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Sample records for antiangiogenic drug assessed

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    BACKGROUND: Angiogenesis is a mechanism, which tumors use to recruit oxygen and nutrients in order to maintain growth. The vascular endothelial growth factor family is the primary mediator of this process. For the last couple of decades, inhibition of angiogenesis has been the subject of extensiv...... mechanisms are necessary. Moreover, biomarker studies in future clinical investigations are important for the development of the next generation of anti-angiogenic drugs....... research, but so far anti-angiogenic drugs have only shown a modest effect. METHODS: This paper reviews four relevant anti-angiogenic drugs: bevacizumab, ramucirumab, nintedanib and sunitinib. The primary focus will be recent trials investigating the effects of the drugs in lung, breast...... 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...

  2. Antiangiogenic drugs used with chemotherapy for patients with recurrent ovarian cancer: a meta-analysis

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    Yi, SuYi; Zeng, LongJia; Kuang, Yan; Cao, ZhiJuan; Zheng, ChengJun; Zhang, Yue; Liao, Meng; Yang, Lu

    2017-01-01

    Objective The value of antiangiogenic inhibitors for patients with recurrent ovarian cancer has not been completely affirmed. Therefore, we aimed to assess the effectiveness and toxicities of various antiangiogenic drugs for the treatment of recurrent ovarian cancer. Methods In this meta-analysis, we searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials databases for complete randomized controlled trials. The searches were extended to May 15, 2016. The risk of bias of the included studies was evaluated via a Cochrane systematic evaluation, and the statistical analyses were performed using RevMan 5.2 software. Results In total, we included 8 randomized controlled trials involving 3,211 patients and divided them into 3 groups, vascular endothelial growth factor receptor inhibitors (VEGFRIs), vascular endothelial growth factor (VEGF) inhibitors (bevacizumab), and angiopoietin inhibitors (trebananib). The progression-free survival improved significantly in all the groups being given antiangiogenic drugs (hazard ratio [HR]: 0.55, 95% confidence interval [CI]: 0.45–0.67, I2=0%, Phypokalemia. Conclusion This meta-analysis showed that antiangiogenic drugs improved the progression-free survival. The VEGFRI, bevacizumab, and trebananib groups showed increased overall survival. Adding antiangiogenic drugs to chemotherapy treatment resulted in a higher incidence of grade 3/4 side effects, but these were manageable. PMID:28255243

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

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    Vincenza Granata

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

  4. Dual-targeting anti-angiogenic cyclic peptides as potential drug leads for cancer therapy

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    Chan, Lai Yue; Craik, David J.; Daly, Norelle L.

    2016-01-01

    Peptide analogues derived from bioactive hormones such as somatostatin or certain growth factors have great potential as angiogenesis inhibitors for cancer applications. In an attempt to combat emerging drug resistance many FDA-approved anti-angiogenesis therapies are co-administered with cytotoxic drugs as a combination therapy to target multiple signaling pathways of cancers. However, cancer therapies often encounter limiting factors such as high toxicities and side effects. Here, we combined two anti-angiogenic epitopes that act on different pathways of angiogenesis into a single non-toxic cyclic peptide framework, namely MCoTI-II (Momordica cochinchinensis trypsin inhibitor-II), and subsequently assessed the anti-angiogenic activity of the novel compound. We hypothesized that the combination of these two epitopes would elicit a synergistic effect by targeting different angiogenesis pathways and result in improved potency, compared to that of a single epitope. This novel approach has resulted in the development of a potent, non-toxic, stable and cyclic analogue with nanomolar potency inhibition in in vitro endothelial cell migration and in vivo chorioallantoic membrane angiogenesis assays. This is the first report to use the MCoTI-II framework to develop a 2-in-1 anti-angiogenic peptide, which has the potential to be used as a form of combination therapy for targeting a wide range of cancers. PMID:27734947

  5. Dopamine is a safe antiangiogenic drug which can also prevent 5-fluorouracil induced neutropenia.

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    Sarkar, Chandrani; Chakroborty, Debanjan; Dasgupta, Partha Sarathi; Basu, Sujit

    2015-08-01

    The role of vascular endothelial growth factor A (VEGFA) in tumor angiogenesis is well established and accordingly, molecules targeting VEGFA or its receptors are being presently used in the clinics for treatment of several types of cancer. However, these antiangiogenic agents are expensive and have serious side effects. Thus identification of newer drugs with manageable systemic side effects or toxicities is of immense clinical importance. Since we have reported earlier that dopamine (DA) inhibits VEGFA induced angiogenesis in experimental tumor models, we therefore sought to investigate whether DA treatment results in similar toxicities like other antiangiogenic agents. Our results indicated that unlike sunitinib, another commonly used antiangiogenic agent in the clinics which targets VEGF receptors, DA [50 mg/kg/days × 7days intraperitoneally (i.p.)] not only could inhibit tumor angiogenesis and growth of HT29 human colon cancer and LLC (Lewis lung carcinoma) in mice, it also did not cause hypertension, hematological, renal and hepatic toxicities in normal, HT29 and LLC tumor bearing animals. Furthermore and interestingly, in contrast to the currently used antiangiogenic agents, DA also prevented 5-fluorouracil (5FU) induced neutropenia in HT29 colon cancer bearing mice. This action of DA was through inhibition of 5FU mediated suppression of colony forming unit-granulocyte macrophage colony forming units in the bone marrow. Thus our results indicate that DA may be safely used as an antiangiogenic drug for the treatment of malignant tumors.

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

    OpenAIRE

    Ricardo Casaroli-Marano; Roberto Gallego-Pinazo; Clemencia Torrón Fernández-Blanco; Figueroa, Marta S.; Begoña Pina Marín; Gustavo Fernández-Baca Vaca; Antonio Piñero-Bustamante; Juan Donate López; José García-Arumí; Jordi Farrés Martí

    2014-01-01

    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 ...

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

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    R.-D. Hofheinz

    2016-01-01

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

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

    Science.gov (United States)

    Kubicka, S.; Falcone, A.; Burkholder, I.; Hacker, U. T.

    2016-01-01

    Background. In metastatic colorectal cancer (mCRC), continuing antiangiogenic drugs beyond progression might provide clinical benefit. We synthesized the available evidence in a meta-analysis. Patients and Methods. We conducted a meta-analysis of studies investigating the use of antiangiogenic drugs beyond progression. Eligible studies were randomized phase II/III trials. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints were the impact of continuing antiangiogenic drugs (i) in subgroups, (ii) in different types of compounds targeting the VEGF-axis (monoclonal antibodies versus tyrosine kinase inhibitors), and (iii) on remission rates and prevention of progression. Results. Eight studies (3,668 patients) were included. Continuing antiangiogenic treatment beyond progression significantly improved PFS (HR 0.64; 95%-CI, 0.55–0.75) and OS (HR 0.83; 95%-CI, 0.76–0.89). PFS was significantly improved in all subgroups with comparable HR. OS was improved in all subgroups stratified by age, gender, and ECOG status. The rate of patients achieving at least stable disease was improved with an OR of 2.25 (95%-CI, 1.41–3.58). Conclusions. This analysis shows a significant PFS and OS benefit as well as a benefit regarding disease stabilization when using antiangiogenic drugs beyond progression in mCRC. Future studies should focus on the optimal sequence of administering antiangiogenic drugs. PMID:27656206

  9. Angiogenesis and vascular malformations: Antiangiogenic drugs for treatment of gastrointestinal bleeding

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Treatment of gastrointestinal bleeding in patients with angiodysplasias and Osler's disease (hereditary hemorrhagic teleangiectasia) is clinically challenging.Frequently, vascular malformations occur as multiple disseminated lesions, making local treatment an unfavorable choice or impossible. After local therapy,lesions often recur at other sites of the intestine.However, as there are few therapeutic alternatives,repeated endoscopic coagulations or surgical resections are still performed to prevent recurrent bleeding.Hormonal therapy has been employed for more than 50 years but has recently been shown to be ineffective.Therefore, new therapeutic strategies are required.Understanding of the pathophysiology of angiogenesis and vascular malformations has recently substantially increased. Currently, multiple inhibitors of angiogenesis are under development for treatment of malignant diseases. Experimental and clinical data suggest that antiangiogenic substances, which were originally developed for treatment of malignant diseases, may also represent long-awaited specific drugs for the treatment of vascular malformations. However, antiangiogenics display significantly different actions and side-effects.Although antiangiogenics like thalidomide seem to inhibit gastrointestinal bleeding, other substances like bevacizumab can cause mucosal bleeding. Therefore differential and cautious evaluation of this therapeutic strategy is necessary.

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

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

    2012-04-15

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

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

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    Casaroli-Marano, Ricardo; Gallego-Pinazo, Roberto; Fernández-Blanco, Clemencia Torrón; Figueroa, Marta S; Pina Marín, Begoña; Fernández-Baca Vaca, Gustavo; Piñero-Bustamante, Antonio; Donate López, Juan; García-Arumí, José; Farrés Martí, Jordi

    2014-01-01

    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.

  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. Raman spectral study of anti-angiogenic drugs on the role of chick vascular

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    Huang, Ruixiang; Chen, Rong; Chen, Qisong; Lin, Juqiang; Pan, Jianji; Lin, Shaojun; Li, Chao; Li, Yongzeng; Feng, Shangyuan

    2009-08-01

    Inhibit angiogenesis is one of the important tumor therapy. If the mechanism of vascular changes can be detected at molecular level, it will have therapeutic significance. Raman spectroscopy, which can be applied to the structural analysis of solid, liquid or solution of biological molecules, is a non-destructive spectral technology holding very rich information. Basing on Confocal Raman Microscope, a unique system is developed for obtaining the different Raman spectra of the chick embryo vascular with the anti-angiogenic drugs - thalidomide and without. In the study, the location and shape of the average Raman spectra of vessels in drug 5h were very similar to the ones without medicine, and the intensity of some characteristic peaks changed, such as 1441cm-1,1527cm-1 and 1657cm-1 showing markedly increasing, while the 971cm-1 and 1081cm-1 decreasing. This change was due to anti- angiogenic drugs that caused the nucleic acid, protein, phospholipids, and other important biological molecules of the vessels on the structure or content tovary. PCA was used to distinguish between the two kinds of vascular with the result that they were accurately partitioned.The study indicated that Raman spectroscopy could be an effective tool for detection of the mechanism of vascular changes.

  16. Vertebrate embryos as tools for anti-angiogenic drug screening and function.

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    Beedie, Shaunna L; Diamond, Alexandra J; Fraga, Lucas Rosa; Figg, William D; Vargesson, Neil

    2016-11-22

    The development of new angiogenic inhibitors highlights a need for robust screening assays that adequately capture the complexity of vessel formation, and allow for the quantitative evaluation of the teratogenicity of new anti-angiogenic agents. This review discusses the use of screening assays in vertebrate embryos, specifically focusing upon chicken and zebrafish embryos, for the detection of anti-angiogenic agents.

  17. Targeted concurrent and sequential delivery of chemotherapeutic and antiangiogenic agents to the brain by using drug-loaded nanofibrous membranes

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    Tseng, Yuan-Yun; Yang, Tao-Chieh; Wang, Yi-Chuan; Lee, Wei-Hwa; Chang, Tzu-Min; Kau, Yi-Chuan; Liu, Shih-Jung

    2017-01-01

    Glioblastoma is the most frequent and devastating primary brain tumor. Surgery followed by radiotherapy with concomitant and adjuvant chemotherapy is the standard of care for patients with glioblastoma. Chemotherapy is ineffective, because of the low therapeutic levels of pharmaceuticals in tumor tissues and the well-known tumor-cell resistance to chemotherapy. Therefore, we developed bilayered poly(d,l)-lactide-co-glycolide nanofibrous membranes that enabled the sequential and sustained release of chemotherapeutic and antiangiogenic agents by employing an electrospinning technique. The release characteristics of embedded drugs were determined by employing an in vitro elution technique and high-performance liquid chromatography. The experimental results showed that the fabricated nanofibers showed a sequential drug-eluting behavior, with the release of high drug levels of chemotherapeutic carmustine, irinotecan, and cisplatin from day 3, followed by the release of high concentrations of the antiangiogenic combretastatin from day 21. Biodegradable multidrug-eluting nanofibrous membranes were then dispersed into the cerebral cavity of rats by craniectomy, and the in vivo release characteristics of the pharmaceuticals from the membranes were investigated. The results suggested that the nanofibrous membranes released high concentrations of pharmaceuticals for more than 8 weeks in the cerebral parenchyma of rats. The result of histological analysis demonstrated developmental atrophy of brains with no inflammation. Biodegradable nanofibrous membranes can be manufactured for long-term sequential transport of different chemotherapeutic and anti-angiogenic agents in the brain, which can potentially improve the treatment of glioblastoma multiforme and prevent toxic effects due to systemic administration.

  18. Anti-angiogenic drugs for second-line treatment of NSCLC patients: just new pawns on the chessboard?

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    Bronte, Giuseppe; Passiglia, Francesco; Galvano, Antonio; Russo, Antonio

    2016-01-01

    Tumor angiogenesis is one of the main pathways targeted to treat cancer. Bevacizumab added survival benefit when combined with platinum-based chemotherapy in NSCLC. Recently, Phase III trials showed survival benefit when anti-angiogenic drugs are added to docetaxel as second-line treatment for NSCLC. These anti-angiogenic agents include nintedanib and ramucirumab, a tyrosine-kinase inhibitor and a monoclonal antibody, respectively, which target receptors involved in angiogenesis. These studies have some similarities and differences. We propose a new algorithm for treatment sequences in performance status 0-1 patients with non-oncogene-addicted NSCLC type adenocarcinoma. Indeed clearer scientific evidences are available for this subgroup of patients.

  19. Deep sequencing reveals microRNAs predictive of antiangiogenic drug response

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    García-Donas, Jesús; Beuselinck, Benoit; Inglada-Pérez, Lucía; Graña, Osvaldo; Schöffski, Patrick; Wozniak, Agnieszka; Bechter, Oliver; Apellániz-Ruiz, Maria; Leandro-García, Luis Javier; Esteban, Emilio; Castellano, Daniel E.; González del Alba, Aranzazu; Climent, Miguel Angel; Hernando, Susana; Arranz, José Angel; Morente, Manuel; Pisano, David G.; Robledo, Mercedes

    2016-01-01

    The majority of metastatic renal cell carcinoma (RCC) patients are treated with tyrosine kinase inhibitors (TKI) in first-line treatment; however, a fraction are refractory to these antiangiogenic drugs. MicroRNAs (miRNAs) are regulatory molecules proven to be accurate biomarkers in cancer. Here, we identified miRNAs predictive of progressive disease under TKI treatment through deep sequencing of 74 metastatic clear cell RCC cases uniformly treated with these drugs. Twenty-nine miRNAs were differentially expressed in the tumors of patients who progressed under TKI therapy (P values from 6 × 10–9 to 3 × 10–3). Among 6 miRNAs selected for validation in an independent series, the most relevant associations corresponded to miR–1307-3p, miR–155-5p, and miR–221-3p (P = 4.6 × 10–3, 6.5 × 10–3, and 3.4 × 10–2, respectively). Furthermore, a 2 miRNA–based classifier discriminated individuals with progressive disease upon TKI treatment (AUC = 0.75, 95% CI, 0.64–0.85; P = 1.3 × 10–4) with better predictive value than clinicopathological risk factors commonly used. We also identified miRNAs significantly associated with progression-free survival and overall survival (P = 6.8 × 10–8 and 7.8 × 10–7 for top hits, respectively), and 7 overlapped with early progressive disease. In conclusion, this is the first miRNome comprehensive study, to our knowledge, that demonstrates a predictive value of miRNAs for TKI response and provides a new set of relevant markers that can help rationalize metastatic RCC treatment. PMID:27699216

  20. A novel imaging-based high-throughput screening approach to anti-angiogenic drug discovery.

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    Evensen, Lasse; Micklem, David R; Link, Wolfgang; Lorens, James B

    2010-01-01

    The successful progression to the clinic of angiogenesis inhibitors for cancer treatment has spurred interest in developing new classes of anti-angiogenic compounds. The resulting surge in available candidate therapeutics highlights the need for robust, high-throughput angiogenesis screening systems that adequately capture the complexity of new vessel formation while providing quantitative evaluation of the potency of these agents. Available in vitro angiogenesis assays are either cumbersome, impeding adaptation to high-throughput screening formats, or inadequately model the complex multistep process of new vessel formation. We therefore developed an organotypic endothelial-mural cell co-culture assay system that reflects several facets of angiogenesis while remaining compatible with high-throughput/high-content image screening. Co-culture of primary human endothelial cells (EC) and vascular smooth muscle cells (vSMC) results in assembly of a network of tubular endothelial structures enveloped with vascular basement membrane proteins, thus, comprising the three main components of blood vessels. Initially, EC are dependent on vSMC-derived VEGF and sensitive to clinical anti-angiogenic therapeutics. A subsequent phenotypic VEGF-switch renders EC networks resistant to anti-VEGF therapeutics, demarcating a mature vascular phenotype. Conversely, mature EC networks remain sensitive to vascular disrupting agents. Therefore, candidate anti-angiogenic compounds can be interrogated for their relative potency on immature and mature networks and classified as either vascular normalizing or vascular disrupting agents. Here, we demonstrate that the EC-vSMC co-culture assay represents a robust high-content imaging high-throughput screening system for identification of novel anti-angiogenic agents. A pilot high-throughput screening campaign was used to define informative imaging parameters and develop a follow-up dose-response scheme for hit characterization. High

  1. 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.

  2. 3D modeling of effects of increased oxygenation and activity concentration in tumors treated with radionuclides and antiangiogenic drugs

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

    2011-08-15

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

  3. Shared mechanism of teratogenicity of anti-angiogenic drugs identified in the chicken embryo model

    Science.gov (United States)

    Beedie, Shaunna L.; Mahony, Chris; Walker, Heather M.; Chau, Cindy H.; Figg, William D.; Vargesson, Neil

    2016-01-01

    Angiogenesis, the formation of new blood vessels, is essential for tumor growth, stabilization and progression. Angiogenesis inhibitors are now widely used in the clinic; however, there are relatively few published studies on the mechanism of their presumed teratogenic effects. To address this issue, we screened a variety of angiogenesis inhibitors in developing zebrafish and chicken embryo models to assess for developmental defects and potential teratogenic effects. We confirmed previous reports that sunitinib, sorafenib and TNP-470 are teratogenic and demonstrate that axitinib, pazopanib, vandetanib, and everolimus are also teratogens in these models. A dose response study identified the drugs inhibit HUVEC cell proliferation in vitro, and also target the developing blood vessels of embryos in vivo. This provides further evidence for the potential risk of fetal toxicity when using these drugs in a clinical setting, and emphasizes the importance of the development and maintenance of the vasculature in the embryo. We conclude that angiogenesis inhibitors, regardless of the molecular target, are teratogenic when exposed to chicken embryos. PMID:27443489

  4. Anti-angiogenic activity and antitumor efficacy of amphiphilic twin drug from ursolic acid and low molecular weight heparin

    Science.gov (United States)

    Cheng, Wenming; Zohra Dahmani, Fatima; Zhang, Juan; Xiong, Hui; Wu, Yuanyuan; Yin, Lifang; Zhou, Jianping; Yao, Jing

    2017-02-01

    Heparin, a potential blood anti-coagulant, is also known for its binding ability to several angiogenic factors through electrostatic interactions due to its polyanionic character. However, the clinical application of heparin for cancer treatment is limited by several drawbacks, such as unsatisfactory therapeutic effects and severe anticoagulant activity that could induce hemorrhaging. Herein, low molecular weight heparin (LMWH) was conjugated to ursolic acid (UA), which is also an angiogenesis inhibitor, by binding the amine group of aminoethyl-UA (UA-NH2) with the carboxylic groups of LMWH. The resulting LMWH-UA conjugate as an amphiphilic twin drug showed reduced anticoagulant activity and could also self-assemble into nanomicelles with a mean particle size ranging from 200-250 nm. An in vitro endothelial tubular formation assay and an in vivo Matrigel plug assay were performed to verify the anti-angiogenic potential of LMWH-UA. Meanwhile, the in vivo antitumor effect of LMWH-UA was also evaluated using a B16F10 mouse melanoma model. LMWH-UA nanomicelles were shown to inhibit angiogenesis both in vitro and in vivo. In addition, the i.v. administration of LMWH-UA to the B16F10 tumor-bearing mice resulted in a significant inhibition of tumor growth as compared to the free drug solutions. These findings demonstrate the therapeutic potential of LMWH-UA as a new therapeutic remedy for cancer therapy.

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

    Science.gov (United States)

    Tan, Fei; Mo, Xiao-hui; Zhao, Jian; Liang, Hui; Chen, Zhong-jian; Wang, Xiu-li

    2017-02-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

  7. 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.)

  8. Antiangiogenic drugs in the management of ocular diseases: Focus on antivascular endothelial growth factor

    Directory of Open Access Journals (Sweden)

    Yukio Sassa

    2010-04-01

    Full Text Available Yukio Sassa, Yasuaki HataDepartment of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, JapanAbstract: Age-related macular degeneration (AMD complications are the leading cause of severe vision loss among the aging population in the many western countries. The introduction of molecular inhibitors of vascular endothelial growth factor (VEGF, such as pegaptanib, ranibizumab, and bevacizumab, as treatments for wet AMD has provided new hope for affected patients. Now we have these treatment options, which have the possibility to improve or maintain visual acuity for patients suffering from AMD. The treatment needs to be optimized and this is in progress. Based on emerging evidence, adopting a variable VEGF inhibitor-dosing strategy guided by visual acuity assessment and optical coherence tomography are now being tried to reduce the frequency of injections. VEGF inhibitors in combination with photodynamic therapy are another way to optimize treatment. Physicians are waiting for new guidelines for the management of AMD and the results of current and upcoming trials systematically addressing these issues will be expected to provide it.Keywords: age-related macular degeneration, VEGF inhibitor, verteporfin, pegaptanib, ranibizumab, bevacizumab

  9. 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

  10. Antiangiogenic and Radiation Therapy

    Science.gov (United States)

    Ren, Ying; Fleischmann, Dominik; Foygel, Kira; Molvin, Lior; Lutz, Amelie M.; Koong, Albert C.; Jeffrey, R. Brooke; Tian, Lu; Willmann, Jürgen K.

    2015-01-01

    Objectives To assess early treatment effects on computed tomography (CT) perfusion parameters after antiangiogenic and radiation therapy in subcutaneously implanted, human colon cancer xenografts in mice and to correlate in vivo CT perfusion parameters with ex vivo assays of tumor vascularity and hypoxia. Materials and Methods Dynamic contrast-enhanced CT (perfusion CT, 129 mAs, 80 kV, 12 slices × 2.4 mm; 150 μL iodinated contrast agent injected at a rate of 1 mL/min intravenously) was performed in 100 subcutaneous human colon cancer xenografts on baseline day 0. Mice in group 1 (n = 32) received a single dose of the antiangiogenic agent bevacizumab (10 mg/kg body weight), mice in group 2 (n = 32) underwent a single radiation treatment (12 Gy), and mice in group 3 (n = 32) remained untreated. On days 1, 3, 5, and 7 after treatment, 8 mice from each group underwent a second CT perfusion scan, respectively, after which tumors were excised for ex vivo analysis. Four mice were killed after baseline scanning on day 0 for ex vivo analysis. Blood flow (BF), blood volume (BV), and flow extraction product were calculated using the left ventricle as an arterial input function. Correlation of in vivo CT perfusion parameters with ex vivo microvessel density and extent of tumor hypoxia were assessed by immunofluorescence. Reproducibility of CT perfusion parameter measurements was calculated in an additional 8 tumor-bearing mice scanned twice within 5 hours with the same CT perfusion imaging protocol. Results The intraclass correlation coefficients for BF, BV, and flow extraction product from repeated CT perfusion scans were 0.93 (95% confidence interval: 0.78, 0.97), 0.88 (0.66, 0.95), and 0.88 (0.56, 0.95), respectively. Changes in perfusion parameters and tumor volumes over time were different between treatments. After bevacizumab treatment, all 3 perfusion parameters significantly decreased from day 1 (P ≤ 0.006) and remained significantly decreased until day 7 (P ≤ 0

  11. Observation on the quality of life before and after the injection of antiangiogenic drug in the vitreous cavity of patients with wet age-related macular degeneration

    Institute of Scientific and Technical Information of China (English)

    Dan-Dan Wang; Pei-Ying Xu; Tian-Yu Wang; Xiao-Xia Chen; Qing Peng

    2015-01-01

    Objective:To explore the vision-related quality of life(VRQL) before and after the injection of antiangiogenic drug into the vitreous cavity of patients with wet age-related macular degeneration(AMD).Methods:The 2000 edition of the Visual Functioning Questionnaire 25 that was issued by the National Eye Institute was applied,and the VRQL evaluation was conducted on the initially diagnosed patients with wet-AMD before and after the injection of ranibizumab into the vitreous cavity.Results:Among the wet-AMD patients,patients with better distance visual acuity before the intravitreal injection had a lower VFQ-25 score.After the vitreous cavity injection,the VFQ-25 questionnaire score was related to patient care and education from the doctors and nurses;specifically,the better the nursing,the higher the score.Conclusions:Before the vitreous cavity injection,the degree of distance visual acuity is an important factor affecting the VRQL of wet-AMD patients.In addition,patient care and education from the doctors and nurses toward patients during the pre-,intra-and post-operation of the intravitreal injection are also important factors affecting the VRQL.

  12. 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

  13. Antiangiogenic therapy for breast cancer

    DEFF Research Database (Denmark)

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

    2010-01-01

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

  14. 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.

  15. Escaping Antiangiogenic Therapy: Strategies Employed by Cancer Cells

    Directory of Open Access Journals (Sweden)

    Mauricio P. Pinto

    2016-09-01

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

  16. 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.

  17. Anti-metastatic and anti-angiogenic properties of potential new anti-cancer drugs based on metal complexes of selenosemicarbazones.

    Science.gov (United States)

    Zec, Manja; Srdic-Rajic, Tatjana; Konic-Ristic, Aleksandra; Todorovic, Tamara; Andjelkovic, Katarina; Filipovic-Ljeskovic, Ivana; Radulovic, Sinisa

    2012-11-01

    Our previous studies showed that zinc (II), cadmium (II) and nickel (II) complexes with 2-formylpyridine selenosemicarbazone induce apoptosis in cancer cells via activation of mitochondrial pathway. Herein, we reported their antimetastatic properties. Nickel (II), and zinc (II) complexes exhibited the strongest inhibitory potential towards MMP-2/9, while all investigated compounds significantly decreased proteolytic activity of MMP-2/9 in human breast cancer MDA-MB-361 cells. As shown by in vitro transmembrane assays, nickel (II) complex was the most effective in inhibiting invasion of MDA-MB-361 cells, while the cadmium (II) complex was the most active in inhibiting HeLa cells invasion. In malignant cells, the complexes inhibited intracellular accumulation of reactive oxygen species, known for its pro-angiogenic properties via VEGF signaling, but no reduction in total cellular amount of VEGF was found. Furthermore, tubulogenesis test showed anti-angiogenic effect of the complexes in treated endothelial cells. Data indicate multiple mechanisms of the complexes' anti-angiogenic properties. In addition, they could modulate metastatic phenotype of tumor cells. Nickel (II) complex with 2-formylpyridine selenosemicarbazone revealed to be the most potent.

  18. Screening the antiangiogenic activity of medicinal plants grown and sold in Jordan.

    Science.gov (United States)

    Zihlif, Malek; Afifi, Fatma; Muhtaseb, Ruba; Al-Khatib, Sondos; Abaza, Ismail; Naffa, Randa

    2012-02-01

    Angiogenesis is essential for the growth, invasion, and metastasis of most solid tumors and has become a valuable pharmacological target for cancer prevention and treatment. This study was performed to assess the antiangiogenic activity of 31 medicinal plants grown and sold in Jordan. The antiangiogenic activity was assessed using the rat aortic ring assay. Out of 31 extracts, 15 extracts showed more than 50 % inhibition of the blood vessels outgrowth from the primary tissue explants (p = 0.000). Three of these 15 extracts showed a potential cytotoxic effect on normal fibroblast cells. Four extracts shared antiangiogenic and antiproliferative activity towards MCF7 breast cancer cell lines. Eight extracts demonstrated selective antiangiogenic activity. This is the first report demonstrating the potential antiangiogenic activity of Artemisia judaica, Aloysia citriodora, Salvia egyptiaca, and Calendula arvensis. Some extracts with antiangiogenic activity exhibited selectivity against the endothelial cells proliferation, demonstrating a direct inhibitory activity against the key step in tumor angiogenesis.

  19. Antiangiogenic therapies in ovarian cancer

    OpenAIRE

    Reinthaller, Alexander

    2016-01-01

    Summary Angiogenesis plays a pivotal role in normal ovarian physiology as well as in the formation and progression of ovarian cancer. Several well-designed phase II and III trials studied the efficacy of antiangiogenic agents in advanced ovarian cancer. The results of these trials demonstrated significantly prolonged progression-free survival when antiangiogenic agents were used as a maintenance therapy. To date, no effect on overall survival could be ascertained. The most widely studied anti...

  20. Role of the antiangiogenic agent bevacizumab in the treatment of elderly patients with metastatic colorectal cancer.

    Science.gov (United States)

    Di Bartolomeo, Maria; Pietrantonio, Filippo; Martinetti, Antonia; Buzzoni, Roberto; Gevorgyan, Arpine; Bajetta, Emilio

    2011-02-01

    Although major progress has been achieved in the treatment of metastatic colorectal cancer with the employment of biological antiangiogenic agents, several questions remain open for discussion regarding the use of this therapy in elderly patients with metastatic colorectal cancer. In Western countries, the total number of elderly patients with colorectal cancer is expected to increase in the future. As adverse physical or socioeconomic conditions are more common in the elderly, an assessment of the patient's suitability for this therapy should be performed before a treatment decision is made. Most patients in clinical trials of the antiangiogenic drug bevacizumab were aged <65 years and thus the efficacy and tolerability of this agent in older patients has been less well explored. However, this article shows that older and younger patients with metastatic colorectal cancer appeared to derive similar survival benefit from bevacizumab treatment. Elderly patients were also found to have significant prolongation of median progression-free survival with the addition of bevacizumab to their treatment, with a similar magnitude of improvement in this outcome being observed in younger and older patients. It should be emphasized that the patients included in the studies discussed in this article were eligible for clinical trials and therefore may not be representative of a more general elderly population. Careful selection of patients and monitoring of treatment effects are required to optimize use of the antiangiogenic agent bevacizumab in older patients.

  1. Computational systems biology approaches to anti-angiogenic cancer therapeutics.

    Science.gov (United States)

    Finley, Stacey D; Chu, Liang-Hui; Popel, Aleksander S

    2015-02-01

    Angiogenesis is an exquisitely regulated process that is required for physiological processes and is also important in numerous diseases. Tumors utilize angiogenesis to generate the vascular network needed to supply the cancer cells with nutrients and oxygen, and many cancer drugs aim to inhibit tumor angiogenesis. Anti-angiogenic therapy involves inhibiting multiple cell types, molecular targets, and intracellular signaling pathways. Computational tools are useful in guiding treatment strategies, predicting the response to treatment, and identifying new targets of interest. Here, we describe progress that has been made in applying mathematical modeling and bioinformatics approaches to study anti-angiogenic therapeutics in cancer.

  2. Antiangiogenic cancer treatment: The great discovery and greater complexity (Review)

    Science.gov (United States)

    Maj, Ewa; Papiernik, Diana; Wietrzyk, Joanna

    2016-01-01

    The discovery of tumor angiogenesis opened a new path in fighting cancer. The approval of different antiangiogenic agents, most targeting vascular endothelial growth factor (VEGF) signaling, has either increased the effectiveness of standard chemotherapy or even replaced it by offering better patient outcomes. However, an increasing number of preclinical and clinical observations have shown that the process of angiogenesis is far from clearly understood. Apart from targeting the VEGF pathway, novel strategies aim to influence other molecular factors that are involved in tumor angiogenesis. In addition, naturally occurring compounds seem to offer additional agents for influencing angiogenesis. The first concept of antiangiogenic therapy aimed to destroy tumor vessels, while it turned out that, paradoxically, antiangiogenic drugs normalized vasculature and as a result offered an improvement in chemotherapeutic delivery. In order to design an effective treatment schedule, methods for detecting the time window of normalization and biomarkers predicting patient response are needed. The initial idea that antiangiogenic therapy would be resistance-free failed to materialize and currently we still face the obstacle of resistance to antiangiogenic therapy.

  3. Tumour biology: Herceptin acts as an anti-angiogenic cocktail

    Science.gov (United States)

    Izumi, Yotaro; Xu, Lei; di Tomaso, Emmanuelle; Fukumura, Dai; Jain, Rakesh K.

    2002-03-01

    Malignant tumours secrete factors that enable them to commandeer their own blood supply (angiogenesis), and blocking the action of these factors can inhibit tumour growth. But because tumours may become resistant to treatments that target individual angiogenic factors by switching over to other angiogenic molecules, a cocktail of multiple anti-angiogenic agents should be more effective. Here we show that herceptin, a monoclonal antibody against the cell-surface receptor HER2 (for human epidermal growth factor receptor-2; ref. 4), induces normalization and regression of the vasculature in an experimental human breast tumour that overexpresses HER2 in mice, and that it works by modulating the effects of different pro- and anti-angiogenic factors. As a single agent that acts against multiple targets, herceptin, or drugs like it, may offer a simple alternative to combination anti-angiogenic treatments.

  4. Nanotherapeutics in angiogenesis: synthesis and in vivo assessment of drug efficacy and biocompatibility in zebrafish embryos

    Directory of Open Access Journals (Sweden)

    Cheng J

    2011-09-01

    Full Text Available Jinping Cheng1*, Yan-Juan Gu2*, Yajun Wang3, Shuk Han Cheng1, Wing-Tak Wong21Department of Biology and Chemistry, The City University of Hong Kong, Kowloon, 2Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, 3Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, People's Republic of China *These authors contributed equally to this work Background: Carbon nanotubes have shown broad potential in biomedical applications, given their unique mechanical, optical, and chemical properties. In this pilot study, carbon nanotubes have been explored as multimodal drug delivery vectors that facilitate antiangiogenic therapy in zebrafish embryos. Methods: Three different agents, ie, an antiangiogenic binding site (cyclic arginine-glycine-aspartic acid, an antiangiogenic drug (thalidomide, and a tracking dye (rhodamine, were conjugated onto single-walled carbon nanotubes (SWCNT. The biodistribution, efficacy, and biocompatibility of these triple functionalized SWCNT were tested in mammalian cells and validated in transparent zebrafish embryos. Results: Accumulation of SWCNT-associated nanoconjugates in blastoderm cells facilitated drug delivery applications. Mammalian cell xenograft assays demonstrated that these antiangiogenic SWCNT nanoconjugates specifically inhibited ectopic angiogenesis in the engrafted zebrafish embryos. Conclusion: This study highlights the potential of using SWCNT for generating efficient nanotherapeutics. Keywords: carbon nanotubes, drug delivery, antiangiogenic therapy

  5. Observation on the quality of life before and after the injection of antiangiogenic drug in the vitreous cavity of patients with wet age-related macular de-generation

    Institute of Scientific and Technical Information of China (English)

    Dan-Dan Wang; Pei-Ying Xu; Tian-Yu Wang; Xiao-Xia Chen; Qing Peng

    2015-01-01

    Objective: To explore the vision-related quality of life ( VRQL) before and after the injection of antiangiogenic drug into the vitreous cavity of patients with wet age-related macular degeneration ( AMD) . Methods: The 2000 edition of the Visual Functioning Questionnaire 25 that was issued by the Na-tional Eye Institute was applied, and the VRQL evaluation was conducted on the initially diagnosed patients with wet-AMD before and after the injection of ranibizumab into the vitreous cavity. Results: Among the wet-AMD patients, patients with better distance visual acuity before the in-travitreal injection had a lower VFQ-25 score. After the vitreous cavity injection, the VFQ-25 questionnaire score was related to patient care and education from the doctors and nurses; specific-ally, the better the nursing, the higher the score. Conclusions: Before the vitreous cavity injection, the degree of distance visual acuity is an im-portant factor affecting the VRQL of wet-AMD patients. In addition, patient care and education from the doctors and nurses toward patients during the pre-, intra-and post-operation of the intrav-itreal injection are also important factors affecting the VRQL.

  6. Optimal combination of antiangiogenic therapy forhepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    The success of sorafenib in prolonging survival of patientswith hepatocellular carcinoma (HCC) makes therapeuticinhibition of angiogenesis a component of treatmentfor HCC. To enhance therapeutic efficacy, overcome drug resistance and reduce toxicity, combination ofantiangiogenic agents with chemotherapy,radiotherapyor other targeted agents were evaluated. Nevertheless,the use of antiangiogenic therapy remains suboptimalregarding dosage, schedule and duration of therapy.The issue is further complicated by combinationantiangiogenesis to other cytotoxic or biologic agents.There is no way to determine which patients are mostlikely respond to a given form of antiangiogenic therapy.Activation of alternative pathways associated with diseaseprogression in patients undergoing antiangiogenictherapy has also been recognized. There is increasingimportance in identifying, validating and standardizingpotential response biomarkers for antiangiogenesistherapy for HCC patients. In this review, biomarkers forantiangiogenesis therapy including systemic, circulating,tissue and imaging ones are summarized. The strengthand deficit of circulating and imaging biomarkerswere further demonstrated by a series of studies inHCC patients receiving radiotherapy with or withoutthalidomide.

  7. 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.

  8. Drug Safety Assessment:An Urgent Task

    Institute of Scientific and Technical Information of China (English)

    Guo Haiyan; Zhao Baohua

    2002-01-01

    @@ A CAS scientist has pointed out at an international symposium that it is important for China to step up its efforts in drug safety assessment to address a hidden peril in China's pharmaceuticals industry.

  9. [Antiangiogenic agents in ARMD treatment].

