration results show that regardless of cell type and VEGF background, Sema4D showed an enhanced in vitro proangiogenic effect to induce the migration of human umbilical vein endothelial cells. Finally, in vivo tumor angiogenic assays demonstrated that Sema4D alone can elicit a significant angiogenic response to promote tumor growth independently of VEGF. Conclusion Targeting Sema4D might serve as a parallel option for antiangiogenic therapy for CRC

  2. Antiangiogenic activity of xanthomicrol and calycopterin, two polymethoxylated hydroxyflavones in both in vitro and ex vivo models.

    Science.gov (United States)

    Abbaszadeh, Hassan; Ebrahimi, Soltan Ahmad; Akhavan, Maziar Mohammad

    2014-11-01

    Our previous studies had shown xanthomicrol and calycopterin, two plant-derived flavonoids, to have selective antiproliferative activity against some malignant cell lines. The present study is focused on the investigation of antiangiogenic potential of these two flavonoids, using in vitro and ex vivo models. Xanthomicrol and calycopterin were found to have potent inhibitory effects on microvessel outgrowth in the rat aortic ring assay. Xanthomicrol was able to completely block microvessel sprouting at 10 µg/mL, and calycopterin suppressed microvessel outgrowth by 89% at 5 µg/mL. Suramin and thalidomide, used at 20 µg/mL as positive controls, inhibited microvessel formation by 23% and 64%, respectively. The flavones also inhibited endothelial cell tube formation and human umbilical vein endothelial cell proliferation at 0.5, 5, and 10 µg/mL. In order to delineate the underlying mechanisms of antiangiogenic activity of these flavones, we investigated the influences of xanthomicrol and calycopterin on expression of vascular endothelial growth factor (VEGF) and basic-fibroblast growth factor (b-FGF) in endothelial cells. These flavones were able to inhibit VEGF expression at 0.5, 5, and 10 µg/mL, but they had little or no effect on b-FGF expression. These findings suggest that xanthomicrol and calycopterin possess potent antiangiogenic activities, which may be due to their inhibitory influences on VEGF expression. PMID:24895220

  3. A novel QSAR model of Salmonella mutagenicity and its application in the safety assessment of drug impurities

    Energy Technology Data Exchange (ETDEWEB)

    Valencia, Antoni; Prous, Josep; Mora, Oscar [Prous Institute for Biomedical Research, Rambla de Catalunya, 135, 3-2, Barcelona 08008 (Spain); Sadrieh, Nakissa [Office of Pharmaceutical Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993-0002 (United States); Valerio, Luis G., E-mail: luis.valerio@fda.hhs.gov [Office of Pharmaceutical Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993-0002 (United States)

    2013-12-15

    As indicated in ICH M7 draft guidance, in silico predictive tools including statistically-based QSARs and expert analysis may be used as a computational assessment for bacterial mutagenicity for the qualification of impurities in pharmaceuticals. To address this need, we developed and validated a QSAR model to predict Salmonella t. mutagenicity (Ames assay outcome) of pharmaceutical impurities using Prous Institute's Symmetry℠, a new in silico solution for drug discovery and toxicity screening, and the Mold2 molecular descriptor package (FDA/NCTR). Data was sourced from public benchmark databases with known Ames assay mutagenicity outcomes for 7300 chemicals (57% mutagens). Of these data, 90% was used to train the model and the remaining 10% was set aside as a holdout set for validation. The model's applicability to drug impurities was tested using a FDA/CDER database of 951 structures, of which 94% were found within the model's applicability domain. The predictive performance of the model is acceptable for supporting regulatory decision-making with 84 ± 1% sensitivity, 81 ± 1% specificity, 83 ± 1% concordance and 79 ± 1% negative predictivity based on internal cross-validation, while the holdout dataset yielded 83% sensitivity, 77% specificity, 80% concordance and 78% negative predictivity. Given the importance of having confidence in negative predictions, an additional external validation of the model was also carried out, using marketed drugs known to be Ames-negative, and obtained 98% coverage and 81% specificity. Additionally, Ames mutagenicity data from FDA/CFSAN was used to create another data set of 1535 chemicals for external validation of the model, yielding 98% coverage, 73% sensitivity, 86% specificity, 81% concordance and 84% negative predictivity. - Highlights: • A new in silico QSAR model to predict Ames mutagenicity is described. • The model is extensively validated with chemicals from the FDA and the public domain.

  4. A novel QSAR model of Salmonella mutagenicity and its application in the safety assessment of drug impurities

    International Nuclear Information System (INIS)

    As indicated in ICH M7 draft guidance, in silico predictive tools including statistically-based QSARs and expert analysis may be used as a computational assessment for bacterial mutagenicity for the qualification of impurities in pharmaceuticals. To address this need, we developed and validated a QSAR model to predict Salmonella t. mutagenicity (Ames assay outcome) of pharmaceutical impurities using Prous Institute's Symmetry℠, a new in silico solution for drug discovery and toxicity screening, and the Mold2 molecular descriptor package (FDA/NCTR). Data was sourced from public benchmark databases with known Ames assay mutagenicity outcomes for 7300 chemicals (57% mutagens). Of these data, 90% was used to train the model and the remaining 10% was set aside as a holdout set for validation. The model's applicability to drug impurities was tested using a FDA/CDER database of 951 structures, of which 94% were found within the model's applicability domain. The predictive performance of the model is acceptable for supporting regulatory decision-making with 84 ± 1% sensitivity, 81 ± 1% specificity, 83 ± 1% concordance and 79 ± 1% negative predictivity based on internal cross-validation, while the holdout dataset yielded 83% sensitivity, 77% specificity, 80% concordance and 78% negative predictivity. Given the importance of having confidence in negative predictions, an additional external validation of the model was also carried out, using marketed drugs known to be Ames-negative, and obtained 98% coverage and 81% specificity. Additionally, Ames mutagenicity data from FDA/CFSAN was used to create another data set of 1535 chemicals for external validation of the model, yielding 98% coverage, 73% sensitivity, 86% specificity, 81% concordance and 84% negative predictivity. - Highlights: • A new in silico QSAR model to predict Ames mutagenicity is described. • The model is extensively validated with chemicals from the FDA and the public domain. • Validation tests

  5. Thoughts on the current assessment of Polo-like kinase inhibitor drug discovery.

    Science.gov (United States)

    Strebhardt, Klaus; Becker, Sven; Matthess, Yves

    2015-01-01

    The Polo-like kinase 1 (Plk1) plays a key role in regulating a broad spectrum of critical cell cycle events. Plk1 is a marker of cellular proliferation and has prognostic potential in different types of human tumors. In a series of preclinical studies, Plk1 has been validated as a cancer target. This prompted many pharmaceutical companies to develop small-molecule inhibitors targeting the classical ATP-binding site of Plk1 for anticancer drug development. Recently, FDA has granted a Breakthrough Therapy designation to the Plk inhibitor BI 6727 (volasertib), which provided a survival benefit for patients suffering from acute myeloid leukemia. Remarkably, a new generation of Plk1 inhibitors that target the second druggable domain of Plk1, the Polo-box domain, is currently being tested preclinically. Since various ATP-competitive compounds of Plk1 inhibit also the activities of Plk2 and Plk3, which act as tumor suppressors, the roles of closely related Plk-family members in cancer cells need to be considered carefully. In this article, the authors highlight recent insights into the biology of Plks in cancer cells and discuss the progress in the development of small-molecule Plk1 inhibitors. The authors believe that the greatest therapeutic benefit might come through leukemic cells that are in direct contact with the inhibitor in the blood stream. The identification of biomarkers and studies that document Plk activities in treated patients would also be beneficial to better understand the role of Plk inhibition in tumor development and anticancer therapy. PMID:25263688

  6. ASSESSMENT AND EVALUATION OF DRUG INFORMATION SERVICE PROVIDED BY PHARMACY PRACTICE DEPARTMENT BASED ON ENQUIRER’S PERSPECTIVE

    OpenAIRE

    Jeevangi V M; Neelkantreddy Patil; Anand B Geni; Hinchageri SS; Manjunath G; Shantveer H

    2012-01-01

    Drug information service refers to activities carried out by pharmacists in providing any drug related information to healthcare professionals to provide better patient care. Providing drug information is a clinical pharmacy service and delivered as part of the multidisciplinary approach to patient care. Accurate information about safety of drugs is very essential for health care professionals in identifying, preventing and managing Adverse Drug Reactions (ADRs), thereby ensuring safe use of ...

  7. Modern pharmacokinetic-pharmacodynamic techniques to study physiological mechanisms of pharmacokinetic drug-drug interactions and disposition of antibiotics and to assess clinical relevance

    OpenAIRE

    Landersdorfer, Cornelia

    2006-01-01

    There are numerous areas of application for which PKPD models are a valuable tool. We studied dose linearity, bone penetration and drug-drug interactions of antibiotics by PKPD modeling. Knowledge about possible saturation of elimination pathways at therapeutic concentrations is important for studying the probability of successful treatment of dosage regimens via MCS at various doses, other modes of administration, or both. We studied the dose linearity of flucloxacillin and piperacillin. For...

  8. 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.

  9. Toxicity of radiation therapy and anti-angiogenics combination: a case report

    International Nuclear Information System (INIS)

    The combined administration of anti-angiogenic agents (AA) and radiation is being evaluated. No AA has yet received Marketing Authorization in this indication. However, they are widely used in medical oncology and criteria for stopping their administration in case of irradiation have not been defined.We report the case of a 63-year-old man experiencing grade 2 skin toxicity while on radiation treatment and sorafenib (400 mg twice daily) for a metastatic lesion developing between the vastus medialis muscle and the cortical of the mid-diaphysis of the right femur. Toxicity occurred at 21 Gy, for a total dose of 36 Gy (12 fractions of 3 Gy). Cutaneous symptoms rapidly disappeared after treatment discontinuation. Radiotherapy alone was resumed after a few days and the total dose could be delivered, with good tolerance. At 2-month follow-up, the intramuscular lesion had regressed. Several other cases of patients with poor tolerance to the association of AA and radiotherapy have been reported. Further studies of the effectiveness and tolerance of the combination treatment are needed before indications for AA can be extended to other diseases. (authors)

  10. The antiangiogenic compound aeroplysinin-1 induces apoptosis in endothelial cells by activating the mitochondrial pathway.

    Science.gov (United States)

    Martínez-Poveda, Beatriz; Rodríguez-Nieto, Salvador; García-Caballero, Melissa; Medina, Miguel-Ángel; Quesada, Ana R

    2012-09-01

    Aeroplysinin-1 is a brominated metabolite extracted from the marine sponge Aplysina aerophoba that has been previously characterized by our group as a potent antiangiogenic compound in vitro and in vivo. In this work, we provide evidence of a selective induction of apoptosis by aeroplysinin-1 in endothelial cells. Studies on the nuclear morphology of treated cells revealed that aeroplysinin-1 induces chromatin condensation and nuclear fragmentation, and it increases the percentage of cells with sub-diploid DNA content in endothelial, but not in HCT-116, human colon carcinoma and HT-1080 human fibrosarcoma cells. Treatment of endothelial cells with aeroplysinin-1 induces activation of caspases-2, -3, -8 and -9, as well as the cleavage of apoptotic substrates, such as poly (ADP-ribose) polymerase and lamin-A in a caspase-dependent mechanism. Our data indicate a relevant role of the mitochondria in the apoptogenic activity of this compound. The observation that aeroplysinin-1 prevents the phosphorylation of Bad relates to the mitochondria-mediated induction of apoptosis by this compound. PMID:23118719

  11. Anti-angiogenic and anti-inflammatory effects of SERPINA3K on corneal injury.

    Directory of Open Access Journals (Sweden)

    Xiaochen Liu

    Full Text Available SERPINA3K is a member of the serine proteinase inhibitor (SERPIN family. Here we evaluated the therapeutic effects of SERPINA3K on neovascularization and inflammation in a rat cornea alkali burn model that is commonly employed to study corneal wounding. Topical treatment of the injured rat cornea with SERPINA3K (20 µg/eye/day for 7 days significantly decreased the neovascular area, compared with the groups treated with BSA or PBS. The SERPINA3K treatment also ameliorated the corneal inflammation as evaluated by the inflammatory index. Furthermore, SERPINA3K enhanced the recovery of corneal epithelium after the alkali injury. Toward the mechanism of action, SERPINA3K down-regulated the expression of the pro-angiogenic and pro-inflammatory factors, vascular endothelial growth factor and tumor necrosis factor-α and up-regulated the expression of the anti-angiogenic factor, pigment epithelium-derived factor. SERPINA3K specifically inhibited growth of vascular endothelial cells. Meanwhile, SERPINA3K significantly up-regulated the expression of EGFR in the corneal epithelium. These findings suggest that SERPINA3K has therapeutic potential for corneal inflammation and NV.

  12. 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

  13. Odisolane, a Novel Oxolane Derivative, and Antiangiogenic Constituents from the Fruits of Mulberry (Morus alba L.).

    Science.gov (United States)

    Lee, Seoung Rak; Park, Jun Yeon; Yu, Jae Sik; Lee, Sung Ok; Ryu, Ja-Young; Choi, Sang-Zin; Kang, Ki Sung; Yamabe, Noriko; Kim, Ki Hyun

    2016-05-18

    Mulberry, the fruit of Morus alba L., is known as an edible fruit and commonly used in Chinese medicines as a warming agent and as a sedative, tonic, laxative, odontalgic, expectorant, anthelmintic, and emetic. Systemic investigation of the chemical constituents of M. alba fruits led to the identification of a novel oxolane derivative, (R*)-2-((2S*,3R*)-tetrahydro-2-hydroxy-2-methylfuran-3-yl)propanoic acid (1), namely, odisolane, along with five known heterocyclic compounds (2-6). The structure of the new compound was elucidated on the basis of HR-MS, 1D and 2D NMR ((1)H-(1)H COSY, HSQC, HMBC, and NOESY) data analysis. Compound 1 has a novel skeleton that consists of 8 carbon units with an oxolane ring, which until now has never been identified in natural products. The isolated compounds were subjected to several activity tests to verify their biological function. Among them, compounds 1, 3, and 5 significantly inhibited cord formation in HUVECs. The action mechanism of compound 3, which had the strongest antiangiogenic activity, was mediated by decreasing VEGF, p-Akt, and p-ERK protein expression. These results suggest that compounds isolated from M. alba fruits might be beneficial in antiangiogenesis therapy for cancer treatment. PMID:27115720

  14. The carboxyl terminus of VEGF-A is a potential target for anti-angiogenic therapy.

    Science.gov (United States)

    Carter, James G; Gammons, Melissa V R; Damodaran, Gopinath; Churchill, Amanda J; Harper, Steven J; Bates, David O

    2015-01-01

    Anti-VEGF-A therapy has become a mainstay of treatment for ocular neovascularisation and in cancer; however, their effectiveness is not universal, in some cases only benefiting a minority of patients. Anti-VEGF-A therapies bind and block both pro-angiogenic VEGF-Axxx and the partial agonist VEGF-Axxxb isoforms, but their anti-angiogenic benefit only comes about from targeting the pro-angiogenic isoforms. Therefore, antibodies that exclusively target the pro-angiogenic isoforms may be more effective. To determine whether C-terminal-targeted antibodies could inhibit angiogenesis, we generated a polyclonal antibody to the last nine amino acids of VEGF-A165 and tested it in vitro and in vivo. The exon8a polyclonal antibody (Exon8apab) did not bind VEGF-A165b even at greater than 100-fold excess concentration, and dose dependently inhibited VEGF-A165 induced endothelial migration in vitro at concentrations similar to the VEGF-A antibody fragment ranibizumab. Exon8apab can inhibit tumour growth of LS174t cells implanted in vivo and blood vessel growth in the eye in models of age-related macular degeneration, with equal efficacy to non-selective anti-VEGF-A antibodies. It also showed that it was the VEGF-Axxx levels specifically that were upregulated in plasma from patients with proliferative diabetic retinopathy. These results suggest that VEGF-A165-specific antibodies can be therapeutically useful. PMID:25274272

  15. 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 PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSION: 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.