    Science.gov (United States)

    Coroi, Mihaela-Cristiana; Demea, Sorina; Todor, Meda; Apopei, Emmanuela

    2012-01-01

    The aim of antiangiogenic agents in the treatment of age related senile macular degeneration is to destroy coroidian neoformation vessels by minimally affecting the central vision. We present a case of important central vision recovery after 3 intravitreal injections of Avastin. The therapeutic decision and patient monitoring have been made using imaging studies, such as OCT and AFG. A modern therapeutic approach of neovascular forms of age related macular degeneration, backed up by AFG and OCT is a modern treatment method of this disabling illness which brings patients optimal functional and structural improvement.

  10. Current protein-based anti-angiogenic therapeutics.

    Science.gov (United States)

    Chakrabarti, Sanjukta; Barrow, Colin J; Kanwar, Rupinder K; Ramana, Venkata; Kanwar, Jagat R

    2014-01-01

    Angiogenesis is a multistep process for the formation of new blood vessels. Interactions between several cellular factors including growth factors, cytokines and hematopoietic factors lead to activation of various cellular pathways finally resulting in the extracellular matrix (ECM) degradation, endothelial cell proliferation, survival and migration. Normally, angiogenesis is an essential requirement for vascular development in growing embryos as well as in adult tissues where this process depends on the intricate balance between the activities of the pro- and anti-angiogenic factors. Abnormal angiogenesis results in aberrant vasculature leading to various pathological conditions. The most important factor implicated in angiogenic processes is vascular endothelial growth factor (VEGF) and its family of ligands and receptors. Several anti-angiogenic drugs have been developed and many more are currently in different phases of clinical trials, which target various angiogenesis-inducing agents including VEGF, VEGF receptors, angiopoietins and ECM components such as integrins. Anti-angiogenic therapy can be divided into gene-based therapy and protein-based therapy. Gene-based therapies include the use of antisense oligonucleotides, siRNA, aptamers, catalytic oligonucleotides including ribozymes and DNAzymes and transcription decoys. Protein-based therapeutics includes monoclonal antibodies, peptidomimetics, fusion proteins and decoy receptors. The later class of therapeutics has several advantages over gene-based and small molecule drugs, including specificity and complexity in functions, better tolerability, less interference with normal biological processes and lesser adverse effects due to decreased immune response by virtue of being mostly body's natural proteins. This review provides a comprehensive overview of angiogenesis and on the current protein-based anti-angiogenic therapeutics under research and in the clinic.

  11. Assessment of cutaneous drug delivery using microdialysis

    DEFF Research Database (Denmark)

    Kreilgaard, Mads

    2002-01-01

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

  12. In vitro and ex vivo antiangiogenic activity of Salvia officinalis.

    Science.gov (United States)

    Keshavarz, Maryam; Mostafaie, Ali; Mansouri, Kamran; Bidmeshkipour, Ali; Motlagh, Hamid Reza Mohammadi; Parvaneh, Shahram

    2010-10-01

    Angiogenesis is a key process in the promotion of cancer and its metastasis. Herein, the antiangiogenic activity of Salvia officinalis extract and its fractions was investigated. S. officinalis aerial parts were extracted with ethanol and its successive hexane, ethyl acetate, n-butanol and aqueous fractions were evaluated for their antiangiogenic activities using human umbilical vein endothelial cells (HUVEC) capillary tube formation and rat aorta models in a three-dimensional collagen matrix. Furthermore, antimigrative effects of the fractions were assessed using a wound healing model. The ethanol extract of S. officinalis (ESO) potently inhibited capillary tube formation in HUVEC and rat aorta models of angiogenesis, and its hexane fraction (HSO) exerted the highest inhibitory effect. In addition, the ethanol extract of S. officinalis and its hexane fraction showed a dose-dependent inhibitory activity on the migration of the endothelial cells in the wound healing model. Furthermore, ESO inhibited endothelial cell proliferation at 50-200 μg/mL in a dose-dependent manner. These findings indicated some new pharmacological activities of S. officinalis such as antiangiogenic in vitro and ex vivo, and antimigrative activity in vitro. Therefore, S. officinalis could be a candidate as a useful herb with therapeutic or preventive activity against angiogenesis related disorders.

  13. 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

  14. 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

  15. Assessing the proarrhythmic potential of drugs

    DEFF Research Database (Denmark)

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

    2006-01-01

    Torsades de pointes (TdP) is a potentially lethal cardiac arrhythmia that can occur as an unwanted adverse effect of various pharmacological therapies. Before a drug is approved for marketing, its effects on cardiac repolarisation are examined clinically and experimentally. This paper expresses...... the opinion that effects on repolarisation duration cannot directly be translated to risk of proarrhythmia. Current safety assessments of drugs only involve repolarisation assays, however the proarrhythmic profile can only be determined in the predisposed model. The availability of these proarrhythmic animal...... 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...

  16. 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.

  17. Monitoring Response to Antiangiogenic Therapy in Non-Small Cell Lung Cancer Using Imaging Markers Derived from PET and Dynamic Contrast-Enhanced MRI

    NARCIS (Netherlands)

    de Langen, Adrianus J.; van den Boogaart, Vivian; Lubberink, Mark; Backes, Walter H.; Marcus, Johannes T.; van Tinteren, Harm; Pruim, Jan; Brans, Boudewijn; Leffers, Pieter; Dingemans, Anne-Marie C.; Smit, Egbert F.; Groen, Harry J. M.; Hoekstra, Otto S.

    2011-01-01

    With antiangiogenic agents, tumor shrinkage may be absent, despite survival benefit. The present study assessed the predictive value of molecular imaging for the identification of survival benefit during antiangiogenic treatment with bevacizumab and erlotinib in patients with advanced non-small cell

  18. Quantitative methods for assessing drug synergism.

    Science.gov (United States)

    Tallarida, Ronald J

    2011-11-01

    Two or more drugs that individually produce overtly similar effects will sometimes display greatly enhanced effects when given in combination. When the combined effect is greater than that predicted by their individual potencies, the combination is said to be synergistic. A synergistic interaction allows the use of lower doses of the combination constituents, a situation that may reduce adverse reactions. Drug combinations are quite common in the treatment of cancers, infections, pain, and many other diseases and situations. The determination of synergism is a quantitative pursuit that involves a rigorous demonstration that the combination effect is greater than that which is expected from the individual drug's potencies. The basis of that demonstration is the concept of dose equivalence, which is discussed here and applied to an experimental design and data analysis known as isobolographic analysis. That method, and a related method of analysis that also uses dose equivalence, are presented in this brief review, which provides the mathematical basis for assessing synergy and an optimization strategy for determining the dose combination.

  19. Angiogenesis and antiangiogenic agents in cervical cancer

    Directory of Open Access Journals (Sweden)

    Tomao F

    2014-12-01

    Full Text Available Federica Tomao,1 Anselmo Papa,2 Luigi Rossi,2 Eleonora Zaccarelli,2 Davide Caruso,2 Federica Zoratto,2 Pierluigi Benedetti Panici,1 Silverio Tomao2 1Department of Gynecology and Obstetrics, Sapienza University of Rome, Policlinico Umberto I, Rome, 2Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Oncology Unit, ICOT, Latina, Italy Abstract: Standard treatment of cervical cancer (CC consists of surgery in the early stages and of chemoradiation in locally advanced disease. Metastatic CC has a poor prognosis and is usually treated with palliative platinum-based chemotherapy. Current chemotherapeutic regimens are associated with significant adverse effects and only limited activity, making identification of active and tolerable novel targeted agents a high priority. Angiogenesis is a complex process that plays a crucial role in the development of many types of cancer. The dominant role of angiogenesis in CC seems to be directly related to human papillomavirus-related inhibition of p53 and stabilization of hypoxia-inducible factor-1α. Both of these mechanisms are able to increase expression of vascular endothelial growth factor (VEGF. Activation of VEGF promotes endothelial cell proliferation and migration, favoring formation of new blood vessels and increasing permeability of existing blood vessels. Since bevacizumab, a recombinant humanized monoclonal antibody binding to all isoforms of VEGF, has been demonstrated to significantly improve survival in gynecologic cancer, some recent clinical research has explored the possibility of using novel therapies directed toward inhibition of angiogenesis in CC too. Here we review the main results from studies concerning the use of antiangiogenic drugs that are being investigated for the treatment of CC. Keywords: cervical cancer, angiogenesis, human papillomavirus, bevacizumab, target therapies

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

    Science.gov (United States)

    Sylvest, Lene; Friis, Tina; Staerk, Dan; Jørgensen, Flemming Steen; Olsen, Christian A.; Houen, Gunnar

    2012-01-01

    Inhibition of angiogenesis is a promising addition to current cancer treatment strategies. Neutralization of vascular endothelial growth factor by monoclonal antibodies is clinically effective but may cause side effects due to thrombosis. Low molecular weight angiogenesis inhibitors are currently less effective than antibody treatment and are also associated with serious side effects. The discovery of new chemotypes with efficient antiangiogenic activity is therefore of pertinent interest. (S)-Levamisole hydrochloride, an anthelminthic drug approved for human use and with a known clinical profile, was recently shown to be an inhibitor of angiogenesis in vitro and exhibited tumor growth inhibition in mice. Here we describe the synthesis and in vitro evaluation of a series of N-alkylated analogues of levamisole with the aim of characterizing structure–activity relationships with regard to inhibition of angiogenesis. N-Methyllevamisole and p-bromolevamisole proved more effective than the parent compound, (S)-levamisole hydrochloride, with respect to inhibition of angiogenesis and induction of undifferentiated cluster morphology in human umbilical vein endothelial cells grown in co-culture with 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 exhibiting antiangiogenic effects in vitro are thus described, and further investigation of their underlying mechanism of action is warranted. PMID:23024819

  1. Synthesis and antiangiogenic activity of N-alkylated levamisole derivatives.

    Directory of Open Access Journals (Sweden)

    Anders N Hansen

    Full Text Available Inhibition of angiogenesis is a promising addition to current cancer treatment strategies. Neutralization of vascular endothelial growth factor by monoclonal antibodies is clinically effective but may cause side effects due to thrombosis. Low molecular weight angiogenesis inhibitors are currently less effective than antibody treatment and are also associated with serious side effects. The discovery of new chemotypes with efficient antiangiogenic activity is therefore of pertinent interest. (S-levamisole hydrochloride, an anthelminthic drug approved for human use and with a known clinical profile, was recently shown to be an inhibitor of angiogenesis in vitro and exhibited tumor growth inhibition in mice. Here we describe the synthesis and in vitro evaluation of a series of N-alkylated analogues of levamisole with the aim of characterizing structure-activity relationships with regard to inhibition of angiogenesis. N-methyllevamisole and p-bromolevamisole proved more effective than the parent compound, (S-levamisole hydrochloride, with respect to inhibition of angiogenesis and induction of undifferentiated cluster morphology in human umbilical vein endothelial cells grown in co-culture with 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 exhibiting antiangiogenic effects in vitro are thus described, and further investigation of their underlying mechanism of action is warranted.

  2. STUDY OF IDENTIFICATION AND ASSESSMENT OF DRUG - DRUG INTERACTIONS

    Directory of Open Access Journals (Sweden)

    Shekar

    2014-02-01

    Full Text Available INTRODUCTION : Drugdrug interactions can be defined as pharmacological or clinical respons e to the administration of drug combination s that is different from its known effects of two or more than two medicines. It frequently conjures images of a sudden catastrophic and even fatal outcome. While such an event can occur and it is important to prevent in the clinical set up. Drug interactio ns can occur by pharmacokinetic & pharmacodynamic interactions. The antipsychotics are known to have more drug interactions compared to any other class of drugs hence we aimed for the identification of drug interactions of psychiatric drugs. METHODOLOGY : T he data was collected from medication chart of inpatients in the psychiatric department and analyzed the interactions using Stockley’s drug interactions , Dipiro etc. RESULTS AND DISCUSSION : The study includes 508 samples out of which 368 case were found to have interactions. The cobalamine and panto prazole interactions were found to be 36.14% and the combination of antipsychotics , anticonvulsants with anxiolytics and anticonvulsants were 10.22 %

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

    Data.gov (United States)

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

  4. Inulin based micelles loaded with curcumin or celecoxib with effective anti-angiogenic activity.

    Science.gov (United States)

    Mandracchia, Delia; Tripodo, Giuseppe; Trapani, Adriana; Ruggieri, Simona; Annese, Tiziana; Chlapanidas, Theodora; Trapani, Giuseppe; Ribatti, Domenico

    2016-10-10

    Curcumin (CUR) and celecoxib (CLX) are two highly hydrophobic drugs which show bioavailability problems due to their poor aqueous solubility. The aim of this study was to encapsulate each of these drugs in micelles based on biodegradable and amphiphilic polymers to investigate their anti-angiogenesis activity. Here we use an amphiphilic polymer, based on two natural substances from renewable resources (Inulin and Vitamin E, INVITE), as a self-assembling system for the drug delivery of CUR and CLX. By the in vivo assay of chick embryo chorioallantoic membrane (CAM) it was assessed that both INVITE-CUR and INVITE-CLX micelles possess remarkable anti-angiogenic activity, while the INVITE micelles alone resulted intrinsically pro-angiogenic. Furthermore, it has been shown that encapsulation of CUR and CLX in INVITE micelles enhances of several magnitudes the water-solubility of CUR and CLX (14·10(5) and 3·10(2) times for CUR and CLX, respectively). These results may have interesting implications not only in anticancer or diabetic maculopathy therapy based on the anti-angiogenesis strategy but also for regenerative medicine where over-production of new vessels is required.

  5. Antiangiogenic therapy for breast cancer

    DEFF Research Database (Denmark)

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

    2010-01-01

    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...

  6. Antiangiogenic strategies in medulloblastoma: reality or mystery.

    Science.gov (United States)

    Grizzi, Fabio; Weber, Christina; Di Ieva, Antonio

    2008-05-01

    Medulloblastoma is the most common malignant brain tumor of childhood. Surgery, radiation therapy, and chemotherapy successfully cure many patients, but survivors can suffer long-term toxicities affecting their neurocognitive and growth potential; furthermore, there is no curative therapy in up to 30% of cases, mainly because of our incomplete understanding of many of the underlying molecular and cellular processes. Angiogenesis is a hallmark of the progression of medulloblastoma and, over the last years, investigators have sought to develop effective and less toxic antiangiogenic strategies, including the inhibition or destruction of abnormal blood vessels using either antiangiogenic or vascular disrupting agents. However, the results are conflicting principally because of the complex biology of tumor vasculature and the irregular geometry of the vascular system in real space. In addition, current targets of antiangiogenic therapy, such as vascular endothelial growth factor (VEGF), are thought to be critical for both physiologic and pathologic angiogenesis, and clinical side effects of anti-VEGF therapy are beginning to emerge. We here review the state-of-the-art concerning antiangiogenic targets for medulloblastoma treatment, and discuss the complexity of the vascular system that intrinsically limits the efficacy of current strategies.

  7. Experienced drug users assess the relative harms and benefits of drugs: a web-based survey.

    Science.gov (United States)

    Carhart-Harris, Robin Lester; Nutt, David John

    2013-01-01

    A web-based survey was used to consult the opinions of experienced drug users on matters related to drug harms. We identified a rare sample of 93 drug users with personal experience with 11 different illicit drugs that are widely used in the UK. Asked to assess the relative harms of these drugs, they ranked alcohol and tobacco as the most harmful, and three "Class A" drugs (MDMA, LSD, and psilocybin) and one class B (cannabis) were ranked as the four least harmful drugs. When asked to assess the relative potential for benefit of the 11 drugs, MDMA, LSD, psilocybin, and cannabis were ranked in the top four; and when asked why these drugs are beneficial, rather than simply report hedonic properties, they referred to potential therapeutic applications (e.g., as tools to assist psychotherapy). These results provide a useful insight into the opinions of experienced drug users on a subject about which they have a rare and intimate knowledge.

  8. 抑制血管生成治疗肿瘤的策略和展望%Current Strategies and Future Directions of Antiangiogenic Tumor Therapy

    Institute of Scientific and Technical Information of China (English)

    张紫莱; 王晋慧; 刘新垣

    2003-01-01

    , including antiangiogenic gene therapy strategy, targeted drug delivery system, and the combination of antiangiogenic agents with immunotherapy, chemotherapy or radiotherapy are being explored. With the development of tumor model assessment system, clinical use of the above antiangiogenic tumor therapy methods could be achieved.

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

    Directory of Open Access Journals (Sweden)

    Larissa de Godoy Borges

    2003-01-01

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

  10. Radiotherapy and antiangiogenic TM in lung cancer.

    Science.gov (United States)

    Khan, Mohamed K; Miller, Meredith W; Taylor, Jeremy; Gill, Navkiranjit K; Dick, Robert D; Van Golen, Kenneth; Brewer, George J; Merajver, Sofia D

    2002-01-01

    Tetrathiomolybdate (TM) is a potent nontoxic orally delivered copper complexing agent under development for the last several years for the treatment of Wilson's disease. It has been shown to block angiogenesis in primary and metastatic tumors. Therefore, the combination of cytotoxic radiotherapy (RT) and antiangiogenic TM could target both the existing tumor and the tumor microvasculature in a comprehensive strategy. Using a Lewis lung high metastatic (LLHM) carcinoma mouse tumor model, we demonstrate that the combination of TM and RT is more effective than either used as monotherapy. We also show that their therapeutic effects are additive, with no additional toxicity. We show that TM has no significant cytotoxicity in vitro against LLHM tumor cells, further supporting the antiangiogenic mechanism for its action.

  11. Radiotherapy and Antiangiogenic TM in Lung Cancer

    Directory of Open Access Journals (Sweden)

    Mohamed K. Khan

    2002-01-01

    Full Text Available Tetrathiomolybdate (TM is a potent nontoxic orally delivered copper complexing agent under development for the last several years for the treatment of Wilson's disease. It has been shown to block angiogenesis in primary and metastatic tumors. Therefore, the combination of cytotoxic radiotherapy (RT and antiangiogenic TM could target both the existing tumor and the tumor microvasculature in a comprehensive strategy. Using a Lewis lung high metastatic (LLHM carcinoma mouse tumor model, we demonstrate that the combination of TM and RT is more effective than either used as monotherapy. We also show that their therapeutic effects are additive, with no additional toxicity. We show that TM has no significant cytotoxicity in vitro against LLHM tumor cells, further supporting the antiangiogenic mechanism for its action.

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

    Directory of Open Access Journals (Sweden)

    Roger Bate

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

  13. Antiangiogenic VEGF Isoform in Inflammatory Myopathies

    Directory of Open Access Journals (Sweden)

    Nila Volpi

    2013-01-01

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

  14. 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.)

  15. Quantitative Methods for Assessing Drug Synergism

    OpenAIRE

    Tallarida, Ronald J.

    2011-01-01

    Two or more drugs that individually produce overtly similar effects will sometimes display greatly enhanced effects when given in combination. When the combined effect is greater than that predicted by their individual potencies, the combination is said to be synergistic. A synergistic interaction allows the use of lower doses of the combination constituents, a situation that may reduce adverse reactions. Drug combinations are quite common in the treatment of cancers, infections, pain, and ma...

  16. Exploratory and regulatory assessments on photosafety of new drug entities.

    Science.gov (United States)

    Seto, Yoshiki; Hosoi, Kazuhiro; Takagi, Hironori; Nakamura, Kazuichi; Kojima, Hajime; Yamada, Shizuo; Onoue, Satomi

    2012-04-01

    Drug-induced phototoxicity is elicited after exposure of the skin and/or eyes to topically or systemically administered pharmaceutical substances, followed by exposure to sunlight. This undesirable side effect is one of the impediments in drug discovery and development, and substantial efforts have been made to avoid drug-induced phototoxic reactions. To evaluate the phototoxic potential of compounds, effective methodologies have been developed over the past few years, and screening strategies have also been proposed for predicting in vivo phototoxic reactions. European and American regulatory agencies have published guidelines for predicting and avoiding drug-induced phototoxicity in an early phase of drug discovery. The guidelines have indicated the requirements for assessing the photosafety of chemicals on the basis of their photochemical behaviors and have recommended some phototoxic assessment tools for aiding new drug development. A number of phototoxic screening systems have also been proposed on the basis of the pathogenesis of drug-induced phototoxicity, and some of them have already been applied to the phototoxic evaluation of new drug entities in drug discovery and development. The present review aims to summarize the current status of research tools, screening strategy and regulations for evaluating the photosafety of new drug candidates and to introduce our thoughts on the phototoxic risk assessments of compounds.

  17. Designer drugs 2015: assessment and management.

    Science.gov (United States)

    Weaver, Michael F; Hopper, John A; Gunderson, Erik W

    2015-01-01

    Recent designer drugs, also known as "legal highs," include substituted cathinones (e.g., mephedrone, methylone, and methylenedioxypyrovalerone, often referred to as "bath salts"); synthetic cannabinoids (SCs; e.g., Spice); and synthetic hallucinogens (25I-NBOMe, or N-bomb). Compound availability has evolved rapidly to evade legal regulation and detection by routine drug testing. Young adults are the primary users, but trends are changing rapidly; use has become popular among members of the military. Acute toxicity is common and often manifests with a constellation of psychiatric and medical effects, which may be severe (e.g., anxiety, agitation, psychosis, and tachycardia), and multiple deaths have been reported with each of these types of designer drugs. Clinicians should keep designer drugs in mind when evaluating substance use in young adults or in anyone presenting with acute neuropsychiatric complaints. Treatment of acute intoxication involves supportive care targeting manifesting signs and symptoms. Long-term treatment of designer drug use disorder can be challenging and is complicated by a lack of evidence to guide treatment.

  18. 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

  19. 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

  20. 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.

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

    Directory of Open Access Journals (Sweden)

    Eduardo Büchele Rodrigues

    2006-10-01

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

  2. Assessing drug target association using semantic linked data.

    Directory of Open Access Journals (Sweden)

    Bin Chen

    Full Text Available The rapidly increasing amount of public data in chemistry and biology provides new opportunities for large-scale data mining for drug discovery. Systematic integration of these heterogeneous sets and provision of algorithms to data mine the integrated sets would permit investigation of complex mechanisms of action of drugs. In this work we integrated and annotated data from public datasets relating to drugs, chemical compounds, protein targets, diseases, side effects and pathways, building a semantic linked network consisting of over 290,000 nodes and 720,000 edges. We developed a statistical model to assess the association of drug target pairs based on their relation with other linked objects. Validation experiments demonstrate the model can correctly identify known direct drug target pairs with high precision. Indirect drug target pairs (for example drugs which change gene expression level are also identified but not as strongly as direct pairs. We further calculated the association scores for 157 drugs from 10 disease areas against 1683 human targets, and measured their similarity using a [Formula: see text] score matrix. The similarity network indicates that drugs from the same disease area tend to cluster together in ways that are not captured by structural similarity, with several potential new drug pairings being identified. This work thus provides a novel, validated alternative to existing drug target prediction algorithms. The web service is freely available at: http://chem2bio2rdf.org/slap.

  3. Assessing drug target association using semantic linked data.

    Science.gov (United States)

    Chen, Bin; Ding, Ying; Wild, David J

    2012-01-01

    The rapidly increasing amount of public data in chemistry and biology provides new opportunities for large-scale data mining for drug discovery. Systematic integration of these heterogeneous sets and provision of algorithms to data mine the integrated sets would permit investigation of complex mechanisms of action of drugs. In this work we integrated and annotated data from public datasets relating to drugs, chemical compounds, protein targets, diseases, side effects and pathways, building a semantic linked network consisting of over 290,000 nodes and 720,000 edges. We developed a statistical model to assess the association of drug target pairs based on their relation with other linked objects. Validation experiments demonstrate the model can correctly identify known direct drug target pairs with high precision. Indirect drug target pairs (for example drugs which change gene expression level) are also identified but not as strongly as direct pairs. We further calculated the association scores for 157 drugs from 10 disease areas against 1683 human targets, and measured their similarity using a [Formula: see text] score matrix. The similarity network indicates that drugs from the same disease area tend to cluster together in ways that are not captured by structural similarity, with several potential new drug pairings being identified. This work thus provides a novel, validated alternative to existing drug target prediction algorithms. The web service is freely available at: http://chem2bio2rdf.org/slap.

  4. PLANT PRODUCTS POTENTIAL AS ANTI-ANGIOGENIC AND IN CANCER MANAGEMENT

    Directory of Open Access Journals (Sweden)

    Patil Kalpana S.

    2010-12-01

    Full Text Available Cancer is a disease that knows no geographic boundaries. Cancer is abnormal malignant growth of body tissue or cell. A cancerous growth is called a malignant tumor or malignancy. A non cancerous growth is called benign tumor. The process of cancer metastasis is consisting of series of sequential interrelated steps, each of which is rate limiting. Plants are loaded with chemical with chemo preventive activities of some of them are undergoing clinical trial. Angiogenesis, the formation of new blood vessels important during fatal life and growth of adult blood. It is essential step in tumor growth, as tumors cant grow approximately to 2mm3 without developing new blood supply. The complex interplay of positive and negative regulators of angiogenic process determines the degree of new blood vessels formation in and around a tumor. Inhibition of angiogenesis is a potentially novel method of cancer therapy. The anti-angiogenic agents in current use are unable to destroy the tumor vasculature completely. Extensive screening of plants for anti-cancer profile has shown some good results. Some plants are already in use. Isolation of active principle of these plants may provide the basic nucleus upon which synthetic drug can be produced. The selected and careful use of this plant products may definitely help in anti-angiogenic therapy and thus, in cancer management. Hence it is possible that herbal remedies definitely hold hope for the discovery of potent anti-angiogenic and drugs on metastasis.

  5. 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....... In total, four pilot studies and internal workshops were conducted. The method was therefore developed in an iterative fashion. The method involves eight successive steps: 1) establishment of the decision context, 2) identification of benefit and risk criteria, 3) weighting, 4) scoring, 5) evaluation...... biases and feedback distort the assessment, and to make it possible for the industrial partner and the regulatory agency to compare the results of their evaluation on a point-by-point basis. The qualitative framework ensures a structured approach to the assessment and a transparent communication...

  6. 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...... study investigated safety and tolerability of intratumoral plasmid AMEP electrotransfer into cutaneous metastatic melanoma. Secondary objectives were efficacy and pharmacokinetics. Five patients with disseminated melanoma without further treatment options were treated at two dose levels (1 and 2 mg DNA...... lesions increased more than 20%. No response occurred in distant lesions. This first-in-man study on electrotransfer of plasmid AMEP into cutaneous melanoma shows that the procedure and drug are safe and that local transfection was obtained....

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    , and structurally related triterpenoids with a cytotoxic semibenzoquinone, jacaranone. The cytotoxic, antiproliferative and antiangiogenic activities of segments and conjugates were determined. The possible targets of conjugates 6a-6h were predicted using Similarity Ensemble Approach (SEA). Results: The results...... with cytotoxic agents. The conjugation or hybridization of bifunctional molecules is one of the alternative rational design strategies for co-administration of anticancer drugs. Objective and Methods: The goal of this work is to prepare the conjugates of an antiangiogenic triterpene, 3-oxo oleanolic acid...... antiangiogenesis related targets could involve glycogen phosphorylase, neuraminidase, interferon gamma, and tubulin beta chain. Conclusion: The bifunctional conjugates could be useful as dual acting antitumor/antigiogenic agents....

  8. Evolving regulatory paradigm for proarrhythmic risk assessment for new drugs.

    Science.gov (United States)

    Vicente, Jose; Stockbridge, Norman; Strauss, David G

    Fourteen drugs were removed from the market worldwide because their potential to cause torsade de pointes (torsade), a potentially fatal ventricular arrhythmia. The observation that most drugs that cause torsade block the potassium channel encoded by the human ether-à-go-go related gene (hERG) and prolong the heart rate corrected QT interval (QTc) on the ECG, led to a focus on screening new drugs for their potential to block the hERG potassium channel and prolong QTc. This has been a successful strategy keeping torsadogenic drugs off the market, but has resulted in drugs being dropped from development, sometimes inappropriately. This is because not all drugs that block the hERG potassium channel and prolong QTc cause torsade, sometimes because they block other channels. The regulatory paradigm is evolving to improve proarrhythmic risk prediction. ECG studies can now use exposure-response modeling for assessing the effect of a drug on the QTc in small sample size first-in-human studies. Furthermore, the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a new in vitro paradigm for cardiac safety evaluation of new drugs that provides a more accurate and comprehensive mechanistic-based assessment of proarrhythmic potential. Under CiPA, the prediction of proarrhythmic potential will come from in vitro ion channel assessments coupled with an in silico model of the human ventricular myocyte. The preclinical assessment will be checked with an assessment of human phase 1 ECG data to determine if there are unexpected ion channel effects in humans compared to preclinical ion channel data. While there is ongoing validation work, the heart rate corrected J-Tpeak interval is likely to be assessed under CiPA to detect inward current block in presence of hERG potassium channel block.

  9. PSYCHOLOGICAL ASSESSMENT OF OPIOID DRUG ABUSE

    Directory of Open Access Journals (Sweden)

    José Luis Carballo

    2016-01-01

    Full Text Available The increase in the prescription of opioid analgesics is related to increased rates of opioid abuse and the negative consequences of medication misuse. Several international health organisations recommend comprehensive and multidisciplinary patient assessment for the duration of the opioid treatment in order to identify and prevent medication abuse. Due to the lack of specific clinical guidelines in the Spanish National Health System, the aim of this paper is to present a proposal for psychological assessment based on the main psychological tools currently available for assessing opioid abuse. The assessment guidelines have been established based on the psychological variables that can predict and prolong the abuse, classifying all of the variables depending on the current stage of the therapeutic process for each patient. Although there are instruments with good psychometric properties, further research is necessary to adapt, translate and validate these instruments for use in the Spanish population. Future studies are also needed to investigate intervention and prevention strategies in depth in order to reduce the likelihood of abuse in patients treated with opioids.

  10. 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.

  11. THE CHANGE IN CONCENTRATIONS OF ANGIOGENIC AND ANTI-ANGIOGENIC FACTORS IN MATERNAL PLASMA BETWEEN THE FIRST AND SECOND TRIMESTERS IN RISK ASSESSMENT FOR THE SUBSEQUENT DEVELOPMENT OF PREECLAMPSIA AND SGA

    Science.gov (United States)

    Erez, Offer; Romero, Roberto; Espinoza, Jimmy; Fu, Wenjiang; Todem, David; Kusanovic, Juan Pedro; Gotsch, Francesca; Edwin, Samuel; Nien, Jyh Kae; Chaiworapongsa, Tinnakorn; Mittal, Pooja; Mazaki-Tovi, Shali; Than, Nandor Gabor; Gomez, Ricardo; Hassan, Sonia

    2009-01-01

    Introduction An imbalance between angiogenic and anti-angiogenic factors has been proposed as central to the pathophysiology of preeclampsia (PE). Indeed, patients with PE and those delivering small-for-gestational age (SGA) neonates have higher plasma concentrations of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and the soluble form of endoglin (s-Eng), as well as lower plasma concentrations of vascual endothelial growth factor (VEGF) and placental growth factor (PlGF) than do patients with normal pregnancies. Of note, this imbalance has been observed before the clinical presentation of PE or the delivery of an SGA neonate. The objective of this study was to determine if changes in the profile of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters are associated with a high risk for the subsequent development of preeclampsia and/or delivery of an SGA neonate. Methods This longitudinal case-control study included 402 singleton pregnancies in the following groups: 1) normal pregnancies with appropiate for gestational age (AGA) neonates (n=201); 2) patients who delivered an SGA neonate (n=145); and 3) patients who developed PE (n=56). Maternal plasma samples were obtained at the time of each prenatal visit, scheduled at 4-week intervals from the first or early second trimester until delivery. In this study, we included two samples per patient: 1) first sample obtained between 6 and 15 weeks of gestation (“first trimester” sample); and 2) second sample obtained between 20 and 25 weeks of gestation (“second trimester” sample). Plasma concentrations of s-Eng, sVEGFR-1 and PlGF were determined by specific and sensitive immunoassays. Changes in the maternal plasma concentrations of these angiogenesis-related factors were compared among normal patients and those destined to develop PE or deliver an SGA neonate while adjusting for maternal age, nulliparity and body mass index (BMI). General linear

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

    Science.gov (United States)

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

    2013-08-01

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

  13. Antiangiogenic mechanisms of PJ-8, a novel inhibitor of vascular endothelial growth factor receptor signaling.

    Science.gov (United States)

    Huang, Shiu-Wen; Lien, Jin-Cherng; Kuo, Sheng-Chu; Huang, Tur-Fu

    2012-05-01

    Angiogenesis occurs not only during tissue growth and development but also during wound healing and tumor progression. Angiogenesis is a balanced process controlled by proangiogenic and antiangiogenic molecules. As a critical factor in the induction of angiogenesis, vascular endothelial growth factor (VEGF) has become an attractive target for antiangiogenic and cancer therapeutic agents. In an effort to develop novel inhibitors to block VEGF signaling, we selected Pj-8, a benzimidazole derivative, and investigated its inhibitory mechanisms in human umbilical vascular endothelial cells (HUVECs). Pj-8 concentration-dependently inhibited VEGF-induced proliferation, migration and tube formation of HUVECs. Pj-8 also suppressed VEGF-induced microvessel sprouting from aortic rings ex vivo and suppressed neovascularization of implanted matrigel plugs in vivo. Pj-8 inhibited VEGF-induced phosphorylation of VEGF receptor (VEGFR) 2 and the downstream protein kinases, including Akt, focal adhesion kinase, extracellular signal-regulated kinases and Src. Results from in vitro kinase assay further demonstrated that Pj-8 suppressed the kinase activity of 3-phosphoinositide-dependent kinase 1 (PDK1). Using xenograft tumor angiogenesis model, Pj-8 markedly eliminated tumor-associated angiogenesis. Taken together, our findings suggest that Pj-8 inhibits VEGF and tumor cells MDA-MB-231-induced angiogenesis, and it may be a potential drug candidate in anticancer therapy. Downregulation of VEGFR2-mediated signaling may contribute to its antiangiogenic actions.

  14. 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

  15. Drug: D00754 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 1] 4 Agents affecting cellular function 42 Antineoplastics 429 Miscellaneous 4291...drug classification [BR:br08302] Antineoplastics Antiangiogenic Agents Thalidomide D00754 Thalidomide (JAN/USP/INN) Antineoplastics

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

    Energy Technology Data Exchange (ETDEWEB)

    Kinuya, Seigo; Yokoyama, Kunihiko; Bai, Jingming; Michigishi, Takatoshi; Tonami, Norihisa [Department of Biotracer Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa (Japan); Koshida, Kiyoshi [Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa (Japan); Mori, Hirofumi; Shiba, Kazuhiro [Radioisotope Center, Kanazawa University, Kanazawa, Ishikawa (Japan); Watanabe, Naoto [Department of Radiology, Toyama Medical and Pharmaceutical University, Toyama (Japan); Shuke, Noriyuki [Department of Radiology, Asahikawa Medical College, Asahikawa, Hokkaido (Japan)

    2004-07-01

    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 {sup 131}I-A7, an IgG1 anti-colorectal monoclonal antibody, or {sup 131}I-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) (P<0.05). {sup 131}I-A7 RIT displayed a marked therapeutic effect (n=8) (P<0.001); however, all animals eventually died due to metastases by 99 days. The combined regimen of {sup 131}I-A7 RIT and antiangiogenic therapy demonstrated a superior therapeutic effect in comparison to monotherapy consisting of either RIT or antiangiogenic therapy (n=10) (P<0.05); three mice survived the entire 160-day observation period. The combination of antiangiogenic therapy and {sup 131}I-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.)

  17. Ellagic Acid, the Active Compound of Phyllanthus urinaria, Exerts In Vivo Anti-Angiogenic Effect and Inhibits MMP-2 Activity

    Directory of Open Access Journals (Sweden)

    Sheng-Teng Huang

    2011-01-01

    Full Text Available This study aimed to assess the potential anti-angiogenic mechanism of Phyllanthus urinaria (P. urinaria and characterize the major compound in P. urinaria that exerts anti-angiogenic effect. The water extract of P. urinaria and Ellagic Acid were used to evaluate the anti-angiogenic effect in chorioallantoic membrane (CAM in chicken embryo and human vascular endothelial cells (HUVECs. The matrix metalloproteinase-2 (MMP-2 activity was determined by gelatin zymography. The mRNA expressions of MMP-2, MMP-14 and tissue inhibitor of metalloproteinase-2 (TIMP-2 were analyzed by reverse transcription polymerase chain reaction (RT-PCR. Level of MMP-2 proteins in conditioned medium or cytosol was determined by western blot analysis. We confirmed that P. urinaria's in vivo anti-angiogenic effect was associated with a reduction in MMP-2 activity. Ellagic acid, one of the major polyphenolic components as identified in P. urinaria by high performance liquid chromatography mass spectrometry (HPLC/MS, exhibited the same anti-angiogenic effect in vivo. Both P. urinaria and Ellagic Acid inhibited MMP-2 activity in HUVECs with unchanged mRNA level. The mRNA expression levels of MMP-14 and TIMP-2 were not altered either. Results from comparing the change of MMP-2 protein levels in conditioned medium and cytosol of HUVECs after the P. urinaria or Ellagic Acid treatment revealed an inhibitory effect on the secretion of MMP-2 protein. This study concluded that Ellagic Acid is the active compound in P. urinaria to exhibit anti-angiogenic activity and to inhibit the secretion of MMP-2 protein from HUVECs.

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

    Science.gov (United States)

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

    2015-03-01

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

  19. Pharmacoepidemiological assessment of drug interactions with vitamin K antagonists

    DEFF Research Database (Denmark)

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

    2014-01-01

    PurposeWe present a database of prescription drugs and international normalized ratio (INR) data and the applied methodology for its use to assess drug-drug interactions with vitamin K antagonists (VKAs). We use the putative interaction between VKAs and tramadol as a case study. MethodsWe used...... a self-controlled case series to estimate the incidence rate ratio (IRR) comparing the rate of INR measurements of 4.0 in concomitant tramadol and VKA-exposed periods to VKA-only-exposed periods. Secondary analyses considered specific subgroups, alternative exposure criteria, alternative outcome...... definitions, and other drugs. ResultsWe identified 513 VKA users with at least 1 INR measurement 4.0 and concomitant tramadol and VKA exposure during the observation period. The overall IRR was 1.80 (95% confidence interval [CI], 1.53-2.10), with a stronger association among users of phenprocoumon compared...