  16. 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.

  17. Comparative evaluation of the antitumor activity of antiangiogenic proteins delivered by gene transfer.

    Science.gov (United States)

    Kuo, C J; Farnebo, F; Yu, E Y; Christofferson, R; Swearingen, R A; Carter, R; von Recum, H A; Yuan, J; Kamihara, J; Flynn, E; D'Amato, R; Folkman, J; Mulligan, R C

    2001-04-10

    Although the systemic administration of a number of different gene products has been shown to result in the inhibition of angiogenesis and tumor growth in different animal tumor models, the relative potency of those gene products has not been studied rigorously. To address this issue, recombinant adenoviruses encoding angiostatin, endostatin, and the ligand-binding ectodomains of the vascular endothelial growth factor receptors Flk1, Flt1, and neuropilin were generated and used to systemically deliver the different gene products in several different preexisting murine tumor models. Single i.v. injections of viruses encoding soluble forms of Flk1 or Flt1 resulted in approximately 80% inhibition of preexisting tumor growth in murine models involving both murine (Lewis lung carcinoma, T241 fibrosarcoma) and human (BxPC3 pancreatic carcinoma) tumors. In contrast, adenoviruses encoding angiostatin, endostatin, or neuropilin were significantly less effective. A strong correlation was observed between the effects of the different viruses on tumor growth and the activity of the viruses in the inhibition of corneal micropocket angiogenesis. These data underscore the need for comparative analyses of different therapeutic approaches that target tumor angiogenesis and provide a rationale for the selection of specific antiangiogenic gene products as lead candidates for use in gene therapy approaches aimed at the treatment of malignant and ocular disorders. PMID:11274374

  18. The Antiangiogenic Compound Aeroplysinin-1 Induces Apoptosis in Endothelial Cells by Activating the Mitochondrial Pathway

    Directory of Open Access Journals (Sweden)

    Beatriz Martínez-Poveda

    2012-09-01

    Full Text Available Aeroplysinin-1 is a brominated metabolite extracted from the marine sponge Aplysina aerophoba that has been previously characterized by our group as a potent antiangiogenic compound in vitro and in vivo. In this work, we provide evidence of a selective induction of apoptosis by aeroplysinin-1 in endothelial cells. Studies on the nuclear morphology of treated cells revealed that aeroplysinin-1 induces chromatin condensation and nuclear fragmentation, and it increases the percentage of cells with sub-diploid DNA content in endothelial, but not in HCT-116, human colon carcinoma and HT-1080 human fibrosarcoma cells. Treatment of endothelial cells with aeroplysinin-1 induces activation of caspases-2, -3, -8 and -9, as well as the cleavage of apoptotic substrates, such as poly (ADP-ribose polymerase and lamin-A in a caspase-dependent mechanism. Our data indicate a relevant role of the mitochondria in the apoptogenic activity of this compound. The observation that aeroplysinin-1 prevents the phosphorylation of Bad relates to the mitochondria-mediated induction of apoptosis by this compound.

  19. Development of HepG2-derived cells expressing cytochrome P450s for assessing metabolism-associated drug-induced liver toxicity.

    Science.gov (United States)

    Xuan, Jiekun; Chen, Si; Ning, Baitang; Tolleson, William H; Guo, Lei

    2016-08-01

    The generation of reactive metabolites from therapeutic agents is one of the major mechanisms of drug-induced liver injury (DILI). In order to evaluate metabolism-related toxicity and improve drug efficacy and safety, we generated a battery of HepG2-derived cell lines that express 14 cytochrome P450s (CYPs) (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5 and 3A7) individually using a lentiviral expression system. The expression/production of a specific CYP in each cell line was confirmed by an increased abundance of the CYP at both mRNA and protein levels. Moreover, the enzymatic activities of representative CYPs in the corresponding cell lines were also measured. Using our CYP-expressed HepG2 cells, the toxicity of three drugs that could induce DILI (amiodarone, chlorpromazine and primaquine) was assessed, and all of them showed altered (increased or decreased) toxicity compared to the toxicity in drug-treated wild-type HepG2 cells. CYP-mediated drug toxicity examined in our cell system is consistent with previous reports, demonstrating the potential of these cells for assessing metabolism-related drug toxicity. This cell system provides a practical in vitro approach for drug metabolism screening and for early detection of drug toxicity. It is also a surrogate enzyme source for the enzymatic characterization of a particular CYP that contributes to drug-induced liver toxicity. PMID:26477383

  20. Dual blockade of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) exhibits potent anti-angiogenic effects.

    Science.gov (United States)

    Li, Dong; Xie, Kun; Zhang, Longzhen; Yao, Xuejing; Li, Hongwen; Xu, Qiaoyu; Wang, Xin; Jiang, Jing; Fang, Jianmin

    2016-07-28

    Both vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF or FGF-2) are potent pro-angiogenic factors and play a critical role in cancer development and progression. Clinical anti-VEGF therapy trials had a major challenge due to upregulated expression of other pro-angiogenic factor, like FGF-2. This study developed a novel chimeric decoy receptor VF-Trap fusion protein to simultaneously block activity of both VEGF and FGF pathways in order to achieve an additive or synergistic anti-tumor effect. Our in vitro data showed that VF-Trap potently blocked proliferation and migration of both VEGF- and FGF-2-induced vascular endothelial cells. In animal models, treatment of xenograft tumors with VF-Trap resulted in significant inhibition of tumor growth compared to blockage of the single molecule, like VEGF or FGF blocker. In addition, VF-Trap was also more potent in inhibition of ocular angiogenesis in a mouse oxygen-induced retinopathy (OIR) model. These data demonstrated the potent anti-angiogenic effects of this novel VF-Trap fusion protein on blockage of VEGF and FGF-2 activity in vitro and in animal models. Further study will assess its effects in clinic as a therapeutic agent for angiogenesis-related disorders, such as cancer and ocular vascular diseases. PMID:27130666

  1. 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.

  2. An integrative pharmacological approach to radio telemetry and blood sampling in pharmaceutical drug discovery and safety assessment

    Directory of Open Access Journals (Sweden)

    Kamendi Harriet W

    2011-01-01

    Full Text Available Abstract Background A successful integration of the automated blood sampling (ABS and telemetry (ABST system is described. The new ABST system facilitates concomitant collection of physiological variables with blood and urine samples for determination of drug concentrations and other biochemical measures in the same rat without handling artifact. Method Integration was achieved by designing a 13 inch circular receiving antenna that operates as a plug-in replacement for the existing pair of DSI's orthogonal antennas which is compatible with the rotating cage and open floor design of the BASi Culex® ABS system. The circular receiving antenna's electrical configuration consists of a pair of electrically orthogonal half-toroids that reinforce reception of a dipole transmitter operating within the coil's interior while reducing both external noise pickup and interference from other adjacent dipole transmitters. Results For validation, measured baclofen concentration (ABST vs. satellite (μM: 69.6 ± 23.8 vs. 76.6 ± 19.5, p = NS and mean arterial pressure (ABST vs. traditional DSI telemetry (mm Hg: 150 ± 5 vs.147 ± 4, p = NS variables were quantitatively and qualitatively similar between rats housed in the ABST system and traditional home cage approaches. Conclusion The ABST system offers unique advantages over traditional between-group study paradigms that include improved data quality and significantly reduced animal use. The superior within-group model facilitates assessment of multiple physiological and biochemical responses to test compounds in the same animal. The ABST also provides opportunities to evaluate temporal relations between parameters and to investigate anomalous outlier events because drug concentrations, physiological and biochemical measures for each animal are available for comparisons.

  3. Assessment of function and clinical utility of alcohol and other drug web sites: An observational, qualitative study

    Directory of Open Access Journals (Sweden)

    Drennan Judy

    2011-05-01

    Full Text Available Abstract Background The increasing popularity and use of the internet makes it an attractive option for providing health information and treatment, including alcohol/other drug use. There is limited research examining how people identify and access information about alcohol or other drug (AOD use online, or how they assess the usefulness of the information presented. This study examined the strategies that individuals used to identify and navigate a range of AOD websites, along with the attitudes concerning presentation and content. Methods Members of the general community in Brisbane and Roma (Queensland, Australia were invited to participate in a 30-minute search of the internet for sites related to AOD use, followed by a focus group discussion. Fifty one subjects participated in the study across nine focus groups. Results Participants spent a maximum of 6.5 minutes on any one website, and less if the user was under 25 years of age. Time spent was as little as 2 minutes if the website was not the first accessed. Participants recommended that AOD-related websites should have an engaging home or index page, which quickly and accurately portrayed the site's objectives, and provided clear site navigation options. Website content should clearly match the title and description of the site that is used by internet search engines. Participants supported the development of a portal for AOD websites, suggesting that it would greatly facilitate access and navigation. Treatment programs delivered online were initially viewed with caution. This appeared to be due to limited understanding of what constituted online treatment, including its potential efficacy. Conclusions A range of recommendations arise from this study regarding the design and development of websites, particularly those related to AOD use. These include prudent use of text and information on any one webpage, the use of graphics and colours, and clear, uncluttered navigation options

  4. The PHACS SMARTT Study: Assessment of the Safety of In Utero Exposure to Antiretroviral Drugs

    Directory of Open Access Journals (Sweden)

    Russell Barrett Van Dyke

    2016-05-01

    Full Text Available The Surveillance Monitoring for ART Toxicities (SMARTT cohort of the Pediatric HIV/AIDS Cohort Study (PHACS includes over 3500 HIV-exposed but uninfected (HEU infants and children at 22 sites in the U.S. including Puerto Rico. The goal of the study is to determine the safety of in utero exposure to antiretrovirals (ARV and to estimate the incidence of adverse events. Domains being assessed include metabolic, growth and development, cardiac, neurological, neurodevelopmental, behavior, language, and hearing. SMARTT employs an innovative trigger-based design as an efficient means to identify and evaluate adverse events. Participants who met a predefined clinical or laboratory threshold (trigger undergo additional evaluations to define their case status. After adjusting for birth cohort and other factors, there was no significant increase in the likelihood of meeting overall case status (case in any domain with exposure to combination ARVs (cARV, any ARV class, or any specific ARV. However, several individual ARVs were significantly associated with case status in individual domains, including zidovudine for a metabolic case, first trimester stavudine for a language case, and didanosine plus stavudine for a neurodevelopmental case. We found an increased rate of preterm birth with first trimester exposure to protease inhibitor-based cARV. Although there was no overall increase in congenital anomalies with first trimester cARV, a significant increase was seen with exposure to atazanavir, ritonavir, and didanosine plus stavudine. Tenofovir exposure was associated with significantly lower mean whole-body bone mineral content in the newborn period and a lower length and head circumference at 1 year of age. With neurodevelopmental testing at 1 year of age, specific ARVs (atazanavir, ritonavir-boosted lopinavir, nelfinavir, and tenofovir were associated with lower performance, although all groups were within the normal range. No ARVs or classes were

  5. The PHACS SMARTT Study: Assessment of the Safety of In Utero Exposure to Antiretroviral Drugs

    Science.gov (United States)

    Van Dyke, Russell B.; Chadwick, Ellen Gould; Hazra, Rohan; Williams, Paige L.; Seage, George R.

    2016-01-01

    The Surveillance Monitoring for ART Toxicities (SMARTT) cohort of the Pediatric HIV/AIDS Cohort Study includes over 3,500 HIV-exposed but uninfected infants and children at 22 sites in the US, including Puerto Rico. The goal of the study is to determine the safety of in utero exposure to antiretrovirals (ARVs) and to estimate the incidence of adverse events. Domains being assessed include metabolic, growth and development, cardiac, neurological, neurodevelopmental (ND), behavior, language, and hearing. SMARTT employs an innovative trigger-based design as an efficient means to identify and evaluate adverse events. Participants who met a predefined clinical or laboratory threshold (trigger) undergo additional evaluations to define their case status. After adjusting for birth cohort and other factors, there was no significant increase in the likelihood of meeting overall case status (case in any domain) with exposure to combination ARVs (cARVs), any ARV class, or any specific ARV. However, several individual ARVs were significantly associated with case status in individual domains, including zidovudine for a metabolic case, first trimester stavudine for a language case, and didanosine plus stavudine for a ND case. We found an increased rate of preterm birth with first trimester exposure to protease inhibitor-based cARV. Although there was no overall increase in congenital anomalies with first trimester cARV, a significant increase was seen with exposure to atazanavir, ritonavir, and didanosine plus stavudine. Tenofovir exposure was associated with significantly lower mean whole-body bone mineral content in the newborn period and a lower length and head circumference at 1 year of age. With ND testing at 1 year of age, specific ARVs (atazanavir, ritonavir-boosted lopinavir, nelfinavir, and tenofovir) were associated with lower performance, although all groups were within the normal range. No ARVs or classes were associated with lower performance between 5 and 13

  6. Post-marketing assessment of the safety of strontium ranelate; a novel case-only approach to the early detection of adverse drug reactions

    OpenAIRE

    Grosso, A.; Douglas, I.; Hingorani, A.; MacAllister, R.; Smeeth, L

    2008-01-01

    AIMSPost licensing, the evaluation of drug safety relies heavily on the collation of sporadic, spontaneous reports on adverse effects. The aim was to assess the potential utility of a more systematic approach to the detection of adverse events that utilizes routinely collected clinical data from a large primary care population.METHODSWe used the UK General Practice Research Database to assess the risk of several recently reported adverse events linked to the use of strontium ranelate for oste...

  7. Drug Interactions of Thalidomide with Midazolam and Cyclosporine A: Heterotropic Cooperativity of Human Cytochrome P450 3A5

    OpenAIRE

    Okada, Yusuke; Murayama, Norie; Yanagida, Chihiro; Shimizu, Makiko; Guengerich, F. Peter; Yamazaki, Hiroshi

    2008-01-01

    There is growing clinical interest of thalidomide because of its immunomodulatory and antiangiogenic properties, despite its teratogenicity. However, little information about thalidomide has been reported regarding its precise effects on drug-metabolizing enzymes. We investigated the effects of thalidomide on cytochrome P450 (P450) enzymes in human liver microsomes to clarify the potential for possible drug interactions. Thalidomide inhibited S-mephenytoin 4′-hydroxyla...

  8. Chemotherapy and anti-angiogenic drugs affect composition and coagulant phenotype of cell-derived vesicles in cancer patients

    NARCIS (Netherlands)

    Kleinjan, A.; Verhoeff, J.; Berckmans, R.; Kunst, P.; Van Doormaal, F.; Di Nisio, M.; Richel, D.; Kamphuisen, P.W.; Büller, H.R.; Nieuwland, R.

    2013-01-01

    Background: The relationship between chemotherapy and circulating microparticles in patients with cancer is complex. First, release of cancer cell-derived microparticles may contribute to resistance of cancer cells to chemotherapy. Second, chemotherapy and angiogenesis inhibiting agents promote a pr

  9. Anti-Angiogenic Drugs in the Treatment of Metastatic Renal Cell Carcinoma:Advances in Clinical Application

    DEFF Research Database (Denmark)

    Nielsen, Ole H; Grimm, Daniela; Wehland, Markus;

    2014-01-01

    The current paradigm in attempting to treat metastatic renal cell carcinoma (mRCC) is a first line treatment with a vascular endothelial growth factor (VEGF) antagonist and second and subsequent treatments with either a vascular endothelial growth factor receptor (VEGFR) or a mTOR (mammalian Targ...

  10. Irradiation-induced angiosarcoma and anti-angiogenic therapy: A therapeutic hope?

    International Nuclear Information System (INIS)

    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

  11. 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

  12. 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

  13. Genome-wide assessment of the carriers involved in the cellular uptake of drugs: a model system in yeast

    Directory of Open Access Journals (Sweden)

    Lanthaler Karin

    2011-10-01

    Full Text Available Abstract Background The uptake of drugs into cells has traditionally been considered to be predominantly via passive diffusion through the bilayer portion of the cell membrane. The recent recognition that drug uptake is mostly carrier-mediated raises the question of which drugs use which carriers. Results To answer this, we have constructed a chemical genomics platform built upon the yeast gene deletion collection, using competition experiments in batch fermenters and robotic automation of cytotoxicity screens, including protection by 'natural' substrates. Using these, we tested 26 different drugs and identified the carriers required for 18 of the drugs to gain entry into yeast cells. Conclusions As well as providing a useful platform technology, these results further substantiate the notion that the cellular uptake of pharmaceutical drugs normally occurs via carrier-mediated transport and indicates that establishing the identity and tissue distribution of such carriers should be a major consideration in the design of safe and effective drugs.

  14. Imaging Biomarker Dynamics in an Intracranial Murine Glioma Study of Radiation and Antiangiogenic Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Caroline, E-mail: caroline.chung@rmp.uhn.on.ca [Department of Radiation Oncology, University Health Network-Princess Margaret Hospital, Toronto, Ontario (Canada); Jalali, Shahrzad [Brain Tumor Research Centre, SickKids Hospital, Toronto, Ontario (Canada); Foltz, Warren [Department of Radiation Oncology, University Health Network-Princess Margaret Hospital, Ontario (Canada); Burrell, Kelly [Brain Tumor Research Centre, SickKids Hospital, Toronto, Ontario (Canada); Wildgoose, Petra; Lindsay, Patricia [Department of Radiation Oncology, University Health Network-Princess Margaret Hospital, Ontario (Canada); Graves, Christian; Camphausen, Kevin [Department of Radiation Oncology, National Cancer Institute, Bethesda, Maryland (United States); Milosevic, Michael; Jaffray, David [Department of Radiation Oncology, University Health Network-Princess Margaret Hospital, Toronto, Ontario (Canada); Zadeh, Gelareh [Neurosurgery, University Health Network-Toronto Western Hospital, Toronto, Ontario (Canada); Ménard, Cynthia [Department of Radiation Oncology, University Health Network-Princess Margaret Hospital, Toronto, Ontario (Canada)

    2013-03-01

    Purpose: There is a growing need for noninvasive biomarkers to guide individualized spatiotemporal delivery of radiation therapy (RT) and antiangiogenic (AA) therapy for brain tumors. This study explored early biomarkers of response to RT and the AA agent sunitinib (SU), in a murine intracranial glioma model, using serial magnetic resonance imaging (MRI). Methods and Materials: Mice with MRI-visible tumors were stratified by tumor size into 4 therapy arms: control, RT, SU, and SU plus RT (SURT). Single-fraction conformal RT was delivered using MRI and on-line cone beam computed tomography (CT) guidance. Serial MR images (T2-weighted, diffusion, dynamic contrast-enhanced and gadolinium-enhanced T1-weighted scans) were acquired biweekly to evaluate tumor volume, apparent diffusion coefficient (ADC), and tumor perfusion and permeability responses (K{sub trans}, K{sub ep}). Results: Mice in all treatment arms survived longer than those in control, with a median survival of 35 days for SURT (P<.0001) and 30 days for RT (P=.009) and SU (P=.01) mice vs 26 days for control mice. At Day 3, ADC rise was greater with RT than without (P=.002). Sunitinib treatment reduced tumor perfusion/permeability values with mean K{sub trans} reduction of 27.6% for SU (P=.04) and 26.3% for SURT (P=.04) mice and mean K{sub ep} reduction of 38.1% for SU (P=.01) and 27.3% for SURT (P=.02) mice. The magnitude of individual mouse ADC responses at Days 3 and 7 correlated with subsequent tumor growth rate R values of −0.878 (P=.002) and −0.80 (P=.01), respectively. Conclusions: Early quantitative changes in diffusion and perfusion MRI measures reflect treatment responses soon after starting therapy and thereby raise the potential for these imaging biomarkers to guide adaptive and potentially individualized therapy approaches in the future.

  15. Change in Pattern of Relapse After Antiangiogenic Therapy in High-Grade Glioma

    International Nuclear Information System (INIS)

    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 (R2 = 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.

  16. A comprehensive assessment of lymphatic filariasis in Sri Lanka six years after cessation of mass drug administration.

    Directory of Open Access Journals (Sweden)

    Ramakrishna U Rao

    Full Text Available The Sri Lankan Anti-Filariasis Campaign conducted 5 rounds of mass drug administration (MDA with diethycarbamazine plus albendazole between 2002 and 2006. We now report results of a comprehensive surveillance program that assessed the lymphatic filariasis (LF situation in Sri Lanka 6 years after cessation of MDA.Transmission assessment surveys (TAS were performed per WHO guidelines in primary school children in 11 evaluation units (EUs in all 8 formerly endemic districts. All EUs easily satisfied WHO criteria for stopping MDA. Comprehensive surveillance was performed in 19 Public Health Inspector (PHI areas (subdistrict health administrative units. The surveillance package included cross-sectional community surveys for microfilaremia (Mf and circulating filarial antigenemia (CFA, school surveys for CFA and anti-filarial antibodies, and collection of Culex mosquitoes with gravid traps for detection of filarial DNA (molecular xenomonitoring, MX. Provisional target rates for interruption of LF transmission were community CFA <2%, antibody in school children <2%, and filarial DNA in mosquitoes <0.25%. Community Mf and CFA prevalence rates ranged from 0-0.9% and 0-3.4%, respectively. Infection rates were significantly higher in males and lower in people who denied prior treatment. Antibody rates in school children exceeded 2% in 10 study sites; the area that had the highest community and school CFA rates also had the highest school antibody rate (6.9%. Filarial DNA rates in mosquitoes exceeded 0.25% in 10 PHI areas.Comprehensive surveillance is feasible for some national filariasis elimination programs. Low-level persistence of LF was present in all study sites; several sites failed to meet provisional endpoint criteria for LF elimination, and follow-up testing will be needed in these areas. TAS was not sensitive for detecting low-level persistence of filariasis in Sri Lanka. We recommend use of antibody and MX testing as tools to complement TAS for

  17. A Comprehensive Assessment of Lymphatic Filariasis in Sri Lanka Six Years after Cessation of Mass Drug Administration

    Science.gov (United States)

    Rao, Ramakrishna U.; Nagodavithana, Kumara C.; Samarasekera, Sandhya D.; Wijegunawardana, Asha D.; Premakumara, Welmillage D. Y.; Perera, Samudrika N.; Settinayake, Sunil; Miller, J. Phillip; Weil, Gary J.

    2014-01-01

    Background The Sri Lankan Anti-Filariasis Campaign conducted 5 rounds of mass drug administration (MDA) with diethycarbamazine plus albendazole between 2002 and 2006. We now report results of a comprehensive surveillance program that assessed the lymphatic filariasis (LF) situation in Sri Lanka 6 years after cessation of MDA. Methodology and Principal Findings Transmission assessment surveys (TAS) were performed per WHO guidelines in primary school children in 11 evaluation units (EUs) in all 8 formerly endemic districts. All EUs easily satisfied WHO criteria for stopping MDA. Comprehensive surveillance was performed in 19 Public Health Inspector (PHI) areas (subdistrict health administrative units). The surveillance package included cross-sectional community surveys for microfilaremia (Mf) and circulating filarial antigenemia (CFA), school surveys for CFA and anti-filarial antibodies, and collection of Culex mosquitoes with gravid traps for detection of filarial DNA (molecular xenomonitoring, MX). Provisional target rates for interruption of LF transmission were community CFA <2%, antibody in school children <2%, and filarial DNA in mosquitoes <0.25%. Community Mf and CFA prevalence rates ranged from 0–0.9% and 0–3.4%, respectively. Infection rates were significantly higher in males and lower in people who denied prior treatment. Antibody rates in school children exceeded 2% in 10 study sites; the area that had the highest community and school CFA rates also had the highest school antibody rate (6.9%). Filarial DNA rates in mosquitoes exceeded 0.25% in 10 PHI areas. Conclusions Comprehensive surveillance is feasible for some national filariasis elimination programs. Low-level persistence of LF was present in all study sites; several sites failed to meet provisional endpoint criteria for LF elimination, and follow-up testing will be needed in these areas. TAS was not sensitive for detecting low-level persistence of filariasis in Sri Lanka. We recommend use of

  18. Determination of the impurities in drug products containing montelukast and in silico/in vitro genotoxicological assessments of sulfoxide impurity.

    Science.gov (United States)

    Emerce, Esra; Cok, Ismet; Degim, I Tuncer

    2015-10-14

    Impurities affecting safety, efficacy, and quality of pharmaceuticals are of increasing concern for regulatory agencies and pharmaceutical industries, since genotoxic impurities are understood to play important role in carcinogenesis. The study aimed to analyse impurities of montelukast chronically used in asthma theraphy and perform genotoxicological assessment considering regulatory approaches. Impurities (sulfoxide, cis-isomer, Michael adducts-I&II, methylketone, methylstyrene) were quantified using RP-HPLC analysis on commercial products available in Turkish market. For sulfoxide impurity, having no toxicity data and found to be above the qualification limit, in silico mutagenicity prediction analysis, miniaturized bacterial gene mutation test, mitotic index determination and in vitro chromosomal aberration test w/wo metabolic activation system were conducted. In the analysis of different batches of 20 commercial drug products from 11 companies, only sulfoxide impurity exceeded qualification limit in pediatric tablets from 2 companies and in adult tablets from 7 companies. Leadscope and ToxTree programs predicted sulfoxide impurity as nonmutagenic. It was also found to be nonmutagenic in Ames MPF Penta I assay. Sulfoxide impurity was dose-dependent cytotoxic in human peripheral lymphocytes, however, it was found to be nongenotoxic. It was concluded that sulfoxide impurity should be considered as nonmutagenic and can be classified as ordinary impurity according to guidelines. PMID:26205398

  19. The application of the Accelerated Stability Assessment Program (ASAP) to quality by design (QbD) for drug product stability.

    Science.gov (United States)

    Waterman, Kenneth Craig

    2011-09-01

    An isoconversion paradigm, where times in different temperature and humidity-controlled stability chambers are set to provide a fixed degradant level, is shown to compensate for the complex, non-single order kinetics of solid drug products. A humidity-corrected Arrhenius equation provides reliable estimates for temperature and relative humidity effects on degradation rates. A statistical protocol is employed to determine best fits for chemical stability data, which in turn allows for accurate estimations of shelf life (with appropriate confidence intervals) at any storage condition including inside packaging (based on the moisture vapor transmission rate of the packaging and moisture sorption isotherms of the internal components). These methodologies provide both faster results and far better predictions of chemical stability limited shelf life (expiry) than previously possible. Precise shelf-life estimations are generally determined using a 2-week, product-specific protocol. Once the model for a product is developed, it can play a critical role in providing the product understanding necessary for a quality by design (QbD) filing for product approval and enable rational control strategies to assure product stability. Moreover, this Accelerated Stability Assessment Program (ASAP) enables the coupling of product attributes (e.g., moisture content, packaging options) to allow for flexibility in how control strategies are implemented to provide a balance of cost, speed, and other factors while maintaining adequate stability. PMID:21748541

  20. Assessment of multi-wavelength pulse photometry for non-invasive dose estimation of circulating drugs and nanoparticles

    Science.gov (United States)

    Adhikari, Pratik; Eklund, Wakako; Sherer, Eric A.; O'Neal, D. Patrick

    2016-03-01

    The feasibility of multi-wavelength photoplethysmography for the real-time sensing of absorptive and scattering agents in pulsatile blood is discussed. The use of pulsatile signals extracted from trans-illumination of an accessible section of tissue allows us to calculate the concentration of the optically extinctive species in the pulsatile blood. This technology, initially used for pulse oximetry and dye densitometry, can be applied to monitor in vivo concentration and clearance of various absorptive species. Recently, our prototype has been used monitor the concentration of therapeutic gold nanoparticles, antimalarial quinine, and the antifungal agent amphotericin B. The assessment of the optical properties, device specifications, and signal quality for each compound are presented. We observe that this technology can be used to monitor numerous extinctive drug and nano-materials that present features in the 350-1100 nm range. The rationale for using this technology in a clinical setting would be to improve outcomes by real-time pharmacological feedback and/or control at point of care in addition to the elimination of invasive blood draws for collection of data.