  20. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors.

    Science.gov (United States)

    Masferrer, J L; Leahy, K M; Koki, A T; Zweifel, B S; Settle, S L; Woerner, B M; Edwards, D A; Flickinger, A G; Moore, R J; Seibert, K

    2000-03-01

    We provide evidence that cyclooxygenase (COX)-2-derived prostaglandins contribute to tumor growth by inducing newly formed blood vessels (neoangiogenesis) that sustain tumor cell viability and growth. COX-2 is expressed within human tumor neovasculature as well as in neoplastic cells present in human colon, breast, prostate, and lung cancer biopsy tissue. COX-1 is broadly distributed in normal, as well as in neoplastic, tissues. The contribution of COX-2 to human tumor growth was indicated by the ability of celecoxib, an agent that inhibits the COX-2 enzyme, to suppress growth of lung and colon tumors implanted into recipient mice. Mechanistically, celecoxib demonstrated a potent antiangiogenic activity. In a rat model of angiogenesis, we observe that corneal blood vessel formation is suppressed by celecoxib, but not by a COX-1 inhibitor. These and other data indicate that COX-2 and COX-2-derived prostaglandins may play a major role in development of cancer through numerous biochemical mechanisms, including stimulation of tumor cell growth and neovascularization. The ability of celecoxib to block angiogenesis and suppress tumor growth suggests a novel application of this anti-inflammatory drug in the treatment of human cancer.

  1. Antiangiogenic VEGF-Ax: A New Participant in Tumor Angiogenesis.

    Science.gov (United States)

    Eswarappa, Sandeepa M; Fox, Paul L

    2015-07-15

    The transcript of the angiogenic factor vascular endothelial growth factor A (VEGF-A) is subject to a multitude of stimulus-dependent, posttranscriptional regulatory events, consistent with its unusually long 3' untranslated region. We have recently reported translational readthrough of VEGFA mRNA whereby translating ribosomes traverse the canonical stop codon to a conserved, downstream stop codon, generating VEGF-Ax ("x" for extended), a novel, extended isoform with an additional 22 amino acids appended at the C-terminus. This event is the first vertebrate example of protein-regulated, programmed translational readthrough that generates a protein with a known function. Remarkably, VEGF-Ax exhibits potent antiangiogenic activity, both in vitro and in vivo, thus raising profound clinical implications, particularly with respect to cancer treatment. In this review, we discuss the potential of VEGF-Ax as a therapeutic agent and drug target, as well as its possible role in the failure of, or resistance to, conventional anti-VEGF therapies in many types of cancers.

  2. 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.......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....

  3. Aponecrotic, antiangiogenic and antiproliferative effects of a novel dextran derivative on breast cancer growth in vitro and in vivo.

    Science.gov (United States)

    Di Benedetto, Mélanie; Starzec, Anna; Colombo, Bruno M; Briane, Dominique; Perret, Gérard Y; Kraemer, Michel; Crépin, Michel

    2002-04-01

    1. Since the sodium phenylacetate (NaPa) was reported to enhance the inhibitory effect of carboxymethyl benzylamide dextran (CMDB) on the breast cancer growth, we performed the esterification of CMDB with NaPa to obtain a new drug carrying the characteristics of these two components. A new molecule, phenylacetate carboxymethyl benzylamide dextran, was named NaPaC. 2. We investigated in vitro and in vivo the effects of NaPaC on MCF-7ras cell growth as well as its apoptotic and antiangiogenic effects in comparison to NaPa and CMDB. In addition, we assessed in vitro the antiproliferative effects of these drugs on other breast cancer cells, including MDA-MB-231, MDA-MB-435 and MCF-7. 3. In vitro, NaPaC inhibited MCF-7ras cell proliferation by 40% at concentration lower than that of CMDB and NaPa (12 microM vs 73 microM and 10 mM). IC(50)s were 6 and 28 microM for NaPaC and CMDB, respectively. The similar results were obtained for three other breast cancer cell lines. NaPaC reduced the DNA replication and induced cell recruitment in G(0)/G(1) phase more efficiently than its components. Moreover, it induced a cell death at concentration 1000-fold lower than NaPa. 4. In vivo, CMDB (150 mg kg(-1)) and NaPa (40 mg kg(-1)) inhibited the MCF-7ras tumour growth by 37 and 57%, respectively, whereas NaPaC (15 mg kg(-1)) decreased tumour growth by 66% without toxicity. 5. NaPa or CMDB reduced the microvessel number in tumour by 50% after 7 weeks of treatment. NaPaC had the same effect after only 2 weeks. After 7 weeks, it generated a large necrosis area without detectable microvessels. In vitro, NaPaC inhibited human endothelial cell proliferation more efficiently than CMDB or NaPa. NaPaC interacts with vascular endothelial growth factor as observed by affinity electrophoresis. 6. NaPaC acts like NaPa and CMDB but in more potent manner than components used separately. Its antiproliferative, aponecrotic and anti-angiogenic actions make it a good candidate for a new anti

  4. Assessing transmissibility of HIV-1 drug resistance mutations from treated and from drug-naive individuals

    Science.gov (United States)

    Winand, Raf; Theys, Kristof; Eusébio, Mónica; Aerts, Jan; Camacho, Ricardo J.; Gomes, Perpetua; Suchard, Marc A.; Vandamme, Anne-Mieke; Abecasis, Ana B.

    2015-01-01

    Objectives: Surveillance drug resistance mutations (SDRMs) in drug-naive patients are typically used to survey HIV-1-transmitted drug resistance (TDR). We test here how SDRMs in patients failing treatment, the original source of TDR, contribute to assessing TDR, transmissibility and transmission source of SDRMs. Design: This is a retrospective observational study analyzing a Portuguese cohort of HIV-1-infected patients. Methods: The prevalence of SDRMs to protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) in drug-naive and treatment-failing patients was measured for 3554 HIV-1 subtype B patients. Transmission ratio (prevalence in drug-naive/prevalence in treatment-failing patients), average viral load and robust linear regression with outlier detection (prevalence in drug-naive versus in treatment-failing patients) were analyzed and used to interpret transmissibility. Results: Prevalence of SDRMs in drug-naive and treatment-failing patients were linearly correlated, but some SDRMs were classified as outliers – above (PRO: D30N, N88D/S, L90 M, RT: G190A/S/E) or below (RT: M184I/V) expectations. The normalized regression slope was 0.073 for protease inhibitors, 0.084 for NRTIs and 0.116 for NNRTIs. Differences between SDRMs transmission ratios were not associated with differences in viral loads. Conclusion: The significant linear correlation between prevalence of SDRMs in drug-naive and in treatment-failing patients indicates that the prevalence in treatment-failing patients can be useful to predict levels of TDR. The slope is a cohort-dependent estimate of rate of TDR per drug class and outlier detection reveals comparative persistence of SDRMs. Outlier SDRMs with higher transmissibility are more persistent and more likely to have been acquired from drug-naive patients. Those with lower transmissibility have faster reversion dynamics after transmission and are associated with

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

    Directory of Open Access Journals (Sweden)

    Siew-Li Lai

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

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

    Science.gov (United States)

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

    2016-10-01

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

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

    Directory of Open Access Journals (Sweden)

    Daniele Tibullo

    2016-10-01

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

  8. Current Status of Methods to Assess Cancer Drug Resistance

    Directory of Open Access Journals (Sweden)

    Theodor H. Lippert, Hans-Jörg Ruoff, Manfred Volm

    2011-01-01

    Full Text Available Drug resistance is the main cause of the failure of chemotherapy of malignant tumors, resistance being either preexisting (intrinsic resistance or induced by the drugs (acquired resistance. At present, resistance is usually diagnosed during treatment after a long period of drug administration.In the present paper, methods for a rapid assessment of drug resistance are described. Three main classes of test procedures can be found in the literature, i.e. fresh tumor cell culture tests, cancer biomarker tests and positron emission tomography (PET tests. The methods are based on the evaluation of molecular processes, i.e. metabolic activities of cancer cells. Drug resistance can be diagnosed before treatment in-vitro with fresh tumor cell culture tests, and after a short time of treatment in-vivo with PET tests. Cancer biomarker tests, for which great potential has been predicted, are largely still in the development stage. Individual resistance surveillance with tests delivering rapid results signifies progress in cancer therapy management, by providing the possibility to avoid drug therapies that are ineffective and only harmful.

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

    Directory of Open Access Journals (Sweden)

    Andrea eHawkins-Daarud

    2013-04-01

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

  11. 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.

  12. Pharmacogenetics of antiangiogenic and antineovascular therapies of age-related macular degeneration.

    Science.gov (United States)

    Agosta, Elisa; Lazzeri, Stefano; Orlandi, Paola; Figus, Michele; Fioravanti, Anna; Di Desidero, Teresa; Sartini, Maria Sole; Nardi, Marco; Danesi, Romano; Bocci, Guido

    2012-07-01

    Age-related macular degeneration (AMD), the most common age-related disease causing irreversible visual loss in industrialized countries, is a complex and multifactorial illness. Researchers have found components of the complement alternative pathway inside drusen and Bruch's membrane of AMD patients, underlying a possible important role of complement factor H in the pathogenesis of AMD. The neovascular (wet) AMD is the most destructive form and it is characterized by invasion of new blood vessels into subretinal spaces with subsequent exudation and bleeding, resulting in scarring of the macular region and loss of the central vision. The hallmark of the neovascular form is the choroidal neovascularization, where VEGF-A has an important role in the pathogenesis of the disease. SNPs of these genes have recently been investigated as potential pharmacogenetic markers of the antiangiogenic and antineovascular therapy of AMD, which includes verteporfin photodynamic therapy and anti-VEGF-A drugs, such as pegaptanib, bevacizumab and ranibizumab. The CFH rs1061170 CT and TT genotypes have been associated with an improvement of visual acuity in bevacizumab or ranibizumab treated patients, whereas patients harboring VEGF-A rs699946 G allele responded better to bevacizumab-based therapy if compared with patients carrying the A allele. In conclusion, the discovery of pharmacogenetic markers for the personalization of the antiangiogenic and/or antineovascular therapy could be, in the future, a key issue in ophthalmology to obtain a personalization of the therapy and to avoid unnecessary costs and adverse drug reactions.

  13. 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.

  14. High antiangiogenic and low anticoagulant efficacy of orally active low molecular weight heparin derivatives.

    Science.gov (United States)

    Park, Jin Woo; Jeon, Ok Cheol; Kim, Sang Kyoon; Al-Hilal, Taslim Ahmed; Jin, Shun Ji; Moon, Hyun Tae; Yang, Victor C; Kim, Sang Yoon; Byun, Youngro

    2010-12-20

    Heparin, an anticoagulant that is widely used clinically, is also known to bind to several kinds of proteins through electrostatic interactions because of its polyanionic character. These interactions are mediated by the physicochemical properties of heparin such as sequence composition, sulfation patterns, charge distribution, overall charge density, and molecular size. Although this electrostatic character mediates its binding to many proteins related with tumor progression, thereby providing its antiangiogenic property, the administration of heparin for treating cancer is limited in clinical applications due to several drawbacks, such as its low oral absorption, unsatisfactory therapeutic effects, and strong anticoagulant activity which induces hemorrhaging. Here, we evaluated novel, orally active, low molecular weight heparin (LMWH) derivatives (LHD) conjugated with deoxycholic acid (DOCA) that show reduced anticoagulant activity and enhanced antiangiogenic activity. The chemical conjugate of LMWH and DOCA was synthesized by conjugating the amine group of N-deoxycholylethylamine (EtDOCA) with the carboxylic groups of heparin at various DOCA conjugation ratios. The LMWH-DOCA conjugate series (LHD1, LHD1.5, LHD2, and LHD4) were further formulated with poloxamer 407 as a solubilizer for oral administration. An in vitro endothelial tubular formation and in vivo Matrigel plug assay were performed to verify the antiangiogenic potential of LHD. Finally, we evaluated tumor growth inhibition of oral LHD administration in a SCC7 model as well as in A549 human cancer cell lines in a mouse xenograft model. Increasing DOCA conjugation ratios showed decreased anticoagulant activity, eventually to zero. LHD could block angiogenesis in the tubular formation assay and the Matrigel plug assay. In particular, oral administration of LHD4, which has 4 molecules of DOCA per mole of LMWH, inhibited tumor growth in SCC7 mice model as well as A549 mice xenograft model. LHD4 was orally

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

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    Suwadee Phowichit

    2016-09-01

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

  16. 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

  17. Anti-angiogenic activity of inositol hexaphosphate (IP6).

    Science.gov (United States)

    Vucenik, Ivana; Passaniti, Antonino; Vitolo, Michele I; Tantivejkul, Kwanchanit; Eggleton, Paul; Shamsuddin, Abulkalam M

    2004-11-01

    A significant anticancer activity of the naturally occurring carbohydrate inositol hexaphosphate (IP(6)) has been reported against numerous cancer models. Since tumors require angiogenesis for growth and metastasis, we hypothesize that IP(6) reduces tumor growth by inhibiting angiogenesis. Because angiogenesis depends on the interaction between endothelial and tumor cells, we investigated the effect of IP(6) on both. IP(6) inhibited the proliferation and induced the differentiation of endothelial cells in vitro; the growth of bovine aortic endothelial cells (BAECs) evaluated by MTT proliferation assay was inhibited in a dose-dependent manner (IC(50) = 0.74 mM). The combination of IP(6) and vasostatin, a calreticulin fragment with anti-angiogenic activity, was synergistically superior in growth inhibition than either compound. IP(6) inhibited human umbilical vein endothelial cell (HUVEC) tube formation (in vitro capillary differentiation) on a reconstituted extracellular matrix, Matrigel, and disrupted pre-formed tubes. IP(6) significantly reduced basic fibroblast growth factor (bFGF)-induced vessel formation (P < 0.01) in vivo in Matrigel plug assay. Exposure of HepG2, a human hepatoma cell line, to IP(6) for 8 h, resulted in a dose-dependent decrease in the mRNA levels of vascular endothelial growth factor (VEGF), as assessed by RT-PCR. IP(6) treatment of HepG2 cells for 24 h also significantly reduced the VEGF protein levels in conditioned medium, in a concentration-dependent manner (P = 0.012). Thus, IP(6) has an inhibitory effect on induced angiogenesis.

  18. Systems Pharmacology Approaches for Optimization of Antiangiogenic Therapies: Challenges and Opportunities

    Directory of Open Access Journals (Sweden)

    Satish eSharan

    2015-02-01

    Full Text Available Targeted therapies have become an important therapeutic paradigm for multiple malignancies. The rapid development of resistance to these therapies impedes the successful management of advanced cancer. Due to the redundancy in angiogenic signaling, alternative proangiogenic factors are activated upon treatment with anti-VEGF agents. Higher doses of the agents lead to greater stimulation of compensatory proangiogenic pathways that limit the therapeutic efficacy of VEGF-targeted drugs and produce escape mechanisms for tumor. Evidence suggests that dose intensity and schedules affect the dynamics of the development of this resistance. Thus, an optimal dosing regimen is crucial to maximizing the therapeutic benefit of antiangiogenic agents and limiting treatment resistance. A systems pharmacology approach using multiscale computational modeling can facilitate a mechanistic understanding of these dynamics of angiogenic biomarkers and their impacts on tumor reduction and resistance. Herein, we discuss a systems pharmacology approach integrating the biology of VEGF-targeted therapy resistance, including circulating biomarkers, and pharmacodynamics to enable the optimization of antiangiogenic therapy for therapeutic gains.

  19. Anti-angiogenic Nanotherapy Inhibits Airway Remodeling and Hyper-responsiveness of Dust Mite Triggered Asthma in the Brown Norway Rat

    Science.gov (United States)

    Lanza, Gregory M.; Jenkins, John; Schmieder, Anne H.; Moldobaeva, Aigul; Cui, Grace; Zhang, Huiying; Yang, Xiaoxia; Zhong, Qiong; Keupp, Jochen; Sergin, Ismail; Paranandi, Krishna S.; Eldridge, Lindsey; Allen, John S.; Williams, Todd; Scott, Michael J.; Razani, Babak; Wagner, Elizabeth M.

    2017-01-01

    Although angiogenesis is a hallmark feature of asthmatic inflammatory responses, therapeutic anti-angiogenesis interventions have received little attention. Objective: Assess the effectiveness of anti-angiogenic Sn2 lipase-labile prodrugs delivered via αvβ3-micellar nanotherapy to suppress microvascular expansion, bronchial remodeling, and airway hyper-responsiveness in Brown Norway rats exposed to serial house dust mite (HDM) inhalation challenges. Results: Anti-neovascular effectiveness of αvβ3-mixed micelles incorporating docetaxel-prodrug (Dxtl-PD) or fumagillin-prodrug (Fum-PD) were shown to robustly suppress neovascular expansion (p<0.01) in the upper airways/bronchi of HDM rats using simultaneous 19F/1H MR neovascular imaging, which was corroborated by adjunctive fluorescent microscopy. Micelles without a drug payload (αvβ3-No-Drug) served as a carrier-only control. Morphometric measurements of HDM rat airway size (perimeter) and vessel number at 21d revealed classic vascular expansion in control rats but less vascularity (p<0.001) after the anti-angiogenic nanotherapies. CD31 RNA expression independently corroborated the decrease in airway microvasculature. Methacholine (MCh) induced respiratory system resistance (Rrs) was high in the HDM rats receiving αvβ3-No-Drug micelles while αvβ3-Dxtl-PD or αvβ3-Fum-PD micelles markedly and equivalently attenuated airway hyper-responsiveness and improved airway compliance. Total inflammatory BAL cells among HDM challenged rats did not differ with treatment, but αvβ3+ macrophages/monocytes were significantly reduced by both nanotherapies (p<0.001), most notably by the αvβ3-Dxtl-PD micelles. Additionally, αvβ3-Dxtl-PD decreased BAL eosinophil and αvβ3+ CD45+ leukocytes relative to αvβ3-No-Drug micelles, whereas αvβ3-Fum-PD micelles did not. Conclusion: These results demonstrate the potential of targeted anti-angiogenesis nanotherapy to ameliorate the inflammatory hallmarks of asthma in a

  20. 75 FR 4400 - Draft Guidance for Industry on Assessment of Abuse Potential of Drugs; Availability

    Science.gov (United States)

    2010-01-27

    ... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Assessment of Abuse Potential... and Drug Administration (FDA) is announcing the availability of a draft guidance for industry entitled... availability of a draft guidance for industry entitled ``Assessment of Abuse Potential of Drugs.'' Under...

  1. 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.

  2. 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

  3. Targeting Tumor Mitochondrial Metabolism Overcomes Resistance to Antiangiogenics

    Directory of Open Access Journals (Sweden)

    Paloma Navarro

    2016-06-01

    Full Text Available Epithelial malignancies are effectively treated by antiangiogenics; however, acquired resistance is a major problem in cancer therapeutics. Epithelial tumors commonly have mutations in the MAPK/Pi3K-AKT pathways, which leads to high-rate aerobic glycolysis. Here, we show how multikinase inhibitor antiangiogenics (TKIs induce hypoxia correction in spontaneous breast and lung tumor models. When this happens, the tumors downregulate glycolysis and switch to long-term reliance on mitochondrial respiration. A transcriptomic, metabolomic, and phosphoproteomic study revealed that this metabolic switch is mediated by downregulation of HIF1α and AKT and upregulation of AMPK, allowing uptake and degradation of fatty acids and ketone bodies. The switch renders mitochondrial respiration necessary for tumor survival. Agents like phenformin or ME344 induce synergistic tumor control when combined with TKIs, leading to metabolic synthetic lethality. Our study uncovers mechanistic insights in the process of tumor resistance to TKIs and may have clinical applicability.

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

    DEFF Research Database (Denmark)

    Wierzbicki, Mateusz; Sawosz, Ewa; Grodzik, Marta;

    2013-01-01

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

  5. Open drug scenes and drug-related public nuisance: a visual rapid assessment research study in Dublin, Ireland.

    Science.gov (United States)

    Van Hout, Marie Claire; Bingham, Tim

    2013-01-01

    The research was undertaken at a time of increasing public concerns for drug- and alcohol-related public nuisance in the city center of Dublin, Ireland. Rapid Assessment Research was conducted involving qualitative interviewing with drug service users; business, transport, community, voluntary, and statutory stakeholders (n = 61); and an environmental mapping exercise. The interplay between homelessness, loitering, an influx of drug users via city metro systems, transient open drug scenes, street drinking, drug injecting, intimidation, knife crime, and prescribed medication abuse was evident. Potential strategies to address drug and alcohol related public nuisance are advised to include the relocation of treatment services, targeted harm reduction initiatives, urban regeneration, improved community rehabilitation pathways, and heightened policing intensity.

  6. Anti-angiogenic therapeutic strategies in hereditary hemorrhagic telangiectasia

    Directory of Open Access Journals (Sweden)

    Daniela S. Ardelean

    2015-02-01

    Full Text Available Hereditary hemorrhagic telangiectasia (HHT is an autosomal dominant vascular dysplastic disorder, characterized by recurrent nosebleeds (epistaxis, multiple telangiectases and arteriovenous malformations (AVMs in major organs. Mutations in Endoglin (ENG or CD105 and Activin receptor-like kinase 1 (ACVRL1 or ALK1 genes of the TGF-β superfamily receptors are responsible for HHT1 and HHT2 respectively and account for the majority of HHT cases. Haploinsufficiency in ENG and ALK1 is recognized at the underlying cause of HHT. However, the mechanisms responsible for the predisposition to and generation of AVMs, the hallmark of this disease, are poorly understood. Recent data suggest that dysregulated angiogenesis contributes to the pathogenesis of HHT and that the vascular endothelial growth factor, VEGF, may be implicated in this disease, by modulating the angiogenic balance in the affected tissues. Hence, anti-angiogenic therapies that target the abnormal vessels and restore the angiogenic balance are candidates for treatment of HHT. Here we review the experimental evidence for dysregulated angiogenesis in HHT, the anti-angiogenic therapeutic strategies used in animal models and some patients with HHT and the potential benefit of the anti-angiogenic treatment for ameliorating this severe, progressive vascular disease.

  7. 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

  8. 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.

  9. Utility of population pharmacokinetic modeling in the assessment of therapeutic protein-drug interactions.

    Science.gov (United States)

    Chow, Andrew T; Earp, Justin C; Gupta, Manish; Hanley, William; Hu, Chuanpu; Wang, Diane D; Zajic, Stefan; Zhu, Min

    2014-05-01

    Assessment of pharmacokinetic (PK) based drug-drug interactions (DDI) is essential for ensuring patient safety and drug efficacy. With the substantial increase in therapeutic proteins (TP) entering the market and drug development, evaluation of TP-drug interaction (TPDI) has become increasingly important. Unlike for small molecule (e.g., chemical-based) drugs, conducting TPDI studies often presents logistical challenges, while the population PK (PPK) modeling may be a viable approach dealing with the issues. A working group was formed with members from the pharmaceutical industry and the FDA to assess the utility of PPK-based TPDI assessment including study designs, data analysis methods, and implementation strategy. This paper summarizes key issues for consideration as well as a proposed strategy with focuses on (1) PPK approach for exploratory assessment; (2) PPK approach for confirmatory assessment; (3) importance of data quality; (4) implementation strategy; and (5) potential regulatory implications. Advantages and limitations of the approach are also discussed.

  10. Aponecrotic, antiangiogenic and antiproliferative effects of a novel dextran derivative on breast cancer growth in vitro and in vivo

    OpenAIRE

    Benedetto, Mélanie Di; Starzec, Anna; Colombo, Bruno M; Briane, Dominique; Perret, Gérard Y; Kraemer, Michel; Crépin, Michel

    2002-01-01

    1 Since the sodium phenylacetate (NaPa) was reported to enhance the inhibitory effect of carboxymethyl benzylamide dextran (CMDB) on the breast cancer growth, we performed the esterification of CMDB with NaPa to obtain a new drug carrying the characteristics of these two components. A new molecule, phenylacetate carboxymethyl benzylamide dextran, was named NaPaC.We investigated in vitro and in vivo the effects of NaPaC on MCF-7ras cell growth as well as its apoptotic and antiangiogenic effect...

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

    NARCIS (Netherlands)

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

    2005-01-01

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

  12. 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

  13. 磁共振扩散加权成像监测恩度与贝伐单抗抗肿瘤血管生成的实验研究%Monitoring the effect of anti-angiogenic drugs by MR diffusion weighted imaging:an experimental study

    Institute of Scientific and Technical Information of China (English)

    史红媛; 田迎; 罗松; 朱飞鹏; 王守巨; 金利新; 王建东; 卢光明

    2012-01-01

    目的 评价磁共振扩散加权成像(diffusion weighted imaging,DWI)早期监测抗肿瘤血管生成药物疗效的可行性.方法 将20只荷人肺腺癌裸鼠随机分为3组,对照组和恩度(Endostar)组各7只,联合贝伐单抗(Bevacizumab,Avastin)组6只.治疗第3天对照组和恩度组行DWI成像并测量ADC值,采用t检验比较2组ADC值.扫描完成后每组各取1只裸鼠肿瘤组织行透射电镜观察.治疗第10天3组均行DWI成像,采用方差分析比较各组的ADC值.扫描完成后剖取肿瘤组织行病理学检查.结果 治疗第3天,恩度组的ADC值明显高于对照组,两者差异有统计学意义(t=-5.505,P<0.01),此时2组肿瘤体积没有明显差异.透射电镜结果显示恩度组肿瘤组织内部分细胞发生变性,并出现凋亡现象.治疗第10天恩度组和联合贝伐单抗组的ADC值均高于对照组(P值分别为0.018和0.001),联合贝伐单抗组ADC值高于恩度组,差异没有统计学意义(P=0.211).此时恩度组和联合贝伐单抗组肿瘤体积均小于对照组,差异有统计学意义(P值分别为0.000和0.003),联合贝伐单抗组体积小于恩度组,差异无统计学意义(P=0.100).病理学HE染色显示恩度组可见少部分坏死区域,联合贝伐单抗组的坏死区域范围较大.免疫组化结果显示对照组、恩度组及联合贝伐单抗组肿瘤组织MVD值和VEGF的表达均呈下降趋势,其中MVD值两两之间差异均有统计学意义(P<0.05),各组间VEGF差异无统计学意义(χ2=3.455,P=0.178).结论 DWI成像能够提供肿瘤组织的微观结构和水分子扩散信息,可以无创地早期监测给予抗肿瘤血管生成药物后肿瘤微环境的变化.%Objective To evaluate the feasibility of MR diffusion weighted imaging (DWI) in monitoring the effect of anti-angio-genic drugs. Methods 20 nude mice bearing human lung carcinoma A549 were randomly divided into 3 groups: control group (group A,n=7) .Endostar group (group B,n=7)and Endostar

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

    Energy Technology Data Exchange (ETDEWEB)

    Kamisasanuki, Taro [Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Tokushige, Saori [Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Terasaki, Hiroto [Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Khai, Ngin Cin; Wang, Yuqing [Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Sakamoto, Taiji [Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Kosai, Ken-ichiro, E-mail: kosai@m2.kufm.kagoshima-u.ac.jp [Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan)

    2011-09-16

    Highlights: {yields} CD9 plays stimulus-independent roles in angiogenesis in vitro and in vivo. {yields} Targeting CD9 expression is effective in an angiogenic disease model. {yields} Targeting CD9 expression predominantly affects activated endothelial cells. {yields} CD9 is involved in endothelial cell proliferation, but not survival. {yields} 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

  15. Health technology assessment in the Balkans: opportunities for a balanced drug assessment system.

    Science.gov (United States)

    Dankó, Dávid; Petrova, Guenka

    2014-11-02

    Countries in the Balkan region use pharmaco-economic data for decisions about the inclusion of new pharmaceuticals into their positive drug lists, but no predefined frameworks are used and resources for health technology assessment (HTA) are limited. The goal of this analysis is to investigate into possible development directions for the HTA system in the region, and provide some practical recommendations for a sustainable model. For this purpose, the main factors currently influencing HTA in Balkan countries are briefly presented, and possible development strategies are compared. A resource-saving balanced assessment approach is proposed. It is aligned with available resources and capabilities, and helps access to new pharmaceuticals while ensuring the transparency of decision-making processes and the stability of the pharmaceutical budget.

  16. 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.

  17. Drug interactions involving antiepileptic drugs: assessment of the consistency among three drug compendia and FDA-approved labels.

    Science.gov (United States)

    Ekstein, Dana; Tirosh, Matanya; Eyal, Yonatan; Eyal, Sara

    2015-03-01

    Interactions of antiepileptic drugs (AEDs) with other substances may lead to adverse effects and treatment failure. To avoid such interactions, clinicians often rely on drug interaction compendia. Our objective was to compare the concordance for twenty-two AEDs among three drug interaction compendia (Micromedex, Lexi-Interact, and Clinical Pharmacology) and the US Food and Drug Administration-approved product labels. For each AED, the overall concordance among data sources regarding existence of interactions and their classification was poor, with less than twenty percent of interactions listed in all four sources. Concordance among the three drug compendia decreased with the fraction of the drug excreted unchanged and was greater for established inducers of hepatic drug-metabolizing enzymes than for the drugs that are not inducers (R-square=0.83, P<0.01). For interactions classified as contraindications, major, and severe, concordance among the four data sources was, in most cases, less than 30%. Prescribers should be aware of the differences between drug interaction sources of information for both older AEDs and newer AEDs, in particular for those AEDs which are not involved in hepatic enzyme-mediated interactions.

  18. Assessment of AIDS Risk among Treatment Seeking Drug Abusers.

    Science.gov (United States)

    Black, John L.; And Others

    Intravenous (IV) drug abusers are at risk for contracting transmittable diseases such as acquired immunodeficiency syndrome (AIDS) and hepatitis B. This study was conducted to investigate the prevalence of risk behaviors for acquiring and transmitting AIDS and hepatitis B among treatment-seeking drug abusers (N=168). Subjects participated in a…

  19. An Assessment of Drug Testing within the Construction Industry.

    Science.gov (United States)

    Gerber, Jonathan K.; Yacoubian, George S., Jr.

    2002-01-01

    Investigates the efficacy of workplace drug-testing programs in reducing injury incident rates and workers' compensation experience-rating modification factors within the construction industry. Analyses indicate that companies with drug-testing programs experienced a 51 percent reduction in incident rates within two years of implementation.…

  20. Perfusion MRI in the early clinical development of antivascular drugs: decorations or decision making tools?

    Energy Technology Data Exchange (ETDEWEB)

    Zweifel, Martin [Mount Vernon Cancer Centre, Department of Medical Oncology, Northwood, Middlesex (United Kingdom); Padhani, Anwar R. [Mount Vernon Hospital, Paul Strickland Scanner Centre, Northwood, Middlesex (United Kingdom)

    2010-08-15

    Classically, the first step in the clinical development of drugs in oncology involves assessments of dose limiting toxicity (DLT) and maximum tolerated dose (MTD). New paradigms are needed for antiangiogenic drugs and vascular disrupting agents (VDAs) as they are active at doses well below the MTD and as single agents their use might not translate into anti-tumour efficacy. MRI is able to assess the antivascular effects of antivascular drugs via changes in functional kinetic parameters; however, the usefulness of MRI in decision making has been questioned by many. Our aim is to review the experience of using dynamic contrast-enhanced MRI (DCE-MRI) in early clinical development of vascular directed anticancer therapies over the last decade. Thirty-nine phase I and II studies including data on more than 700 patients have been published as abstracts and/or papers, documenting DCE-MRI changes after the administration of antiangiogenic drugs and VDAs. Perfusion MRI is helpful in assessing whether mechanistic goals are achieved, in assisting dose selection for phase II studies, in selecting subpopulations enriched for response and in predicting patient benefit. Imaging tools are increasingly available. Future challenges for imaging include correlation with clinical measures of efficacy and determining relationships with blood and serum biomarkers. (orig.)

  1. Drug assessment by a Pharmacy and Therapeutics committee: from drug selection criteria to use in clinical practice

    Directory of Open Access Journals (Sweden)

    Lozano-Blázquez A

    2014-07-01

    Full Text Available Ana Lozano-Blázquez,1 Cecilia Calvo-Pita,2 Mónica Carbajales-Álvarez,1 Patricio Suárez-Gil,3 Fernando Martínez-Martínez,4 Miguel Ángel Calleja-Hernández51Pharmacy Department, Hospital de Cabueñes, Gijón, Spain; 2Pharmacy Department, Primary Health Care, Servicio Madrileño de Salud, Dirección Asistencial Oeste, Madrid, Spain; 3Research Unit Área V, Hospital de Cabueñes, Gijón, Spain; 4Responsable del Grupo de Investigación en Atención Farmacéutica, Universidad de Granada, 5UGC Provincial de Farmacia de Granada Instituto de Biomedicina de Granada, Hospital Virgen de las Nieves, Granada, SpainBackground: In Spain, hospital medicines are assessed and selected by local Pharmacy and Therapeutics committees (PTCs. Of all the drugs assessed, cancer drugs are particularly important because of their budgetary impact and the sometimes arguable added value with respect to existing alternatives. This study analyzed the PTC drug selection process and the main objective was to evaluate the degree of compliance of prescriptions for oncology drugs with their criteria for use.Methods: This was a retrospective observational study (May 2007 to April 2010 of PTC-assessed drugs. The variables measured to describe the committee's activity were number of drugs assessed per year and number of drugs included in any of these settings: without restrictions, with criteria for use, and not included in formulary. These drugs were also analyzed by therapeutic group. To assess the degree of compliance of prescriptions, a score was calculated to determine whether prescriptions for bevacizumab, cetuximab, trastuzumab, and bortezomib were issued in accordance with PTC drug use criteria.Results: The PTC received requests for inclusion of 40 drugs, of which 32 were included in the hospital formulary (80.0%. Criteria for use were established for 28 (87.5% of the drugs included. In total, 293 patients were treated with the four cancer drugs in eight different

  2. POTENTIAL OF INDUCED METABOLIC BIOLUMINESCENCE IMAGING TO UNCOVER METABOLIC EFFECTS OF ANTI-ANGIOGENIC THERAPY IN TUMORS

    Directory of Open Access Journals (Sweden)

    Stefano eIndraccolo

    2016-02-01

    Full Text Available Tumor heterogeneity at the genetic level has been illustrated by a multitude of studies on the genomics of cancer, but whether tumors can be heterogeneous at the metabolic level is an issue which has been less systematically investigated so far. A burning related question is whether the metabolic features of tumors can change either following natural tumor progression (i.e. in primary tumors versus metastasis or therapeutic interventions. In this regard, recent findings by independent teams indicate that anti-angiogenic drugs cause metabolic perturbations in tumors as well as metabolic adaptations associated with increased malignancy. Induced metabolic bioluminescence imaging (imBI is an imaging technique which enables detection of key metabolites associated with glycolysis, including lactate, glucose, pyruvate and ATP in tumor sections. Signals captured by imBI can be used to visualize the topographic distribution of these metabolites and quantify their absolute amount. ImBI can be very useful for metabolic classification of tumors as well as to track metabolic changes in the glycolytic pathway associated with certain therapies. Imaging of the metabolic changes induced by anti-angiogenic drugs in tumors by imBI or other emerging technologies is a valuable tool to uncover molecular sensors engaged by metabolic stress and offers an opportunity to understand how metabolism-based approaches could improve cancer therapy.

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

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    Moorman KL

    2017-03-01

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

  4. Embolization biomaterial reinforced with nanotechnology for an in-situ release of anti-angiogenic agent in the treatment of hyper-vascularized tumors and arteriovenous malformations.

    Science.gov (United States)

    Jubeli, E; Yagoubi, N; Pascale, F; Bédouet, L; Slimani, K; Labarre, D; Saint-Maurice, J P; Laurent, A; Moine, L

    2015-10-01

    A polymer based material was developed to act as an embolic agent and drug reservoir for the treatment of arteriovenous malformations (AVM) and hyper vascularized solid tumors. The aim was to combine the blocking of blood supply to the target region and the inhibition of the embolization-stimulated angiogenesis. The material is composed of an ethanolic solution of a linear acrylate based copolymer and acrylate calibrated microparticles containing nanospheres loaded with sunitinib, an anti-angiogenic agent. The precipitation of the linear copolymer in aqueous environment after injection through microcatheter results in the formation of an in-situ embolization gel whereas the microparticles serve to increase the cohesive properties of the embolization agent and to form a reservoir from which the sunitinib-loaded nanospheres are released post-embolization. The swollen state of the microparticles in contact with aqueous medium results in the release of the nanospheres out of microparticles macromolecular structure. After the synthesis, the formulation and the characterization of the different components of the material, anti-angiogenic activity was evaluated in vitro using endothelial cells and in vivo using corneal neovascularization model in rabbit. The efficiency of the arterial embolization was tested in vivo in a sheep model. Results proved the feasibility of this new system for vascular embolization in association with an in situ delivery of anti-angiogenic drug. This combination is a promising strategy for the management of arteriovenous malformations and solid tumors.

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

    Science.gov (United States)

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

    2014-06-01

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

  6. Assessment of Drug Related Problems in Patients with Cardiovascular Diseases in a Tertiary Care Teaching Hospital

    Directory of Open Access Journals (Sweden)

    Javedh Shareef

    2015-10-01

    Full Text Available Backgrounds: Drug related problems can be defined as any event (or circumstance involving the drug treatment, which interferes or potentially interferes with the patient in achieving an optimum outcome of medical care. The aim of the study was to identify drug therapy problems and to assess the pharmacist interventions in patients with cardiovascular diseases.Methods: The inpatient case records including drug history and other relevant details of the admitted patients under the cardiology department were collected and reviewed by the clinical pharmacist for drug related problems. In case if any drug related problem was identified, was discussed with the concerned physician and suitable interventions was provided and documented.Results: A total of 112 patient case sheets were reviewed during the study period, out of which 53 drug related problems were identified from 44 patients. The most common drug related problem was found to be drug Interactions (49.05% followed by Adverse Drug Reaction (18.86%, and failure to receive drugs (9.43%. The most frequent suggestions provided by the intervening pharmacist were cessation of drug (24.52%, followed by Change in frequency of administration (22.64%, change in drug dose (20.75%. The majority of level of significance of drug related problems was seen to have moderate significance in grade. The acceptance rate of recommendations and change in drug therapy was found to be high (96.21%.Conclusion: The current study highlights the importance of a pharmacist in a multidisciplinary team of routinely reviewing the drug therapy for identification and resolution of drug related problems which helps in achieving better therapeutic outcomes and improved patient care.

  7. 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.

  8. 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…

  9. 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…

  10. An informatics approach to assess pediatric pharmacotherapy: design and implementation of a hospital drug utilization system.

    Science.gov (United States)

    Zuppa, Athena; Vijayakumar, Sundararajan; Jayaraman, Bhuvana; Patel, Dimple; Narayan, Mahesh; Vijayakumar, Kalpana; Mondick, John T; Barrett, Jeffrey S

    2007-09-01

    Drug utilization in the inpatient setting can provide a mechanism to assess drug prescribing trends, efficiency, and cost-effectiveness of hospital formularies and examine subpopulations for which prescribing habits may be different. Such data can be used to correlate trends with time-dependent or seasonal changes in clinical event rates or the introduction of new pharmaceuticals. It is now possible to provide a robust, dynamic analysis of drug utilization in a large pediatric inpatient setting through the creation of a Web-based hospital drug utilization system that retrieves source data from our accounting database. The production implementation provides a dynamic and historical account of drug utilization at the authors' institution. The existing application can easily be extended to accommodate a multi-institution environment. The creation of a national or even global drug utilization network would facilitate the examination of geographical and/or socioeconomic influences in drug utilization and prescribing practices in general.

  11. The influence of comprehensive geriatric assessment on drug therapy in elderly patients

    DEFF Research Database (Denmark)

    Larsen, Michael Due; Rosholm, Jens Ulrik; Hallas, Jesper

    2014-01-01

    Comprehensive geriatric assessment of hospitalised patients implies optimising patients' medical treatment, and good coordination between hospital and general practice is essential for the quality of the drug treatment. Only a few studies have investigated the continuation of patients' medication...

  12. 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.

  13. 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.

  14. Drug Assessment Program; A Community Guide. The Drug Abuse Council Handbook Series, No. 2.

    Science.gov (United States)

    Blair, Louis H.; Sessler, John

    Addiction to illicit hard drugs, and particularly opiates, has increased in the past few years. Yet, there are few comprehensive evaluations of the treatment systems, and there is little systematic planning for programs to meet current and anticipated changes in the community's need for treatment. This report has been written to assist community…

  15. Diminished oligomerization in the synthesis of new anti-angiogenic cyclic peptide using solution instead of solid-phase cyclization.

    Science.gov (United States)

    Rubio, Sandra; Clarhaut, Jonathan; Péraudeau, Elodie; Vincenzi, Marian; Soum, Claire; Rossi, Filomena; Guillon, Jean; Papot, Sébastien; Ronga, Luisa

    2016-05-01

    The design and synthesis of novel peptides that inhibit angiogenesis is an important area for anti-angiogenic drug development. Cyclic and small peptides present several advantages for therapeutic application, including stability, solubility, increased bio-availability and lack of immune response in the host cell. We describe here the synthesis and biological evaluations of a new cyclic peptide analog of CBO-P11: cyclo(RIKPHE), designated herein as CBO-P23M, a hexamer peptide encompassing residues 82 to 86 of VEGF which are involved in the interaction with VEGF receptor-2. CBO-P23M was prepared using in solution cyclization, therefore reducing the peptide cyclodimerization occurred during solid-phase cyclization. The cyclic dimer of CBO-P23M, which was obtained as the main side product during synthesis of the corresponding monomer, was also isolated and investigated. Both peptides markedly reduce VEGF-A-induced phosphorylation of VEGFR-2 and Erk1/2. Moreover, they exhibit anti-angiogenic activity in an in vitro morphogenesis study. Therefore CBO-P23M and CBO-P23M dimer appear as attractive candidates for the development of novel angiogenesis inhibitors for the treatment of cancer and other angiogenesis-related diseases. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 368-375, 2016.

  16. Blocking the FGF/FGFR system as a "two-compartment" antiangiogenic/antitumor approach in cancer therapy.

    Science.gov (United States)

    Giacomini, Arianna; Chiodelli, Paola; Matarazzo, Sara; Rusnati, Marco; Presta, Marco; Ronca, Roberto

    2016-05-01

    Fibroblast growth factors (FGFs) are a family of pleiotropic factors produced by stromal and parenchymal tumor cells. Even though FGFs have been firstly characterized as angiogenic factors, they exert autocrine and paracrine functions not only on endothelial cells but also on tumor cells and other stromal components. Thus, the FGF/FGF receptor (FGFR) pathway may represent a key player in tumor growth by regulating the complex cross-talk between stromal and tumor compartments. The ligand dependent or independent activation of the FGF/FGFR system by gene upregulation, oncogenic mutation or amplification occurs in a variety of human tumors and is implicated in various key steps of tumor growth and progression. In addition, FGF/FGFR activation has been described as a mechanism of tumor escape in response to antiangiogenic/anti-VEGF therapies. Experimental and clinical evidences provide a compelling biologic rationale for the development of anti-FGF/FGFR targeting agents in cancer therapy. However, the development of drugs specifically targeting the FGF/FGFR pathway proved to be difficult, also due to the high redundancy and pleiotropic effects of FGF and FGFR family members. On the other hand, the possibility to develop "two-compartment" targeting agents endowed with both antiangiogenic and antitumor activities remains promising. Here we will review the preclinical and clinical approaches and potential therapeutics currently available to block the FGF/FGFR system in human cancer.

  17. 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.

  18. Predicting Drug Extraction in the Human Gut Wall: Assessing Contributions from Drug Metabolizing Enzymes and Transporter Proteins using Preclinical Models.

    Science.gov (United States)

    Peters, Sheila Annie; Jones, Christopher R; Ungell, Anna-Lena; Hatley, Oliver J D

    2016-06-01

    Intestinal metabolism can limit oral bioavailability of drugs and increase the risk of drug interactions. It is therefore important to be able to predict and quantify it in drug discovery and early development. In recent years, a plethora of models-in vivo, in situ and in vitro-have been discussed in the literature. The primary objective of this review is to summarize the current knowledge in the quantitative prediction of gut-wall metabolism. As well as discussing the successes of current models for intestinal metabolism, the challenges in the establishment of good preclinical models are highlighted, including species differences in the isoforms; regional abundances and activities of drug metabolizing enzymes; the interplay of enzyme-transporter proteins; and lack of knowledge on enzyme abundances and availability of empirical scaling factors. Due to its broad specificity and high abundance in the intestine, CYP3A is the enzyme that is frequently implicated in human gut metabolism and is therefore the major focus of this review. A strategy to assess the impact of gut wall metabolism on oral bioavailability during drug discovery and early development phases is presented. Current gaps in the mechanistic understanding and the prediction of gut metabolism are highlighted, with suggestions on how they can be overcome in the future.

  19. Assessing organizational effectiveness in higher education drug prevention consortia.

    Science.gov (United States)

    Sheldon-Keller, A E; Lloyd-McGarvey, E; Canterbury, R J

    1995-01-01

    Eighty-three consortia of institutions of higher education, organized under funding from the Fund for the Improvement of Post-Secondary Education (FIPSE) Drug Prevention Programs of the Department of Education, were surveyed to measure organizational effectiveness. Generalized satisfaction with the functioning of the consortia was related to the number of active members, the average miles traveled to meetings, satisfaction with performance of task functions, members' roles, the level of trust among members and the level of creativity and innovation in problem-solving. Satisfaction with goal attainment was significantly related to the presence of at least one "internal" goal for the consortium.

  20. A Novel Method for Assessing Drug Degradation Product Safety Using Physiologically-Based Pharmacokinetic Models and Stochastic Risk Assessment.

    Science.gov (United States)

    Nguyen, Hoa Q; Stamatis, Stephen D; Kirsch, Lee E

    2015-09-01

    Patient safety risk due to toxic degradation products is a potentially critical quality issue for a small group of useful drug substances. Although the pharmacokinetics of toxic drug degradation products may impact product safety, these data are frequently unavailable. The objective of this study is to incorporate the prediction capability of physiologically based pharmacokinetic (PBPK) models into a rational drug degradation product risk assessment procedure using a series of model drug degradants (substituted anilines). The PBPK models were parameterized using a combination of experimental and literature data and computational methods. The impact of model parameter uncertainty was incorporated into stochastic risk assessment procedure for estimating human safe exposure levels based on the novel use of a statistical metric called "PROB" for comparing probability that a human toxicity-target tissue exposure exceeds the rat exposure level at a critical no-observed-adverse-effect level. When compared with traditional risk assessment calculations, this novel PBPK approach appeared to provide a rational basis for drug instability risk assessment by focusing on target tissue exposure and leveraging physiological, biochemical, biophysical knowledge of compounds and species.

  1. Early benefit assessment of new drugs in Germany - results from 2011 to 2012.

    Science.gov (United States)

    Hörn, Helmut; Nink, Katrin; McGauran, Natalie; Wieseler, Beate

    2014-06-01

    Rising drug costs in Germany led to the Act on the Reform of the Market for Medicinal Products (AMNOG) in January 2011. For new drugs, pharmaceutical companies have to submit dossiers containing all available evidence to demonstrate an added benefit versus an appropriate comparator therapy. The Federal Joint Committee (G-BA), the main decision-making body of the statutory healthcare system, is responsible for the overall procedure of "early benefit assessment". The Institute for Quality and Efficiency in Health Care (IQWiG) largely conducts the dossier assessments, which inform decisions by the G-BA on added benefit and support price negotiations. Of the 25 dossiers (excluding orphan drugs) assessed until 31 December 2012, 14 contained sufficient data from randomized active-controlled trials investigating patient-relevant outcomes or at least acceptable surrogates; 11 contained insufficient data. The most common indications were oncology (6) and viral infections (4). For the 14 drugs assessed, the extent of added benefit was rated as minor, considerable, and non-quantifiable in 3, 8, and 2 cases; the remaining drug showed no added benefit. Despite some shortcomings, for the first time it has been possible in Germany to implement a systematic procedure for assessing new drugs at market entry, thus providing support for price negotiations and informed decision-making for patients, clinicians and policy makers.

  2. 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.

  3. 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.

  4. Emerging Roles of Propolis: Antioxidant, Cardioprotective, and Antiangiogenic Actions

    Science.gov (United States)

    Daleprane, Julio Beltrame; Abdalla, Dulcinéia Saes

    2013-01-01

    Propolis has attracted attention in recent years due to its beneficial effects, which make it a potential preventive and therapeutic agent as well as a useful additive in food and cosmetics. The aim of this review is to discuss the growing evidence that propolis may, via a diverse array of biological actions, assist in the prevention of some inflammation-mediated pathologies including cardiovascular disease. The active components of propolis that have been identified so far include polyphenols and flavonoids. These compounds have cardioprotective, vasoprotective, antioxidant, antiatherosclerotic, anti-inflammatory and antiangiogenic actions. Many studies have been undertaken to elucidate the mechanism(s) by which propolis acts, which involve cellular signaling targets and interactions at the genomic level. This review will highlight the effects of propolis that may assist in the prevention of chronic degenerative diseases, such as cardiovascular disease. PMID:23662115

  5. Emerging Roles of Propolis: Antioxidant, Cardioprotective, and Antiangiogenic Actions

    Directory of Open Access Journals (Sweden)

    Julio Beltrame Daleprane

    2013-01-01

    Full Text Available Propolis has attracted attention in recent years due to its beneficial effects, which make it a potential preventive and therapeutic agent as well as a useful additive in food and cosmetics. The aim of this review is to discuss the growing evidence that propolis may, via a diverse array of biological actions, assist in the prevention of some inflammation-mediated pathologies including cardiovascular disease. The active components of propolis that have been identified so far include polyphenols and flavonoids. These compounds have cardioprotective, vasoprotective, antioxidant, antiatherosclerotic, anti-inflammatory and antiangiogenic actions. Many studies have been undertaken to elucidate the mechanism(s by which propolis acts, which involve cellular signaling targets and interactions at the genomic level. This review will highlight the effects of propolis that may assist in the prevention of chronic degenerative diseases, such as cardiovascular disease.

  6. 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.

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

    Science.gov (United States)

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

    2007-01-01

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

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

    Science.gov (United States)

    Cuevas, Alejandro; Saavedra, Nicolás; Rudnicki, Martina; Abdalla, Dulcineia S. P.; Salazar, Luis A.

    2015-01-01

    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. PMID:26347785

  9. 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.

  10. Assessing medical students’ competence in calculating drug doses

    Directory of Open Access Journals (Sweden)

    Catherine Harries

    2013-09-01

    Full Text Available Evidence suggests that healthcare professionals are not optimally able to calculate medicine doses and various strategies have been employed to improve these skills. In this study, the performance of third and fourth year medical students was assessed and the success of various educational interventions investigated. Students were given four types of dosing calculations typical of those required in an emergency setting. Full competence (at the 100% level was defined as correctly answering all four categories of calculation at any one time. Three categories correct meant competence at the 75% level. Interventions comprised an assignment with a model answer for self-assessment in the third year and a small group tutorial in the fourth year. The small groups provided opportunities for peer-assisted learning. A subgroup of 23 students received individual tuition from the lecturer prior to the start of the fourth year. Amongst the 364 eligible students, full competence rose from 23% at the beginning of the third year to 66% by the end of the fourth year. More students succeeded during the fourth than the third year of study. Success of small group tuition was assessed in a sample of 200 students who had formal assessments both before and after the fourth year tuition. Competence at the 75% level improved by 10% in attendees and decreased by 3% in non-attendees, providing evidence of the value of students receiving assistance from more able same-language peers. Good results were achieved with one-on-one tuition where individualised assistance allowed even struggling students to improve.

  11. 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.

  12. Anti-Angiogenic Therapy: Strategies to Develop Potent VEGFR-2 Tyrosine Kinase Inhibitors and Future Prospect.

    Science.gov (United States)

    Shi, Leilei; Zhou, Jianfeng; Wu, Jifeng; Shen, Yuemao; Li, Xun

    2016-01-01

    Tumor angiogenesis has always been a major gap for effective cancer therapy. Interruption of aberrant angiogenesis by specific inhibitors targeting receptor tyrosine kinases (RTKs) has been of great interests to medicinal chemists. Among the factors that are involved in tumor angiogenesis, vascular endothelial growth factor receptor-2 (VEGFR-2) is validated as the most closely related factor which can drive angiogenesis through binding with its natural ligand VEGF. The well-validated VEGF-driven VEGFR-2 signaling pathway can stimulate many endothelial responses, including increasing vessel permeability and enhancing endothelial cell proliferation, migration and differentiation. Consequently, circumventing angiogenesis by VEGFR-2 inhibitors represents a promising strategy for counteracting various VEGFR-2-mediated disorders as well as drug resistance. Over the past decades, a considerable number of novel small molecular VEGFR-2 inhibitors have been exploited with diverse chemical scaffolds. Especially, recent frequently launched inhibitors have declared their research values and therapeutic potentials in oncology. Still, the antiangiogenesis based treatment remains an ongoing challenge. In this review, a comprehensive retrospective of newly emerged VEGFR-2 inhibitors have been summarized, with the emphasis on the structure-activity relationship (SAR) investigation, and also binding patterns of representative inhibitors with biotargets. On the basis of all of this information, varied strategies for developing potent VEGFR-2 inhibitors and the future prospect of the clinical application of antiangiogenic inhibitors are discussed hereby.

  13. VEGFR2-Targeted Three-Dimensional Ultrasound Imaging Can Predict Responses to Antiangiogenic Therapy in Preclinical Models of Colon Cancer.

    Science.gov (United States)

    Zhou, Jianhua; Wang, Huaijun; Zhang, Huiping; Lutz, Amelie M; Tian, Lu; Hristov, Dimitre; Willmann, Jürgen K

    2016-07-15

    Three-dimensional (3D) imaging capabilities to assess responses to anticancer therapies are needed to minimize sampling errors common to two-dimensional approaches as a result of spatial heterogeneity in tumors. Recently, the feasibility and reproducibility of 3D ultrasound molecular imaging (3D USMI) using contrast agents, which target molecular markers, have greatly improved, due to the development of clinical 3D matrix array transducers. Here we report preclinical proof-of-concept studies showing that 3D USMI of VEGFR2/KDR expression accurately gauges longitudinal treatment responses to antiangiogenesis therapy in responding versus nonresponding mouse models of colon cancer. Tumors in these models exhibited differential patterns of VEGFR2-targeted 3D USMI signals during the course of antiangiogenic treatment with bevacizumab. In responding tumors, the VEGFR2 signal decreased as soon as 24 hours after therapy was started, whereas in nonresponding tumors there was no change in signal at any time point. The early decrease in VEGFR2 signal was highly predictive of treatment outcome at the end of therapy. Our results offer preclinical proof that 3D USMI can predict responses to antiangiogenic therapy, warranting further investigation of its clinical translatability to predicting treatment outcomes in patients. Cancer Res; 76(14); 4081-9. ©2016 AACR.

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

    OpenAIRE

    Nemati, Zeinab; Matlabi, Hossein

    2017-01-01

    Background Internet addiction and drug abuse isolate adolescents from their family and friends and cause damage to their health, relations, emotions, and spirit. In the society, adolescents’ addiction extracts high cost on health care, educational failure and mental health services. Objectives The aim of this study was to assess the behavioral patterns of Internet and drug addiction among urban and rural students in Urmia, Iran. Methods A sectional and descriptive–analytical approach with str...

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

    OpenAIRE

    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 each of two levers with concurrently available fixed-ratio 1 schedules of food reinforcement. Intravenous histamine was delivered along with food when...

  16. [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.

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

    Science.gov (United States)

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

    2014-11-01

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

  18. Anti-Angiogenic Treatment (Sunitinib for Disseminated Malignant Haemangiopericytoma: A Case Study and Review of the Literature

    Directory of Open Access Journals (Sweden)

    M. Delgado

    2011-02-01

    Full Text Available Introduction: A meningeal haemangiopericytoma (HP is a mesenchymal tumour that makes up less than 1% of all CNS tumours. HPs arise from pericytes and present high rates of recurrence and distant metastasis. The primary treatment option is surgery. When the disease is disseminated, chemotherapy produces a weak and short-lived response; therefore, new drugs are needed. Case Presentation: We describe the case of a 65-year-old woman with a 13-year history of recurrent HP. After local treatment with radiotherapy, she developed metastases that required systemic treatment, and treatment with sunitinib, an oral inhibitor of the vascular endothelial growth factor receptor and the platelet-derived growth factor receptor, was initiated. As a result, radiological stabilisation of the systemic disease was maintained for over 12 months. Conclusions: Anti-angiogenic agents can be useful for treating disseminated HP, but further studies are needed to confirm their possible role in controlling metastatic disease.

  19. Causality Assessment in Premarketing Drug Clinical Trials: Regulatory Evolution in the USA and Ongoing Concerns.

    Science.gov (United States)

    Goldman, Stephen A

    2016-10-01

    Since 1993, how to assess the causality of serious adverse events in premarketing drug clinical trials has undergone sustained regulatory evolution in the USA. In that year, an investigational drug study for chronic hepatitis B virus infection was emergently stopped after a patient suddenly exhibited hepatic failure and lactic acidosis, which later developed, along with pancreatitis and peripheral neuropathy, in several others after drug discontinuation. Five patients eventually died, including three despite emergency liver transplantation. The drug's multisystem toxicity was not predicted by preclinical animal studies, with grave injury to human mitochondria subsequently implicated. A concerned US Food and Drug Administration (FDA) created a task force whose findings would have a lasting impact on the agency's thinking. In 1994, the FDA proposed to amend its investigational new drug reporting requirements largely based on task force recommendations for ways to enhance the likelihood that sponsors and investigators would consider investigational agents as a possible cause of serious adverse events mimicking the underlying disease or concomitant drug toxicity. Then, in its 1997 final rule for expedited safety reporting requirements for drugs and biologics, the FDA advised sponsors that such reporting of serious, unexpected clinical trial cases would be expected when "there is a reasonable suspected causal relationship between the investigational product and the adverse event (i.e., the causal relationship cannot be ruled out)." This last clause was codified into the suspected adverse drug reaction definition in the FDA's 2003 safety reporting requirements for drugs and biologics proposed rule. The negatively received suspected adverse drug reaction and proposed causality standard were not adopted in the FDA's 2010 finalized investigational new drug safety reporting regulations, the agency stating that "'reasonable possibility' means there is evidence to suggest a

  20. 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

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

    Science.gov (United States)

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

    2011-12-01

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

  2. Antiangiogenic factors and maternal hemodynamics during intensive hemodialysis in pregnancy.

    Science.gov (United States)

    Cornelis, Tom; Spaanderman, Marc; Beerenhout, Charles; Perschel, Frank H; Verlohren, Stefan; Schalkwijk, Casper G; van der Sande, Frank M; Kooman, Jeroen P; Hladunewich, Michelle

    2013-10-01

    We report on a 21-year-old pregnant patient with IgA nephropathy who was initiated on intensive hemodialysis (8 hours of hemodialysis 3 times a week) at a gestational age of 26 weeks on the basis of worsening kidney function resulting in rapidly progressive fatigue and difficulties in metabolic control. Throughout the pregnancy, and while on intensive hemodialysis, 24-hour ambulatory blood pressure control was within the target, and results of weekly 24-hour measurement of central hemodynamics and pulse wave velocity, and of serial levels of circulating (anti-)angiogenic factors were comparable to normal pregnancies. Estimated fetal growth evolved along the 50th percentile, and no polyhydramnios was detected. After induction for a sudden, unexplained increase in blood pressure, she delivered a healthy boy of 2480 g at a gestational age of 36 weeks. This case adds to the expanding literature that supports the use of intensive hemodialysis in pregnant patients with end-stage renal disease and illustrates, for the first time, the potential use of serial (anti-) angiogenic factors and 24-hour measurements of blood pressure and hemodynamic indices in order to facilitate monitoring of these complicated patients.

  3. Programmed translational readthrough generates antiangiogenic VEGF-Ax.

    Science.gov (United States)

    Eswarappa, Sandeepa M; Potdar, Alka A; Koch, William J; Fan, Yi; Vasu, Kommireddy; Lindner, Daniel; Willard, Belinda; Graham, Linda M; DiCorleto, Paul E; Fox, Paul L

    2014-06-19

    Translational readthrough, observed primarily in less complex organisms from viruses to Drosophila, expands the proteome by translating select transcripts beyond the canonical stop codon. Here, we show that vascular endothelial growth factor A (VEGFA) mRNA in mammalian endothelial cells undergoes programmed translational readthrough (PTR) generating VEGF-Ax, an isoform containing a unique 22-amino-acid C terminus extension. A cis-acting element in the VEGFA 3' UTR serves a dual function, not only encoding the appended peptide but also directing the PTR by decoding the UGA stop codon as serine. Heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 binds this element and promotes readthrough. Remarkably, VEGF-Ax exhibits antiangiogenic activity in contrast to the proangiogenic activity of VEGF-A. Pathophysiological significance of VEGF-Ax is indicated by robust expression in multiple human tissues but depletion in colon adenocarcinoma. Furthermore, genome-wide analysis revealed AGO1 and MTCH2 as authentic readthrough targets. Overall, our studies reveal a novel protein-regulated PTR event in a vertebrate system.

  4. 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.

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

    Science.gov (United States)

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

    2007-01-04

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

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

    Science.gov (United States)

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

    2014-03-12

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

  7. Embryonic Zebrafish Model - A Well-Established Method for Rapidly Assessing the Toxicity of Homeopathic Drugs

    Science.gov (United States)

    Gupta, Himanshu R; Patil, Yogesh; Singh, Dipty

    2016-01-01

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

  8. Children Exposed to Drugs in Utero: Their Scores on the Miller Assessment for Preschoolers.

    Science.gov (United States)

    Fulks, Mary-Ann L.; Harris, Susan R.

    1995-01-01

    The Miller Assessment for Preschoolers was administered to 54 children who had been prenatally exposed to drugs. Results indicated a tendency toward the lower end of the spectrum with poorer performance identified on test items measuring tactile, proprioceptive, and vestibular processing and language. (JOW)

  9. Reliability of the assessment of preventable adverse drug events in daily clinical practice

    NARCIS (Netherlands)

    van Doormaal, J.E.; Mol, P.G.; van den Bemt, P.M.; Egberts, A.C.; Kosterink, J.G.; Haaijer-Ruskamp, F.M.; Zaal, Rianne J.

    2008-01-01

    Purpose To determine the reliability of the assessment of preventable adverse drug events (ADES) in daily practice and to explore the impact of the assessors' professional background and the case characteristics on reliability. Methods We used a combination of the simplified Yale algorithm and the N

  10. Use of the "Personal Delivery" System for Assessment of Drug and Alcohol Attitudes and Usage Patterns.

    Science.gov (United States)

    Crabtree, J. Michael; Myers, Stanley B.

    Community data concerning drug and alcohol usage patterns was assessed via a unique "personal delivery" system. The system, which can be used for collecting other community data produced a return rate of 45% and was very economical. This system largely overcomes the main drawback of the mailed questionnaire (low return rate) by (1) having…

  11. Assessment of disease profiles and drug prescribing patterns of health care facilities in Edo State, Nigeria

    Directory of Open Access Journals (Sweden)

    Ehijie F.O. Enato

    2012-10-01

    Full Text Available Few studies have systematically characterized drug-prescribing patterns, particularly at the primary care level in Nigeria, a country disproportionately burdened with disease. The aim of this study was to assess the disease profiles and drug-prescribing pattern in two health care facilities in Edo State, Nigeria. The medical records of 495 patients who attended a primary or secondary health care facility in Owan-East Local Government Area of Edo State, Nigeria, between June and November 2009 were reviewed. Disease profiles and drug prescribing patterns were assessed. Data were analyzed based on the World Health Organization Anatomic Therapeutic Chemical classification system, and core drug prescribing indicators. Five hundred and twelve clinical conditions were identified. Infectious disease was most prevalent (38.3%, followed by disorder of the alimentary tract (16.4%. Malaria was responsible for 55.6% of the infectious diseases seen, and 21.3% (109/512 of the total clinical conditions managed at the two health facilities during the study period. Consequently, anti-infective medications were the most frequently prescribed medicines (21.5%, followed by vitamins (18.2%. Use of artesunate monotherapy at both facilities (15.7%, and chloroquine at the primary health facility (24.9% were common. Paracetamol (41.8% and non-steroidal anti-inflammatory drugs (24.9% were the most frequently used analgesic/antipyretic. At the primary health care facility, dipyrone was used in 21.6% of cases. The core drug prescribing use indicators showed inappropriate prescribing, indicating poly-pharmacy, overuse of antibiotics and injectio. Inappropriate drug use patterns were identified at both health care facilities, especially with regard to the use of ineffective antimalarial drugs and the use of dipyrone.

  12. 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

  13. The use of rapid assessment methodology to compliment existing national assessment and surveillance data: a study among injecting drug users in Penang, Malaysia.

    Science.gov (United States)

    Vicknasingam, B; Navaratnam, V

    2008-02-01

    The study explores how data collated from rapid assessment can enhance those produced by national level surveillance systems, in this case the national drug information (NADI) system in Malaysia. Qualitative data were collected in keeping with internationally accepted guidance on rapid assessment methods in the field of substance use. An inductive research strategy was employed. The rapid assessment produced multiple data on local drug use practices and how these were influenced by the contexts of use. The assessment points to the importance of collecting data not only on patterns of drug use but also on the health and social consequences of drug use. We suggest that the current national drug information system places greater emphasis on behavioural and health-related variables in order to better understand the potential relationships between drug use and health-related risk, including HIV/AIDS.

  14. 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.

  15. Independent anti-angiogenic capacities of coagulation factors X and Xa.

    Science.gov (United States)

    Lange, Soledad; Gonzalez, Ibeth; Pinto, Mauricio P; Arce, Maximiliano; Valenzuela, Rodrigo; Aranda, Evelyn; Elliot, Matias; Alvarez, Marjorie; Henriquez, Soledad; Velasquez, Ethel V; Orge, Felipe; Oliva, Barbara; Gonzalez, Pamela; Villalon, Manuel; Cautivo, Kelly M; Kalergis, Alexis M; Pereira, Karla; Mendoza, Camila; Saez, Claudia; Kato, Sumie; Cuello, Mauricio A; Parborell, Fernanda; Irusta, Griselda; Palma, Veronica; Allende, Miguel L; Owen, Gareth I

    2014-11-01

    Knockout models have shown that the coagulation system has a role in vascular development and angiogenesis. Herein, we report for the first time that zymogen FX and its active form (FXa) possess anti-angiogenic properties. Both the recombinant FX and FXa inhibit angiogenesis in vitro using endothelial EA.hy926 and human umbilical cord vascular endothelial cells (HUVEC). This effect is dependent on the Gla domain of FX. We demonstrate that FX and FXa use different mechanisms: the use of Rivaroxaban (RX) a specific inhibitor of FXa attenuated its anti-angiogenic properties but did not modify the anti-angiogenic effect of FX. Furthermore, only the anti-angiogenic activity of FXa is PAR-1dependent. Using in vivo models, we show that FX and FXa are anti-angiogenic in the zebrafish intersegmental vasculature (ISV) formation and in the chick embryo chorioallantoic membrane (CAM) assays. Our results provide further evidence for the non-hemostatic functions of FX and FXa and demonstrate for the first time a biological role for the zymogen FX.

  16. The anti-angiogenic and antibacterial effect of Tinomiscium philippinense Miers. (Menispermaceae leaf extract

    Directory of Open Access Journals (Sweden)

    Sheryl Rena-Aguila

    2016-01-01

    Full Text Available Objective: To determine the toxicity profile, anti-angiogenic and antibacterial activity of the crude and semi-crude leaf extracts of Tinomiscium philippinense (T. philippinense. Methods: The leaves of T. 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 of T. philippinense at 1 000 µg/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 with Pseudomonas 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 of T. philippinense is non-toxic at a maximum dose of 5000 mg/kg. Conclusions: The dichloromethane leaf extract of T. philippinense is a potential antiangiogenic 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.

  17. Assessing the risk of drug-induced cholestasis using unbound intrahepatic concentrations.

    Science.gov (United States)

    Riede, Julia; Poller, Birk; Huwyler, Jorg; Camenisch, Gian

    2017-03-02

    Inhibition of the bile salt export pump (BSEP) has been recognized as a key factor in the development of drug-induced cholestasis (DIC). The risk of DIC in human has previously been assessed using in vitro BSEP inhibition data (IC50) and unbound systemic drug exposure under assumption of the "free drug hypothesis". This concept, however, is unlikely valid as unbound intrahepatic drug concentrations are affected by active transport and metabolism. To investigate this hypothesis we experimentally determined the in vitro liver-to-blood partition coefficients (Kp,uu) for 18 drug compounds using the hepatic Extended Clearance Model (ECM). In vitro-in vivo translatability of Kp,uu values was verified for a subset of compounds in rat. Consequently, unbound intrahepatic concentrations were calculated from clinical exposure (systemic and hepatic inlet) and measured Kp,uu data. Using these values, corresponding safety margins against BSEP IC50 values were determined and compared to the clinical incidence of DIC. Depending on the ECM class of a drug, in vitro Kp,uu values deviated up to 14-fold from unity and unbound intrahepatic concentrations were affected accordingly. The use of in vitro Kp,uu-based safety margins allowed to separate clinical cholestasis frequency into three classes (no cholestasis, cholestasis in ≤ 2%, and in > 2% of subjects) for 17 out of 18 compounds. This assessment was significantly superior compared to using unbound extracellular concentrations as a surrogate for intrahepatic concentrations. Furthermore, the assessment of Kpuu according to ECM provides useful guidance for the quantitative evaluation of genetic and physiological risk factors for the development of cholestasis.

  18. Novel approach to in vitro drug susceptibility assessment of clinical strains of Leishmania spp.

    Science.gov (United States)

    Fernández, Olga; Diaz-Toro, Yira; Valderrama, Liliana; Ovalle, Clemencia; Valderrama, Mabel; Castillo, Harry; Perez, Mauricio; Saravia, Nancy Gore

    2012-07-01

    Resistance to antimonial drugs has been documented in Leishmania isolates transmitted in South America, Europe, and Asia. The frequency and distribution of resistance to these and other antileishmanial drugs are unknown. Technical constraints have limited the assessment of drug susceptibility of clinical strains of Leishmania. Susceptibility of experimentally selected lines and 130 clinical strains of Leishmania panamensis, L. braziliensis, and L. guyanensis to meglumine antimoniate and miltefosine was determined on the basis of parasite burden and percentage of infected U-937 human macrophages. Reductions of infection at single predefined concentrations of meglumine antimoniate and miltefosine and 50% effective doses (ED(50)s) were measured and correlated. The effects of 34°C and 37°C incubation temperatures and different parasite-to-host cell ratios on drug susceptibility were evaluated at 5, 10, and 20 parasites/cell. Reduction of the intracellular burden of Leishmania amastigotes in U-937 cells exposed to the predefined concentrations of meglumine antimoniate or miltefosine discriminated sensitive and experimentally derived resistant Leishmania populations and was significantly correlated with ED(50) values of clinical strains (for meglumine antimoniate, ρ = -0.926 and P < 0.001; for miltefosine, ρ = -0.906 and P < 0.001). Incubation at 37°C significantly inhibited parasite growth compared to that at 34°C in the absence of antileishmanial drugs and resulted in a significantly lower ED(50) in the presence of drugs. Susceptibility assessment was not altered by the parasite-to-cell ratio over the range evaluated. In conclusion, measurement of the reduction of parasite burden at a single predetermined drug concentration under standardized conditions provides an efficient and reliable strategy for susceptibility evaluation and monitoring of clinical strains of Leishmania.

  19. 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.

  20. Improving the assessment of heart toxicity for all new drugs through translational regulatory science.

    Science.gov (United States)

    Johannesen, L; Vicente, J; Gray, R A; Galeotti, L; Loring, Z; Garnett, C E; Florian, J; Ugander, M; Stockbridge, N; Strauss, D G

    2014-05-01

    Fourteen drugs have been removed from the market worldwide because they cause torsade de pointes. Most drugs that cause torsade can be identified by assessing whether they block the human ether à gogo related gene (hERG) potassium channel and prolong the QT interval on the electrocardiogram. In response, regulatory agencies require new drugs to undergo "thorough QT" studies. However, some drugs block hERG potassium channels and prolong QT with minimal torsade risk because they also block calcium and/or sodium channels. Through analysis of clinical and preclinical data from 34 studies submitted to the US Food and Drug Administration and by computer simulations, we demonstrate that by dividing the QT interval into its components of depolarization (QRS), early repolarization (J-Tpeak), and late repolarization (Tpeak-Tend), along with atrioventricular conduction delay (PR), it may be possible to determine which hERG potassium channel blockers also have calcium and/or sodium channel blocking activity. This translational regulatory science approach may enable innovative drugs that otherwise would have been labeled unsafe to come to market.

  1. Assessing sexuality attitudes and behaviors and correlates of alcohol and drugs.

    Science.gov (United States)

    Donnelly, J; Goldfarb, E S; Ferraro, H; Eadie, C; Duncan, D F

    2001-06-01

    The association between sexual abstinence and use of alcohol, cigarettes, and marijuana was examined in data from questionnaires completed by 874 students in Grades 6 through 8 at six urban schools. These students participated in a program that implemented and evaluated an educational program on abstinence sexuality. It focused on raising self-esteem, improving communication skills, and learning to set life goals. The evaluation instrument contained items assessing sexuality and attitudes toward behaviors related to drug use. Use of each drug (alcohol, tobacco, and marijuana) was significantly (p < .00001) and positively associated with self-report of having experienced sexual intercourse and expectation of having intercourse during the next year.

  2. The use of formulation technology to assess regional gastrointestinal drug absorption in humans.

    Science.gov (United States)

    Basit, Abdul W; Podczeck, Fridrun; Newton, J Michael; Waddington, Wendy A; Ell, Peter J; Lacey, Larry F

    2004-02-01

    The aim of this study was to assess the feasibility of using oral modified-release formulations for the purposes of site-specific targeting and regional drug absorption assessment in man. An immediate release pellet formulation containing ranitidine as the model drug of choice for the study was fabricated by extrusion-spheronisation, and then film coated with either the enteric polymer polyvinyl acetate phthalate or the bacteria-degradable polymer amylose, in combination with ethylcellulose, to effect drug release within the small intestine and colon, respectively. Optimised formulations were evaluated in vivo in ten healthy volunteers, who each received, on four separate occasions, the immediate release, small intestinal release and colonic release formulations (each equivalent to 150mg ranitidine), and an intravenous injection of ranitidine (equivalent to 50mg ranitidine). Blood samples were collected and assessed for ranitidine concentration, and radiolabelled placebo pellets were co-administered with the coated ranitidine pellets to monitor their gastrointestinal transit using a gamma camera. Ranitidine was rapidly released and absorbed from the immediate release formulation, whereas the enteric formulation (10% coat weight gain) delayed drug release until some or all of the pellets had emptied into the small intestine. The amylose-ethylcellulose coated formulation (coat ratio 1:3, coat weight gain 25%) retarded ranitidine release until the pellets had reached the colon. The mean absolute bioavailability of ranitidine from the immediate release, small intestinal release and colonic release formulations were 50.6, 46.1 and 5.5%, respectively. These data are in general agreement to those obtained from a previous regional intubation study. The present study therefore demonstrates the practical potential of utilising a non-invasive, formulation-based approach to assess drug absorption from different regions of the human gastrointestinal tract.