  1. Evaluation of Antiangiogenic Effect of the Leaves of Justicia gendarussa (Burm. f (Acanthaceae by Chrio Allontoic Membrane Method

    Directory of Open Access Journals (Sweden)

    K. Periyanayagam

    2009-01-01

    Full Text Available Problem statement: Angiogenesis involves the formation of new blood vessels from pre-existing blood vessels plays a crucial role in pathological processes such as diabetic retinopathy, arthritis and in the growth of solid tumors. Numerous reports had pointed out to the crucial role of neovascularization in the malignancy of tumors and other angiogenesis dependant diseases. Antiangiogenic therapy which targets activated endothelial cells having several advantages over therapy directed against tumor cells. Determine the antiangiogenic potential of the leaves of Justicia gendarussa by CAM (Chrio Allontoic Membrane assay method. Approach: A chick chrio allontoic membrane assay was carried out. Six eggs were used per experiment to test one extract at a given dose. The upper part of the shell of the eggs were removed like a window, covered with a plastic film and incubated for 72 h. When the CAM is about 1.8-2.6 cm development the pellets containing test solution both aqueous and ethanolic placed on the CAM by means of micropipette. After 24 h antiangiogenic effect was measured by means of a stereomicroscope to observe the avascular zone surrounding the pellet. Results: Below 10 µg both extracts showed no effect. In the dose range of 50 µg mL-1 of ethanolic extract and 100 µg mL-1 of aqueous extract showed inhibition of neovascularization. The effect was in dose dependant manner. Conclusion: These results indicated that both aqueous and ethanolic extracts of the leaves of Justica gendarussa inhibits the angiogenesois in dose dependant fashion and it provides a scientific basis for its traditional use in the treatment of arthtitis which is an angiogenesis dependant disease.

  2. Antioxidant and Antiangiogenic Properties, and Gas Chromatographic-Time of Flight Analysis of Sonchus arvensis Leaves Extracts

    International Nuclear Information System (INIS)

    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)

  3. Anti-angiogenic effects of a mutant endostatin: a new prospect for treating retinal and choroidal neovascularization.

    Directory of Open Access Journals (Sweden)

    Yujing Bai

    Full Text Available Pathological fundus angiogenesis is a major cause of vision loss in retina diseases. Endostatin, a C-terminal fragment of collagen XVIII, is an endogenous anti-angiogenic protein. The present study aimed to investigate the in vitro and in vivo anti-angiogenic properties of two proteins: an N-terminal H1D/H3D mutant endostatin (M-ES and a polyethylene glycol propionaldehyde (PEG covalent M-ES (PEG-M-ES.M-ES and PEG-M-ES properties were characterized in vitro using a zinc ion binding assay and a stability test. Activity assays, including migration, proliferation, and tube formation assays, were performed with human retinal microvascular endothelial cells (HRMECs and human umbilical vein endothelial cells (HUVECs. Mouse oxygen-induced retinopathy (OIR and choroidal neovascularization (CNV models were used to evaluate in vivo anti-angiogenic effects. In addition, a rabbit model was used to study the retinal pharmacokinetic profile following an intravitreal injection.The results indicated that the H1D/H3D mutations of endostatin reduced the zinc binding capacity of M-ES and facilitated PEG covalent binding. PEG-M-ES was more stable and persisted longer in the retina compared with M-ES. The in vitro studies demonstrated that M-ES and PEG-M-ES inhibited HRMEC and HUVEC proliferation, migration, and tube formation more efficiently than ES. In vivo, a single intravitreal injection of M-ES and PEG-M-ES significantly decreased neovascularization in both the OIR and CNV animal models.The present study demonstrated for the first time that PEG-M-ES exhibits a long-term inhibitory effect on neovascularization in vitro and in vivo. These data suggest that PEG-M-ES may represent an innovative therapeutic strategy to prevent fundus neovascularization.

  4. PARENTING QUALITY IN DRUG-ADDICTED MOTHERS IN A THERAPEUTIC MOTHER-CHILD COMMUNITY: THE CONTRIBUTION OF ATTACHMENT AND PERSONALITY ASSESSMENT

    Directory of Open Access Journals (Sweden)

    Francesca eDe Palo

    2014-09-01

    Full Text Available Growing evidence shows that attachment is a key risk factor for the diagnosis and treatment of clinical diseases in Axis I, such as drug addiction. Recent literature regarding attachment, psychiatric pathology and drug addiction demonstrates that there is a clear prevalence of insecure attachment patterns in clinical and drug addicted subjects. Specifically, some authors emphasize that the anxious-insecure attachment pattern is prevalent among drug-addicted women with double diagnosis (Fonagy et al., 1996. The construct of attachment as a risk factor in clinical samples of drug-addicted mothers needs to be studied more in depth though. The present explorative study focused on the evaluation of parenting quality in a therapeutic mother-child community using attachment and personality assessment tools able to outline drug-addicted mothers’ profiles. This study involved 30 drug addicted mothers, inpatients of a therapeutic community. Attachment representations were assessed via the Adult Attachment Interview; personality diagnosis and symptomatic profiles were performed using the Structured Clinical Interview of the DSM-IV (SCID-II and the Symptom Check List-90-R (SCL-90-R respectively. Both instruments were administered during the first six months of residence in a therapeutic community. Results confirmed the prevalence of insecure attachment representations (90%, with a high presence of U patterns, prevalently scored for dangerous and/or not protective experiences in infanthood. Very high values (>5 were found for some experience scales (i.e. neglect and rejection scales. Data also showed very low values (1-3 in metacognitive monitoring, coherence of transcript and coherence of mind scales. Patients’ different profiles (U vs. E vs. Ds were linked to SCID-II diagnosis, providing insightful indications both for treatment planning and intervention on parenting functions and for deciding if to start foster care or adoption proceedings for

  5. Systems to assess the progression of finger joint osteoarthritis and the effects of disease modifying osteoarthritis drugs.

    Science.gov (United States)

    Verbruggen, G; Goemaere, S; Veys, E M

    2002-06-01

    Our objective was to assess the progression of osteoarthritis (OA) using scoring systems based on the anatomical changes recorded in the finger joints on standard radiographs and to test how far these scoring systems could be used to evaluate the effects of candidate "disease modifying osteoarthritis drugs" (DMOAD). The appearance and growth of osteophytes, narrowing of the joint space and subchondral bone changes allowed the classic OA-associated anatomical lesions to be used to score the progression of finger joint OA. Progression of OA in the finger joints was also assessed by the their evolution through previously described and predictable anatomical phases on standard X-rays. These phases were characterised by complete loss of the joint space preceding or coinciding with the appearance of subchondral cysts eroding the entire subchondral plate, and have been described in "inflammatory" or "erosive" OA. The erosive episodes were followed by processes of remodelling. In order to interfere with the progression of osteoarthritis, two chondroitin sulphates with possible DMOAD effects were used in two series of patients with OA of the finger joints. The patients were included in two separate randomised, double-blind placebo-controlled trials: 46 of them received chondroitin polysulphate and 34 received chondroitin sulphate. Eighty-five patients were kept on placebo medication and were used as controls. All 165 patients were followed for 3 years. Posteroanterior X-rays of the metacarpophalangeal and interphalangeal (IP) finger joints were obtained at the start of this prospective study and at yearly intervals thereafter. Almost 80% of the distal IP and 50% of the proximal IP were affected at study entry. In approximately 40% of the patients the classic picture of OA of the IP joints was complicated by manifest erosive OA changes. The two systems to score the progression of OA (Anatomical Lesion and Anatomical Phase Progression Score System) showed definite progression

  6. In Vitro Infectivity Assessment by Drug Susceptibility Comparison of Recombinant Leishmania major Expressing Enhanced Green Fluorescent Protein or EGFP-Luciferase Fused Genes with Wild-Type Parasite

    Science.gov (United States)

    Sadeghi, Somayeh; Seyed, Negar; Etemadzadeh, Mohammad-Hossein; Abediankenari, Saeid; Rafati, Sima; Taheri, Tahereh

    2015-01-01

    Leishmaniasis is a worldwide uncontrolled parasitic disease due to the lack of effective drug and vaccine. To speed up effective drug development, we need powerful methods to rapidly assess drug effectiveness against the intracellular form of Leishmania in high throughput assays. Reporter gene technology has proven to be an excellent tool for drug screening in vitro. The effects of reporter proteins on parasite infectivity should be identified both in vitro and in vivo. In this research, we initially compared the infectivity rate of recombinant Leishmania major expressing stably enhanced green fluorescent protein (EGFP) alone or EGFP-luciferase (EGFP-LUC) with the wild-type strain. Next, we evaluated the sensitivity of these parasites to amphotericin B (AmB) as a standard drug in 2 parasitic phases, promastigote and amastigote. This comparison was made by MTT and nitric oxide (NO) assay and by quantifying the specific signals derived from reporter genes like EGFP intensity and luciferase activity. To study the amastigote form, both B10R and THP-1 macrophage cell lines were infected in the stationary phase and were exposed to AmB at different time points. Our results clearly revealed that the 3 parasite lines had similar in vitro infectivity rates with comparable parasite-induced levels of NO following interferon-γ/lipopolysaccharide induction. Based on our results we proposed the more reporter gene, the faster and more sensitive evaluation of the drug efficiency. PMID:26323836

  7. Natural phenolic metabolites with anti-angiogenic properties – a review from the chemical point of view

    Directory of Open Access Journals (Sweden)

    Qiu Sun

    2015-02-01

    Full Text Available Considering the many secondary natural metabolites available from plants, phenolic compounds play a particularly important role in human health as they occur in significant amounts in many fruits, vegetables and medicinal plants. In this review natural phenolic compounds of plant origin with significant anti-angiogenic properties are discussed. Thirteen representatives from eight different natural or natural-like phenolic subclasses are presented with an emphasis on their synthesis and methods to modify the parent compounds. When available, the consequence of structural variation on the pharmacological activity of the molecules is described.

  8. Organs-on-Chips in Drug Development: The Importance of Involving Stakeholders in Early Health Technology Assessment

    OpenAIRE

    Middelkamp, Heleen H.T.; Meer, Van Der; Hummel, J. Marjan; Stamatialis, Dimitrios F.; Mummery, Christine L.; Passier, Robert; IJzerman, Maarten J.

    2016-01-01

    Organs-on-chips are three-dimensional, microfluidic cell culture systems that simulate the function of tissues and organ subunits. Organ-on-chip systems are expected to contribute to drug candidate screening and the reduction of animal tests in preclinical drug development and may increase efficiency of these processes. To maximize the future impact of the technology on drug development, it is important to make informed decisions regarding the attributes and features of organs-on-chips even t...

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

    OpenAIRE

    Monika Szpringer; Marzena Olędzka; Justyna Kosecka; Bogumił Sobczyk; Paulina Grabowska

    2015-01-01

    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 ...

  10. Antineoplastic drugs in veterinary oncology: excretion in dogs, contamination of the environment and exposure assessment of people at risk

    OpenAIRE

    Janssens, T.

    2012-01-01

    Anticancer drugs themselves can cause adverse health effects when administered to human patients. In addition, it has become apparent that personnel in human medicine, occupationally exposed to these anticancer drugs, may also be at risk. The past decades, the use of chemotherapy in veterinary medicine has been gaining popularity. Consequently, an increasing number of people in veterinary medicine may be exposed to anticancer drugs. This raises the question whether veterinary personnel and ow...

  11. Risk Assessment of Drug Interaction Potential and Concomitant Dosing Pattern on Targeted Toxicities in Pediatric Cancer Patients

    OpenAIRE

    Barrett, Jeffrey S.; Patel, Dimple; Dombrowsky, Erin; Bajaj, Gaurav; Skolnik, Jeffrey M.

    2013-01-01

    This investigation evaluated the impact of potential drug interactions on the incidence of reported toxicities seen with common dosing patterns in children with cancer, with the intent of being able to screen and reduce the incidence of adverse drug reactions (ADRs) in the future. Toxicity reported in pediatric cancer patients treated at the Children’s Hospital of Philadelphia from 2004 to 2010 were abstracted from a cancer tumor registry and merged with drug order profiles from the medical r...

  12. 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.

  13. Antineoplastic drugs in veterinary oncology: excretion in dogs, contamination of the environment and exposure assessment of people at risk

    NARCIS (Netherlands)

    Janssens, T.

    2012-01-01

    Anticancer drugs themselves can cause adverse health effects when administered to human patients. In addition, it has become apparent that personnel in human medicine, occupationally exposed to these anticancer drugs, may also be at risk. The past decades, the use of chemotherapy in veterinary medic

  14. Neurodevelopmental and Psychological Assessment of Adolescents Born to Drug-Addicted Parents: Effects of SES and Adoption

    Science.gov (United States)

    Ornoy, Asher; Daka, Lulu; Goldzweig, Gil; Gil, Yoni; Mjen, Ludmila; Levit, Shabtai; Shufman, Emi; Bar-Hamburger, Rachel; Greenbaum, Charles W.

    2010-01-01

    Objectives: Prenatal exposure to heroin may have long-term consequences for development during early and middle childhood. The present research studied the cognitive, social, and emotional functioning of adolescents exposed to drugs prenatally, and investigated the extent to which the early adoption of children exposed prenatally to drugs would…

  15. Synthesis and biological evaluation of novel 1,5-benzothiazepin-4(5H)-ones as potent antiangiogenic and antioxidant agents

    OpenAIRE

    Channegowda V. Deepu; Goravanahalli M. Raghavendra; Nanjappagowda D. Rekha; K. Mantelingu; Rangappa, Kanchugarakoppal S.; Doddamedur G. Bhadregowda

    2015-01-01

    Novel 1,5-benzothiazepin-4-(5H)-one derivatives (8a-8g) have been synthesized by intramolecular cyclization of 6 using propyl phosphonic anhydride (T3P) as a cyclodehydrating agent. The anti-angiogenic and anti-oxidant properties of the new derivatives were then evaluated. Compounds 8b, 8d, 8e, 8f and 8g exhibited very good inhibition of capillary proliferation, thus proving their anti-angiogenic properties. In addition, the in vitro antioxidant activities of these compounds were evaluated us...