  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 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.

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

    Directory of Open Access Journals (Sweden)

    Tianyu Zhang

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

  6. Scientific factors for assessing biosimilarity and drug interchangeability of follow-on biologics

    Directory of Open Access Journals (Sweden)

    Chow SC

    2011-06-01

    Full Text Available Shein-Chung Chow1, Laszlo Endrenyi2, Peter A Lachenbruch3, Lan-Yan Yang1, Eric Chi41Duke University School of Medicine, Durham, NC, USA; 2University of Toronto, Toronto, Canada; 3Oregon State University, Corvallis, OR, USA; 4Amgen, Inc, Thousand Oaks, CA, USAAbstract: Biological products are therapeutic agents produced using a living system or organism. In practice, access to these life-saving biological products is limited due to their expensive cost. In the next few years, patents of the early biological products will expire. This provides other biopharmaceutical/biotech companies the opportunity to manufacture follow-on biologics. For the conventional pharmaceuticals of small molecules, regulations and statistical methods for the assessment of bioequivalence for generic approval are well established. However, unlike the conventional drug products, the complexity and heterogeneity of the molecular structure, complicated manufacturing process, different analytical methods, and the possibility of severe immunogenicity reactions make evaluation of equivalence (similarity between an innovator and its follow-on biologics a great challenge for both the scientific community and regulatory agencies. This article reviews past experiences for the assessment of bioequivalence for conventional drug products. Detailed descriptions of the fundamental differences and assumptions between the chemical generic products and follow-on biologics are given. An overview of current regulatory requirements for assessing biosimilarity of follow-on biologics is provided. Statistical considerations for scientific factors for assessing biosimilarity and drug interchangeability of the follow-on biologics as posted at the recent FDA Public Hearing on Approval Pathway for Biosimilar and Interchangeability Biological Products are discussed. In addition, current statistical issues that are commonly encountered when assessing biosimilarity of follow-on biologics are reviewed

  7. 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.

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

    Science.gov (United States)

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

    2016-04-12

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

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

    Science.gov (United States)

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

    2010-10-01

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

  10. The Role of Antiangiogenic Therapy in the Development of Osteonecrosis of the Jaw.

    Science.gov (United States)

    Fantasia, John E

    2015-11-01

    There is an increasing use of established and newer medications that have antiangiogenic properties. Inhibition of angiogenesis likely has either a primary or secondary role in the development of osteonecrosis of the jaw (ONJ). These medications are being used in the treatment of various cancers and in the treatment of several non-oncologic conditions. Antiangiogenic medications when used in combination with antiresorptive medications, such as nitrogen-containing bisphosphonates or denosumab, seem to increase the likelihood of osteonecrosis of the jaw. This review highlights the role of inhibitors of angiogenesis and their role in the development of osteonecrosis of the jaws.

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

    DEFF Research Database (Denmark)

    Alstrøm, Tommy Sonne

    ; 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......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...... 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...

  12. Anti-malarial drug quality in Lagos and Accra - a comparison of various quality assessments

    OpenAIRE

    2010-01-01

    Abstract Background Two major cities in West Africa, Accra, the capital of Ghana, and Lagos, the largest city of Nigeria, have significant problems with substandard pharmaceuticals. Both have actively combated the problem in recent years, particularly by screening products on the market using the Global Pharma Health Fund e.V. Minilab® protocol. Random sampling of medicines from the two cities at least twice over the past 30 months allows a tentative assessment of whether improvements in drug...

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

    Science.gov (United States)

    Wild, Claudia; Nachtnebel, Anna

    2013-01-01

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

  14. Using the level of Service Inventory-Revised to improve assessment and treatment in drug court.

    Science.gov (United States)

    Guastaferro, Wendy P

    2012-08-01

    More than 2,000 drug courts in the United States provide supervision and substance-abuse treatment to thousands of offenders. Yet the treatment continuum from assessment to aftercare is underexplored. The effectiveness of the Level of Service Inventory-Revised (LSI-R) as a risk assessment tool is well established. However, fewer studies have considered its use in guiding treatment strategies. In using the LSI-R, the drug court program relied on the structured interview protocol (not the risk classification scores) to identify criminogenic needs that then helped determine placement in a high- or low-needs treatment track. To evaluate the effectiveness of these treatment placement decisions, this research used the LSI-R scores to examine individual and group differences (N = 182). Significant and substantive differences at the individual and group levels were found thus providing empirical support for using the LSI-R as a link between assessment and treatment. Implications for developing standards and practice protocols for drug courts are discussed.

  15. Association of Maternal Antiangiogenic Profile at Birth With Early Postnatal Loss of Microvascular Density in Offspring of Hypertensive Pregnancies

    Science.gov (United States)

    Yu, Grace Z.; Aye, Christina Y.L.; Lewandowski, Adam J.; Davis, Esther F.; Khoo, Cheen P.; Newton, Laura; Yang, Cheng T.; Al Haj Zen, Ayman; Simpson, Lisa J.; O’Brien, Kathryn; Cook, David A.; Granne, Ingrid; Kyriakou, Theodosios; Channon, Keith M.; Watt, Suzanne M.

    2016-01-01

    Offspring of hypertensive pregnancies are more likely to have microvascular rarefaction and increased blood pressure in later life. We tested the hypothesis that maternal angiogenic profile during a hypertensive pregnancy is associated with fetal vasculogenic capacity and abnormal postnatal microvascular remodeling. Infants (n=255) born after either hypertensive or normotensive pregnancies were recruited for quantification of postnatal dermal microvascular structure at birth and 3 months of age. Vasculogenic cell potential was assessed in umbilical vein endothelial cells from 55 offspring based on in vitro microvessel tube formation and proliferation assays. Maternal angiogenic profile (soluble fms-like tyrosine kinase-1, soluble endoglin, vascular endothelial growth factor, and placental growth factor) was measured from postpartum plasma samples to characterize severity of pregnancy disorder. At birth, offspring born after hypertensive pregnancy had similar microvessel density to those born after a normotensive pregnancy, but during the first 3 postnatal months, they had an almost 2-fold greater reduction in total vessel density (−17.7±16.4% versus −9.9±18.7%; P=0.002). This postnatal loss varied according to the vasculogenic capacity of the endothelial cells of the infant at birth (r=0.49; P=0.02). The degree of reduction in both in vitro and postnatal in vivo vascular development was proportional to levels of antiangiogenic factors in the maternal circulation. In conclusion, our data indicate that offspring born to hypertensive pregnancies have reduced vasculogenic capacity at birth that predicts microvessel density loss over the first 3 postnatal months. Degree of postnatal microvessel reduction is proportional to levels of antiangiogenic factors in the maternal circulation at birth. PMID:27456522

  16. Drug levels, immunogenicity and assessment of active sacroiliitis in patients with axial spondyloarthritis under biologic tapering strategy.

    Science.gov (United States)

    Almirall, Miriam; Gimeno, Ramón; Salman-Monte, Tarek Carlos; Iniesta, Silvia; Lisbona, Maria Pilar; Maymó, Joan

    2016-04-01

    The aim of the study was to assess drug levels, immunogenicity and sacroiliitis on MRI in patients with axial spondyloarthritis under biologic tapering strategy. Consecutive patients with axial spondyloarthritis who remained in low disease activity more than 1 year after dose tapering of infliximab and adalimumab were included. Plasma drug concentrations of TNF inhibitors and anti-drug antibodies were determined, and MRI of sacroiliac joints was evaluated. Of twenty patients included, eighteen had therapeutic drug levels, no patient had anti-drug antibodies, and no patient had active sacroiliitis on MRI. These data could support the biologic tapering strategy and their maintenance over time.

  17. 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.

  18. 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

  19. Effects of 5HPP-33,an antiangiogenic thalidomide analog, in mouse whole embryo culture

    Science.gov (United States)

    Thalidomide is a well-known example of a teratogen which has been shown to have an inhibitory effect on angiogenesis. As a result of its targeted effect on immature blood vessels, anti-angiogenic specific chemical analogs were developed to maximize this mechanism of thalidomide e...

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

    Science.gov (United States)

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

    2016-01-01

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

  1. 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

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

    NARCIS (Netherlands)

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

    2006-01-01

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

  3. Anti-angiogenic activity of Morinda citrifolia extracts and its chemical constituents.

    Science.gov (United States)

    Beh, Hooi-Kheng; Seow, Lay-Jing; Asmawi, Mohd Zaini; Abdul Majid, Amin Malik Shah; Murugaiyah, Vikneswaran; Ismail, Norhayati; Ismail, Zhari

    2012-01-01

    Morinda citrifolia L. has been used for the treatment of a wide variety of diseases, including cancer. This study was undertaken to evaluate the anti-angiogenic effect of M. citrifolia fruits and leaves. Anti-angiogenic activity was evaluated in vivo using the chick chorioallantoic membrane assay. Bioactivity-guided fractionation and isolation were performed to identify the active constituent, and high-performance liquid chromatography analysis was then used to quantify the amount of this active constituent in the active extracts and fraction. The methanol extracts of fruits and leaves of M. citrifolia and the subsequent chloroform fraction of the fruit methanolic extract were found to have potential anti-angiogenic activity and were more potent compared to suramin. Scopoletin was identified as one of the chemical constituents that may be partly responsible for the anti-angiogenic activity of M. citrifolia fruits. The present findings further support the use of M. citrifolia in cancer or other pathological conditions related to angiogenesis.

  4. [Experimental and morphological study of the effect of antiangiogenic therapy on corneal neovessels].

    Science.gov (United States)

    Mamikonian, V R; Voevodina, T M; Fedorov, A A; Budzinskaia, M V; Balaian, M L

    2013-01-01

    The article presents the results of an experimental and morphological study of combined antiangiogenic effect of photodynamic therapy with Photosens photosensitizer and Avastin (bevacizumab) on neovascularization process in corneal stroma. The combined approach has demonstrated an advantage over separate application of these methods, what, however, has to be proved clinically.

  5. Structural Determinant and Its Underlying Molecular Mechanism of STPC2 Related to Anti-Angiogenic Activity

    Science.gov (United States)

    Hu, Min; Cui, Ning; Bo, Zhixiang; Xiang, Feixiang

    2017-01-01

    In this study, we aimed to use different strategies to further uncover the anti-angiogenic molecular mechanism of a fucoidan-like polysaccharide STPC2, isolated from brown alga Sargassum thunbergii. A desulfated derivative, STPC2-DeS, was successfully prepared and identified. The native polysaccharide and desulfated product were subjected to evaluate their anti-angiogenic effects. In the tube formation assay, STPC2 showed dose-dependent inhibition. In addition, STPC2 could distinctly inhibit the permeation of HUVEC cells into the lower chamber. Moreover, a significant reduction of microvessel density was observed in chick chorioallantoic membrane assay treated with STPC2. Meanwhile, STPC2 was found to repress the VEGF-induced neovessel formation in the matrigel plug assay in vivo. However, STPC2-DeS failed to suppress the anti-angiogenic activity via these in vitro and in vivo strategies. In addition, we demonstrated that STPC2 could significantly downregulate the phosphorylation of VEGFR2 and its related downstream Src family kinase, focal adhesion kinase, and AKT kinase. Furthermore, surface plasmon resonance assay revealed that STPC2 bound strongly to VEGF to interfere with VEGF–VEGFR2 interaction. Taken together, these results evidently demonstrated that STPC2 exhibited a potent anti-angiogenic activity through binding to VEGF via sulfated groups to impede VEGF–VEGFR2 interaction, thus affected the downstream signaling molecules. PMID:28230794

  6. 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.

  7. Clinical assessment of a new anaesthetic drug administration system: a prospective, controlled, longitudinal incident monitoring study.

    Science.gov (United States)

    Webster, C S; Larsson, L; Frampton, C M; Weller, J; McKenzie, A; Cumin, D; Merry, Alan F

    2010-05-01

    A safety-orientated system of delivering parenteral anaesthetic drugs was assessed in a prospective incident monitoring study at two hospitals. Anaesthetists completed an incident form for every anaesthetic, indicating if an incident occurred. Case mix data were collected and the number of drug administrations made during procedures estimated. From February 1998 at Hospital A and from June 1999 at Hospital B, until November 2003, 74,478 anaesthetics were included, for which 59,273 incident forms were returned (a 79.6% response rate). Fewer parenteral drug errors occurred with the new system than with conventional methods (58 errors in an estimated 183,852 drug administrations (0.032%, 95% CI 0.024-0.041%) vs 268 in 550,105 (0.049%, 95% CI 0.043-0.055%) respectively, p = 0.002), a relative reduction of 35% (difference 0.017%, 95% CI 0.006-0.028%). No major adverse outcomes from these errors were reported with the new system while 11 (0.002%) were reported with conventional methods (p = 0.055). We conclude that targeted system re-design can reduce medical error.

  8. Tiered analytics for purity assessment of macrocyclic peptides in drug discovery: Analytical consideration and method development.

    Science.gov (United States)

    Qian Cutrone, Jingfang Jenny; Huang, Xiaohua Stella; Kozlowski, Edward S; Bao, Ye; Wang, Yingzi; Poronsky, Christopher S; Drexler, Dieter M; Tymiak, Adrienne A

    2017-05-10

    Synthetic macrocyclic peptides with natural and unnatural amino acids have gained considerable attention from a number of pharmaceutical/biopharmaceutical companies in recent years as a promising approach to drug discovery, particularly for targets involving protein-protein or protein-peptide interactions. Analytical scientists charged with characterizing these leads face multiple challenges including dealing with a class of complex molecules with the potential for multiple isomers and variable charge states and no established standards for acceptable analytical characterization of materials used in drug discovery. In addition, due to the lack of intermediate purification during solid phase peptide synthesis, the final products usually contain a complex profile of impurities. In this paper, practical analytical strategies and methodologies were developed to address these challenges, including a tiered approach to assessing the purity of macrocyclic peptides at different stages of drug discovery. Our results also showed that successful progression and characterization of a new drug discovery modality benefited from active analytical engagement, focusing on fit-for-purpose analyses and leveraging a broad palette of analytical technologies and resources.

  9. Multi-criteria decision analysis for assessment and appraisal of orphan drugs

    Directory of Open Access Journals (Sweden)

    Georgi Iskrov

    2016-09-01

    Full Text Available Background: Limited resources and expanding expectations push all countries and types of health systems to adopt new approaches in priority setting and resources allocation. Despite best efforts, it is difficult to reconcile all competing interests and trade-offs are inevitable. This is why multi-criteria decision analysis (MCDA has played a major role in recent uptake of value-based reimbursement. MCDA framework enables exploration of stakeholders’ preferences, as well as explicit organization of broad range of criteria on which real-world decisions are made.Assessment and appraisal of orphan drugs tend to be one of the most complicated health technology assessment (HTA tasks. Access to market approved orphan therapies remains an issue. Early constructive dialogue among rare disease stakeholders and elaboration of orphan drug-tailored decision support tools could set the scene for ongoing accumulation of evidence, as well as for proper reimbursement decision-making.Objective: The objective of this study was to create a MCDA value measurement model to assess and appraise orphan drugs. This was achieved by exploring the preferences on decision criteria’s weights and performance scores through a stakeholder-representative survey and a focus group discussion that were both organized in Bulgaria.Results/Conclusions: Decision criteria that describe the health technology’s characteristics were unanimously agreed as the most important group of reimbursement considerations. This outcome, combined with the high individual weight of disease severity and disease burden criteria underlined some of the fundamental principles of healthcare – equity and fairness. Our study proved that strength of evidence may be a key criterion in orphan drug assessment and appraisal. Evidence is not only used to shape reimbursement decision-making, but also to lend legitimacy to policies pursued. The need for real-world data on orphan drugs was largely stressed

  10. 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.

  11. The inhibition of MAPK potentiates the anti-angiogenic efficacy of mTOR inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Dormond-Meuwly, Anne; Roulin, Didier; Dufour, Marc; Benoit, Michael; Demartines, Nicolas [Department of Visceral Surgery, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Pavillon 3, Av. de Beaumont, 1011 Lausanne (Switzerland); Dormond, Olivier, E-mail: olivier.dormond@chuv.ch [Department of Visceral Surgery, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Pavillon 3, Av. de Beaumont, 1011 Lausanne (Switzerland)

    2011-04-22

    Highlights: {yields} Targeting mTOR in endothelial cell activates MAPK. {yields} Blocking MAPK enhances the anti-angiogenic effects of mTOR inhibitors. {yields} The anti-angiogenic efficacy of ATP-competitive inhibitors of mTOR is superior to that of rapamycin. -- Abstract: The mammalian target of rapamycin (mTOR) which is part of two functionally distinct complexes, mTORC1 and mTORC2, plays an important role in vascular endothelial cells. Indeed, the inhibition of mTOR with an allosteric inhibitor such as rapamycin reduces the growth of endothelial cell in vitro and inhibits angiogenesis in vivo. Recent studies have shown that blocking mTOR results in the activation of other prosurvival signals such as Akt or MAPK which counteract the growth inhibitory properties of mTOR inhibitors. However, little is known about the interactions between mTOR and MAPK in endothelial cells and their relevance to angiogenesis. Here we found that blocking mTOR with ATP-competitive inhibitors of mTOR or with rapamycin induced the activation of the mitogen-activated protein kinase (MAPK) in endothelial cells. Downregulation of mTORC1 but not mTORC2 had similar effects showing that the inhibition of mTORC1 is responsible for the activation of MAPK. Treatment of endothelial cells with mTOR inhibitors in combination with MAPK inhibitors reduced endothelial cell survival, proliferation, migration and tube formation more significantly than either inhibition alone. Similarly, in a tumor xenograft model, the anti-angiogenic efficacy of mTOR inhibitors was enhanced by the pharmacological blockade of MAPK. Taken together these results show that blocking mTORC1 in endothelial cells activates MAPK and that a combined inhibition of MAPK and mTOR has additive anti-angiogenic effects. They also provide a rationale to target both mTOR and MAPK simultaneously in anti-angiogenic treatment.

  12. 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.

  13. 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...

  14. Assessing the HIV-1 Epidemic in Brazilian Drug Users: A Molecular Epidemiology Approach.

    Directory of Open Access Journals (Sweden)

    Monick Lindenmeyer Guimarães

    Full Text Available Person who inject illicit substances have an important role in HIV-1 blood and sexual transmission and together with person who uses heavy non-injecting drugs may have less than optimal adherence to anti-retroviral treatment and eventually could transmit resistant HIV variants. Unfortunately, molecular biology data on such key population remain fragmentary in most low and middle-income countries. The aim of the present study was to assess HIV infection rates, evaluate HIV-1 genetic diversity, drug resistance, and to identify HIV transmission clusters in heavy drug users (DUs. For this purpose, DUs were recruited in the context of a Respondent-Driven Sampling (RDS study in different Brazilian cities during 2009. Overall, 2,812 individuals were tested for HIV, and 168 (6% of them were positive, of which 19 (11.3% were classified as recent seroconverters, corresponding to an estimated incidence rate of 1.58%/year (95% CI 0.92-2.43%. Neighbor joining phylogenetic trees from env and pol regions and bootscan analyses were employed to subtype the virus from132 HIV-1-infected individuals. HIV-1 subtype B was prevalent in most of the cities under analysis, followed by BF recombinants (9%-35%. HIV-1 subtype C was the most prevalent in Curitiba (46% and Itajaí (86% and was also detected in Brasília (9% and Campo Grande (20%. Pure HIV-1F infections were detected in Rio de Janeiro (9%, Recife (6%, Salvador (6% and Brasília (9%. Clusters of HIV transmission were assessed by Maximum likelihood analyses and were cross-compared with the RDS network structure. Drug resistance mutations were verified in 12.2% of DUs. Our findings reinforce the importance of the permanent HIV-1 surveillance in distinct Brazilian cities due to viral resistance and increasing subtype heterogeneity all over Brazil, with relevant implications in terms of treatment monitoring, prophylaxis and vaccine development.

  15. Causality assessment of adverse drug reaction in Pulmonology Department of a Tertiary Care Hospital

    Science.gov (United States)

    Khan, Amer; Adil, Mir S.; Nematullah, K.; Ihtisham, S.; Aamer, K.; Aamir, Syed

    2015-01-01

    Background: Adverse drug reaction (ADR) is considered to be the sixth leading cause of death. The incidence rate estimates approximately 2% of hospital admissions are due to ADRs. Objective: To monitor ADRs in Pulmonology department of a tertiary care hospital patient with pulmonary diseases in an inpatient department of pulmonology. Materials and Methods: A prospective, single centered, observational and open labeled study was carried out in Princess Esra Hospital. The patient population was broadly divided into four categories based on diagnosis - chronic obstructive pulmonary disease, Infections, Asthma and Others. Suspected ADRs were reported, analyzed, and causality assessment was carried out using Naranjo's algorithm scale. Results: A total of 302 patients were observed, of which 98 patients experienced ADRs, which accounted for 32.23% of the incidence and totally 160 ADEs were observed. Adult Patients were found to have higher incidence (32.09%) while the incidence rate was slightly greater in geriatric patients (32.39%). The highest incidence of ADEs were found in others group (78.57%). Majority of ADRs were suspected to be due to theophylline (19.39%). Gastrointestinal system (38.75%) was the most common organ system affected due to ADRs. Drug was withdrawn in 12 patients, and specific treatment was administered to 32 patients in view of clinical status. Specific treatment for the management of suspected reaction was administered in 32.65% of ADR reports. Conclusion: A relatively high incidence of adverse drug events (32.2%) have been recorded which shows that not only Geriatric patients, but also adults are more susceptible to adverse drug effects. A number of drugs in combination were used, and ADEs often get multiplied. Careful therapeutic monitoring and dose individualization is necessary. PMID:26229344

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

    Directory of Open Access Journals (Sweden)

    Rocchi A

    2015-06-01

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

  17. Parametric time-to-onset models were developed to improve causality assessment of adverse drug reactions from antidiabetic drugs

    NARCIS (Netherlands)

    Scholl, Joep H G; van de Ven, Peter M; van Puijenbroek, Eugène P

    2015-01-01

    OBJECTIVES: The aim of this study was to investigate whether the time to onset (TTO) of common adverse drug reactions (ADRs) of antidiabetic drugs could be modeled using parametric distributions and whether these TTO distributions were dependent on patient characteristics. Furthermore, information r

  18. 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

  19. Identifying alemtuzumab as an anti-myeloid cell antiangiogenic therapy for the treatment of ovarian cancer

    Directory of Open Access Journals (Sweden)

    Coukos George

    2009-06-01

    Full Text Available Abstract Background Murine studies suggest that myeloid cells such as vascular leukocytes (VLC and Tie2+ monocytes play a critical role in tumor angiogenesis and vasculogenesis. Myeloid cells are a primary cause of resistance to anti-VEGF therapy. The elimination of these cells from the tumor microenvironment significantly restricts tumor growth in both spontaneous and xenograft murine tumor models. Thus animal studies indicate that myeloid cells are potential therapeutic targets for solid tumor therapy. Abundant VLC and Tie2+ monocytes have been reported in human cancer. Unfortunately, the importance of VLC in human cancer growth remains untested as there are no confirmed therapeutics to target human VLC. Methods We used FACS to analyze VLC in ovarian and non-ovarian tumors, and characterize the relationship of VLC and Tie2-monocytes. We performed qRT-PCR and FACS on human VLC to assess the expression of the CD52 antigen, the target of the immunotherapeutic Alemtuzumab. We assessed Alemtuzumab's ability to induce complement-mediated VLC killing in vitro and in human tumor ascites. Finally we assessed the impact of anti-CD52 immuno-toxin therapy on murine ovarian tumor growth. Results Human VLC are present in ovarian and non-ovarian tumors. The majority of VLC appear to be Tie2+ monocytes. VLC and Tie2+ monocytes express high levels of CD52, the target of the immunotherapeutic Alemtuzumab. Alemtuzumab potently induces complement-mediated lysis of VLC in vitro and ex-vivo in ovarian tumor ascites. Anti-CD52 immunotherapy targeting VLC restricts tumor angiogenesis and growth in murine ovarian cancer. Conclusion These studies confirm VLC/myeloid cells as therapeutic targets in ovarian cancer. Our data provide critical pre-clinical evidence supporting the use of Alemtuzumab in clinical trials to test its efficacy as an anti-myeloid cell antiangiogenic therapeutic in ovarian cancer. The identification of an FDA approved anti-VLC agent with a history

  20. 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.

  1. 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.

  2. 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.

  3. Multimodal assessment of spatial distribution of drug-tracer uptake by brain tissue after intra-arterial injections

    Science.gov (United States)

    Singh-Moon, Rajinder; Chaudhuri, Durba; Wang, Mei; Straubinger, Robert; Bigio, Irving J.; Joshi, Shailendra

    2014-02-01

    It is challenging to track the rapid changes in drug concentrations after intra-arterial (IA) administration to elucidate the pharmacokinetics of this method of drug delivery. Traditional pharmacokinetic parameters (such as protein binding) that are highly relevant to intravenous (IV) administration do not seem to apply to IA injections. Regional drug delivery is affected by the biomechanics of drug injection, resting blood flow, and local tissue extraction. In-vivo and ex-vivo, optical methods for spatial mapping of drug deposition can assist in visualizing drug distributions and aid in the screening of potential drugs and carrier candidates. We present a multimodal approach for the assessment of drug distribution in postmortem tissue specimens using diffuse reflectance spectroscopy, multispectral imaging, and confocal microscopy and demonstrate feasibility of distinguishing route of administration advantages of liposome-dye conjugate delivery. The results of this study suggest that insight on drug dynamics gained by this aggregated approach can be used to help screen and/or optimize potential drug candidates and drug delivery protocols.

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

    Science.gov (United States)

    Nemati, Zeinab; Matlabi, Hossein

    2017-01-01

    Background Internet addiction and drug abuse isolate adolescents from their family and friends and cause damage to their health, relations, emotions, and spirit. In the society, adolescents’ addiction extracts high cost on health care, educational failure and mental health services. Objectives The aim of this study was to assess the behavioral patterns of Internet and drug addiction among urban and rural students in Urmia, Iran. Methods A sectional and descriptive–analytical approach with stratified sampling method was employed to recruit 385 high school students from urban and rural areas. The Internet Addiction Test (IAT) and the Addiction Acknowledgement Scale (AAS) were used for data collection. Results The total score of Internet addiction among the students was 41.72 ± 17.41. Approximately two-third of the students were not addicted to the Internet. The mean score of the AAS was 1.87 ± 1.23 among boys and 1.75 ± 1.31 among girls. Moreover, 8.31% of the students were prone to abusing substances. A statistically significant relationship was found between mother’s literacy level and Internet addiction behavior of students (p=0.009). Conclusion Concentrating on adolescents’ behavioral patterns and their tendency toward misusing Internet and drugs is a notable procedure. Therefore, focusing on adolescents’ health and institutionalizing appropriate training programs for adolescents and their families are vital. PMID:28182139

  5. Use of the whole-embryo culture system in drug safety assessment?

    Science.gov (United States)

    Bechter, R; Schön, H

    1988-01-01

    The embryotoxicity and, in particular, the teratogenic potential of three new drug combinations were investigated. The interactions of the single components (all already on the market) in the different drug mixtures were determined by testing the single components in addition to the drug combinations. In order to evaluate the usefulness of these results for safety assessment, the no-effect concentrations (NEC) of the single compounds or the mixed drug preparations, with respect to embryonic growth and differentiation and the presence of anomalies, were compared with human plasma/serum levels during therapeutic use. In addition, in vivo animal data of the single components were used to put into perspective the NEC values after direct in vitro exposure of embryos. Embryotoxicity, measured as a retardation of growth and of differentiation, as well as an increased percentage of cultured embryos with morphological abnormalities, was present at concentrations of 100 mug/ml for the preparation KT 1/300 (ketotifen/theophylline). These effects could be attributed to the component theophylline, as ketotifen was free of an embryotoxic/teratogenic potential in vitro. In the case of the compound mix VKB/BQ, a combination of pindolol, clopamide and endralazine, the in vitro effects of the mixture on embryonic development could also be attributed to one of the compounds (pindolol) in the mixture. In the case of HYCT 4520, the effects of the components hydergine (co-dergocrine mesylate), clopamide and triamterene on embryonic growth, differentiation and anomalies were additive in the drug mixture. None of the compounds was reported to be associated with human teratogenicity. The NEC of the components in the whole-embryo culture system, tested either as a mixture or as individual compounds, were higher than the human peak plasma levels measured during therapeutic use of the compounds. In addition, the single components were reported to be non-teratogenic in in vivo teratogenicity

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

    Directory of Open Access Journals (Sweden)

    Nemati Z

    2017-01-01

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

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

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    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.

  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.

  9. Potentiation of Prostate Cancer Radiotherapy Using Antiangiogenic and Antitumor Therapies

    Science.gov (United States)

    2007-10-01

    University of Rochester Rochester, NY 14642 REPORT DATE: October 2007 TYPE OF REPORT: Final PREPARED FOR: U.S. Army Medical...Research and given once daily by gavage in a volume of 0.13 mL. Control animals received 0.5% carboxymethylcellulose drug carrier. Irradiations were

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

    Directory of Open Access Journals (Sweden)

    Louise S. Strauch

    2016-07-01

    Full Text Available The aim of this study was to provide an overview of the literature available on dynamic contrast-enhanced computed tomography (DCE-CT as a tool to evaluate treatment response in patients with lung cancer. This systematic review was compiled according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA guidelines. Only original research articles concerning treatment response in patients with lung cancer assessed with DCE-CT were included. To assess the validity of each study we implemented Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2. The initial search yielded 651 publications, and 16 articles were included in this study. The articles were divided into groups of treatment. In studies where patients were treated with systemic chemotherapy with or without anti-angiogenic drugs, four out of the seven studies found a significant decrease in permeability after treatment. Four out of five studies that measured blood flow post anti-angiogenic treatments found that blood flow was significantly decreased. DCE-CT may be a useful tool in assessing treatment response in patients with lung cancer. It seems that particularly permeability and blood flow are important perfusion values for predicting treatment outcome. However, the heterogeneity in scan protocols, scan parameters, and time between scans makes it difficult to compare the included studies.

  11. Effect of Vascular Normalization by Antiangiogenic Therapy on Interstitial Hypertension, Peritumor Edema, and Lymphatic Metastasis: Insights from a Mathematical Model

    OpenAIRE

    Jain, Rakesh K.; Tong, Ricky T; Munn, Lance L.

    2007-01-01

    Preclinical and clinical evidence shows that antiangiogenic agents can decrease tumor vessel permeability and interstitial fluid pressure (IFP) in a process of vessel “normalization.” The resulting normalized vasculature has more efficient perfusion, but little is known about how tumor IFP and interstitial fluid velocity (IFV) are affected by changes in transport properties of the vessels and interstitium that are associated with antiangiogenic therapy. By using a mathematical model to simula...

  12. 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.

  13. Drug Repositioning for Preeclampsia Therapeutics by In Vitro Screening: Phosphodiesterase-5 Inhibitor Vardenafil Restores Endothelial Dysfunction via Induction of Placental Growth Factor.

    Science.gov (United States)

    Kakigano, Aiko; Tomimatsu, Takuji; Mimura, Kazuya; Kanayama, Tomoko; Fujita, Satoko; Minato, Kenji; Kumasawa, Keiichi; Taniguchi, Yukiko; Kanagawa, Takeshi; Endo, Masayuki; Ishihara, Tomoaki; Namba, Takushi; Mizushima, Tohru; Kimura, Tadashi

    2015-10-01

    We screened a library of 528 approved drugs to identify candidate compounds with therapeutic potential as preeclampsia treatments via their proangiogenic properties. Using human umbilical vein endothelial cells (HUVECs), we assessed whether the screened drugs induced placental growth factor (PIGF) and restored damaged endothelial cell function. Enzyme-linked immunosorbent assays (ELISAs) were carried out to measure levels of PlGF in conditioned media treated with each drug (100 µmol/L) in the drug library. Tube formation assays were performed using HUVECs to evaluate the angiogenic effects of drugs that induced PlGF. We also performed ELISA, quantitative reverse transcription polymerase chain reaction, and tube formation assays after treatment with a range of concentrations of the candidate drug. Of the drugs that induced PlGF, vardenafil was the only compound that significantly facilitated tube formation in comparison with the control cells (P preeclampsia was significantly elevated by administration of vardenafil (250 µmol/L). By assessing drug repositioning through screening a library of approved drugs, we identified vardenafil as a potential protective agent against preeclampsia. The therapeutic mechanism of vardenafil may involve inhibition of the systemic maternal antiangiogenic state that leads to preeclampsia, in addition to its vasodilating effect. As concentrations used are high and unlikely to be useful clinically, further work is needed before testing it in humans.

  14. Antiangiogenic activity of mononuclear copper(II) polypyridyl complexes for the treatment of cancers.

    Science.gov (United States)

    Nagababu, Penumaka; Barui, Ayan Kumar; Thulasiram, Bathini; Devi, C Shobha; Satyanarayana, S; Patra, Chitta Ranjan; Sreedhar, Bojja

    2015-07-09

    A series of four new mononuclear copper(II) polypyridyl complexes (1-4) have been designed, developed, and thoroughly characterized by several physicochemical techniques. The CT-DNA binding properties of 1-4 have been investigated by absorption, emission spectroscopy, and viscosity measurements. All the complexes especially 1 and 4 exhibit cytotoxicity toward several cancer cell lines, suggesting their anticancer properties as observed by several in vitro assays. Additionally, the complexes show inhibition of endothelial cell (HUVECs) proliferation, indicating their antiangiogenic nature. In vivo chick embryo angiogenesis assay again confirms the antiangiogenic properties of 1 and 4. The formation of excessive intracellular ROS (H2O2 and O2(•-)) and upregulation of BAX induced by copper(II) complexes may be the plausible mechanisms behind their anticancer activities. The present study may offer a basis for the development of new transition metal complexes through suitable choice of ligands for cancer therapeutics by controlling tumor angiogenesis.

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

    Science.gov (United States)

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

    2017-01-01

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

  16. Beyond chemotherapy : proapoptotic and antiangiogenic drug effects in preclinical ovarian cancer models

    NARCIS (Netherlands)

    Bilt, Arne Roderic Maria van der

    2012-01-01

    Sinds de introductie van de huidige standaardbehandeling voor ovariumkanker met platine-bevattende chemotherapie en chirurgische tumorreductie, inmiddels 10 jaar geleden, is er weinig veranderd. Andere chemotherapeutische regimes verbeterden de slechte prognose van patiënten met vergevorderde ovariu

  17. 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.

  18. Tumor angiogenesis and anti-angiogenic therapy in malignant gliomas revisited

    OpenAIRE

    Plate, Karl H.; Scholz, Alexander; Dumont, Daniel J.

    2012-01-01

    The cellular and molecular mechanisms of tumor angiogenesis and its prospects for anti-angiogenic cancer therapy are major issues in almost all current concepts of both cancer biology and targeted cancer therapy. Currently, (1) sprouting angiogenesis, (2) vascular co-option, (3) vascular intussusception, (4) vasculogenic mimicry, (5) bone marrow-derived vasculogenesis, (6) cancer stem-like cell-derived vasculogenesis and (7) myeloid cell-driven angiogenesis are all considered to contribute to...

  19. Assessing cancer drugs for reimbursement: methodology, relationship between effect size and medical need.

    Science.gov (United States)

    de Sahb-Berkovitch, Rima; Woronoff-Lemsi, Marie-Christine; Molimard, Mathieu

    2010-01-01

    Reimbursement is assessed by the Transparency Commission from the Health Authority (HAS) using a medical benefit (SMR) score that gives access to reimbursement, an "improvement of medical service rendered" (ASMR) that determines the added therapeutic value, and the target population. Assessing cancer drugs for reimbursement raises the same issues as other therapeutic classes, with some key differences. Overall survival (OS) is considered by the Transparency Commission as the endpoint for assessing clinical benefit, and yet it is not an applicable primary endpoint in all types of cancer. Later lines of treatment, particularly during the development process, may make it difficult to interpret OS as the primary endpoint. Therefore, progression-free survival (PFS) for metastatic situations and disease-free survival (DFS) in adjuvant situations are wholly relevant endpoints for decisions on the reimbursement of a new cancer drug. Effect size is assessed using actuarial survival curves of the product versus the comparator, and it is difficult to summarise them into one single parameter. Results are generally interpreted based on median survival, which is fragmented because it only measures one point of the curve. The hazard ratio measures the effect of treatment throughout the duration of survival and is therefore more comprehensive in quantifying clinical benefit. Determining an effect size threshold for granting reimbursement is difficult given the diversity of cancer settings and the level of medical need, which influences assessment of the clinical relevance of the observed difference. Rapid progress in comparators (700 molecules in development) and the identification of predictive factors of efficacy (biomarkers, histology, etc.) during development may lead to different ASMR scores per population, or to the restriction of the target population to a subgroup of the marketing authorisation (MA) population in which the expected effect size is greater. To address these

  20. "Herbal incense": designer drug blends as cannabimimetics and their assessment by drug discrimination and other in vivo bioassays.

    Science.gov (United States)

    Järbe, Torbjörn U C; Gifford, Roger S

    2014-02-27

    Recently, synthetic cannabinoids originally designed for testing in the laboratory only have found use recreationally in designer herbal blends, originally called "Spice". The myriad of compounds found are for the most part potent full agonists of the cannabinoid receptor 1, producing effects similar to tetrahydrocannabinol (THC) and marijuana. Drug discrimination of these compounds offers a specific behavioral test that can help determine whether these new synthetic compounds share a similar "subjective high" with the effects of marijuana/THC. By utilization of drug discrimination and other behavioral techniques, a better understanding of these new "designer" cannabinoids may be reached to assist in treating both the acute and chronic effects of these drugs. The paper provides a brief exposé of modern cannabinoid research as a backdrop to the recreational use of designer herbal blend cannabimimetics.

  1. Disease modifying and antiangiogenic activity of 2-Methoxyestradiol in a murine model of rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    Moore Elizabeth G

    2009-05-01

    Full Text Available Abstract Background A critical component of disease progression in rheumatoid arthritis (RA involves neovascularization associated with pannus formation. 2-methoxyestradiol (2ME2 is a naturally occurring molecule with no known physiologic function, although at pharmacologic concentrations it has antiproliferative and antiangiogenic activities. We investigated the impact of orally administered 2ME2 on the initiation and development of proliferative synovitis using the anti-collagen monoclonal antibodies (CAIA model. Methods Severe polyarticular arthritis was induced in Balb/c female mice by administration of 2 mg of a monoclonal antibody cocktail intravenously into the tail vein of mice. Twenty-four hours following monoclonal antibody administration, mice were injected with 25 μg of LPS (E. coli strain 0111:B4 via the intraperitoneal route. Treatment with 2ME2 (100, 75, 50, 25, 10, 1 mg/kg, p.o., daily, or vehicle control began 24 hrs following LPS challenge and continued to day 21. Hind limbs were harvested, sectioned and evaluated for DMARD activity and general histopathology by histomorphometric analysis and immunohistochemistry (vWF staining. In a separate study, different dosing regimens of 2ME2 (100 mg/kg; q.d. vs q.w. vs q.w. × 2 were evaluated. The effect of treatment with 2ME2 on gene expression of inflammatory cytokines and angiogenic growth factors in the joint space was evaluated 5 and 14 days after the induction of arthritis. Results Mice treated with 2ME2 beginning 24 hours post anti-collagen monoclonal antibody injection, showed a dose-dependent inhibition in mean arthritic scores. At study termination (day 21, blinded histomorphometric assessments of sectioned hind limbs demonstrated decreases in synovial inflammation, articular cartilage degradation, pannus formation, osteoclast activity and bone resorption. At the maximal efficacious dosing regimen (100 mg/kg/day, administration of 2ME2 resulted in total inhibition of the

  2. Human RNASET2 derivatives as potential anti-angiogenic agents: actin binding sequence identification and characterization

    Science.gov (United States)

    Nesiel-Nuttman, Liron; Doron, Shani; Schwartz, Betty; Shoseyov, Oded

    2015-01-01

    Human RNASET2 (hRNASET2) has been demonstrated to exert antiangiogenic and antitumorigenic effects independent of its ribonuclease capacity. We suggested that RNASET2 exerts its antiangiogenic and antitumorigenic activities via binding to actin and consequently inhibits cell motility. We focused herein on the identification of the actin binding site of hRNASET2 using defined sequences encountered within the whole hRNASET2 protein. For that purpose we designed 29 different hRNASET2-derived peptides. The 29 peptides were examined for their ability to bind immobilized actin. Two selected peptides-A103-Q159 consisting of 57 amino acids and peptide K108-K133 consisting of 26 amino acids were demonstrated to have the highest actin binding ability and concomitantly the most potent anti-angiogenic activity. Further analyses on the putative mechanisms associated with angiogenesis inhibition exerted by peptide K108-K133 involved its location during treatment within the HUVE cells. Peptide K108-K133 readily penetrates the cell membrane within 10 min of incubation. In addition, supplementation with angiogenin delays the entrance of peptide K108-K133 to the cell suggesting competition on the same cell internalization route. The peptide was demonstrated to co-localize with angiogenin, suggesting that both molecules bind analogous cellular epitopes, similar to our previously reported data for ACTIBIND and trT2-50. PMID:25815360

  3. 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.

  4. 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.

  5. Pleiotropic Anti-Angiogenic and Anti-Oncogenic Activities of the Novel Mithralog Demycarosyl-3D-ß-D-Digitoxosyl-Mithramycin SK (EC-8042.

    Directory of Open Access Journals (Sweden)

    Azahara Fernández-Guizán

    Full Text Available Demycarosyl-3D-ß-D-digitoxosyl-mithramycin SK (DIG-MSK is a recently isolated analogue of mithramycin A (MTA that showed differences with MTA in the DNA binding strength and selectivity. These differences correlated with a better therapeutic index and less toxicity in animal studies. Herein, we show that DIG-MSK displays a potent anti-tumor activity against different types of cancer cell lines, ovarian tumor cells being particularly sensitive to this drug. Of relevance, DIG-MSK exerts low toxicity on fibroblasts and peripheral blood mononuclear cells, this toxicity being significantly lower than that of MTA. In correlation with its antitumor activity, DIG-MSK strongly inhibited Sp1-mediated transcription and endogenous Sp1 mRNA expression, which correlated with the inhibition of the expression of key Sp1-regulated genes involved in tumorigenesis, including VEGFA, BCL2L1 (Bcl-XL, hTERT, BRCA2, MYC and SRC in several ovarian cells. Significantly, DIG-MSK was a stronger inhibitor of VEGFA expression than MTA. Accordingly, DIG-MSK also exhibited potent anti-angiogenic activity on microvascular endothelial cells. Likewise, it significantly inhibited the gene expression of VEGFR1, VEGFR2, FGFR, PDGFB and PDGFRA and, additionally, it induced the expression of the anti-angiogenic factors angiostatin and tunstatin. These effects correlated with a pro-apoptotic effect on proliferating microvascular endothelial cells and the inhibition of the formation of endothelial capillary structures. Overall, the pleiotropic activity of DIG-MSK in inhibiting key oncogenic and angiogenic pathways, together with its low toxicity profile, highlight the therapeutic potential of this new drug.

  6. Critique of the two-fold measure of prediction success for ratios: application for the assessment of drug-drug interactions.

    Science.gov (United States)

    Guest, Eleanor J; Aarons, Leon; Houston, J Brian; Rostami-Hodjegan, Amin; Galetin, Aleksandra

    2011-02-01

    Current assessment of drug-drug interaction (DDI) prediction success is based on whether predictions fall within a two-fold range of the observed data. This strategy results in a potential bias toward successful prediction at lower interaction levels [ratio of the area under the concentration-time profile (AUC) in the presence of inhibitor/inducer compared with control is assessment of different DDI prediction algorithms if databases contain large proportion of interactions in this lower range. Therefore, the current study proposes an alternative method to assess prediction success with a variable prediction margin dependent on the particular AUC ratio. The method is applicable for assessment of both induction and inhibition-related algorithms. The inclusion of variability into this predictive measure is also considered using midazolam as a case study. Comparison of the traditional two-fold and the new predictive method was performed on a subset of midazolam DDIs collated from previous databases; in each case, DDIs were predicted using the dynamic model in Simcyp simulator. A 21% reduction in prediction accuracy was evident using the new predictive measure, in particular at the level of no/weak interaction (AUC ratio assessed via the new predictive measure. Thus, the study proposes a more logical method for the assessment of prediction success and its application for induction and inhibition DDIs.

  7. Dendrimer, liposomes, carbon nanotubes and PLGA nanoparticles: one platform assessment of drug delivery potential.

    Science.gov (United States)

    Mody, Nishi; Tekade, Rakesh Kumar; Mehra, Neelesh Kumar; Chopdey, Prashant; Jain, Narendra Kumar

    2014-04-01

    Liposomes (LIP), nanoparticles (NP), dendrimers (DEN), and carbon nanotubes (CNTs), represent eminent classes of drug delivery devices. A study was carried out herewith by employing docetaxel (DTX) as model drug to assess their comparative drug delivery potentials. Under optimized conditions, highest entrapment of DTX was observed in CNT-based formulation (DTX-CNTs, 74.70 ± 4.9%) followed by nanoparticles (DTX-NP, 62.34 ± 1.5%), liposome (49.2 ± 1.51%), and dendrimers (28.26 ± 1.74%). All the formulations were found to be of nanometric size. In vitro release studies were carried out in PBS (pH 7.0 and 4.0), wherein all the formulations showed biphasic release pattern. Cytotoxicity assay in human cervical cancer SiHa cells inferred lowest IC50 value of 1,235.09 ± 41.93 nM with DTX-CNTs, followed by DTX-DEN, DTX-LIP, DTX-NP with IC50 values of 1,571.22 ± 151.27, 1,653.98 ± 72.89, 1,922.75 ± 75.15 nM, respectively. Plain DTX showed higher hemolytic toxicity of 22.48 ± 0.94%, however loading of DTX inside nanocarriers drastically reduced its hemolytic toxicity (DTX-DEN, 17.22 ± 0.48%; DTX-LIP, 4.13 ± 0.19%; DTX-NP, 6.43 ± 0.44%; DTX-CNTs, 14.87 ± 1.69%).

  8. Recent developments in the risk assessment of potentially genotoxic impurities in pharmaceutical drug substances.

    Science.gov (United States)

    Humfrey, Charles D N

    2007-11-01

    Controlling the quality of medicines is just as important as demonstrating efficacy. The International Conference on Harmonisation has published general guidance on the quality and safety assessment of impurities in pharmaceutical drug substances and drug products. More recently, the European Medicines Evaluation Agency has published a guideline focusing on limits for genotoxic impurities. This is based on a Threshold of Toxicological Concern (TTC) derived from animal carcinogenicity data using multiple worst case assumptions to estimate a daily dose (1.5 microg/day) associated with a lifetime cancer risk of 1 in 100,000, a risk level considered acceptable for genotoxic impurities in human medicines. Based on these assumptions, presentation of the TTC as a single figure infers an unwarranted level of precision and supports the adoption of a more flexible approach by regulatory authorities when evaluating new drug products; a range within fivefold of the TTC limit would seem sensible. Furthermore, the limit is based on 70 years continuous daily exposure, a scenario that is uncommon for most medicines and irrelevant to the preregistration clinical development phase. To address this latter point, a staged TTC has been developed that proposes limits based on shorter durations of treatment, e.g., up to 1 year. Based on recent history, this approach has been acceptable to some authorities but not to others, and it is imperative that steps are taken to reach a common agreement between the pharmaceutical industry and regulatory authorities globally in order that new medicines can continue to be developed and delivered to benefit patients in a safe and timely manner.

  9. 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.

  10. Using zebrafish to assess the impact of drugs on neural development and function

    Science.gov (United States)

    Guo, Su

    2009-01-01

    Background Zebrafish is becoming an increasingly attractive model organism for understanding biology and developing therapeutics, because as a vertebrate, it shares considerable similarity with mammals in both genetic compositions and tissue/organ structures, and yet remains accessible to high throughput phenotype-based genetic and small molecule compound screening. Objective/method The focus of this review is on the nervous system, which is arguably the most complex organ and known to be afflicted by more than six hundred disorders in humans. I discuss the past, present, and future of using zebrafish to assess the impact of small molecule drugs on neural development and function, in light of understanding and treating neurodevelopmental disorders such as autism, neurodegenerative disorders including Alzheimer’s, Parkinson’s, and Hungtington’s disease, and neural system dysfunctions such as anxiety/depression and addiction. Conclusion These studies hold promise to reveal fundamental mechanisms governing nervous system development and function, and to facilitate small molecule drug discovery for the many types of neurological disorders. PMID:19774094

  11. Nanoparticles Made From Xyloglucan-Block-Polycaprolactone Copolymers: Safety Assessment for Drug Delivery.

    Science.gov (United States)

    Mazzarino, Letícia; Loch-Neckel, Gecioni; Dos Santos Bubniak, Lorena; Ourique, Fabiana; Otsuka, Issei; Halila, Sami; Curi Pedrosa, Rozangela; Santos-Silva, Maria Cláudia; Lemos-Senna, Elenara; Curti Muniz, Edvani; Borsali, Redouane

    2015-09-01

    Xyloglucan-block-polycaprolactone (XGO-PCL) copolymer nanoparticles have been proposed as nanocarriers for drug delivery. However, the possible harmful effects of exposure to nanoparticles still remain a concern. Therefore, the aim of this study is to evaluate the potential toxicity of XGO-PCL nanoparticles using in vitro and in vivo assays. Cytotoxicity and genotoxicity studies were conducted on MRC-5 human fetal lung fibroblast cells upon exposure to XGO-PCL nanoparticles. No significant reduction in the cell viability and no DNA damage were observed at the different concentrations tested. Erythrocyte toxicity was assessed by the incubation of nanoparticles with human blood. XGO-PCL nanoparticles induced a hemolytic ratio of less than 1%, indicating good blood compatibility. Finally, the subacute toxicity of XGO-PCL nanoparticles (10 mg/kg/day) was evaluated in BALB/c mice when administered orally or intraperitoneally for 14 days. Results of the in vivo toxicity study showed no clinical signs of toxicity, mortality, weight loss, or hematological and biochemical alterations after treatment with nanoparticles. Also, microscopic analysis of the major organs revealed no histopathological abnormalities, corroborating the previous results. Thus, it can be concluded that XGO-PCL nanoparticles induced no effect indicative of toxicity, indicating their potential use as drug delivery systems.

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    Fluorinated phospholipid analogues are investigated as potential substrates for phospholipase A(2) (PLA(2)) using classical molecular dynamics simulations and quantum mechanics/density functional theory calculations. The fluorinated phospholipid analogues are a-fluoro (HF-ProAEL) and alpha......,alpha-difluoro (F-2-ProAEL) conjugates of (R)-1-O-hexadecyl-2-palmitoyl-sn-glycero-3-phoshocholineglycerol (ProAEL). Our results provide a theoretical assessment of the potential usefulness of these fluorinated lipids in the rational design of liposomal drug-delivery systems. The a-fluorine-substituted phospholipid...... at a progressively faster rate; the more electronegative substituent at the a-position effectively lowers the energy barrier for hydrolysis. We conclude that the partially fluorinated phospholipid analogues facilitate rational design of liposomal vesicles of phospholipid mixtures with desirable physicochemical...

  13. 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.

  14. Predictive accuracy of the Miller assessment for preschoolers in children with prenatal drug exposure.

    Science.gov (United States)

    Fulks, Mary-Ann L; Harris, Susan R

    2005-01-01

    The Miller Assessment for Preschoolers (MAP) is a standardized test purported to identify preschool-aged children at risk for later learning difficulties. We evaluated the predictive validity of the MAP Total Score, relative to later cognitive performance and across a range of possible cut-points, in 37 preschool-aged children with prenatal drug exposure. Criterion measures were the Wechsler Preschool & Primary Scale of Intelligence-Revised (WPPSI-R), Test of Early Reading Ability-2, Peabody Picture Vocabulary Test-Revised, and Developmental Test of Visual Motor Integration. The highest predictive accuracy was demonstrated when the WPPSI-R was the criterion measure. The 14th percentile cutoff point demonstrated the highest predictive accuracy across all measures.

  15. A new method to assess Pavlovian conditioning of psychostimulant drug effects.

    Science.gov (United States)

    Damianopoulos, E N; Carey, R J

    1994-07-01

    Experimental studies of psychoactive drugs by pavlovian drug-conditioning methods, which originally began with investigations of drug-induced responses mediated by the autonomic nervous system, have now been expanded to include drug-induced response effects expressed as modulations of spontaneous motoric behaviors. In the latter application, however, equivalent behavioral response outcomes in post-treatment tests for conditioning can occur following a psychostimulant drug treatment either through drug interference effects on habituation processes, drug-induced stress effects and/or by pavlovian conditioning of the drug-induced motoric activation effect. Current methodologies for the study of pavlovian conditioned drug effects and/or drug sensitization cannot distinguish among these possibilities. This methodological inadequacy was addressed by a modification of the conventional paired-unpaired treatment protocol. In the new protocol, the animal is sequentially placed into two test compartments with the drug treatment administered in conjunction with placement into the second test compartment. This design permits a differentiation of a pavlovian conditioned drug responses from non-conditioned drug effects through continuous measurement of the non-drug behavioral baseline in both the drug and non-drug control treatment groups combined with multiple response measurements and post-treatment tests for conditioning at variable post-conditioning intervals. The present study details the use of the new modified pavlovian protocol with repeated cocaine (10 mg/kg) treatment. A cocaine conditioned response at 1, 7, and 21 days post-conditioning was identified and distinguished from habituation and stress effects.

  16. 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.

  17. 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.

  18. 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

  19. Anti-malarial drug quality in Lagos and Accra - a comparison of various quality assessments

    Directory of Open Access Journals (Sweden)

    Bate Roger

    2010-06-01

    Full Text Available Abstract Background Two major cities in West Africa, Accra, the capital of Ghana, and Lagos, the largest city of Nigeria, have significant problems with substandard pharmaceuticals. Both have actively combated the problem in recent years, particularly by screening products on the market using the Global Pharma Health Fund e.V. Minilab® protocol. Random sampling of medicines from the two cities at least twice over the past 30 months allows a tentative assessment of whether improvements in drug quality have occurred. Since intelligence provided by investigators indicates that some counterfeit producers may be adapting products to pass Minilab tests, the results are compared with those from a Raman spectrometer and discrepancies are discussed. Methods Between mid-2007 and early-2010, samples of anti-malarial drugs were bought covertly from pharmacies in Lagos on three different occasions (October 2007, December 2008, February 2010, and from pharmacies in Accra on two different occasions (October 2007, February 2010. All samples were tested using the Minilab® protocol, which includes disintegration and active ingredient assays as well as visual inspection, and most samples were also tested by Raman spectrometry. Results In Lagos, the failure rate in the 2010 sampling fell to 29% of the 2007 finding using the Minilab® protocol, 53% using Raman spectrometry, and 46% using visual inspection. In Accra, the failure rate in the 2010 sampling fell to 54% of the 2007 finding using the Minilab® protocol, 72% using Raman spectrometry, and 90% using visual inspection. Conclusions The evidence presented shows that drug quality is probably improving in both cities, especially Lagos, since major reductions of failure rates over time occur with all means of assessment. Many more samples failed when examined by Raman spectrometry than by Minilab® protocol. The discrepancy is most likely caused by the two techniques measuring different aspects of the medication

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

    Directory of Open Access Journals (Sweden)

    Ciani O

    2014-11-01

    Full Text Available Oriana Ciani,1,3 Claudio Jommi1,2 1Centre for Research on Health and Social Care Management (CERGAS, Bocconi University, Milan, Italy; 2Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara, Italy; 3University of Exeter Medical School, Exeter, UK Abstract: The use of health technology assessment (HTA to inform policy-making is established in most developed countries. Compared to licensing agencies, HTA agencies have different interests and, therefore, different evidence requirements. Criteria for coverage or reimbursement decisions on pharmaceutical compounds vary; however, it is common to include, as part of the HTA, a comparative effectiveness evaluation. This type of clinical data might go beyond that required for market authorization, thus creating an additional evidence gap between the regulatory and the reimbursement submission. The relevance of submissions to HTA agencies is consistently increasing in a pharmaceutical company’s perspective, as market prospects are strongly influenced by third-party payers’ coverage. In this study, we aim to describe current HTA activities with a potential impact throughout the drug development process of pharmaceuticals, with a comparative emphasis on the systems in place in Italy and in the UK. Based on an extensive literature and website review, we identified three major classes of HTA activities, beyond mainstream HTA, with the potential to influence the drug development program: 1 horizon scanning and early HTA; 2 bipartite and tripartite early dialogue between manufacturers, regulators, and HTA assessors; and 3 managed market entry agreements. From early stages of clinical research up to postauthorization studies, there is a trend toward increased collaboration between parties, anticipation of market access evidence collection, and postmarketing risk-sharing. Heterogeneity of HTA practices increases the complexity of the market access environment. Overall, there are

  1. 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.

  2. 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

  3. 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.

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

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    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

  5. Development of an adverse drug reaction risk assessment score among hospitalized patients with chronic kidney disease.

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    Fatemeh Saheb Sharif-Askari

    Full Text Available 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.

  6. Cortical EEG oscillations and network connectivity as efficacy indices for assessing drugs with cognition enhancing potential.

    Science.gov (United States)

    Ahnaou, A; Huysmans, H; Jacobs, T; Drinkenburg, W H I M

    2014-11-01

    assess efficacy of novel therapeutic drugs with cognition enhancing potential.

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

    Science.gov (United States)

    Ciani, Oriana; Jommi, Claudio

    2014-01-01

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

  8. Selection and utilization of assessment instruments in substance abuse treatment trials: the National Drug Abuse Treatment Clinical Trials Network experience

    Directory of Open Access Journals (Sweden)

    Rosa C

    2012-07-01

    Full Text Available Carmen Rosa, Udi Ghitza, Betty TaiCenter for the Clinical Trials Network, National Institute on Drug Abuse, Bethesda, MD, USAAbstract: Based on recommendations from a US Institute of Medicine report, the National Institute on Drug Abuse established the National Drug Abuse Treatment Clinical Trials Network (CTN in 1999, to accelerate the translation of science-based addiction treatment research into community-based practice, and to improve the quality of addiction treatment, using science as the vehicle. One of the CTN's primary tasks is to serve as a platform to forge bi-directional communications and collaborations between providers and scientists, to enhance the relevance of research, which generates empirical results that impact practice. Among many obstacles in moving research into real-world settings, this commentary mainly describes challenges and iterative experiences in regard to how the CTN develops its research protocols, with focus on how the CTN study teams select and utilize assessment instruments, which can reasonably balance the interests of both research scientists and practicing providers when applied in CTN trials. This commentary also discusses the process by which the CTN further selects a core set of common assessment instruments that may be applied across all trials, to allow easier cross-study analyses of comparable data.Keywords: addiction, assessment, drug abuse treatment, drug dependence, NIDA Clinical Trials Network, substance use disorder

  9. High-Throughput Assessment of Drug Cardiac Safety Using a High-Speed Impedance Detection Technology-Based Heart-on-a-Chip

    Directory of Open Access Journals (Sweden)

    Xi Zhang

    2016-07-01

    Full Text Available Drug cardiac safety assessments play a significant role in drug discovery. Drug-induced cardiotoxicity is one of the main reasons for drug attrition, even when antiarrhythmic drugs can otherwise effectively treat the arrhythmias. Consequently, efficient drug preclinical assessments are needed in the drug industry. However, most drug efficacy assessments are performed based on electrophysiological tests of cardiomyocytes in vitro and cannot effectively provide information on drug-induced dysfunction of cardiomyocyte beating. Here we present a heart-on-a-chip device for evaluating the drug cardiac efficacy using a high-speed impedance detection technology. Verapamil and doxorubicin were utilized to test this heart-on-a-chip, and multiple parameters of cardiomyocyte beating status are used to reveal the effects of drugs. The results show that drug efficacy or cardiotoxicity can be determined by this heart-on-a-chip. We believe this heart-on-a-chip will be a promising tool for the preclinical assessment of drug cardiac efficacy.

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

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    Yeyin Liang

    2017-01-01

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

  11. Cellular Adaptation to VEGF-Targeted Antiangiogenic Therapy Induces Evasive Resistance by Overproduction of Alternative Endothelial Cell Growth Factors in Renal Cell Carcinoma.

    Science.gov (United States)

    Han, Kyung Seok; Raven, Peter A; Frees, Sebastian; Gust, Kilian; Fazli, Ladan; Ettinger, Susan; Hong, Sung Joon; Kollmannsberger, Cristian; Gleave, Martin E; So, Alan I

    2015-11-01

    Vascular endothelial growth factor (VEGF)-targeted antiangiogenic therapy significantly inhibits the growth of clear cell renal cell carcinoma (RCC). Eventually, therapy resistance develops in even the most responsive cases, but the mechanisms of resistance remain unclear. Herein, we developed two tumor models derived from an RCC cell line by conditioning the parental cells to two different stresses caused by VEGF-targeted therapy (sunitinib exposure and hypoxia) to investigate the mechanism of resistance to such therapy in RCC. Sunitinib-conditioned Caki-1 cells in vitro did not show resistance to sunitinib compared with parental cells, but when tested in vivo, these cells appeared to be highly resistant to sunitinib treatment. Hypoxia-conditioned Caki-1 cells are more resistant to hypoxia and have increased vascularity due to the upregulation of VEGF production; however, they did not develop sunitinib resistance either in vitro or in vivo. Human endothelial cells were more proliferative and showed increased tube formation in conditioned media from sunitinib-conditioned Caki-1 cells compared with parental cells. Gene expression profiling using RNA microarrays revealed that several genes related to tissue development and remodeling, including the development and migration of endothelial cells, were upregulated in sunitinib-conditioned Caki-1 cells compared with parental and hypoxia-conditioned cells. These findings suggest that evasive resistance to VEGF-targeted therapy is acquired by activation of VEGF-independent angiogenesis pathways induced through interactions with VEGF-targeted drugs, but not by hypoxia. These results emphasize that increased inhibition of tumor angiogenesis is required to delay the development of resistance to antiangiogenic therapy and maintain the therapeutic response in RCC.

  12. Assessment of Navy Alcohol and Drug Abuse Education and Training Curricula, Revision Requirements

    Science.gov (United States)

    1986-02-01

    include the following: Introduction to Psychology Adolescent Psychology Maslow’s Hierarchy Abnormal Psychology Defense Mechanisms Anxiety...basic mechanics of how the equipment detects drug usage from body fluids. (Note: Full lesson book is available with EMIT kit from SYVA Corporation...identification procedures, organization of assets for control of alchohol and drug abuse, supervisory role in alcohol and drug abuse programs, local

  13. Toward an increased understanding of the barriers to colonic drug absorption in humans: implications for early controlled release candidate assessment.

    Science.gov (United States)

    Tannergren, Christer; Bergendal, Anna; Lennernäs, Hans; Abrahamsson, Bertil

    2009-01-01

    The purpose of this study was to increase the understanding of in vivo colonic drug absorption in humans by summarizing and evaluating all regional in vivo human absorption data with focus on the interpretation of the colonic absorption data in relation to intestinal permeability and solubility. In addition, the usefulness of the Biopharmaceutics Classification System (BCS) in early assessment of the in vivo colonic absorption potential of controlled release drug candidates was investigated. Clinical regional absorption data (Cmax, Tmax, and AUC) of 42 drugs were collected from journal articles, abstracts, and internal reports, and the relative bioavailability in the colon (Frel(colon)) was obtained directly or calculated. Bioavailability, fraction dose absorbed, and information if the compounds were substrates for P-glycoprotein (P-gp) or cytochrome P450 3A (CYP3A) were also obtained. The BCS I drugs were well absorbed in the colon (Frel(colon) > 70%), although some drugs had lower values due to bacterial degradation in the colon. The low permeability drugs (BCS III/IV) had a lower degree of absorption in the colon (Frel(colon) colon), and atenolol and metoprolol may function as permeability markers for low and high colonic absorption, respectively. No obvious effect of P-gp on the colonic absorption of the drugs in this study was detected. There was insufficient data available to fully assess the impact of low solubility and slow dissolution rate. The estimated in vivo fractions dissolved of the only two compounds administered to the colon as both a solution and as solid particles were 55% and 92%, respectively. In conclusion, permeability and solubility are important barriers to colonic absorption in humans, and in vitro testing of these properties is recommended in early assessment of colonic absorption potential.

  14. 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....

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

    Institute of Scientific and Technical Information of China (English)

    Adrian S(a)ftoiu; Peter Vilmann

    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-theart 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 through molecular-based drug-delivery systems.

  16. Interrater agreement of two adverse drug reaction causality assessment methods: A randomised comparison of the Liverpool Adverse Drug Reaction Causality Assessment Tool and the World Health Organization-Uppsala Monitoring Centre system

    Science.gov (United States)

    Mehta, Ushma; Rossiter, Dawn P.; Maartens, Gary; Cohen, Karen

    2017-01-01

    Introduction A new method to assess causality of suspected adverse drug reactions, the Liverpool Adverse Drug Reaction Causality Assessment Tool (LCAT), showed high interrater agreement when used by its developers. Our aim was to compare the interrater agreement achieved by LCAT to that achieved by another causality assessment method, the World Health Organization-Uppsala Monitoring Centre system for standardised case causality assessment (WHO-UMC system), in our setting. Methods Four raters independently assessed adverse drug reaction causality of 48 drug-event pairs, identified during a hospital-based survey. A randomised design ensured that no washout period was required between assessments with the two methods. We compared the methods’ interrater agreement by calculating agreement proportions, kappa statistics, and the intraclass correlation coefficient. We identified potentially problematic questions in the LCAT by comparing raters’ responses to individual questions. Results Overall unweighted kappa was 0.61 (95% CI 0.43 to 0.80) on the WHO-UMC system and 0.27 (95% CI 0.074 to 0.46) on the LCAT. Pairwise unweighted Cohen kappa ranged from 0.33 to 1.0 on the WHO-UMC system and from 0.094 to 0.71 on the LCAT. The intraclass correlation coefficient was 0.86 (95% CI 0.74 to 0.92) on the WHO-UMC system and 0.61 (95% CI 0.39 to 0.77) on the LCAT. Two LCAT questions were identified as significant points of disagreement. Discussion We were unable to replicate the high interrater agreement achieved by the LCAT developers and instead found its interrater agreement to be lower than that achieved when using the WHO-UMC system. We identified potential reasons for this and recommend priority areas for improving the LCAT. PMID:28235001

  17. 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

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

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    Wu Wei-Zhong

    2011-01-01

    Full Text Available Abstract Background 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. Methods 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. Results 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. Conclusions 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.

  19. 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.

  20. 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

  1. 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.

  2. Simultaneous confocal fluorescence microscopy and optical coherence tomography for drug distribution and tissue integrity assessment

    Science.gov (United States)

    Rinehart, Matthew T.; LaCroix, Jeffrey; Henderson, Marcus; Katz, David; Wax, Adam

    2011-03-01

    The effectiveness of microbicidal gels, topical products developed to prevent infection by sexually transmitted diseases including HIV/AIDS, is governed by extent of gel coverage, pharmacokinetics of active pharmaceutical ingredients (APIs), and integrity of vaginal epithelium. While biopsies provide localized information about drug delivery and tissue structure, in vivo measurements are preferable in providing objective data on API and gel coating distribution as well as tissue integrity. We are developing a system combining confocal fluorescence microscopy with optical coherence tomography (OCT) to simultaneously measure local concentrations and diffusion coefficients of APIs during transport from microbicidal gels into tissue, while assessing tissue integrity. The confocal module acquires 2-D images of fluorescent APIs multiple times per second allowing analysis of lateral diffusion kinetics. The custom Fourier domain OCT module has a maximum a-scan rate of 54 kHz and provides depth-resolved tissue integrity information coregistered with the confocal fluorescence measurements. The combined system is validated by imaging phantoms with a surrogate fluorophore. Time-resolved API concentration measured at fixed depths is analyzed for diffusion kinetics. This multimodal system will eventually be implemented in vivo for objective evaluation of microbicide product performance.

  3. Assessment of colour vision in epileptic patients exposed to single-drug therapy.

    Science.gov (United States)

    López, L; Thomson, A; Rabinowicz, A L

    1999-01-01

    Diplopia, blurred vision and colour disturbances are well-known side effects associated with anti-epileptic drugs (AEDs). Farnsworth-Munsell 100-hue colour test (F-100) is an accepted and sensitive tool to detect changes in colour perception. To determine the impact of AEDs upon colour vision, we evaluated 37 consecutive patients with complex partial seizures exposed to monotherapy with phenytoin (PHT, carbamazepine (CBZ) or valproic acid (VPA). All had normal IQ and no congenital disturbances in colour vision or ocular diseases. Twenty normal controls were used for statistical analysis. Thirteen patients were exposed to PHT, 12 to CBZ and 12 to VPA. Visual colour perception was impaired in 30/37 (82%) of the study group. The most significant abnormality was detected in the blue-yellow axis in 10/13 patients exposed to PHT (p < 0.02) and in 8/12 treated with CBZ (p < 0.009). In 8/12 patients taking VPA, no significant abnormality was observed (p < 0.06). None of the studied patients complained of colour vision disturbances. Our findings strongly support the negative effect of AEDs upon colour vision discrimination, most likely due to changes at the retinal processing level. F-100 proved to be very useful to assess early toxicity due to AEDs.

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

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    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.

  5. Optical coherence tomography assessment of edge dissections after drug-eluting stent implantation in coronary artery

    Institute of Scientific and Technical Information of China (English)

    GUO Jun; HAN Bao-shi; GAI Lu-yue; YANG Ting-shu; CHEN Yun-dai; TIAN Feng; LIU Hong-bin; CHEN Lian; SUN Zhi-jun; REN Yi-hong; JIN Qin-hua; LIU Chang-fu

    2012-01-01

    Background Edge dissections after coronary stent implantation are associated with increased short-term risk of major adverse cardiovascular events.The incidence and outcome of edge dissections after coronary stent implantation were reportedly different using different imaging techniques.We used optical coherence tomography (OCT) to assess the incidence,morphological findings and related factors of edge dissections after drug-eluting stent (DES) implantation.Methods Totally 42 patients with 43 de novo lesions in 43 native arteries undergoing DES implantation with OCT imaging were enrolled in this study.Results Nine edge dissections were detected in 43 arteries after DES implantation.There were four morphological patterns of stent edge dissections indentified in this study:(1) superficial intimal tears (n=3),(2) subintimal dissections (n=4),(3) split of media (n=1),(4) disruption of the fibrotic cap of plaque (n=1).Stent edge expansion and stent expansion were both higher in the group with dissections than those in the group without dissections (1.682±0.425 vs.1.229±0.285,P=0.0290; 1.507±0.445 vs.1.174±0.265,P=0.0072).Conclusions The incidence of stent edge dissections detected by OCT was 21%.Stent edge dissection is related with stent edge expansion and stent expansion.

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

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    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.

  7. Resveratrol and related stilbenes: their anti-aging and anti-angiogenic properties.

    Science.gov (United States)

    Kasiotis, Konstantinos M; Pratsinis, Harris; Kletsas, Dimitris; Haroutounian, Serkos A

    2013-11-01

    Dietary stilbenes comprise a class of natural compounds that display significant biological activities of medicinal interest. Among them, their antioxidant, anti-aging and anti-angiogenesic properties are well established and subjects of numerous research endeavors. This mini-review aspires to account and present the literature reports published on research concerning various natural and synthetic stilbenes, such as trans-resveratrol. Special focus was given to most recent research findings, while the mechanisms underlying their anti-aging and anti-angiogenic effects as well as the respective signaling pathways involved were also presented and discussed.

  8. Roles of main pro-and anti-angiogenic factors in tumor angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Zhi Huang; Shi-Deng Bao

    2004-01-01

    Tumor growth without size restriction depends on vascular supply. The ability of tumor to induce new blood-vessel formation has been a major focus of cancer research over the past decade. It is now known that members of the vascular endothelial growth factor and angiopoietin families,mainly secreted by tumor cells, induce tumor angiogenesis,whereas other endogenous angiogenic inhibitors, including thrombospondin-1 and angiostatin, keep tumor in dormancy.Experimental and clinical evidence has suggested that the process of tumor metastasis depends on angiogenesis or lymphangiogenesis. This article summarizes the recent research progress for some basic pro- or anti-angiogenic factors in tumor angiogenesis.

  9. Gorham-Stout Disease of the Skull Base With Hearing Loss: Dramatic Recovery and Antiangiogenic Therapy.

    Science.gov (United States)

    Nozawa, Akifumi; Ozeki, Michio; Kuze, Bunya; Asano, Takahiko; Matsuoka, Kentaro; Fukao, Toshiyuki

    2016-05-01

    Gorham-Stout disease (GSD) is a rare disorder of unknown etiology. We present a 6-year-old male with GSD involving the skull base who presented with recurrent cerebrospinal fluid (CSF) rhinorrhea, severe hearing loss, and facial palsy secondary to cerebellar herniation into the internal auditory canal. After 2 months of treatment with pegylated interferon (IFN) α-2b (50 μg/week), his hearing recovered dramatically. Two years later, new bone formation appeared radiologically and IFN was switched to sirolimus. One year after the switch, CSF rhinorrhea disappeared. Antiangiogenic therapy might inhibit proliferation of vascular endothelial cells in osteolytic lesions and lead to new bone formation.

  10. 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.

  11. Synthesis and biological evaluation of novel indolocarbazoles with anti-angiogenic activity.

    Science.gov (United States)

    Acero, Nuria; Braña, Miguel F; Añorbe, Loreto; Domínguez, Gema; Muñoz-Mingarro, Dolores; Mitjans, Francesc; Piulats, Jaume

    2012-02-01

    A novel series of indolocarbazoles were synthesized and their antiproliferative activity against HUVEC, LoVo, DLD-1 and ST-486 cell lines, was investigated. Those staurosporine analogs in which a substituted dimethylaminoalkoxy chain was attached to the indolic nitrogen showed interesting activity and selectivity with respect to HUVEC proliferation. The effect on capillary tube formation in 3-dimensional matrigel matrix was studied using the most active compounds. Evaluation of their in vivo anti-angiogenic activity in a murine Lewis lung cancer model was also analyzed.

  12. Assessment of adherence to drug and non-drug treatments and its changes under the influence of an education program in patients with rheumatoid arthritis

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    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

  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. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. GLUT3 upregulation promotes metabolic reprogramming associated with antiangiogenic therapy resistance

    Science.gov (United States)

    Kuang, Ruby; Jahangiri, Arman; Mascharak, Smita; Nguyen, Alan; Flanigan, Patrick M.; Yagnik, Garima; Wagner, Jeffrey R.; De Lay, Michael; Carrera, Diego; Castro, Brandyn A.; Hayes, Josie; Sidorov, Maxim; Garcia, Jose Luiz Izquierdo; Eriksson, Pia; Ronen, Sabrina; Phillips, Joanna; Koliwad, Suneil; Aghi, Manish K.