  16. Drug Facts

    Medline Plus

    Full Text Available ... Why Is It So Hard to Quit Drugs? Effects of Drugs Drug Abuse Hurts Other People Drug Abuse Hurts Families Drug Abuse Hurts Kids Drug Abuse Hurts Unborn Children Drug Abuse Hurts Your Health Drug Abuse Hurts Bodies Drug Abuse Hurts Brains Drug Abuse and Mental ...

  17. Butyrate-induced proapoptotic and antiangiogenic pathways in EAT cells require activation of CAD and downregulation of VEGF

    International Nuclear Information System (INIS)

    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

  18. IGFBP-4 Anti-Angiogenic and Anti-Tumorigenic Effects Are Associated with Anti-Cathepsin B Activity

    Directory of Open Access Journals (Sweden)

    María J Moreno

    2013-05-01

    Full Text Available Insulin-like growth factor-binding protein 4 (IGFBP-4/IBP-4 has potent IGF-independent anti-angiogenic and antitumorigenic effects. In this study, we demonstrated that these activities are located in the IGFBP-4 C-terminal protein fragment (CIBP-4, a region containing a thyroglobulin type 1 (Tg1 domain. Proteins bearing Tg1 domains have been shown to inhibit cathepsins, lysosomal enzymes involved in basement membrane degradation and implicated in tumor invasion and angiogenesis. In our studies, CIBP-4 was shown to internalize and co-localize with lysosomal-like structures in both endothelial cells (ECs and glioblastoma U87MG cells. CIBP-4 also inhibited both growth factor-induced EC tubulogenesis in Matrigel and the concomitant increases in intracellular cathepsin B (CatB activity. In vitro assays confirmed CIBP-4 capacity to block recombinant CatB activity. Biodistribution analysis of intravenously injected CIBP-4-Cy5.5 in a glioblastoma tumor xenograft model indicated targeted accumulation of CIBP-4 in tumors. Most importantly, CIBP-4 reduced tumor growth in this animal model by 60%. Pleiotropic anti-angiogenic and anti-tumorigenic activities of CIBP-4 most likely underlie its observed therapeutic potential against glioblastoma.

  19. IGFBP-4 Anti-Angiogenic and Anti-Tumorigenic Effects Are Associated with Anti-Cathepsin B Activity1

    Science.gov (United States)

    Moreno, María J; Ball, Marguerite; Rukhlova, Marina; Slinn, Jacqueline; L'Abbe, Denis; Iqbal, Umar; Monette, Robert; Hagedorn, Martin; O'Connor-McCourt, Maureen D; Durocher, Yves; Stanimirovic, Danica B

    2013-01-01

    Insulin-like growth factor-binding protein 4 (IGFBP-4/IBP-4) has potent IGF-independent anti-angiogenic and antitumorigenic effects. In this study, we demonstrated that these activities are located in the IGFBP-4 C-terminal protein fragment (CIBP-4), a region containing a thyroglobulin type 1 (Tg1) domain. Proteins bearing Tg1 domains have been shown to inhibit cathepsins, lysosomal enzymes involved in basement membrane degradation and implicated in tumor invasion and angiogenesis. In our studies, CIBP-4 was shown to internalize and co-localize with lysosomal-like structures in both endothelial cells (ECs) and glioblastoma U87MG cells. CIBP-4 also inhibited both growth factor-induced EC tubulogenesis in Matrigel and the concomitant increases in intracellular cathepsin B (CatB) activity. In vitro assays confirmed CIBP-4 capacity to block recombinant CatB activity. Biodistribution analysis of intravenously injected CIBP-4-Cy5.5 in a glioblastoma tumor xenograft model indicated targeted accumulation of CIBP-4 in tumors. Most importantly, CIBP-4 reduced tumor growth in this animal model by 60%. Pleiotropic anti-angiogenic and anti-tumorigenic activities of CIBP-4 most likely underlie its observed therapeutic potential against glioblastoma. PMID:23633927

  20. 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.

  1. Drug penetration and metabolism in 3D cell cultures treated in a 3D printed fluidic device: assessment of irinotecan via MALDI imaging mass spectrometry.

    Science.gov (United States)

    LaBonia, Gabriel J; Lockwood, Sarah Y; Heller, Andrew A; Spence, Dana M; Hummon, Amanda B

    2016-06-01

    Realistic in vitro models are critical in the drug development process. In this study, a novel in vitro platform is employed to assess drug penetration and metabolism. This platform, which utilizes a 3D printed fluidic device, allows for dynamic dosing of three dimensional cell cultures, also known as spheroids. The penetration of the chemotherapeutic irinotecan into HCT 116 colon cancer spheroids was examined with MALDI imaging mass spectrometry (IMS). The active metabolite of irinotecan, SN-38, was also detected. After twenty-four hours of treatment, SN-38 was concentrated to the outside of the spheroid, a region of actively dividing cells. The irinotecan prodrug localization contrasted with SN-38 and was concentrated to the necrotic core of the spheroids, a region containing mostly dead and dying cells. These results demonstrate that this unique in vitro platform is an effective means to assess drug penetration and metabolism in 3D cell cultures. This innovative system can have a transformative impact on the preclinical evaluation of drug candidates due to its cost effectiveness and high throughput. PMID:27198560

  2. Drug Facts

    Medline Plus

    Full Text Available ... Drug Abuse Hurts Kids Drug Abuse Hurts Unborn Children Drug Abuse Hurts Your Health Drug Abuse Hurts ... and Family Can Help Prevent Drug Abuse Help Children and Teens Stay Drug-Free Talking to Kids ...

  3. Drug Facts

    Medline Plus

    Full Text Available ... People Drug Abuse Hurts Families Drug Abuse Hurts Kids Drug Abuse Hurts Unborn Children Drug Abuse Hurts ... Children and Teens Stay Drug-Free Talking to Kids About Drugs: What To Say if You Were ...

  4. Methods and strategies for assessing uncontrolled drug-drug interactions in population pharmacokinetic analyses: results from the International Society of Pharmacometrics (ISOP) Working Group.

    Science.gov (United States)

    Bonate, Peter L; Ahamadi, Malidi; Budha, Nageshwar; de la Peña, Amparo; Earp, Justin C; Hong, Ying; Karlsson, Mats O; Ravva, Patanjali; Ruiz-Garcia, Ana; Struemper, Herbert; Wade, Janet R

    2016-04-01

    The purpose of this work was to present a consolidated set of guidelines for the analysis of uncontrolled concomitant medications (ConMed) as a covariate and potential perpetrator in population pharmacokinetic (PopPK) analyses. This white paper is the result of an industry-academia-regulatory collaboration. It is the recommendation of the working group that greater focus be given to the analysis of uncontrolled ConMeds as part of a PopPK analysis of Phase 2/3 data to ensure that the resulting outcome in the PopPK analysis can be viewed as reliable. Other recommendations include: (1) collection of start and stop date and clock time, as well as dose and frequency, in Case Report Forms regarding ConMed administration schedule; (2) prespecification of goals and the methods of analysis, (3) consideration of alternate models, other than the binary covariate model, that might more fully characterize the interaction between perpetrator and victim drug, (4) analysts should consider whether the sample size, not the percent of subjects taking a ConMed, is sufficient to detect a ConMed effect if one is present and to consider the correlation with other covariates when the analysis is conducted, (5) grouping of ConMeds should be based on mechanism (e.g., PGP-inhibitor) and not drug class (e.g., beta-blocker), and (6) when reporting the results in a publication, all details related to the ConMed analysis should be presented allowing the reader to understand the methods and be able to appropriately interpret the results. PMID:26837775

  5. Mid –Term Assessment of Mass Drug Administration of DEC for Filariasis in Rewa and Chhindwara Districts of Madhya Pradesh

    OpenAIRE

    Pankaj Prasad, Rajendra Singh Arya, Manoj Bansal, S P Singh

    2013-01-01

    Background: Filariasis has been a major public health problem in India which leads to irreversible chronic manifestations, which are responsible for social stigma besides causing considerable economic loss and severe physical disability to the affected individuals. Objective: Mid –Term Assessment of Mass Drug Administration of DEC was carried out with objectives to review the progress of activities of single dose DEC mass administration with respect to process and outcome indicators and t...

  6.  α-Cyclodextrin dimer complexes of dopamine and levodopa derivatives to assess drug delivery to the central nervous system: ADME and molecular docking studies

    OpenAIRE

    Shityakov S; Broscheit J; Förster C

    2012-01-01

    Sergey Shityakov, Jens Broscheit, Carola FörsterDepartment of Anesthesiology and Critical Care, University of Würzburg, Würzburg, GermanyAbstract: This paper attempts to predict and emphasize molecular interactions of dopamine, levodopa, and their derivatives (Dopimid compounds) containing 2-phenyl-imidazopyridine moiety with the α-cyclodextrin dimer in order to assess and improve drug delivery to the central nervous system. The molecular docking method is...

  7. α-Cyclodextrin dimer complexes of dopamine and levodopa derivatives to assess drug delivery to the central nervous system: ADME and molecular docking studies

    OpenAIRE

    Shityakov, Sergey

    2012-01-01

    Sergey Shityakov, Jens Broscheit, Carola FörsterDepartment of Anesthesiology and Critical Care, University of Würzburg, Würzburg, GermanyAbstract: This paper attempts to predict and emphasize molecular interactions of dopamine, levodopa, and their derivatives (Dopimid compounds) containing 2-phenyl-imidazopyridine moiety with the α-cyclodextrin dimer in order to assess and improve drug delivery to the central nervous system. The molecular docking method is...

  8. α-Cyclodextrin dimer complexes of dopamine and levodopa derivatives to assess drug delivery to the central nervous system: ADME and molecular docking studies

    OpenAIRE

    Shityakov, Sergey; Broscheit, Jens; Förster, Carola

    2012-01-01

    This paper attempts to predict and emphasize molecular interactions of dopamine, levodopa, and their derivatives (Dopimid compounds) containing 2-phenyl-imidazopyridine moiety with the α-cyclodextrin dimer in order to assess and improve drug delivery to the central nervous system. The molecular docking method is used to determine the energetic profiles, hydrogen bond formation, and hydrophobic effect of 14 host–guest complexes. The results show that the “chemical branching” represented by add...

  9. Priority-based assessment of food additives database of the U.S. Food and Drug Administration Center for Food Safety and Applied Nutrition.

    OpenAIRE

    Benz, R D; Irausquin, H

    1991-01-01

    The priority-based assessment of food additives (PAFA) is a database maintained by the U.S. Food and Drug Administration (FDA) Center for Food Safety and Applied Nutrition. PAFA contains extensive administrative, chemical, and toxicological information on 1685 regulated direct food additives. The database also has limited administrative and chemical information on an additional 1236 direct additives. The total 2921 substances represent everything added to food in the United States. PAFA conta...

  10. S-glutathionylated serine proteinase inhibitors as plasma biomarkers in assessing response to redox-modulating drugs.

    Science.gov (United States)

    Grek, Christina L; Townsend, Danyelle M; Uys, Joachim D; Manevich, Yefim; Coker, Woodrow J; Pazoles, Christopher J; Tew, Kenneth D

    2012-05-01

    Many cancer drugs impact cancer cell redox regulatory mechanisms and disrupt redox homeostasis. Pharmacodynamic biomarkers that measure therapeutic efficacy or toxicity could improve patient management. Using immunoblot analyses and mass spectrometry, we identified that serpins A1 and A3 were S-glutathionylated in a dose- and time-dependent manner following treatment of mice with drugs that alter reactive oxygen or nitrogen species. Tandem mass spectrometry analyses identified Cys(256) of serpin A1 and Cys(263) of serpin A3 as the S-glutathionylated residues. In human plasma from cancer patients, there were higher levels of unmodified serpin A1 and A3, but following treatments with redox active drugs, relative S-glutathionylation of these serpins was higher in plasma from normal individuals. There is potential for S-glutathionylated serpins A1 and A3 to act as pharmacodynamic biomarkers for evaluation of patient response to drugs that target redox pathways. PMID:22406622

  11. Diagnostic imaging of herpes simplex virus encephalitis using a radiolabeled antiviral drug: autoradiographic assessment in an animal model

    International Nuclear Information System (INIS)

    To develop a new approach to the diagnosis of herpes simplex encephalitis, we used a radiolabeled antiviral drug, 2'-fluoro-5-methyl-1-beta-D-arabinosyluracil labeled with carbon 14 ([14C]FMAU), as a probe for selectively imaging brain infection in a rat model by quantitative autoradiography. A high correlation was found between focal infection, as defined by immunoperoxidase viral antigen staining, and increased regional [14C]FMAU uptake in brain sections. Two potential sources of false-positive imaging were defined: high concentrations of drug in the choroid plexus because of its higher permeability compared with brain, and drug sequestration by proliferating uninfected cell populations. Our results support the soundness of the proposed strategy of using a labeled antiviral drug that is selectively phosphorylated by herpes simplex virus type 1 thymidine kinase in conjunction with scanning methods for human diagnosis, and also define some of the factors that must be taken into account when planning clinical application

  12. Assessment of hearing loss in multi-drug resistant tuberculosis (MDR-TB) patients undergoing Aminoglycoside treatment

    OpenAIRE

    Sheikh Nizamuddin; Farhan Ahmad Khan; Abdur Rehman Khan; Chand Miyan Kamaal

    2015-01-01

    Background: Incomplete treatments and treatment failures has led to Multi-drug resistant tuberculosis, which has emerged as a significant problem in treating tuberculosis and thus the second line drugs are used with the concomitant increase in the incidence of adverse effects. Methods: This prospective study was carried out from June 2009 to May 2014 in the department of ENT in collaboration with TB and Chest at Teerthanker Mahaveer Medical College and Research Centre. Out of 104, ...

  13. Zebrafish assessment of cognitive improvement and anxiolysis: Filling the gap between in vitro and rodent models for drug development

    OpenAIRE

    Levin, Edward D.

    2011-01-01

    Zebrafish can provide a valuable animal model to screen potential cognitive enhancing and anxiolytic drugs. They are economical and can provide a relatively quick indication of possible functional efficacy. In as much as they have a complex nervous system and elaborate behavioral repertoire, zebrafish can provide a good intermediate model between in vitro receptor and cell-based assays and classic mammalian models for drug screening. In addition, the variety of molecular tools available in ze...

  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)

    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. Assessment of surface concentrations in resorbable ocular implants: controlled drug delivery devices for 5-fluorouracil (5-FU)

    Science.gov (United States)

    Milne, Peter J.; Gautier, Sandrine; Parel, Jean-Marie A.; Jallet, Valerie

    1997-05-01

    The antineoplastic drug 5-fluorouracil (5-fluoro- 2,4,(1H,3H)-pyrimidinedione; 5-FU) has been used to control proliferation of penetrating fibroblasts and to prevent channel closure following glaucoma filtration surgery (trabeculectomy) or laser sclerectomy. Because of the toxicity of the drug, administration of low dosages slowly over time, at the site of the desired treatment, is indicated for optimum efficacy. Repeated injections of low dosages of the drug represent an undesirable intervention and may also result in unwanted toxicity to the corneal epithelium. A suitable biocompatible and resorbable polymer matrix composed of a poly (D,L-lactic-co-glycolic acid: PLGA) has been admixed with varying amounts of 5-FU and cast as shapes suitable for intracorneal implantation. Slow biodegradation of this polymer over a one to two week period has been shown to result in an acceptably slow drug release mechanism. An issue arising during the clinical evaluation of the efficacy of this drug delivery system was how best to quantify the concentration of 5-FU and its distribution spatially in the solid implant. FT-IR and FT-Raman spectroscopies distinguishes between the drug and the polymer matrix and were used to differentiate and quantitate the 5-FU concentration of the implants.

  18. Modelling PK/QT relationships from Phase I dose-escalation trials for drug combinations and developing quantitative risk assessments of clinically relevant QT prolongations.

    Science.gov (United States)

    Sinclair, Karen; Kinable, Els; Grosch, Kai; Wang, Jixian

    2016-05-01

    In current industry practice, it is difficult to assess QT effects at potential therapeutic doses based on Phase I dose-escalation trials in oncology due to data scarcity, particularly in combinations trials. In this paper, we propose to use dose-concentration and concentration-QT models jointly to model the exposures and effects of multiple drugs in combination. The fitted models then can be used to make early predictions for QT prolongation to aid choosing recommended dose combinations for further investigation. The models consider potential correlation between concentrations of test drugs and potential drug-drug interactions at PK and QT levels. In addition, this approach allows for the assessment of the probability of QT prolongation exceeding given thresholds of clinical significance. The performance of this approach was examined via simulation under practical scenarios for dose-escalation trials for a combination of two drugs. The simulation results show that invaluable information of QT effects at therapeutic dose combinations can be gained by the proposed approaches. Early detection of dose combinations with substantial QT prolongation is evaluated effectively through the CIs of the predicted peak QT prolongation at each dose combination. Furthermore, the probability of QT prolongation exceeding a certain threshold is also computed to support early detection of safety signals while accounting for uncertainty associated with data from Phase I studies. While the prediction of QT effects is sensitive to the dose escalation process, the sensitivity and limited sample size should be considered when providing support to the decision-making process for further developing certain dose combinations. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26991506

  19. Increased serum levels of anti-angiogenic factors soluble fms-like tyrosine kinase and soluble endoglin in sickle cell disease

    NARCIS (Netherlands)

    Landburg, P P; Elsenga, H; Schnog, J B; Duits, A J

    2008-01-01

    The anti-angiogenic factors soluble fms-like tyrosine kinase (sFlt)-1 and soluble endoglin (sEng) have been shown to be of importance in angiogenesis by sequestering and inhibiting vascular endothelial growth factor, placenta-like growth factor and transforming growth factor-beta(1) signaling. Given

  20. Combination angiostatin and endostatin gene transfer induces synergistic antiangiogenic activity in vitro and antitumor efficacy in leukemia and solid tumors in mice.

    Science.gov (United States)

    Scappaticci, F A; Smith, R; Pathak, A; Schloss, D; Lum, B; Cao, Y; Johnson, F; Engleman, E G; Nolan, G P

    2001-02-01

    Angiostatin and endostatin are potent endothelial cell growth inhibitors that have been shown to inhibit angiogenesis in vivo and tumor growth in mice. However, tumor shrinkage requires chronic delivery of large doses of these proteins. Here we report synergistic antitumor activity and survival of animals when these factors are delivered in combination to tumors by retroviral gene transfer. We have demonstrated this efficacy in both murine leukemia and melanoma models. Complete loss of tumorigenicity was seen in 40% of the animals receiving tumors transduced by the combination of angiostatin and endostatin in the leukemia model. The synergy was also demonstrated in vitro on human umbilical vein endothelial cell differentiation and this antiangiogenic activity may suggest a mechanism for the antitumor activity in vivo. These findings imply separate pathways by which angiostatin and endostatin mediate their antiangiogenic effects. Together, these data suggest that a combination of antiangiogenic factors delivered by retroviral gene transfer may produce synergistic antitumor effects in both leukemia and solid tumors, thus avoiding long-term administration of recombinant proteins. The data also suggest that novel combinations of antiangiogenic factors delivered into tumors require further investigation as therapeutic modalities. PMID:11237675

  1. ACTIBIND, an actin-binding fungal T2-RNase with antiangiogenic and anticarcinogenic characteristics.

    OpenAIRE

    Roiz, Levava; Smirnoff, Patricia; Bar-Eli, Menashe; Schwartz, Betty; Shoseyov, Oded

    2006-01-01

    KEYWORDS CLASSIFICATION: Agriculture;Angiogenesis Inhibitors;Animals;Anticarcinogenic Agents;Aspergillus niger;blood;Biopsy,Needle;Breast Neoplasms;cytology;Colorectal Neoplasms;dietary modulation of cancer & cancer biomarkers;drug effects;drug therapy;Disease Models,Animal;Endoribonucleases;Female;Food;Humans;Immunohistochemistry;Israel;lifestyle modulation of cancer & cancer biomarkers;Male;Mice;Mice,Nude;Neoplasm Transplantation;Neovascularization,Pathologic;pathology;pharmacology;preventi...

  2. Transdermal drug targeting and functional imaging of tumor blood vessels in the mouse auricle.

    Science.gov (United States)

    Schröder, Hannes; Komljenovic, Dorde; Hecker, Markus; Korff, Thomas

    2016-02-01

    Subcutaneously growing tumors are widely utilized to study tumor angiogenesis and the efficacy of antiangiogenic therapies in mice. To additionally assess functional and morphologic alterations of the vasculature in the periphery of a growing tumor, we exploited the easily accessible and hierarchically organized vasculature of the mouse auricle. By site-specific subcutaneous implantation of a defined preformed mouse B16/F0 melanoma aggregate, a solid tumor nodule developed within 14 d. Growth of the tumor nodule was accompanied by a 4-fold increase in its perfusion as well as a 2- to 4-fold elevated diameter and perfusion of peripheral blood vessels that had connected to the tumor capillary microvasculature. By transdermal application of the anticancer drug bortezomib, tumor growth was significantly diminished by about 50% without provoking side effects. Moreover, perfusion and tumor microvessel diameter as well as growth and perfusion of arterial or venous blood vessels supplying or draining the tumor microvasculature were decreased under these conditions by up to 80%. Collectively, we observed that the progressive tumor growth is accompanied by the enlargement of supplying and draining extratumoral blood vessels. This process was effectively suppressed by bortezomib, thereby restricting the perfusion capacity of both extra and intratumoral blood vessels. PMID:26546130

  3. Use of biorelevant media for assessment of a poorly soluble weakly basic drug in the form of liquisolid compacts: in vitro and in vivo study.

    Science.gov (United States)

    Badawy, Mahmoud A; Kamel, Amany O; Sammour, Omaima A

    2016-01-01

    The purpose of this work is to use biorelevant media to evaluate the robustness of a poorly water soluble weakly basic drug to variations along the gastrointestinal tract (GIT) after incorporation in liquisolid compacts and to assess the success of these models in predicting the in vivo performance. Liquisolid tablets were prepared using mosapride citrate as a model drug. A factorial design experiment was used to study the effect of three factors, namely: drug concentration at two levels (5% and 10%), carriers at three levels (avicel, mannitol and lactose) and powder excipients ratio (R) of the coating material at two levels (25 and 30). The in vitro dissolution media utilized were 0.1 N HCl, hypoacidic stomach model and a transfer model simulating the transfer from the stomach to the intestine. All compacts released above 95% of drug after 10 min in 0.1 N HCl. In the hypoacidic model, the compacts with R 30 were superior compared to R 25, where they released >90% of drug after 10 min compared to 80% for R 25. After the transfer of the optimum compacts from Simulated gastric fluid fast (SGFfast) to fasted state simulated intestinal fluid, slight turbidity appeared after 30 min, and the amount of drug dissolved slightly decreased from 96.91% to 90.59%. However, after the transfer from SGFfast to fed state simulated intestinal fluid, no turbidity or precipitation occurred throughout time of the test (60 min). In vivo pharmacokinetic study in human volunteers proved the success of the in vitro models with enhancement of the oral bioavailability (121.20%) compared to the commercial product. PMID:24892630

  4. Availability of human induced pluripotent stem cell-derived cardiomyocytes in assessment of drug potential for QT prolongation

    Energy Technology Data Exchange (ETDEWEB)

    Nozaki, Yumiko, E-mail: yumiko-nozaki@ds-pharma.co.jp [Preclinical Research Laboratories, Dainippon Sumitomo Pharma. Co., Ltd., Suita, Osaka 564-0053 (Japan); Honda, Yayoi, E-mail: yayoi-honda@ds-pharma.co.jp [Preclinical Research Laboratories, Dainippon Sumitomo Pharma. Co., Ltd., Suita, Osaka 564-0053 (Japan); Tsujimoto, Shinji, E-mail: shinji-tsujimoto@ds-pharma.co.jp [Regenerative and Cellular Medicine Office, Dainippon Sumitomo Pharma. Co., Ltd., Chuo-ku, Tokyo 104-0031 (Japan); Watanabe, Hitoshi, E-mail: hitoshi-1-watanabe@ds-pharma.co.jp [Preclinical Research Laboratories, Dainippon Sumitomo Pharma. Co., Ltd., Suita, Osaka 564-0053 (Japan); Kunimatsu, Takeshi, E-mail: takeshi-kunimatsu@ds-pharma.co.jp [Preclinical Research Laboratories, Dainippon Sumitomo Pharma. Co., Ltd., Suita, Osaka 564-0053 (Japan); Funabashi, Hitoshi, E-mail: hitoshi-funabashi@ds-pharma.co.jp [Preclinical Research Laboratories, Dainippon Sumitomo Pharma. Co., Ltd., Suita, Osaka 564-0053 (Japan)

    2014-07-01

    Field potential duration (FPD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which can express QT interval in an electrocardiogram, is reported to be a useful tool to predict K{sup +} channel and Ca{sup 2+} channel blocker effects on QT interval. However, there is no report showing that this technique can be used to predict multichannel blocker potential for QT prolongation. The aim of this study is to show that FPD from MEA (Multielectrode array) of hiPS-CMs can detect QT prolongation induced by multichannel blockers. hiPS-CMs were seeded onto MEA and FPD was measured for 2 min every 10 min for 30 min after drug exposure for the vehicle and each drug concentration. I{sub Kr} and I{sub Ks} blockers concentration-dependently prolonged corrected FPD (FPDc), whereas Ca{sup 2+} channel blockers concentration-dependently shortened FPDc. Also, the multichannel blockers Amiodarone, Paroxetine, Terfenadine and Citalopram prolonged FPDc in a concentration dependent manner. Finally, the I{sub Kr} blockers, Terfenadine and Citalopram, which are reported to cause Torsade de Pointes (TdP) in clinical practice, produced early afterdepolarization (EAD). hiPS-CMs using MEA system and FPDc can predict the effects of drug candidates on QT interval. This study also shows that this assay can help detect EAD for drugs with TdP potential. - Highlights: • We focused on hiPS-CMs to replace in vitro assays in preclinical screening studies. • hiPS-CMs FPD is useful as an indicator to predict drug potential for QT prolongation. • MEA assay can help detect EAD for drugs with TdP potentials. • MEA assay in hiPS-CMs is useful for accurately predicting drug TdP risk in humans.

  5. Quantitative MR imaging in planning and assessing novel cancer treatments Radiotherapy

    CERN Document Server

    Baustert, I C

    2001-01-01

    Novel treatments in cancer, like conformal radiotherapy and anticancer drugs, require new MRI techniques to assess their benefits and potential. In conformal radiotherapy, MRI can be used to measure the shape and dose of the conformed radiation field in dose sensitive gel test-objects thus validating the predicted dose computed by complex programs. In antiangiogenic drug treatment, the vascular dysfunction of the tumour can be assessed by MRI prior to treatment. Response to treatment may also be monitored by measuring the changes in vascular function. In this thesis, MRI of polyacrylamide gels is investigated as a 3D dosimeter for conformal radiotherapy treatment planning. Quantitative MRI sequences capable of measuring the wide range of T2 values typically expected in gel dosimetry, are identified. Different T2 measurement methods are compared in terms of accuracy, signal to noise ratio and acquisition time. Examples of a complex dose distribution in 2D and 3D are presented and compared to the planned dose p...