    2017-01-01

    Clinical trials revealed limited response duration of glioblastomas to VEGF-neutralizing antibody bevacizumab. Thriving in the devascularized microenvironment occurring after antiangiogenic therapy requires tumor cell adaptation to decreased glucose, with 50% less glucose identified in bevacizumab-treated xenografts. Compared with bevacizumab-responsive xenograft cells, resistant cells exhibited increased glucose uptake, glycolysis, 13C NMR pyruvate to lactate conversion, and survival in low glucose. Glucose transporter 3 (GLUT3) was upregulated in bevacizumab-resistant versus sensitive xenografts and patient specimens in a HIF-1α–dependent manner. Resistant versus sensitive cell mitochondria in oxidative phosphorylation–selective conditions produced less ATP. Despite unchanged mitochondrial numbers, normoxic resistant cells had lower mitochondrial membrane potential than sensitive cells, confirming poorer mitochondrial health, but avoided the mitochondrial dysfunction of hypoxic sensitive cells. Thin-layer chromatography revealed increased triglycerides in bevacizumab-resistant versus sensitive xenografts, a change driven by mitochondrial stress. A glycogen synthase kinase-3β inhibitor suppressing GLUT3 transcription caused greater cell death in bevacizumab-resistant than -responsive cells. Overexpressing GLUT3 in tumor cells recapitulated bevacizumab-resistant cell features: survival and proliferation in low glucose, increased glycolysis, impaired oxidative phosphorylation, and rapid in vivo proliferation only slowed by bevacizumab to that of untreated bevacizumab-responsive tumors. Targeting GLUT3 or the increased glycolysis reliance in resistant tumors could unlock the potential of antiangiogenic treatments. PMID:28138554

  20. 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.

  1. Antitumor and antiangiogenic activity of Schisandra chinensis polysaccharide in a renal cell carcinoma model.

    Science.gov (United States)

    Qu, Hai-Ming; Liu, Shi-Jian; Zhang, Chun-Ying

    2014-05-01

    The aim of this study was to determine the antitumor and antiangiogenic effects of the Schisandra chinensis polysaccharides (SCP) in selected renal cell carcinoma (RCC) cells and evaluate its potential mechanism of action. In vitro, endothelial growth factor (VEGF) secretion by Caki-1 was blockaded in response to SCP treatment for 48h. In vivo, a significant tumor growth inhibition effect was observed after SCP administration for 4 weeks. Moreover, SCP treatment decreased the level of VEGF, CD31 and CD34 in RCC tumor tissues. Further analysis of the tumor inhibition mechanism indicated that the number of apoptotic tumor cells increased significantly; the expression of Bax and p53 increased; and the expression of Bcl-2 decreased dramatically in transplanted tumor tissues following SCP administration. These results indicated that the potential mechanisms involved by which SCP exerted its antitumor and antiangiogenic activity might be associated with the up-regulation of Bax and p53, downregulation of Bcl-2, as well as the reduction of VEGF, CD31 and CD34 in xenografted tumors. These findings demonstrated that the SCP is a potential antitumor agent for RCC treatment.

  2. Synthesis, Anti-Tumor and Anti-Angiogenic Activity Evaluations of Asiatic Acid Amino Acid Derivatives

    Directory of Open Access Journals (Sweden)

    Yue Jing

    2015-04-01

    Full Text Available Fifteen semi-synthetic derivatives of asiatic acid (AA have been synthesized and evaluated for their biological activities. The successful modification of these compounds at the C-2, C-3, C-23 and C-28 positions was confirmed using NMR, MS and IR spectra. Further, their anti-tumor effects were evaluated in vitro using different cancer cell lines (HeLa, HepG2, B16F10, SGC7901, A549, MCF7 and PC3, while their anti-angiogenic activities were evaluated in vivo using a larval zebrafish model. Among the derivatives, compounds 4–10 showed more potent cytotoxic and anti-angiogenic effects than AA, while compounds 11–17 had significantly less effects. The new derivative 10 was also included in finished formulations to evaluate its stability using HPLC due to its potential topical use. The derivative 10 had markedly better anti-tumor activities than both AA and other derivatives, with similar stability as its parent compound AA.

  3. 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.

  4. 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.

  5. 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

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

    Directory of Open Access Journals (Sweden)

    Deborah G Nguyen

    Full Text Available Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI. This is mainly because existing liver models lack longevity and tissue-level complexity which limits their utility in predictive toxicology. In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates. Unlike what was seen in 2D hepatocyte cultures, the tissues maintained levels of ATP, Albumin as well as expression and drug-induced enzyme activity of Cytochrome P450s over 4 weeks in culture. To assess the ability of the 3D liver cultures to model tissue-level DILI, dose responses of Trovafloxacin, a drug whose hepatotoxic potential could not be assessed by standard pre-clinical models, were compared to the structurally related non-toxic drug Levofloxacin. Trovafloxacin induced significant, dose-dependent toxicity at clinically relevant doses (≤ 4uM. Interestingly, Trovafloxacin toxicity was observed without lipopolysaccharide stimulation and in the absence of resident macrophages in contrast to earlier reports. Together, these results demonstrate that 3D bioprinted liver tissues can both effectively model DILI and distinguish between highly related compounds with differential profile. Thus, the combination of patient-derived primary cells with bioprinting technology here for the first time demonstrates superior performance in terms of mimicking human drug response in a known target organ at the tissue level.

  7. Assessment of absorption potential of poorly water-soluble drugs by using the dissolution/permeation system.

    Science.gov (United States)

    Kataoka, Makoto; Yano, Koji; Hamatsu, Yoriko; Masaoka, Yoshie; Sakuma, Shinji; Yamashita, Shinji

    2013-11-01

    This study aims to assess the absorption potential of oral absorption of poorly water-soluble drugs by using the dissolution/permeation system (D/P system). The D/P system can be used to perform analysis of drug permeation under dissolution process and can predict the fraction of absorbed dose in humans. When celecoxib at 1/100 of a clinical dose was applied to the D/P system, percentage of dose dissolved and permeated significantly decreased with an increase in the applied amount, resulting in the oral absorption being predicted to be 22-55%. Whereas similar dissolution and permeation profiles of montelukast sodium were observed, estimated absorption (69-85%) was slightly affected. Zafirlukast absorption (33-36%) was not significantly affected by the dose, although zafirlukast did not show complete dissolution. The relationship between clinical dose and predicted oral absorption of drugs corresponded well to clinical observations. The limiting step of the oral absorption of celecoxib and montelukast sodium was solubility, while that of zafirlukast was dissolution rate. However, due to high permeability of montelukast, oral absorption was not affected by dose. Therefore, the D/P system is a useful tool to assess the absorption potential of poorly water-soluble drugs for oral use.

  8. Combining PET biodistribution and equilibrium dialysis assays to assess the free brain concentration and BBB transport of CNS drugs

    Science.gov (United States)

    Gunn, Roger N; Summerfield, Scott G; Salinas, Cristian A; Read, Kevin D; Guo, Qi; Searle, Graham E; Parker, Christine A; Jeffrey, Phil; Laruelle, Marc

    2012-01-01

    The passage of drugs in and out of the brain is controlled by the blood–brain barrier (BBB), typically, using either passive diffusion across a concentration gradient or active transport via a protein carrier. In-vitro and preclinical measurements of BBB penetration do not always accurately predict the in-vivo situation in humans. Thus, the ability to assay the concentration of novel drug candidates in the human brain in vivo provides valuable information for derisking of candidate molecules early in drug development. Here, positron emission tomography (PET) measurements are combined with in-vitro equilibrium dialysis assays to enable assessment of transport and estimation of the free brain concentration in vivo. The PET and equilibrium dialysis data were obtained for 36 compounds in the pig. Predicted P-glycoprotein (P-gp) status of the compounds was consistent with the PET/equilibrium dialysis results. In particular, Loperamide, a well-known P-gp substrate, exhibited a significant concentration gradient consistent with active efflux and after inhibition of the P-gp process the gradient was removed. The ability to measure the free brain concentration and assess transport of novel compounds in the human brain with combined PET and equilibrium dialysis assays can be a useful tool in central nervous system (CNS) drug development. PMID:22274741

  9. 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.

  10. Revisiting the isobole and related quantitative methods for assessing drug synergism.

    Science.gov (United States)

    Tallarida, Ronald J

    2012-07-01

    The isobole is well established and commonly used in the quantitative study of agonist drug combinations. This article reviews the isobole, its derivation from the concept of dose equivalence, and its usefulness in providing the predicted effect of an agonist drug combination, a topic not discussed in pharmacology textbooks. This review addresses that topic and also shows that an alternate method, called "Bliss independence," is inconsistent with the isobolar approach and also has a less clear conceptual basis. In its simplest application the isobole is the familiar linear plot in cartesian coordinates with intercepts representing the individual drug potencies. It is also shown that the isobole can be nonlinear, a fact recognized by its founder (Loewe) but neglected or rejected by virtually all other users. Whether its shape is linear or nonlinear the isobole is equally useful in detecting synergism and antagonism for drug combinations, and its theoretical basis leads to calculations of the expected effect of a drug combination. Numerous applications of isoboles in preclinical testing have shown that synergism or antagonism is not only a property of the two agonist drugs; the dose ratio is also important, a fact of potential importance to the design and testing of drug combinations in clinical trials.

  11. 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.

  12. Reshaping the carcinogenic risk assessment of medicines: international harmonisation for drug safety, industry/regulator efficiency or both?

    Science.gov (United States)

    Abraham, John; Reed, Tim

    2003-07-01

    The most significant institutional entity involved in the harmonisation of drug testing standards worldwide is the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), which comprises the three pharmaceutical industry associations and regulatory agencies of the EU, US and Japan. It is often claimed that such harmonisation will both accelerate the development and approval of new drugs and preserve safety standards, if not strengthen safety regimes. Drawing on extensive documentary research and interviews, this paper systematically examines whether the efforts by the ICH to improve industrial and regulatory efficiency by harmonising drug testing requirements is likely to raise, maintain or compromise safety standards in carcinogenic risk assessment of pharmaceuticals. The evidence suggests that, in the field of carcinogenicity testing, the ICH management of international harmonisation of medicines regulation is not achieving simultaneous improvements in safety standards and acceleration of drug development. Rather, the latter is being achieved at the expense of the former. Indeed, the ICH may be converting permissive regulatory practices of the past into new scientific standards for the future. These findings are significant as many expert scientific advisers to drug regulatory agencies seem to have accepted uncritically the conclusions reached by the ICH, which may affect a potential patient population of half a billion and tens of thousands of clinical trials.

  13. Atom type preferences, structural diversity, and property profiles of known drugs, leads, and nondrugs: a comparative assessment.

    Science.gov (United States)

    Viswanadhan, Vellarkad N; Rajesh, Hariharan; Balaji, Vitukudi N

    2011-05-09

    A new characterization of known drug, lead, and representative nondrug databases was performed taking into account several properties at the atomic and molecular levels. This characterization included atom type preferences, intrinsic structural diversity (Atom Type Diversity, ATD), and other well-known physicochemical properties, as an approach for rapid assessment of druglikeness for small molecule libraries. To characterize ATD, an elaborate united atom classification, UALOGP (United Atom Log P), with 148 atom types, was developed along with associated atomic physicochemical parameters. This classification also enabled an analysis of atom type and physicochemical property distributions (for calculated log P, molar refractivity, molecular weight, total atom count, and ATD) of drug, lead, and nondrug databases, a reassessment of the Ro5 (Rule of Five) and GVW (Ghose−Viswanadhan−Wendoloski) criteria, and development of new criteria and ranges more accurately reflecting the chemical space occupied by small molecule drugs. A relative druglikeness parameter was defined for atom types in drugs, identifying the most preferred types. The present work demonstrates that drug molecules are constitutionally more diverse relative to nondrugs, while being less diverse than leads.

  14. Organotypic functional cultures of human liver cells for long-term maintenance and assessment of drug-induced metabolome effects

    OpenAIRE

    MÜLLER Daniel

    2011-01-01

    The goals of this thesis were (i) to establish and improve organotypic liver cell culture techniques for long-term pharmacological studies and (ii) to develop and apply a metabolomics based approach for the assessment of drug-induced effects. As first model, a 3D bioreactor system was characterized in terms of cell physiology and functionality. Primary human hepatocytes could be kept viable and functional for more than 2 weeks in this system. Optimization of the system allowed determination o...

  15. 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;

    2014-01-01

    comparable to freshly isolated porcine intestinal mucus (PIM). Further, this multicomponent biosimilar mucus mixture was optimized with regards to the lipid content in order to obtain cellular biocompatibility with well-differentiated Caco-2 cell monolayers. In contrast, PIM was found to severely disrupt...... 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....

  16. Adolescent substance-use assessment: methodological issues in the use of the Adolescent Drug Abuse Diagnosis (ADAD).

    Science.gov (United States)

    Chinet, Léonie; Plancherel, Bernard; Bolognini, Monique; Holzer, Laurent; Halfon, Olivier

    2007-01-01

    During the past twenty years, various instruments have been developed for the assessment of substance use in adolescents, mainly in the United States. However, few of them have been adapted to, and validated in, French-speaking populations. Consequently, although increasing alcohol and drug use among teenagers has become a major concern, the various health and social programs developed in response to this specific problem have received little attention with regard to follow-up and outcome assessment. A standardized multidimensional assessment instrument adapted for adolescents is needed to assess the individual needs of adolescents and assign them to the most appropriate treatment setting, to provide a single measurement within and across health and social systems, and to conduct treatment outcome evaluations. Moreover, having an available instrument makes it possible to develop longitudinal and transcultural research studies. For this reason, a French version of the Adolescent Drug Abuse Diagnosis (ADAD) was developed and validated at the University Child and Adolescent Psychiatric Clinic in Lausanne, Switzerland. This article aims to discuss the methodological issues that we faced when using the ADAD instrument in a 4-year longitudinal study including adolescent substance users. Methodological aspects relating to the content and format of the instrument, the assessment administration and the statistical analyses are discussed.

  17. Antiangiogenic therapy using endostatin increases the number of ALDH+ lung cancer stem cells by generating intratumor hypoxia

    Science.gov (United States)

    Yu, Yang; Wang, Yu-yi; Wang, Yi-qin; Wang, Xia; Liu, Yan-Yang; Wang, Jian-Tao; Du, Chi; Wang, Li; Li, Mei; Luo, Feng; Jiang, Ming

    2016-01-01

    Antiangiogenic therapy is becoming a promising option for cancer treatment. However, many investigations have recently indicated that these therapies may have limited efficacy, and the cancers in most patients eventually develop resistance to these therapies. There is considerable recently acquired evidence for an association of such resistance with cancer stem-like cells (CSLCs). Here, we used xenograft tumor murine models to further suggest that antiangiogenic agents actually increase the invasive and metastatic properties of lung cancer cells. In our experiments with murine lung cancer xenografts, we found that the antiangiogenic agent endostatin increased the population of ALDH+ cells, and did so by generating intratumoral hypoxia in the xenografts. We further showed endostatin to cause an increase in the CSLC population by accelerating the generation of tumor hypoxia and by recruiting TAMs, MDSCs and Treg cells, which are inflammatory and immunosuppressive cells and which can secrete cytokines and growth factors such as IL-6, EGF, and TGF-β into the tumor microenvironment. All these factors are related with increased CSLC population in tumors. These results imply that improving the clinical efficacy of antiangiogenic treatments will require the concurrent use of CSLC-targeting agents. PMID:27703219

  18. An Assessment of Alcohol and Drug Education/Prevention Programs in the United States Army

    Science.gov (United States)

    1973-12-01

    who would be more likely to report their motive as a desire for kicks, a desire to raise consciousness, or previous enjoyable experiences with drugs...getting work done. If a soldier is too drunk , hung over, or strung out to work, the senior NCO must immediately face the problem. Any action or... enjoyment use alcohol or drugs because they feel better when they do so, or they experience a heightening of consciousness, feelings of insight, or peace

  19. An assessment of direct-to-consumer advertising of prescription drugs.

    Science.gov (United States)

    Calfee, J E

    2007-10-01

    Advertising is widely seen by economists and regulators as beneficial to markets and consumers. The prescription drug market offers exceptional opportunities for direct-to-consumer advertising (DTCA) to provide new-product information, improve compliance, alleviate widespread underdiagnosis and undertreatment, and motivate new-product development.5 DTCA can also induce excess or even dangerous prescribing, however, partly because patients are poorly informed and usually pay far less than the full cost of drugs. Empirical research can help resolve these issues.

  20. Revisiting the Isobole and Related Quantitative Methods for Assessing Drug Synergism

    OpenAIRE

    Tallarida, Ronald J.

    2012-01-01

    The isobole is well established and commonly used in the quantitative study of agonist drug combinations. This article reviews the isobole, its derivation from the concept of dose equivalence, and its usefulness in providing the predicted effect of an agonist drug combination, a topic not discussed in pharmacology textbooks. This review addresses that topic and also shows that an alternate method, called “Bliss independence,” is inconsistent with the isobolar approach and also has a less clea...

  1. 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

  2. Assessment of drug disposition in the perfused rat brain by statistical moment analysis

    Energy Technology Data Exchange (ETDEWEB)

    Sakane, T.; Nakatsu, M.; Yamamoto, A.; Hashida, M.; Sezaki, H.; Yamashita, S.; Nadai, T. (Faculty of Pharmaceutical Sciences, Setsunan University, Osaka (Japan))

    1991-06-01

    Drug disposition in the brain was investigated by statistical moment analysis using an improved in situ brain perfusion technique. The right cerebral hemisphere of the rat was perfused in situ. The drug and inulin were injected into the right internal carotid artery as a rapid bolus and the venous outflow curve at the posterior facial vein was obtained. The infusion rate was adjusted to minimize the flow of perfusion fluid into the left hemisphere. The obtained disposition parameters were characteristics and considered to reflect the physicochemical properties of each drug. Antipyrine showed a small degree of initial uptake. Therefore, its apparent distribution volume (Vi) and apparent intrinsic clearance (CLint,i) were small. Diazepam showed large degrees of both influx and efflux and, thus, a large Vi. Water showed parameters intermediate between those of antipyrine and those of diazepam. Imipramine, desipramine, and propranolol showed a large CLint,i compared with those of the other drugs. The extraction ratio of propranolol significantly decreased with increasing concentrations of unlabeled propranolol in the perfusion fluid. These findings may be explained partly by the tissue binding of these drugs. In conclusion, the present method is useful for studying drug disposition in the brain.

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

    Directory of Open Access Journals (Sweden)

    Skowronski Karolina

    2010-12-01

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

  4. Is copper chelation an effective anti-angiogenic strategy for cancer treatment?

    Science.gov (United States)

    Antoniades, V; Sioga, A; Dietrich, E M; Meditskou, S; Ekonomou, L; Antoniades, K

    2013-12-01

    Angiogenesis and the acquisition of an angiogenic phenotype is important for cancer cell proliferation. Copper in an essential trace element that participates in many enzymatic complexes like the cytochrome c, superoxide dismutase and lysyl oxidase and it is involved in processes, like embryogenesis, growth, angiogenesis and carcinogenesis. In particular, its involvement in carcinogenesis was described for the first time in oral submucous fibrosis, where fibroblasts produce large amounts of collagen in the presence of copper. Copper's action in carcinogenesis is two-fold: (1) it participates in reactions with an increased redox potential that result in the production of oxidative products and oxidative stress. Through this mechanism, copper may cause DNA mutations in the nucleus and mitochondria or alterations to membrane phospholipids, (2) it participates in angiogenesis even in the absence of angiogenic molecules, as it was reported for the first time in rabbit cornea models with copolymer pellets charged with PGE1. Copper chelation regimens like penicillamine and tetrathiomolybdate are being described in the literature as having anti-angiogenic, anti-fibrotic and anti-inflammatory actions. Animal models of brain cancer that evaluated the anti-angiogenic properties of copper, have proven evidence of the reduction of tumor's microvascular supply, tumor volume and vascular permeability after plasma copper levels reduction. Interestingly, plasma copper levels reduction was shown to suppress micrometastases generation in mice models of breast cancer. We hypothesize that copper chelation therapy: increases oxidative stress in cancer cells to a level that does not allow survival because of the reduction of anti-oxidative enzymes production. It may also result in inhibition of angiogenesis and of the initiation of the angiogenic switch, because copper normally enhances endothelial cell migration and proliferation, improves binding of growth factors to endothelial cells

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

    NARCIS (Netherlands)

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

    2004-01-01

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

  6. TU-G-BRA-07: Characterization of Tumor Proliferation During Successive Cycles of Anti-Angiogenic Therapy Using [F-18]FLT PET/CT

    Energy Technology Data Exchange (ETDEWEB)

    Scarpelli, M; Perlman, S; Harmon, S; Perk, T; Scully, P; Bruce, J; Liu, G; Jeraj, R [University of Wisconsin, Madison, WI (United States)

    2015-06-15

    Purpose: Studies have shown cessation of anti-angiogenic treatment during the first cycle of therapy resulted in rebound of tumor proliferation (flare). This study characterized proliferation dynamics during the first and third cycle of anti-angiogenic treatment using [F-18]FLT PET. Methods: Thirteen patients with various solid cancers were treated with Axitinib (Pfizer, Inc) at a dose of 5mg orally, twice daily, on contiguous three-week cycles with intermittent dosing (two-weeks-on/one-week-off). All patients received three FLT PET/CT scans during cycle 1 (C1): at baseline (C1D0), peak Axitinib concentration (C1D14), and the end of washout (C1D21). Ten patients received up to an additional three scans at corresponding time points during cycle 3 (C3). Lesions were identified by a nuclear medicine physician and manually contoured. Tumor burden was quantified using standard SUV metrics. Correlations between imaging metrics across C1 and C3 were calculated using the Spearman correlation. Results: At C1 peak drug concentration 11/13 patients had decreases in SUVtotal, with median decrease of 50% (change from C1D0 to C1D14). At C3 peak drug concentration 7/7 patients had decreases in SUVtotal, with median decrease of 20% (C3D0 to C3D14). Proliferative flare during C1 washout (>20% increase from C1D14 to C1D21) occurred in 9/13 patients, with median SUVtotal increase of 190%. Flare was also seen in C3 for 5/5 patients, with median SUVtotal increase of 70% (change from C3D14 to C3D21). Correlations were found between changes in imaging metrics across C1 and C3, notably the change in SUVtotal from C1D0 to C1D21 and the change in SUVtotal from C1D0 to C3D0 (ρ = 0.80). Conclusion: Measurements of SUVtotal showed that both patient response to treatment and flare were evident in both cycles of treatment. Correlation between changes in SUVtotal across C1 and C3 suggest early time points could be used to characterize patient response in later cycles. Research funded in part by

  7. 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

  8. 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.

  9. Anticancer and antiangiogenic effects of methanol extracts of Lonicera caprifolium L. on C6 rat glioma cells

    Directory of Open Access Journals (Sweden)

    Nergiz Hacer Turgut

    2016-03-01

    Full Text Available Objective: Gliomas are brain tumors with high morbidity and mortality. For the treatment of gliomas, it is important to develop new and powerful treatments that could complement existing clinical treatment. Lonicera caprifolium L. (L. caprifolium has various uses in herbal traditional medicine. This study was conducted to determine the phenolic acid levels and DNA damage protection potential of L. caprifolium extract, and to explore the antitumor effect of the extract by investigating its toxicity on C6 rat glioma cell lines and normal L929 mouse fibroblast cell lines. We also aimed to investigate the antiangiogenic potential of the extract. Method: Phenolic acid content was determined by HPLC analysis. DNA damage protection potential was evaluated on pBR322 plasmid DNA. The effect of extracts on the proliferation of cancer cells was evaluated by XTT assay. Antiangiogenic effect was determined with Chorioallantoic membrane model. Results: The extract was found rich in vanillic acid (273.003 µg/g; while the amount of chlorogenic acid was almost at negligible level (0.028 µg/g. 0.005-0.05 mg / ml extract protected against the hazardous effects of UV and H2O2 in all DNA bands. The presence of the extract significantly reduced C6 cell proliferation compared to control (p<0.05. The extract had antiproliferative effect with a half maximum inhibition of concentration (IC50 value of 0.45 mg/ml. L. caprifolium extract in 10-6, 10-5 and 10-4 M concentrations caused antiangiogenic effect. Antiangiogenic scores of L. caprifolium were 0.6, 0.73 and 1.6, respectively. Conclusions: These results show that L. caprifolium has potential cytotoxic and antiangiogenic effect on C6 rat glioma cells and that the phenolic acid content of the plant may partially influence these activities.

  10. 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.

  11. 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.

  12. Variability in P-Glycoprotein Inhibitory Potency (IC50) Using Various in Vitro Experimental Systems: Implications for Universal Digoxin Drug-Drug Interaction Risk Assessment Decision Criteria

    Science.gov (United States)

    Bentz, Joe; O’Connor, Michael P.; Bednarczyk, Dallas; Coleman, JoAnn; Lee, Caroline; Palm, Johan; Pak, Y. Anne; Perloff, Elke S.; Reyner, Eric; Balimane, Praveen; Brännström, Marie; Chu, Xiaoyan; Funk, Christoph; Guo, Ailan; Hanna, Imad; Herédi-Szabó, Krisztina; Hillgren, Kate; Li, Libin; Hollnack-Pusch, Evelyn; Jamei, Masoud; Lin, Xuena; Mason, Andrew K.; Neuhoff, Sibylle; Patel, Aarti; Podila, Lalitha; Plise, Emile; Rajaraman, Ganesh; Salphati, Laurent; Sands, Eric; Taub, Mitchell E.; Taur, Jan-Shiang; Weitz, Dietmar; Wortelboer, Heleen M.; Xia, Cindy Q.; Xiao, Guangqing; Yabut, Jocelyn; Yamagata, Tetsuo; Zhang, Lei

    2013-01-01

    A P-glycoprotein (P-gp) IC50 working group was established with 23 participating pharmaceutical and contract research laboratories and one academic institution to assess interlaboratory variability in P-gp IC50 determinations. Each laboratory followed its in-house protocol to determine in vitro IC50 values for 16 inhibitors using four different test systems: human colon adenocarcinoma cells (Caco-2; eleven laboratories), Madin-Darby canine kidney cells transfected with MDR1 cDNA (MDCKII-MDR1; six laboratories), and Lilly Laboratories Cells—Porcine Kidney Nr. 1 cells transfected with MDR1 cDNA (LLC-PK1-MDR1; four laboratories), and membrane vesicles containing human P-glycoprotein (P-gp; five laboratories). For cell models, various equations to calculate remaining transport activity (e.g., efflux ratio, unidirectional flux, net-secretory-flux) were also evaluated. The difference in IC50 values for each of the inhibitors across all test systems and equations ranged from a minimum of 20- and 24-fold between lowest and highest IC50 values for sertraline and isradipine, to a maximum of 407- and 796-fold for telmisartan and verapamil, respectively. For telmisartan and verapamil, variability was greatly influenced by data from one laboratory in each case. Excluding these two data sets brings the range in IC50 values for telmisartan and verapamil down to 69- and 159-fold. The efflux ratio-based equation generally resulted in severalfold lower IC50 values compared with unidirectional or net-secretory-flux equations. Statistical analysis indicated that variability in IC50 values was mainly due to interlaboratory variability, rather than an implicit systematic difference between test systems. Potential reasons for variability are discussed and the simplest, most robust experimental design for P-gp IC50 determination proposed. The impact of these findings on drug-drug interaction risk assessment is discussed in the companion article (Ellens et al., 2013) and recommendations

  13. Biomarkers to assess the efficiency of treatment with platinum-based drugs: what can metallomics add?

    Science.gov (United States)

    Araujo, Thiago de O; Costa, Lilian T; Fernandes, Janaina; Aucélio, Ricardo Queiroz; de Campos, Reinaldo Calixto

    2014-12-01

    Since the approval of cisplatin as an antineoplastic drug, the medical and the scientific communities have been concerned about the side effects of platinum-based drugs, and this has been the dose-limiting factor that leads to reduced treatment efficiency. Another important issue is the intrinsic or acquired resistance of some patients to treatment. Identifying proper biomarkers is crucial in evaluating the efficiency of a treatment, assisting physicians in determining, at early stages, whether or not the patient presents resistance to the drug, minimizing severe side effects, and allowing them to redirect the established course of chemotherapy. A great effort is being made to identify biomarkers that can be used to predict the outcome of the treatment of cancer patients with platinum-based drugs. In this context, the metallomic approach has not yet been used to its full potential. Since the basis of these drugs is platinum, the monitoring of biomarkers containing this metal should be the natural approach to evaluate treatment progress. This review intends to show where the research in this field stands and points out some gaps that can be filled by metallomics.

  14. Assessing Physicochemical Properties of Drug Molecules via Microsolvation Measurements with Differential Mobility Spectrometry.

    Science.gov (United States)

    Liu, Chang; Le Blanc, J C Yves; Schneider, Bradley B; Shields, Jefry; Federico, James J; Zhang, Hui; Stroh, Justin G; Kauffman, Gregory W; Kung, Daniel W; Ieritano, Christian; Shepherdson, Evan; Verbuyst, Mitch; Melo, Luke; Hasan, Moaraj; Naser, Dalia; Janiszewski, John S; Hopkins, W Scott; Campbell, J Larry

    2017-02-22

    The microsolvated state of a molecule, represented by its interactions with only a small number of solvent molecules, can play a key role in determining the observable bulk properties of the molecule. This is especially true in cases where strong local hydrogen bonding exists between the molecule and the solvent. One method that can probe the microsolvated states of charged molecules is differential mobility spectrometry (DMS), which rapidly interrogates an ion's transitions between a solvated and desolvated state in the gas phase (i.e., few solvent molecules present). However, can the results of DMS analyses of a class of molecules reveal information about the bulk physicochemical properties of those species? Our findings presented here show that DMS behaviors correlate strongly with the measured solution phase pKa and pKb values, and cell permeabilities of a set of structurally related drug molecules, even yielding high-resolution discrimination between isomeric forms of these drugs. This is due to DMS's ability to separate species based upon only subtle (yet predictable) changes in structure: the same subtle changes that can influence isomers' different bulk properties. Using 2-methylquinolin-8-ol as the core structure, we demonstrate how DMS shows promise for rapidly and sensitively probing the physicochemical properties of molecules, with particular attention paid to drug candidates at the early stage of drug development. This study serves as a foundation upon which future drug molecules of different structural classes could be examined.

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. EO-199, a specific antagonist of antiarrhythmic drugs: Assessment by binding experiments and in vivo studies

    Energy Technology Data Exchange (ETDEWEB)

    Oppenheimer, E.; Harel, G.; Lipinsky, D.; Sarne, Y. (Tel-Aviv Univ. (Israel))

    1991-01-01

    EO-199, a demethylated analog of the novel class I antiarrhythmic drug EO-122 was found to antagonize the antiarrhythmic activity of EO-122 and that of procainamide (Class I{sub A}). EO-199 did not block significantly the activity of a class I{sub B} antiarrhythmic agent, lidocaine. EO-199 also displaced the specific binding of ({sup 3}H)EO-122 to rate heart membranes similarly to procainamide whereas lidocaine did not. The correlation between binding experiments and pharmacological effects points to a possible subclassification of these drugs; the two chemical analogs EO-199 and EO-122, as well as procainamide (I{sub A}) but not lidocaine (I{sub B}), compete at the same site or the same state of the sodium channel. The availability of a specific antagonist might be useful for studying the mechanism of action of antiarrhythmic drugs as well as an antidote in cases of antiarrhythmics overdose intoxication.

  1. 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.

  2. 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.

  3. 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.

  4. Multimodality multiparametric imaging of early tumor response to a novel antiangiogenic therapy based on anticalins.

    Directory of Open Access Journals (Sweden)

    Reinhard Meier

    Full Text Available Anticalins are a novel class of targeted protein therapeutics. The PEGylated Anticalin Angiocal (PRS-050-PEG40 is directed against VEGF-A. The purpose of our study was to compare the performance of diffusion weighted imaging (DWI, dynamic contrast enhanced magnetic resonance imaging (DCE-MRI and positron emission tomography with the tracer [18F]fluorodeoxyglucose (FDG-PET for monitoring early response to antiangiogenic therapy with PRS-050-PEG40. 31 mice were implanted subcutaneously with A673 rhabdomyosarcoma xenografts and underwent DWI, DCE-MRI and FDG-PET before and 2 days after i.p. injection of PRS-050-PEG40 (n = 13, Avastin (n = 6 or PBS (n = 12. Tumor size was measured manually with a caliper. Imaging results were correlated with histopathology. In the results, the tumor size was not significantly different in the treatment groups when compared to the control group on day 2 after therapy onset (P = 0.09. In contrast the imaging modalities DWI, DCE-MRI and FDG-PET showed significant differences between the therapeutic compared to the control group as early as 2 days after therapy onset (P<0.001. There was a strong correlation of the early changes in DWI, DCE-MRI and FDG-PET at day 2 after therapy onset and the change in tumor size at the end of therapy (r = -0.58, 0.71 and 0.67 respectively. The imaging results were confirmed by histopathology, showing early necrosis and necroptosis in the tumors. Thus multimodality multiparametric imaging was able to predict therapeutic success of PRS-050-PEG40 and Avastin as early as 2 days after onset of therapy and thus promising for monitoring early response of antiangiogenic therapy.

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

    Directory of Open Access Journals (Sweden)

    Casimiro Cárdenas

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

  6. Anti-Angiogenic and Anti-Inflammatory Properties of Kahweol, a Coffee Diterpene

    Science.gov (United States)

    Cárdenas, Casimiro; Quesada, Ana R.; Medina, Miguel A.

    2011-01-01

    Background Epidemiological studies have shown that unfiltered coffee consumption is associated with a low incidence of cancer. This study aims to identify the effects of kahweol, an antioxidant diterpene contained in unfiltered coffee, on angiogenesis and key inflammatory molecules. Methodology/Principal Findings The experimental procedures included in vivo angiogenesis assays (both the chicken and quail choriallantoic membrane assay and the angiogenesis assay with fluorescent zebrafish), the ex vivo mouse aortic ring assay and the in vitro analysis of the effects of treatment of human endothelial cells with kahweol in cell growth, cell viability, cell migration and zymographic assays, as well as the tube formation assay on Matrigel. Additionally, two inflammation markers were determined, namely, the expression levels of cyclooxygenase 2 and the levels of secreted monocyte chemoattractant protein-1. We show for the first time that kahweol is an anti-angiogenic compound with inhibitory effects in two in vivo and one ex vivo angiogenesis models, with effects on specific steps of the angiogenic process: endothelial cell proliferation, migration, invasion and tube formation on Matrigel. We also demonstrate the inhibitory effect of kahweol on the endothelial cell potential to remodel extracellular matrix by targeting two key molecules involved in the process, MMP-2 and uPA. Finally, the anti-inflammatory potential of this compound is demonstrated by its inhibition of both COX-2 expression and MCP-1 secretion in endothelial cells. Conclusion/Significance Taken together, our data indicate that, indeed, kahweol behaves as an anti-inflammatory and anti-angiogenic compound with potential use in antitumoral therapies. These data may contribute to the explanation of the reported antitumoral effects of kahweol, including the recent epidemiological meta-analysis showing that drinking coffee could decrease the risk of certain cancers. PMID:21858104

  7. Assessment of anti-arrhythmic activity of antipsychotic drugs in an animal model

    DEFF Research Database (Denmark)

    Mow, Tomas; Frederiksen, Kristen; Thomsen, Morten B.

    2015-01-01

    limited experimental information exists about the effects of α1-adrenergic receptor activity of antipsychotic drugs in pro-arrhythmic models, we have decided to investigate this. In this study we show that four antipsychotic drugs all have high affinity for α1-adrenergic receptor (sertindole>risperidone......>haloperidol>olanzapine) and all block IKr (sertindole>haloperidol>risperidone>olanzapine). In canine Purkinje fibres, α1-adrenergic stimulation prolonged action potential duration; however, the stimulation does not cause afterdepolarizations, even in the presence of dofetilide-induced delayed repolarization. We showed...

  8. Assessing the effectiveness of Malaysia's drug prevention education and rehabilitation programs.

    Science.gov (United States)

    Scorzelli, J F

    1988-01-01

    The multifaceted drug prevention education and rehabilitation system of Malaysia appears to have contributed to the steady decrease of the number of identified drug abusers in the country. In this article, those components of the Malaysian system that would be most applicable to the American effort were examined. In the same manner, because the fastest growing minority group in the United States are Asian Americans, in which a significant proportion involve persons from Southeast Asia, those components in the Malaysian system that are applicable to Southeast Asian Americans were examined.

  9. Quality assessment of structure and language elements of written responses given by seven Scandinavian drug information centres

    DEFF Research Database (Denmark)

    Reppe, Linda Amundstuen; Spigset, Olav; Kampmann, Jens Peter

    2017-01-01

    for which queries were part of the study. The responses were assessed qualitatively by six clinical pharmacologists (internal experts) and six general practitioners (GPs, external experts). In addition, linguistic aspects of the responses were evaluated by a plain language expert. RESULTS: The quality......PURPOSE: The aim of this study was to identify structure and language elements affecting the quality of responses from Scandinavian drug information centres (DICs). METHODS: Six different fictitious drug-related queries were sent to each of seven Scandinavian DICs. The centres were blinded...... of responses was generally judged as satisfactory to good. Presenting specific advice and conclusions were considered to improve the quality of the responses. However, small nuances in language formulations could affect the individual judgments of the experts, e.g. on whether or not advice was given. Some...

  10. 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.

  11. Assessment of Benzodiazepine dependence in alcohol and drug dependent outpatients: A research report

    NARCIS (Netherlands)

    Kan, C.C.; Breteler, M.H.M.; Ven, A.H.G.S. van der; Timmermans, M.A.Y.; Zitman, F.G.

    2001-01-01

    In this study on 99 outpatients who were being treated for alcohol and/or drug dependence and also using benzodiazepines (BZDs), prevalence rates of DSM-III-R and ICD-10 substance dependence diagnoses were ascertained and scalability, reliability and validity of the scales of the Benzodiazepine Depe

  12. 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...

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

    NARCIS (Netherlands)

    Mesens, N.; Crawfordb, A.D.; Menke, A.; Hung, P.D.; Goethem, F. van; Nuyts, R.; Hansen, E.; Wolterbeek, A.; Gompel, J. van; Witte, P. de; Esguerra, C.V.

    2015-01-01

    Drug-induced liver injury (DILI) is poorly predicted by single-cell-based assays, probably because of the lack of physiological interactions with other cells within the liver. An intact whole liver system such as one present in zebrafish larvae could provide added value in a screening strategy for D

  14. Clinical assessment of drug-eluting stents: Twente trial and beyond

    NARCIS (Netherlands)

    Tandjung, K.