  6. Rational formulation development and in vitro assessment of SMEDDS for oral delivery of poorly water soluble drugs.

    Science.gov (United States)

    Sprunk, Angela; Strachan, Clare J; Graf, Anja

    2012-08-15

    The aims of this study were to formulate a self-microemulsifying drug delivery system (SMEDDS) by a rational formulation approach using mixture experimental design and to derive general concepts that make the development of such systems more feasible. Various types of oils and surfactants were systematically combined and the phase behaviour upon dilution with simulated gastric fluid examined by construction of phase diagrams. The systems solubilising the highest amount of simulated gastric fluid in the continuous microemulsion area were selected for investigation and optimisation of drug solubility. Simvastatin was added as a poorly water-soluble, lipophilic model drug. Two different mixture experimental designs using D-optimal design were set up and used to investigate the solubility of simvastatin in the SMEDDS before and after dilution with simulated gastric fluid respectively. The solubility in each mixture region was analysed by fitting quadratic models using partial least squares analysis. The established models revealed the influence of mixture components on phase behaviour and drug solubility and gave the rationale for formulation optimisation. This study demonstrated that the development of complex self-emulsifying formulations with sufficient solubilisation capacity for poorly water-soluble drugs upon oral administration can be more feasible when using experimental design. PMID:22521277

  7. Trends in the Assessment of Drug Supersaturation and Precipitation In Vitro Using Lipid-Based Delivery Systems.

    Science.gov (United States)

    Stillhart, Cordula; Kuentz, Martin

    2016-09-01

    The generation of drug supersaturation close to the absorptive site is an important mechanism of how several formulation technologies enhance oral absorption and bioavailability. Lipid-based formulations belong to the supersaturating drug delivery systems although this is not the only mechanism of how drug absorption is promoted in vivo. Different methods to determine drug supersaturation and precipitation from lipid-based formulations are described in the literature. Experimental in vitro setups vary according to their complexity and proximity to the in vivo conditions and, therefore, some tests are used for early formulation screening, while others better qualify for a later stage of development. The present commentary discusses this rapidly evolving field of in vitro testing with a special focus on the advancements in analytical techniques and new approaches of mechanistic modeling. The importance of considering a drug absorption sink is particularly emphasized. This commentary should help formulators in the pharmaceutical industry as well as in academia to make informed decisions on how to conduct in vitro tests for lipid-based delivery systems and to decide on the implications of experimental results. PMID:26935881

  8. Drug misuse.

    Science.gov (United States)

    Waller, T

    1992-12-01

    1. Assessment by history and examination should include: a history of all drugs taken during each day for the previous 7 days (including alcohol), length of drug use and route (including the sharing of needles or syringes), the possibility of pregnancy if female, previous psychiatric history and treatment of drug misuse, social factors (including employment, family, friends, involvement in prostitution, legal problems), medical problems, including evidence of hepatitis, injection abscesses and other infections, suicide attempts, and weight loss. 2. Notification to the Chief Medical Officer of the Drug Branch of the Home Office is a legal obligation. 3. Investigations include: liver function tests (LFTs), hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis C antibody, full blood count (FBC), and urine for drug screening. Consider HIV testing if at risk but it is usually better arranged at a later stage. 4. Prescribing may be considered for a variety of drugs but objectives will differ according to drug type and individual. 5. In the case of opioid users, prescribing may be useful to stabilize their lives and to promote attendance for professional help. It may reduce high risk behaviour for contracting and spreading HIV. 6. If medication is given to opioid users, methadone mixture 1 mg/ml given once a day is the prescription of choice. Dispensing should be on a daily basis and the blue prescription form FP10 (MDA) allows the chemist to dispense daily for up to 14 days. A maximum ceiling of 100 mg methadone/day should not be exceeded. The initial dose will depend on the amount of opioid consumed in the previous week.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1345155

  9. Quality Assessment of Serially Ultradiluted and Agitated Drug Digitalis purpurea by Emission Spectroscopy and Clinical Analysis of Its Effect on the Heart Rate of Indian Bufo melanostictus

    Directory of Open Access Journals (Sweden)

    Anup Sharma

    2013-01-01

    Full Text Available The investigation of ultradiluted (homeopathic drugs is extremely interesting and challenging, and from that point of view this study shows novelty. A study of in vivo changes in heart rate of the Indian Bufo melanostictus caused by commercially available serially ultra-diluted and agitated extract of Digitalis purpurea has been tried in order to understand their pharmacological role. RR interval (of ECG was compared after intraperitoneal administration of serially diluted and agitated Digitalis purpurea extract, diluent rectified spirit, and Digoxin in anesthetized animals. The study revealed statistically significant changes in the heart rate after application of these drugs except in case of Digoxin and the 200th serial dilution of Digitalis purpurea. The duration of RR intervals after application of the drugs was corroborative of the effect of Digoxin and Digitalis purpurea extract up to 30th dilution. Emission spectra were obtained for the experimental ultra-diluted Digitalis purpurea extract and Digoxin to identify and characterize them. The observed RR pattern and emission spectra show an association. The quality assessment of the commercial ultra-diluted organic drugs obtained from natural products may be initiated by monitoring in vivo studies on animal models.

  10. A Review of Computer-Based Interventions Used in the Assessment, Treatment, and Research of Drug Addiction

    Science.gov (United States)

    Bickel, Warren K.; Christensen, Darren R.; Marsch, Lisa A.

    2011-01-01

    Computer-based interventions are cost-efficient methods that may result in greater access to drug addiction treatment. We review recent findings from our laboratory where computer-based interventions have produced outcomes that are comparable to therapist-delivered interventions. We also examine how computer-based interventions targeting substance abuse disorders relate to cognitive functioning. This review will suggest that not only are computer-based interventions cost-efficient and accessible but that they are also effective methods for the motivation, engagement, and treatment of drug-dependent individuals. Moreover, computer-based interventions are compatible with a recently proposed biological mechanism implicated as the basis for drug addiction. PMID:21190401

  11. Does mass drug administration for the integrated treatment of neglected tropical diseases really work? Assessing evidence for the control of schistosomiasis and soil-transmitted helminths in Uganda

    Directory of Open Access Journals (Sweden)

    Allen Tim

    2011-01-01

    more effective use of existing public health legislation. Conclusion While it has been an achievement to have offered free drugs to so many adults, current standard practices of monitoring, evaluation and delivery of MDA for NTDs are inconsistent and inadequate. Efforts to integrate programmes have exacerbated the difficulties. Improved assessment of what is really happening on the ground will be an essential step in achieving long-term overall reduction of the NTD burden for impoverished communities.

  12. Developing Outcomes Assessments as Endpoints for Registrational Clinical Trials of Antibacterial Drugs: 2015 Update From the Biomarkers Consortium of the Foundation for the National Institutes of Health.

    Science.gov (United States)

    Talbot, George H; Powers, John H; Hoffmann, Steven C

    2016-03-01

    One important component in determining the benefits and harms of medical interventions is the use of well-defined and reliable outcome assessments as endpoints in clinical trials. Improving endpoints can better define patient benefits, allowing more accurate assessment of drug efficacy and more informed benefit-vs-risk decisions; another potential plus is facilitating efficient trial design. Since our first report in 2012, 2 Foundation for the National Institutes of Health Biomarkers Consortium Project Teams have continued to develop outcome assessments for potential uses as endpoints in registrational clinical trials of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. In addition, the teams have initiated similar work in the indications of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. This report provides an update on progress to date in these 4 diseases. PMID:26668337

  13. Monitoring early tumor response to drug therapy with diffuse optical tomography

    Science.gov (United States)

    Flexman, Molly L.; Vlachos, Fotios; Kim, Hyun Keol; Sirsi, Shashank R.; Huang, Jianzhong; Hernandez, Sonia L.; Johung, Tessa B.; Gander, Jeffrey W.; Reichstein, Ari R.; Lampl, Brooke S.; Wang, Antai; Borden, Mark A.; Yamashiro, Darrell J.; Kandel, Jessica J.; Hielscher, Andreas H.

    2012-01-01

    Although anti-angiogenic agents have shown promise as cancer therapeutics, their efficacy varies between tumor types and individual patients. Providing patient-specific metrics through rapid noninvasive imaging can help tailor drug treatment by optimizing dosages, timing of drug cycles, and duration of therapy--thereby reducing toxicity and cost and improving patient outcome. Diffuse optical tomography (DOT) is a noninvasive three-dimensional imaging modality that has been shown to capture physiologic changes in tumors through visualization of oxygenated, deoxygenated, and total hemoglobin concentrations, using non-ionizing radiation with near-infrared light. We employed a small animal model to ascertain if tumor response to bevacizumab (BV), an anti-angiogenic agent that targets vascular endothelial growth factor (VEGF), could be detected at early time points using DOT. We detected a significant decrease in total hemoglobin levels as soon as one day after BV treatment in responder xenograft tumors (SK-NEP-1), but not in SK-NEP-1 control tumors or in non-responder control or BV-treated NGP tumors. These results are confirmed by magnetic resonance imaging T2 relaxometry and lectin perfusion studies. Noninvasive DOT imaging may allow for earlier and more effective control of anti-angiogenic therapy.

  14. Drug Facts

    Medline Plus

    Full Text Available ... Abuse Hurts Unborn Children Drug Abuse Hurts Your Health Drug Abuse Hurts Bodies Drug Abuse Hurts Brains Drug Abuse and Mental Health Problems Often Happen Together The Link Between Drug ...

  15. Drug Facts

    Medline Plus

    Full Text Available ... Addiction? Addiction Risk Factors Does Addiction Run in Families? Why Is It So Hard to Quit Drugs? ... Drug Abuse Hurts Other People Drug Abuse Hurts Families Drug Abuse Hurts Kids Drug Abuse Hurts Unborn ...

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

    Directory of Open Access Journals (Sweden)

    Gutin Philip H

    2011-01-01

    Full Text Available Abstract 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

  17. Anti-cancer and anti-angiogenic effects of curcumin and tetrahydrocurcumin on implanted hepatocellular carcinoma in nude mice

    Institute of Scientific and Technical Information of China (English)

    Pornprom Yoysungnoen; Ponthip Wirachwong; Chatchawan Changtam; Apichart Suksamrarn; Suthiluk Patumraj

    2008-01-01

    AIM: To determine the effect of tetrahydrocurcumin (THC) on tumor angiogenesis compared with curcumin (CUR) by using both in vitro and in vivo models of human hepatocellular carcinoma cell line (HepG2).METHODS: The 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) assay was used for testing the anti-proliferating activities of CUR and THC. In male BALB/c nude mice, 2 x 106 human HepG2 cells were inoculated onto a dorsal skin-fold chamber. One day after HepG2 inoculation, the experimental groups were fed oral daily with CUR or THC (300 mg/kg or 3000 mg/kg). On d 7, 14 and 21, the tumor microvasculature was observed using fluorescence videomicroscopy and capillary vascularity (CV) was measured.RESULTS: Pathological angiogenic features including microvascular dilatation, tortuosity, and hyper-permeability were observed. CUR and THC could attenuate these pathologic features. In HepG2-groups, the CV were significantly increased on d 7 (52.43%), 14 (69.17%), and 21 (74.08%), as compared to controls (33.04%,P < 0.001). Treatment with CUR and THC resulted in significant decrease in the CV (P < 0.005 and P < 0.001, respectively). In particular, the anti-angiogenic effects of CUR and THC were dose-dependent manner. However, the beneficial effect of THC treatment than CUR was observed, in particular, from the 21 d CV (44.96% and 52.86%, P < 0.05).CONCLUSION: THC expressed its anti-angiogenesis without any cytotoxic activities to HepG2 cells even at the highest doses. It is suggested that anti-angiogenic properties of CUR and THC represent a common potential mechanism for their anti-cancer actions.

  18. Pilot study assessing HIV vaccine trial readiness among female sex workers, injection and non-injection drug users, and men who have sex with men in Spain.

    Science.gov (United States)

    Etcheverry, María Florencia; de Lazzari, Elisa; Fuchs, Jonathan D; Meroño, Mercé; Sierra, Ernesto; Del Romero, Jorge; Evans, Jennifer L; Mendez-Arancibia, Eva; Jacques, Constanza; Rojas, Daniela; Segú, Marta; Gatell, José María; Joseph, Joan

    2010-06-01

    The purpose of this study was to assess HIV risk and willingness to participate in HIV vaccine trials in three high risk populations in Spain. Eight hundred and forty-four participants, comprising female sex workers, injection and non-injection drug users (IDUs and NIDUs, respectively), and men who have sex with men were tested for HIV and surveyed for risk and willingness to participate in future preventive HIV vaccine trials. HIV seroprevalence was 3.8% (95% CI: 2-11). HIV infection was associated with transgender identification, IDU in the past year, and sex with an IDU or other drug-using partner. The majority (82%) expressed their willingness to participate in HIV vaccine trials. Substantial sexual and parenteral risk in all groups and concomitant willingness to participate in vaccine trials was found, particularly among women and IDUs. Additional longitudinal cohort studies in Spain are needed to plan future vaccine efficacy trials. PMID:19037720

  19. Hp-β-CD-voriconazole in situ gelling system for ocular drug delivery: in vitro, stability, and antifungal activities assessment.

    Science.gov (United States)

    Pawar, Pravin; Kashyap, Heena; Malhotra, Sakshi; Sindhu, Rakesh

    2013-01-01

    The objective of the present study was to design ophthalmic delivery systems based on polymeric carriers that undergo sol-to-gel transition upon change in temperature or in the presence of cations so as to prolong the effect of HP- β -CD Voriconazole (VCZ) in situ gelling formulations. The in situ gelling formulations of Voriconazole were prepared by using pluronic F-127 (PF-127) or with combination of pluronic F-68 (PF-68) and sodium alginate by cold method technique. The prepared formulations were evaluated for their physical appearance, drug content, gelation temperature (T gel), in vitro permeation studies, rheological properties, mucoadhesion studies, antifungal studies, and stability studies. All batches of in situ formulations had satisfactory pH ranging from 6.8 to 7.4, drug content between 95% and 100%, showing uniform distribution of drug. As the concentration of each polymeric component was increased, that is, PF-68 and sodium alginate, there was a decrease in T gel with increase in viscosity and mucoadhesive strength. The in vitro drug release decreased with increase in polymeric concentrations. The stability data concluded that all formulations showed the low degradation and maximum shelf life of 2 years. The antifungal efficiency of the selected formulation against Candida albicans and Asperigillus fumigatus confirmed that designed formulation has prolonged effect and retained its properties against fungal infection. PMID:23762839

  20. Use of In Vitro Morphogenesis of Mouse Embryoid Bodies to Assess Developmental Toxicity of Therapeutic Drugs Contraindicated in Pregnancy.

    Science.gov (United States)

    Warkus, Erica L L; Yuen, Angela A Y Q; Lau, Caroline G Y; Marikawa, Yusuke

    2016-01-01

    In utero exposure to certain chemicals can impair embryo development, causing embryonic death, growth retardation, or severe birth defects. Establishment of effective in vitro tests is crucial for identifying developmental toxicants and for reducing the financial and ethical burden of animal-based tests. Previously, we created an in vitro morphogenesis model using pluripotent P19C5 mouse embryonal carcinoma stem cells that mimics the process of gastrulation and axial body elongation of embryos. Because many birth defects are caused by dysregulation of cellular behaviors during embryogenesis, the morphogenesis model may serve as a unique tool to investigate the impacts of developmental toxicants. The aim of this study is to evaluate the applicability and limitations of the model using 20 therapeutic drugs, 16 of which are contraindicated in pregnancy and 4 are considered safe. P19C5 embryoid bodies (EBs) were exposed to different concentrations of drugs during 4 days of 3-dimensional culture. The treatment effects on growth and morphogenesis were analyzed using morphometric measurements of EB size and shape, respectively. Viability assays of P19C5 cells and NIH/3T3 fibroblasts were used to determine the drug concentrations that caused general cytotoxicity and those that selectively diminished P19C5 proliferation relative to NIH/3T3 proliferation. Thirteen contraindicated drugs diminished P19C5 cell proliferation, reduced EB growth, or altered morphogenesis at concentrations below generally cytotoxic levels. Two safe drugs also exhibited these impacts at the highest concentration tested. Although additional validation studies are required, this study introduces morphogenesis-based stem cell models as potentially effective in vitro tools for developmental toxicity research. PMID:26385866

  1. Effect of database profile variation on drug safety assessment: an analysis of spontaneous adverse event reports of Japanese cases

    Directory of Open Access Journals (Sweden)

    Nomura K

    2015-06-01

    Full Text Available Kaori Nomura,1 Kunihiko Takahashi,2 Yasushi Hinomura,3 Genta Kawaguchi,4 Yasuyuki Matsushita,5 Hiroko Marui,6 Tatsuhiko Anzai,7 Masayuki Hashiguchi,8 Mayumi Mochizuki8 1Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo, 2Department of Biostatistics, Nagoya University Graduate School of Medicine, Nagoya, 3Japan Pharmaceutical Information Center, 4Global Pharmacovigilance, Kissei Pharmaceutical Co Ltd, Tokyo, 5Medical Affairs Department, Daiichi Sankyo Co Ltd, 6Drug Safety Division, Chugai Pharmaceutical Co Ltd, 7Data Science Center, EPS Corporation, 8Faculty of Pharmacy, Keio University, Tokyo, Japan Background: The use of a statistical approach to analyze cumulative adverse event (AE reports has been encouraged by regulatory authorities. However, data variations affect statistical analyses (eg, signal detection. Further, differences in regulations, social issues, and health care systems can cause variations in AE data. The present study examined similarities and differences between two publicly available databases, ie, the Japanese Adverse Drug Event Report (JADER database and the US Food and Drug Administration Adverse Event Reporting System (FAERS, and how they affect signal detection.Methods: Two AE data sources from 2010 were examined, ie, JADER cases (JP and Japanese cases extracted from the FAERS (FAERS-JP. Three methods for signals of disproportionate reporting, ie, the reporting odds ratio, Bayesian confidence propagation neural network, and Gamma Poisson Shrinker (GPS, were used on drug-event combinations for three substances frequently recorded in both systems.Results: The two databases showed similar elements of AE reports, but no option was provided for a shareable case identifier. The average number of AEs per case was 1.6±1.3 (maximum 37 in the JP and 3.3±3.5 (maximum 62 in the FAERS-JP. Between 5% and 57% of all AEs were signaled by three quantitative methods for etanercept, infliximab, and

  2. Assessing the structural conservation of protein pockets to study functional and allosteric sites: implications for drug discovery

    Directory of Open Access Journals (Sweden)

    Daura Xavier

    2010-03-01

    Full Text Available Abstract Background With the classical, active-site oriented drug-development approach reaching its limits, protein ligand-binding sites in general and allosteric sites in particular are increasingly attracting the interest of medicinal chemists in the search for new types of targets and strategies to drug development. Given that allostery represents one of the most common and powerful means to regulate protein function, the traditional drug discovery approach of targeting active sites can be extended by targeting allosteric or regulatory protein pockets that may allow the discovery of not only novel drug-like inhibitors, but activators as well. The wealth of available protein structural data can be exploited to further increase our understanding of allosterism, which in turn may have therapeutic applications. A first step in this direction is to identify and characterize putative effector sites that may be present in already available structural data. Results We performed a large-scale study of protein cavities as potential allosteric and functional sites, by integrating publicly available information on protein sequences, structures and active sites for more than a thousand protein families. By identifying common pockets across different structures of the same protein family we developed a method to measure the pocket's structural conservation. The method was first parameterized using known active sites. We characterized the predicted pockets in terms of sequence and structural conservation, backbone flexibility and electrostatic potential. Although these different measures do not tend to correlate, their combination is useful in selecting functional and regulatory sites, as a detailed analysis of a handful of protein families shows. We finally estimated the numbers of potential allosteric or regulatory pockets that may be present in the data set, finding that pockets with putative functional and effector characteristics are widespread across

  3. Assessment of Unsuspected Exposure to Drugs of Abuse in Children from a Mediterranean City by Hair Testing

    Directory of Open Access Journals (Sweden)

    Simona Pichini

    2014-02-01

    Full Text Available Hair testing was used to investigate the prevalence of unsuspected exposure to drugs of abuse in a group of children presenting to an urban paediatric emergency department without suggestive signs or symptoms. Hair samples were obtained from 114 children between 24 months and 10 years of age attending the emergency room of Hospital del Mar in Barcelona, Spain. Hair samples from the accompanying parent were also collected. The samples were analyzed for the presence of opiates, cocaine, amphetamines, and cannabinoids by ultra-performance liquid chromatography-tandem mass spectrometry. Parental sociodemographics and possible drug of abuse history were recorded. Hair samples from twenty-three children (20.1% were positive for cocaine (concentration range 0.15–3.81 ng/mg hair, those of thirteen children (11.4% to cannabinoids (D9-THC concentration range 0.05–0.54 ng/mg hair, with four samples positive to codeine (0.1–0.25 ng/mg hair, one positive for 2.09 ng methadone per mg hair and one to 6-MAM (0.42 ng/mg hair and morphine (0. 15 ng/mg hair . In 69.5 and 69.2% of the positive cocaine and cannabinoids cases respectively, drugs was also found in the hair of accompanying parent. Parental sociodemographics were not associated with children exposure to drugs of abuse. However, the behavioural patterns with potential harmful effects for the child’s health (e.g., tobacco smoking, cannabis, benzodiazepines and/or antidepressants use were significantly higher in the parents of exposed children. In the light of the obtained results (28% overall children exposure to drugs of abuse and in agreement with 2009 unsuspected 23% cocaine exposure in pre-school children from the same hospital, we support general hair screening to disclose exposure to drugs of abuse in children from risky environments to provide the basis for specific social and health interventions.

  4. Assessment of gastrointestinal pH, fluid and lymphoid tissue in the guinea pig, rabbit and pig, and implications for their use in drug development.

    OpenAIRE

    Merchant, Hamid A.; McConnell, Emma L; Liu, Fang; Ramaswamy, Chandrasekaran; Kulkarni, Rucha P; Basit, Abdul W; Murdan, Sudaxshina

    2011-01-01

    Laboratory animals are often used in drug delivery and research. However, basic information about their gastrointestinal pH, fluid volume, and lymphoid tissue is not completely known. We have investigated these post-mortem in healthy guinea pigs, rabbits and pigs, to assess their suitability for pre-clinical studies by comparing the results with reported human literature. The mean gastric pH (fed ad libitum) was 2.9 and 4.4 in guinea pig and pig, respectively. In contrast, a very low pH (1.6)...

  5. Drug Facts

    Medline Plus

    Full Text Available ... Health Drug Abuse Hurts Bodies Drug Abuse Hurts Brains Drug Abuse and Mental Health Problems Often Happen Together The Link Between Drug Abuse and HIV/AIDS Recovery & Treatment Drug Treatment Facts Does Drug Treatment Work? Types of Drug Treatment What Is a Relapse? ...

  6. Assessment of drugs purchased in the public health network of the cities in the Ourinhos micro-region, Brazil

    OpenAIRE

    Obreli Neto, Paulo R.; Nambu, Maurício M.; Cuman, Roberto K. N.

    2011-01-01

    This study aims to evaluate the criteria and procedures for the selection of antidiabetic and antihypertensive drugs purchased by the public health network of the cities in the Ourinhos Micro-region, Sao Paulo, Brazil. A cross-sectional, multi-center, exploratory, quantitative study was developed in the 12 cities that constitute the Ourinhos Micro-region. The data obtained showed that cities standardize and purchase a large number and diverse range of pharmaceutical specialties, i...

  7. A Review of Computer-Based Interventions Used in the Assessment, Treatment, and Research of Drug Addiction

    OpenAIRE

    Bickel, Warren K.; Christensen, Darren R.; Marsch, Lisa A.

    2011-01-01

    Computer-based interventions are cost-efficient methods that may result in greater access to drug addiction treatment. We review recent findings from our laboratory where computer-based interventions have produced outcomes that are comparable to therapist-delivered interventions. We also examine how computer-based interventions targeting substance abuse disorders relate to cognitive functioning. This review will suggest that not only are computer-based interventions cost-efficient and accessi...

  8. Parallel Functional Activity Profiling Reveals Valvulopathogens Are Potent 5-Hydroxytryptamine2B Receptor Agonists: Implications for Drug Safety Assessment

    OpenAIRE

    Huang, Xi-Ping; Setola, Vincent; Yadav, Prem N.; Allen, John A.; Rogan, Sarah C.; Hanson, Bonnie J; Revankar, Chetana; Robers, Matt; Doucette, Chris; Roth, Bryan L.

    2009-01-01

    Drug-induced valvular heart disease (VHD) is a serious side effect of a few medications, including some that are on the market. Pharmacological studies of VHD-associated medications (e.g., fenfluramine, pergolide, methysergide, and cabergoline) have revealed that they and/or their metabolites are potent 5-hydroxytryptamine2B (5-HT2B) receptor agonists. We have shown that activation of 5-HT2B receptors on human heart valve interstitial cells in vitro induces a proliferative response reminiscen...

  9. Assessment of oral side effects of Antiepileptic drugs and traumatic oro-facial injuries encountered in Epileptic children

    OpenAIRE

    Ghafoor, P A Fazal; Rafeeq, Mohammed; Dubey, Alok

    2014-01-01

    Background: Epilepsy is a chronic disorder with unpredictably recurring seizure. Uncontrolled attacks can put patients at risk of suffering oro-facial trauma. Antiepileptic drugs (AED) provide satisfactory control of seizures in most of the patients with epilepsy. However use of AED has been found to cause many side effects inclusive of side effects in the oral cavity also. Materials & Methods: This study was conducted on 150 epileptic children, who were on anti epi...

  10. Preclinical Predictors of Anticancer Drug Efficacy: Critical Assessment with Emphasis on Whether Nanomolar Potency Should Be Required of Candidate Agents

    OpenAIRE

    Wong, C. C.; Cheng, Ka-Wing; Rigas, Basil

    2012-01-01

    In the current paradigm of anticancer drug development, candidate compounds are evaluated by testing their in vitro potency against molecular targets relevant to carcinogenesis, their effect on cultured cancer cells, and their ability to inhibit cancer growth in animal models. We discuss the key assumptions inherent in these approaches. In recent years, great emphasis has been placed on selecting for development compounds with nanomolar in vitro potency, expecting that they will be efficaciou...

  11. Correction for photobleaching in dynamic fluorescence microscopy: application in the assessment of pharmacokinetic parameters in ultrasound-mediated drug delivery

    Science.gov (United States)

    Derieppe, M.; Bos, C.; de Greef, M.; Moonen, C.; de Senneville, B. Denis

    2016-01-01

    We have previously demonstrated the feasibility of monitoring ultrasound-mediated uptake of a hydrophilic model drug in real time with dynamic confocal fluorescence microscopy. In this study, we evaluate and correct the impact of photobleaching to improve the accuracy of pharmacokinetic parameter estimates. To model photobleaching of the fluorescent model drug SYTOX Green, a photobleaching process was added to the current two-compartment model describing cell uptake. After collection of the uptake profile, a second acquisition was performed when SYTOX Green was equilibrated, to evaluate the photobleaching rate experimentally. Photobleaching rates up to 5.0 10-3 s-1 were measured when applying power densities up to 0.2 W.cm-2. By applying the three-compartment model, the model drug uptake rate of 6.0 10-3 s-1 was measured independent of the applied laser power. The impact of photobleaching on uptake rate estimates measured by dynamic fluorescence microscopy was evaluated. Subsequent compensation improved the accuracy of pharmacokinetic parameter estimates in the cell population subjected to sonopermeabilization.

  12. Drug interaction profile of the HIV integrase inhibitor cabotegravir: assessment from in vitro studies and a clinical investigation with midazolam.

    Science.gov (United States)

    Reese, Melinda J; Bowers, Gary D; Humphreys, Joan E; Gould, Elizabeth P; Ford, Susan L; Webster, Lindsey O; Polli, Joseph W

    2016-01-01

    1. Cabotegravir (CAB; GSK1265744) is a potent HIV integrase inhibitor in clinical development as an oral lead-in tablet and long-acting injectable for the treatment and prevention of HIV infection. 2. This work investigated if CAB was a substrate for efflux transporters, the potential for CAB to interact with drug-metabolizing enzymes and transporters to cause clinical drug interactions, and the effect of CAB on the pharmacokinetics of midazolam, a CYP3A4 probe substrate, in humans. 3. CAB is a substrate for Pgp and BCRP; however, its high intrinsic membrane permeability limits the impact of these transporters on its intestinal absorption. 4. At clinically relevant concentrations, CAB did not inhibit or induce any of the CYP or UGT enzymes evaluated in vitro and had no effect on the clinical pharmacokinetics of midazolam. 5. CAB is an inhibitor of OAT1 (IC50 0.81 µM) and OAT3 (IC50 0.41 µM) but did not or only weakly inhibited Pgp, BCRP, MRP2, MRP4, MATE1, MATE2-K, OATP1B1, OATP1B3, OCT1, OCT2 or BSEP. 6. Based on regulatory guidelines and quantitative extrapolations, CAB has a low propensity to cause clinically significant drug interactions, except for coadministration with OAT1 or OAT3 substrates. PMID:26340566

  13. Targeting the environmental assessment of veterinary drugs with the multi-species-soil system (MS centred dot 3) agricultural soil microcosms: the ivermectin case study

    International Nuclear Information System (INIS)

    The environmental risk assessment of the veterinary pharmaceutical ivermectin is receiving significant attention. This paper assesses the capacity of the MS centred dot 3 soil microcosm as a tool for targeting the environmental impact assessment of veterinary drugs, using ivermectin as model. Two screening MS centred dot 3 were performed using different European soils; one with a soil collected in an agricultural station near to Madrid, Spain and a second with a soil collected in a farm area close to York, UK. Soils were fortified with ivermectin at the following ranges: 0.01-10 mg kg-1 and 0.1-100 mg kg-1 in