    2014-01-01

    Stents have revolutionized the treatment of obstructive coronary disease by improving the safety of percutaneous coronary intervention (PCI) and reducing the need for repeat revascularization. First-generation drug-eluting stents (DES) were highly efficacious, as they further reduced the need for re

  15. Assessment of a 96-Well Plate Assay of Quantitative Drug Susceptibility Testing for Mycobacterium Tuberculosis Complex in China

    Science.gov (United States)

    Xia, Hui; Zheng, Yang; Zhao, Bing; van den Hof, Susan; Cobelens, Frank; Zhao, YanLin

    2017-01-01

    Objective To evaluate the performance of the Sensitire MYCOTB MIC Plate (MYCOTB) which could measure the twelve anti-tuberculosis drugs susceptibility on one 96-wells plate. Methods A total of 140 MDR-TB strains and 60 non-MDR strains were sub-cultured and 193 strains were finally tested for drug resistance using MYCOTB and agar proportion method (APM) and another 7 strains failed of subculture. The drugs included ofloxacin (Ofx), moxifloxacin (Mfx), rifampin (RFP), amikacin (Am), rifabutin (Rfb), para-aminosalicylic acid (PAS), ethionamide (Eth), isoniazid (INH), kanamycin (Km), ethambutol (EMB), streptomycin (Sm), and cycloserine(Cs). The categorical agreement, conditional agreement, sensitivity and specificity of MYCOTB were assessed in comparison with APM. For strains with inconsistent results between MYCOTB and APM, the drug resistance related gene fragments were amplified and sequenced: gyrA for Ofx and Mfx; rpoB for RFP and Rfb; embB for EMB; rpsl for Sm; katG and the promoter region of inhA for INH, ethA and the promoter region of inhA for Eth. The sequence results were compared with results of MYCOTB and APM to analyze the consistency between sequence results and MYCOTB or APM. Results The categorical agreement between two methods for each drug ranged from 88.6% to 100%. It was the lowest for INH (88.6%). The sensitivity and specificity of MYCOTB ranged from 71.4% to 100% and 84.3% to 100%, respectively. The sensitivity was lowest for Cs(71.4%), EMB at 10μg/ml (80.0%) and INH at 10.0μg/ml (84.6%). The specificity was lowest for Rfb (84.3%). Overall discordance between the two phenotypic methods was observed for 96 strains, of which 63 (65.6%) were found susceptible with APM and resistant with MYCOTB and the remaining 33(34.4%) strains were resistant by APM and susceptible with MYCOTB. 34/52 (65.4%) sequenced APM susceptible and MYCOTB resistant(APM-S/MYCOTB-R) strains had mutations or insertions in the amplified regions. 20/30 (66.7%) sequenced APM

  16. Drug-Induced Liver Injury Network Causality Assessment: Criteria and Experience in the United States

    Directory of Open Access Journals (Sweden)

    Paul H. Hayashi

    2016-02-01

    Full Text Available Hepatotoxicity due to drugs, herbal or dietary supplements remains largely a clinical diagnosis based on meticulous history taking and exclusion of other causes of liver injury. In 2004, the U.S. Drug-Induced Liver Injury Network (DILIN was created under the auspices of the U.S. National Institute of Diabetes and Digestive and Kidney Diseases with the aims of establishing a large registry of cases for clinical, epidemiological and mechanistic study. From inception, the DILIN has used an expert opinion process that incorporates consensus amongst three different DILIN hepatologists assigned to each case. It is the most well-established, well-described and vigorous expert opinion process for DILI to date, and yet it is an imperfect standard. This review will discuss the DILIN expert opinion process, its strengths and weaknesses, psychometric performance and future.

  17. 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.

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

    OpenAIRE

    Nemati Z; Matlabi H

    2017-01-01

    Zeinab Nemati, Hossein Matlabi Department of Health Education and Promotion, Faculty of Health Sciences, Tabriz University of Medical Sciences, Tabriz, Iran Background: Internet addiction and drug abuse isolate adolescents from their family and friends and cause damage to their health, relations, emotions, and spirit. In the society, adolescents’ addiction extracts high cost on health care, educational failure and mental health services. Objectives: The aim of this study wa...

  19. A Procedure for Performance Assessment of Drugs Hypothesized to be Effective in Controlling Motion Sickness

    Science.gov (United States)

    1990-12-01

    1985 Hyosine, Ocular of alertness Hydrobromide, Accommodation, Cinnarizine Missing Digit, Critical Flicker Frequency, Digit Symbol van Marion Motion...selected by the Tri- (Symbolic) Service Joint Working 15. Visual Group on Drug 4. 2-Column Scanning Dependent Degradation Addition of Military...performance shows up on the Pursuit Meter, it is impossible to tell if the degradation has occurred in mental acuity, judgement, motor control, or any

  20. Assessment of drug-induced hepatotoxicity in clinical practice: A challenge for gastroenterologists

    Institute of Scientific and Technical Information of China (English)

    Raúl J Andrade; Mercedes Robles; Alejandra Fernández-Casta(n)er; Susana López-Ortega; M Carmen López-Vega; M Isabel Lucena

    2007-01-01

    Currently, pharmaceutical preparations are serious contributors to liver disease; hepatotoxicity ranking as the most frequent cause for acute liver failure and postcommercialization regulatory decisions. The diagnosis of hepatotoxicity remains a difficult task because of the lack of reliable markers for use in general clinical practice.To incriminate any given drug in an episode of liver dysfunction is a step-by-step process that requires a high degree of suspicion, compatible chronology, awareness of the drug's hepatotoxic potential, the exclusion of alternative causes of liver damage and the ability to detect the presence of subtle data that favors a toxic etiology. This process is time-consuming and the final result is frequently inaccurate. Diagnostic algorithms may add consistency to the diagnostic process by translating the suspicion into a quantitative score. Such scales are useful since they provide a framework that emphasizes the features that merit attention in cases of suspected hepatic adverse reaction as well. Current efforts in collecting bona fide cases of drug-induced hepatotoxicity will make refinements of existing scales feasible. It is now relatively easy to accommodate relevant data within the scoring system and to delete low-impact items. Efforts should also be directed toward the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be made. The instrument chosen would enable a confident diagnosis to be made on admission of the patient and treatment to be finetuned as further information is collected.

  1. Assessment of time interval between tramadol intake and seizure and second drug-induced attack

    Directory of Open Access Journals (Sweden)

    Bahareh Abbasi

    2015-11-01

    Full Text Available Background: Tramadol is a synthetic drug which is prescribed in moderate and severe pain. Tramadol overdose can induce severe complications such as consciousness impairment and convulsions. This study was done to determine the convulsions incidence after tramadol use until one week after hospital discharge. Methods: This prospective study was done in tramadol overdose patients without uncontrolled epilepsy and head injury history. All cases admitted in Loghman and Rasol Akram Hospitals, Tehran, Iran from 1, April 2011 to 1, April 2012 were included and observed for at least 12 hours. Time interval between tramadol intake and first seizure were record. Then, patients with second drug-induced seizure were recognized and log time between the first and second seizure was analyzed. The patients were transferred to the intensive care unit (ICU if clinical worsening status observed. One week after hospital discharge, telephone follow-up was conducted. Results: A total of 150 patients with a history of tramadol induced seizures (141 men, 9 women, age: 23.23±5.94 years were enrolled in this study. Convulsion was seen in 104 patients (69.3%. In 8 out of 104 patients (7.6% two or more convulsion was seen. Time interval between tramadol use and the onset of the first and second seizure were 0.93±0.17 and 2.5±0.75 hours, respectively. Tramadol induced seizures are more likely to occur in males and patients with a history of drug abuse. Finally, one hundred forty nine patients (99.3% were discharged with good condition and the only one patient died from tramadol overdose. Conclusion: The results of the study showed tramadol induced seizure most frequently occurred within the first 4 hours of tramadol intake. The chance of experiencing a second seizure exists in the susceptible population. Thus, 4 hours after drug intake is the best time for patients to be hospital discharged.

  2. 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

    2016-06-15

    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.

  3. X-ray crystallography: Assessment and validation of protein-small molecule complexes for drug discovery

    Science.gov (United States)

    Cooper, David R.; Porebski, Przemyslaw J.; Chruszcz, Maksymilian; Minor, Wladek

    2011-01-01

    Introduction Crystallography is the key initial component for structure-based and fragment-based drug design and can often generate leads that can be developed into high potency drugs. Therefore, huge sums of money are committed based on the outcome of crystallography experiments and their interpretation. Areas covered This review discusses how to evaluate the correctness of an X-ray structure, focusing on the validation of small molecule-protein complexes. Various types of inaccuracies found within the PDB are identified and the ramifications of these errors are discussed. The reader will gain an understanding of the key parameters that need to be inspected before a structure can be used in drug discovery efforts, as well as an appreciation of the difficulties of correctly interpreting electron density for small molecules. The reader will also be introduced to methods for validating small molecules within the context of a macromolecular structure. Expert opinion One of the reasons that ligand identification and positioning, within a macromolecular crystal structure, is so difficult is that the quality of small molecules widely varies in the PDB. For this reason, the PDB can not always be considered a reliable repository of structural information pertaining to small molecules, and this makes the derivation of general principles that govern small molecule-protein interactions more difficult. PMID:21779303

  4. 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.

  5. 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.

  6. Metabolic impact of anti-angiogenic agents on U87 glioma cells.

    Directory of Open Access Journals (Sweden)

    Tanja Mesti

    Full Text Available BACKGROUND: Glioma cells not only secrete high levels of vascular endothelial growth factor (VEGF but also express VEGF receptors (VEGFR, supporting the existence of an autocrine loop. The direct impact on glioma cells metabolism of drugs targeting the VEGF pathway, such as Bevacizumab (Bev or VEGFR Tyrosine Kinase Inhibitor (TKI, is poorly known. MATERIAL AND METHODS: U87 cells were treated with Bev or SU1498, a selective VEGFR2 TKI. VEGFR expression was checked with FACS flow cytometry and Quantitative Real-Time PCR. VEGF secretion into the medium was assessed with an ELISA kit. Metabolomic studies on cells were performed using High Resolution Magic Angle Spinning Spectroscopy (HR-MAS. RESULTS: U87 cells secreted VEGF and expressed low level of VEGFR2, but no detectable VEGFR1. Exposure to SU1498, but not Bev, significantly impacted cell proliferation and apoptosis. Metabolomic studies with HR MAS showed that Bev had no significant effect on cell metabolism, while SU1498 induced a marked increase in lipids and a decrease in glycerophosphocholine. Accordingly, accumulation of lipid droplets was seen in the cytoplasm of SU1498-treated U87 cells. CONCLUSION: Although both drugs target the VEGF pathway, only SU1498 showed a clear impact on cell proliferation, cell morphology and metabolism. Bevacizumab is thus less likely to modify glioma cells phenotype due to a direct therapeutic pressure on the VEGF autocrine loop. In patients treated with VEGFR TKI, monitoring lipids with magnetic resonance spectroscopic (MRS might be a valuable marker to assess drug cytotoxicity.

  7. Variability in P-glycoprotein inhibitory potency (IC₅₀) using various in vitro experimental systems: implications for universal digoxin drug-drug interaction risk assessment decision criteria.

    Science.gov (United States)

    Bentz, Joe; O'Connor, Michael P; Bednarczyk, Dallas; Coleman, Joann; Lee, Caroline; Palm, Johan; Pak, Y Anne; Perloff, Elke S; Reyner, Eric; Balimane, Praveen; Brännström, Marie; Chu, Xiaoyan; Funk, Christoph; Guo, Ailan; Hanna, Imad; Herédi-Szabó, Krisztina; Hillgren, Kate; Li, Libin; Hollnack-Pusch, Evelyn; Jamei, Masoud; Lin, Xuena; Mason, Andrew K; Neuhoff, Sibylle; Patel, Aarti; Podila, Lalitha; Plise, Emile; Rajaraman, Ganesh; Salphati, Laurent; Sands, Eric; Taub, Mitchell E; Taur, Jan-Shiang; Weitz, Dietmar; Wortelboer, Heleen M; Xia, Cindy Q; Xiao, Guangqing; Yabut, Jocelyn; Yamagata, Tetsuo; Zhang, Lei; Ellens, Harma

    2013-07-01

    A P-glycoprotein (P-gp) IC₅₀ working group was established with 23 participating pharmaceutical and contract research laboratories and one academic institution to assess interlaboratory variability in P-gp IC₅₀ determinations. Each laboratory followed its in-house protocol to determine in vitro IC₅₀ values for 16 inhibitors using four different test systems: human colon adenocarcinoma cells (Caco-2; eleven laboratories), Madin-Darby canine kidney cells transfected with MDR1 cDNA (MDCKII-MDR1; six laboratories), and Lilly Laboratories Cells--Porcine Kidney Nr. 1 cells transfected with MDR1 cDNA (LLC-PK1-MDR1; four laboratories), and membrane vesicles containing human P-glycoprotein (P-gp; five laboratories). For cell models, various equations to calculate remaining transport activity (e.g., efflux ratio, unidirectional flux, net-secretory-flux) were also evaluated. The difference in IC₅₀ values for each of the inhibitors across all test systems and equations ranged from a minimum of 20- and 24-fold between lowest and highest IC₅₀ values for sertraline and isradipine, to a maximum of 407- and 796-fold for telmisartan and verapamil, respectively. For telmisartan and verapamil, variability was greatly influenced by data from one laboratory in each case. Excluding these two data sets brings the range in IC₅₀ values for telmisartan and verapamil down to 69- and 159-fold. The efflux ratio-based equation generally resulted in severalfold lower IC₅₀ values compared with unidirectional or net-secretory-flux equations. Statistical analysis indicated that variability in IC₅₀ values was mainly due to interlaboratory variability, rather than an implicit systematic difference between test systems. Potential reasons for variability are discussed and the simplest, most robust experimental design for P-gp IC₅₀ determination proposed. The impact of these findings on drug-drug interaction risk assessment is discussed in the companion article (Ellens

  8. A cross-sectional national survey assessing self-reported drug intake behavior, contact with the primary sector and drug treatment among service users of Danish drug consumption rooms

    DEFF Research Database (Denmark)

    Toth, Eva Charlotte; Tegner, Jette; Lauridsen, Sigurd

    2016-01-01

    non-EU citizens. As drug intake method, 63 % injected drugs in a vein, 7 % sniffed, and 37 % smoked. Of drugs used in the DCR, 49 % used cocaine, 41 % heroin, 16 % a mix of heroin and cocaine, and 16 % used methadone. Participants who smoked drugs made significantly less use of drug rehabilitation...

  9. A First Assessment of Mycobacterium tuberculosis Genetic Diversity and Drug-Resistance Patterns in Twelve Caribbean Territories

    Directory of Open Access Journals (Sweden)

    Julie Millet

    2014-01-01

    Full Text Available With the exception of some French-speaking islands, data on tuberculosis (TB in the Caribbean are scarce. In this study, we report a first assessment of genetic diversity of a convenience sample of Mycobacterium tuberculosis strains received from twelve Caribbean territories by spoligotyping and describe their drug-resistance patterns. Of the 480 isolates, 40 (8.3% isolates showed resistance to at least one anti-TB drug. The proportion of drug-resistant strains was significantly higher in The Bahamas (21.4%; P=0.02, and Guyana (27.5%; P<0.0001, while it was significantly lower in Jamaica (2.4%; P=0.03 than in other countries of the present study. Regarding genetic diversity, 104 distinct spoligotype patterns were observed: 49 corresponded to clustered strains (2 to 93 strains per cluster, while 55 remained unclustered among which 16 patterns were not reported previously. Combining the study results with regional data retrieved from the international SITVIT2 database underlined a connection between frequency of certain M. tuberculosis phylogenetic lineages and the language spoken, suggesting historical (colonial and ongoing links (trade, tourism, and migratory flows with European countries with which they shared a common past.

  10. 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

  11. Assessment of Drug Sensitivity in Hematopoietic Stem and Progenitor Cells From Acute Myelogenous Leukemia and Myelodysplastic Syndrome Ex Vivo.

    Science.gov (United States)

    Knorr, Katherine L B; Finn, Laura E; Smith, B Douglas; Hess, Allan D; Foran, James M; Karp, Judith E; Kaufmann, Scott H

    2016-11-07

    : Current understanding suggests that malignant stem and progenitor cells must be reduced or eliminated for prolonged remissions in myeloid neoplasms such as acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Multicolor flow cytometry has been widely used to distinguish stem and myeloid progenitor cells from other populations in normal and malignant bone marrow. In this study, we present a method for assessing drug sensitivity in MDS and AML patient hematopoietic stem and myeloid progenitor cell populations ex vivo using the investigational Nedd8-activating enzyme inhibitor MLN4924 and standard-of-care agent cytarabine as examples. Utilizing a multicolor flow cytometry antibody panel for identification of hematopoietic stem cells, multipotent progenitors, common myeloid progenitors, granulocyte-monocyte progenitors, and megakaryocyte-erythroid progenitors present in mononuclear cell fractions isolated from bone marrow aspirates, we compare stem and progenitor cell counts after treatment for 24 hours with drug versus diluent. We demonstrate that MLN4924 exerts a cytotoxic effect on MDS and AML stem and progenitor cell populations, whereas cytarabine has more limited effects. Further application of this method for evaluating drug effects on these populations ex vivo and in vivo may inform rational design and selection of therapies in the clinical setting.

  12. 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

  13. The Mesenteric Lymph Duct Cannulated Rat Model: Application to the Assessment of Intestinal Lymphatic Drug Transport

    Science.gov (United States)

    Trevaskis, Natalie L.; Hu, Luojuan; Caliph, Suzanne M.; Han, Sifei; Porter, Christopher J.H.

    2015-01-01

    The intestinal lymphatic system plays key roles in fluid transport, lipid absorption and immune function. Lymph flows directly from the small intestine via a series of lymphatic vessels and nodes that converge at the superior mesenteric lymph duct. Cannulation of the mesenteric lymph duct thus enables the collection of mesenteric lymph flowing from the intestine. Mesenteric lymph consists of a cellular fraction of immune cells (99% lymphocytes), aqueous fraction (fluid, peptides and proteins such as cytokines and gut hormones) and lipoprotein fraction (lipids, lipophilic molecules and apo-proteins). The mesenteric lymph duct cannulation model can therefore be used to measure the concentration and rate of transport of a range of factors from the intestine via the lymphatic system. Changes to these factors in response to different challenges (e.g., diets, antigens, drugs) and in disease (e.g., inflammatory bowel disease, HIV, diabetes) can also be determined. An area of expanding interest is the role of lymphatic transport in the absorption of orally administered lipophilic drugs and prodrugs that associate with intestinal lipid absorption pathways. Here we describe, in detail, a mesenteric lymph duct cannulated rat model which enables evaluation of the rate and extent of lipid and drug transport via the lymphatic system for several hours following intestinal delivery. The method is easily adaptable to the measurement of other parameters in lymph. We provide detailed descriptions of the difficulties that may be encountered when establishing this complex surgical method, as well as representative data from failed and successful experiments to provide instruction on how to confirm experimental success and interpret the data obtained. PMID:25866901

  14. [Hypolipidemic agents drug interactions: approach to establish and assess its clinical significance. Structured review].

    Science.gov (United States)

    Franco, D; Henao, Y; Monsalve, M; Gutiérrez, F; Hincapie, J; Amariles, P

    2013-01-01

    Objetivo: Realizar una revisión estructurada sobre interacciones medicamentosas de los hipolipemiantes y valorar su relevancia clínica. Método: Revisión estructurada de interacciones medicamentosas con hipolipemiantes en humanos, en PubMed/Medline de artículos publicados sin restricción de idioma, con acceso a texto completo hasta junio 30 de 2012. La búsqueda se realizó con los siguientes terminos Mesh: Drug Interactions, Lipid Regulating Agents, Herb-Drug Interactions, Food-Drug Interactions y Hypolipidemic Agents (Pharmacological Action). La información se complementó con artículos considerados importantes. Por último, se utilizó un método para evaluar la relevancia clínica de la interacción, basado en la probabilidad de ocurrencia y en la gravedad del efecto de la interacción. Resultados: Se obtuvieron 849 publicaciones, de las cuales se seleccionaron 243 referencias, en las los que se identificaron 189 interacciones. De ellas 33 fueron valoradas como de riesgo muy alto (nivel 1) y 42 de riesgo alto (nivel 2), asociadas fundamentalmente al aumento del riesgo de rabdomiólisis. La inhibición enzimática de la CYP450 fue el mecanismo más común de las interacciones. Conclusiones. En los pacientes en tratamiento con hipolipemiantes, de las interacciones identificadas 60,3% (128/189) son clínicamente relevantes (riesgo muy alto o alto), asociadas principalmente a la aparición de rabdomiólisis. La mayoría de dichas interacciones son atribuidas al uso simultáneo de reconocidos inhibidores de la CYP3A4. Por ello, las estatinas metabolizadas por la CYP3A4 (simvastatina, lovastatina y atorvastatina) son las que más interacciones de relevancia clínica presentan.

  15. Assessment of coercive and noncoercive pressures to enter drug abuse treatment.

    Science.gov (United States)

    Marlowe, D B; Kirby, K C; Bonieskie, L M; Glass, D J; Dodds, L D; Husband, S D; Platt, J J; Festinger, D S

    1996-10-01

    This paper reports preliminary data derived from a standardized interview scoring procedure for detecting and characterizing coercive and noncoercive pressures to enter substance abuse treatment. Coercive and noncoercive pressures stemming from multiple psychosocial domains are operationalized through recourse to established behavioral principles. Inter-rater reliability for the scoring procedure was exceptional over numerous rater trials. Substantive analyses indicate that, among clients in outpatient cocaine treatment, 'coercion' is operative in multiple psychosocial domains, and that subjects perceive legal pressures as exerting substantially less influence over their decisions to enter treatment than informal psychosocial pressures. Implications for drug treatment planning, legal and ethical issues, and directions for future research are proposed.

  16. The assessment of potential for QT interval prolongation with new pharmaceuticals: impact on drug development.

    Science.gov (United States)

    Gralinski, M R

    2000-01-01

    Few examinations of a single physiological variable can end the development of a putative new pharmaceutical. Prolongation of the electrocardiographic QT interval is one of these tests. Recognizing the removal of several approved and widely used medicines, worldwide regulatory authorities have raised a heightened awareness on the submission of data surrounding the ventricular repolarization process. This review will discuss the anatomy and physiology surrounding the generation of the electrocardiographic QT interval and the consequences of its alteration. In addition, relevant models of preclinical safety and general guidelines for clinical examination in this area are discussed along with the impact of incorporating these assays into the drug development process.

  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.

  18. 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

  19. 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.

  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. Femoral Head Growth Plate Dysplasia and Fracture in Juvenile Rabbits Induced by Off-target Antiangiogenic Treatment.

    Science.gov (United States)

    Hall, A Peter; Mitchard, T; Rolf, M G; Stewart, J; Duffy, P

    2016-08-01

    Epiphyseal growth plate dysplasia (chondrodysplasia) might be considered as the pathognomonic feature of antiangiogenic treatment in preclinical species as it is reliably and dose-responsively induced in rodents and monkeys with vascular endothelial growth factor receptor (VEGFR) inhibitors, fibroblast growth factor (FGF) receptor inhibitors, matrix metalloproteinase inhibitors, and vascular targeting agents. Here we report epiphyseal growth plate dysplasia in juvenile rabbits treated with an oral spleen tyrosine kinase inhibitor induced by off-target antiangiogenic inhibition of VEGF and FGF family kinase receptors. Epiphyseal growth plate dysplasia resulted in weakening and fracturing of the femoral head physis in 6 of 10 male and 1 of 10 female animals as well as microfracturing and dysplasia of the distal femoral articular cartilage in 1 male animal. Fracture lines ran through the zone of hypertrophic cartilage (as well as adjacent zones), were orientated parallel to the physeal plane, and often involved displacement of the femoral head. We would suggest that the high prevalence of growth plate fracture in the rabbit may represent a potential additional adverse risk to those already established for children treated with antiangiogenic therapy.

  2. 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.

  3. An in vitro approach to assessing a potential drug interaction between MDMA (ecstasy) and caffeine.

    Science.gov (United States)

    Downey, C; Daly, F; O'Boyle, K M

    2014-03-01

    3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a popular recreational drug which causes long-term neurotoxicity and increased risk of fatality. In rats, MDMA toxicity is exacerbated by co-administration of caffeine. The aim of this study was to investigate whether caffeine altered the effects of MDMA in a battery of in vitro tests selected to model some of the known actions of MDMA in vivo. In cytotoxicity studies, caffeine modestly enhanced the effect of MDMA on neuronal N2a cell viability but not that of liver, intestinal or kidney cells. MDMA inhibited the formation of fluorescent metabolites by CYP2D6≫CYP3A4>CYP1A2 but this was not altered by caffeine. Similarly, the inhibition of synaptosomal [(3)H] 5-HT uptake by MDMA was not affected by the presence of caffeine. Thus, these in vitro tests failed to detect any substantial interaction between caffeine and MDMA, highlighting the difficulty of modelling in vivo drug interactions using in vitro tests. However, the results show that the inhibition of synaptosomal [(3)H] 5-HT uptake by MDMA was greater at 41°C and 25°C than at 37°C which raises the possibility that MDMA's effect on SERT in vivo may be increased as body temperature increases, contributing to its harmful effects in users.

  4. Environmental impact assessment of veterinary drug on fish aquaculture for food safety.

    Science.gov (United States)

    Kwon, Jin-Wook

    2016-05-01

    The degradation of veterinary drugs approved for use in aquaculture is very important in the evaluation of the impact of these drugs on the environment and to ensure safe food production. The purpose of this study is to provide guidance on how the interpretation of environmental fate data can be used by applicants to aid in protecting the environment and for the basis for food production, by suggesting the correct interpretation of data as part of an effective registration process. Tests were performed using a modification of the Organisation for Economic Co-operation and Development (OECD) 308 guideline using erythromycin and oxolinic acid under combinations of aerobic and anaerobic conditions, with and without sediment, in sea water and fresh water. Estimated DT50 s of erythromycin in fresh and sea water ranged from 6.8 to 37.9 days and estimated DT90 s were from 22.6 to 125.9 days. Degradation was more rapid in fresh water than in sea water with the formation of three degradation products: anhydroerythomycin A, erythromycin A enol ether, and pseudoerythomycin A enol ether. Estimated DT50 s of oxolinic acid in fresh and sea water were from 10.3 to 63.0 days and estimated DT90 s were from 34.3 to 209.4 days which suggests that oxolinic acid is more persistent in the environment than erythromycin. Copyright © 2016 John Wiley & Sons, Ltd.

  5. 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.

  6. Simplified assays of lipolysis enzymes for drug discovery and specificity assessment of known inhibitors.

    Science.gov (United States)

    Iglesias, Jose; Lamontagne, Julien; Erb, Heidi; Gezzar, Sari; Zhao, Shangang; Joly, Erik; Truong, Vouy Linh; Skorey, Kathryn; Crane, Sheldon; Madiraju, S R Murthy; Prentki, Marc

    2016-01-01

    Lipids are used as cellular building blocks and condensed energy stores and also act as signaling molecules. The glycerolipid/ fatty acid cycle, encompassing lipolysis and lipogenesis, generates many lipid signals. Reliable procedures are not available for measuring activities of several lipolytic enzymes for the purposes of drug screening, and this resulted in questionable selectivity of various known lipase inhibitors. We now describe simple assays for lipolytic enzymes, including adipose triglyceride lipase (ATGL), hormone sensitive lipase (HSL), sn-1-diacylglycerol lipase (DAGL), monoacylglycerol lipase, α/β-hydrolase domain 6, and carboxylesterase 1 (CES1) using recombinant human and mouse enzymes either in cell extracts or using purified enzymes. We observed that many of the reported inhibitors lack specificity. Thus, Cay10499 (HSL inhibitor) and RHC20867 (DAGL inhibitor) also inhibit other lipases. Marked differences in the inhibitor sensitivities of human ATGL and HSL compared with the corresponding mouse enzymes was noticed. Thus, ATGListatin inhibited mouse ATGL but not human ATGL, and the HSL inhibitors WWL11 and Compound 13f were effective against mouse enzyme but much less potent against human enzyme. Many of these lipase inhibitors also inhibited human CES1. Results describe reliable assays for measuring lipase activities that are amenable for drug screening and also caution about the specificity of the many earlier described lipase inhibitors.

  7. Urine phenobarbital drug screening: potential use for compliance assessment in neonates.

    Science.gov (United States)

    Guillet, Ronnie; Kwon, Jennifer M; Chen, Sixaio; McDermott, Michael P

    2012-02-01

    This study was done to determine if urine phenobarbital measurements provide a reliable indicator of presence of the drug in neonates. Urine was collected from neonates treated with phenobarbital for clinical indications within 4 to 6 hours of clinically indicated collection of serum phenobarbital levels. Urine samples were also collected from control neonates not treated with phenobarbital. One aliquot was assayed fresh, another frozen at -30°C and assayed 1 to 3 months later. Phenobarbital was assayed using the ONLINE TDM Roche/Hitachi automated clinical chemistry analyzer. Serum and urine concentrations were compared as were fresh and frozen urine measurements. Serum phenobarbital ranged from 5.6 to 52.7 μg/mL. Matched urine samples were 56.6 ± 12.5% of the serum level. Frozen samples were 98.3 ± 8.0% of the fresh samples. Urine phenobarbital concentrations, either fresh or frozen, can be used in neonates as a noninvasive estimate of drug levels.

  8. New drugs for follicular lymphoma.

    Science.gov (United States)

    Sorigue, Marc; Ribera, Josep-Maria; Motlló, Cristina; Sancho, Juan-Manuel

    2016-10-01

    Despite the improvement in prognosis since the advent of rituximab, follicular lymphoma is still incurable and remains the cause of death of most afflicted patients. With the expanding knowledge of the pathogenesis of B-cell malignancies, in the last few years a plethora of new therapies acting through a variety of mechanisms have shown promising results. This review attempts to analyze the evidence available on these new drugs, which include new monoclonal antibodies and immunoconjugates, the anti-angiogenic and immunomodulatory agent lenalidomide, the proteasome inhibitor bortezomib, inhibitors of B-cell receptor pathway enzymes, such as ibrutinib, idelalisib, duvelisib and entospletinib, BCL2 inhibitors and checkpoint inhibitors. We conclude that despite the high expectations around the new therapeutic options for patients with refractory disease, these new drugs have side effects that require caution with their use, particularly in light of the still short follow up and the lack of both randomized trials and data on combination regimens.

  9. Drug-eluting stents in percutaneous coronary intervention: a benefit-risk assessment.

    Science.gov (United States)

    Byrne, Robert A; Sarafoff, Nikolaus; Kastrati, Adnan; Schömig, Albert

    2009-01-01

    Drug-eluting stent (DES) therapy has represented a very significant milestone in the evolution of percutaneous coronary intervention (PCI) therapy. This review attempts to provide a balanced overview of the unprecedented wealth of data generated on this new technology, by examining the evidence bases for anti-restenotic efficacy, safety and cost effectiveness. The performance of a DES may be related to each of its three components: stent backbone; carrier polymer (to control drug-release kinetics); and active drug. In terms of anti-restenotic efficacy, the most appropriate parameters to examine are target lesion revascularization, angiographic restenosis and late luminal loss. The principal safety parameters are overall mortality, myocardial infarction (MI) and stent thrombosis. Anti-restenotic superiority of DES over bare metal stents (BMS) has been demonstrated across a spectrum of disease from straightforward 'vanilla lesions' through higher disease complexity in pivotal clinical trials to phase IV studies of efficacy in 'off-label' populations. The treatment effect of DES versus BMS is consistent in terms of a reduction in the need for repeat intervention of the order of 35-70%. Regarding differential efficacy of first-generation DES, a benefit may exist in favour of the Cypher (sirolimus-eluting) stent over Taxus (paclitaxel-eluting), particularly in high-risk lesion subsets. The second-generation approved devices are the Endeavor (zotarolimus-eluting) and Xience (everolimus-eluting) DES. While all four of these stents are permanent polymer-based, the current focus of development is towards DES platforms that are devoid of durable polymer, the presence of which has been implicated in late adverse events. In terms of safety concerns raised in relation to DES therapy, it is reasonable to conclude the following at 4- to 5-year post-stent implantation: (i) that there is no increased risk of death or MI with DES (neither is there a general signal of mortality

  10. 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...

  11. Health technology assessment and ill-structured problems: a case study concerning the drug mebeverine.

    NARCIS (Netherlands)

    Moret-Hartman, M.; Wilt, G.J. van der; Grin, J.

    2007-01-01

    OBJECTIVES: The practical significance of health technology assessment (HTA) in policy decisions or clinical practice has been challenged. Possibly, problem definitions underlying HTA do not concur sufficiently with the problem definitions held by policy makers or clinicians. We performed an in-dept

  12. An Assessment of the Hypothetical Impact of Drug Abuse on Combat Capability. Volume I.

    Science.gov (United States)

    1979-12-01

    25 I .4 Jill 1.6 MICROCOPY RESOLUTION TEST CHART NATIONAt BIURIA OF gMANI£ IWOI) A LEVEL AD SAI-80-113-WA AN ASSESSMENT OF THE HYPOTHETICAL IMPACTo OF...potential loss of unit effectiveness in each of these units. The resulting measure of unit effectiveness provides a powerful analy- tic tool for comparing

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

    Institute of Scientific and Technical Information of China (English)

    何莎

    2015-01-01

    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.%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。

  14. 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.

  15. 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.

  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. 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.

  18. 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.

  19. Anti-Oxidant, Anti-Inflammatory and Anti-Angiogenic Properties of Resveratrol in Ocular Diseases.

    Science.gov (United States)

    Lançon, Allan; Frazzi, Raffaele; Latruffe, Norbert

    2016-03-02

    Resveratrol (3,4',5 trihydroxy-trans-stilbene) is one of the best known phytophenols with pleiotropic properties. It is a phytoalexin produced by vine and it leads to the stimulation of natural plant defenses but also exhibits many beneficial effects in animals and humans by acting on a wide range of organs and tissues. These include the prevention of cardiovascular diseases, anti-cancer potential, neuroprotective effects, homeostasia maintenance, aging delay and a decrease in inflammation. Age-related macular degeneration (AMD) is one of the main causes of deterioration of vision in adults in developed countries This review deals with resveratrol and ophthalmology by focusing on the antioxidant, anti-inflammatory, and anti-angiogenic effects of this molecule. The literature reports that resveratrol is able to act on various cell types of the eye by increasing the level of natural antioxidant enzymatic and molecular defenses. Resveratrol anti-inflammatory effects are due to its capacity to limit the expression of pro-inflammatory factors, such as interleukins and prostaglandins, and also to decrease the chemo-attraction and recruitment of immune cells to the inflammatory site. In addition to this, resveratrol was shown to possess anti-VEGF effects and to inhibit the proliferation and migration of vascular endothelial cells. Resveratrol has the potential to be used in a range of human ocular diseases and conditions, based on animal models and in vitro experiments.

  20. Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma.

    Science.gov (United States)

    Kessler, Tobias; Sahm, Felix; Blaes, Jonas; Osswald, Matthias; Rübmann, Petra; Milford, David; Urban, Severino; Jestaedt, Leonie; Heiland, Sabine; Bendszus, Martin; Hertenstein, Anne; Pfenning, Philipp-Niclas; Ruiz de Almodóvar, Carmen; Wick, Antje; Winkler, Frank; von Deimling, Andreas; Platten, Michael; Wick, Wolfgang; Weiler, Markus

    2015-10-13

    Loss of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a prerequisite for tumor cell-specific expression of vascular endothelial growth factor receptor (VEGFR)-2 in glioblastoma defining a subgroup prone to develop evasive resistance towards antiangiogenic treatments. Immunohistochemical analysis of human tumor tissues showed VEGFR-2 expression in glioma cells in 19% of specimens examined, mainly in the infiltration zone. Glioma cell VEGFR-2 positivity was restricted to PTEN-deficient tumor specimens. PTEN overexpression reduced VEGFR-2 expression in vitro, as well as knock-down of raptor or rictor. Genetic interference with VEGFR-2 revealed proproliferative, antiinvasive and chemoprotective functions for VEGFR-2 in glioma cells. VEGFR-2-dependent cellular effects were concomitant with activation of 'kappa-light-chain-enhancer' of activated B-cells, protein kinase B, and N-myc downstream regulated gene 1. Two-photon in vivo microscopy revealed that expression of VEGFR-2 in glioma cells hampers antiangiogenesis. Bevacizumab induces a proinvasive response in VEGFR-2-positive glioma cells. Patients with PTEN-negative glioblastomas had a shorter survival after initiation of bevacizumab therapy compared with PTEN-positive glioblastomas. Conclusively, expression of VEGFR-2 in glioma cells indicates an aggressive glioblastoma subgroup developing early resistance to temozolomide or bevacizumab. Loss of PTEN may serve as a biomarker identifying those tumors upfront by routine neuropathological methods.

  1. Phenolic Compounds as Antiangiogenic CMG2 Inhibitors from Costa Rican Endophytic Fungi

    Science.gov (United States)

    Cao, Shugeng; Cryan, Lorna; Habeshian, Kaiane A.; Murillo, Catalina; Tamayo-Castillo, Giselle; Rogers, Michael S.; Clardy, Jon

    2013-01-01

    Targeting and inhibiting CMG2 (Capillary Morphogenesis Gene protein 2) represents a new strategy for therapeutic agents for cancer and retinal diseases due to CMG2’s role in blood vessel growth (angiogenesis). A high throughput FRET (Förster Resonance Energy Transfer) assay was developed for the identification of CMG2 inhibitors as anti-angiogenetic agents. Bioassay-guided separation led to the isolation and identification of two new compounds (1 and 2) from CR252M, an endophytic fungus Coccomyces proteae collected from a Costa Rican rainforest, and one known compound (3) from CR1207B (Aurapex penicillata). Secondary in vitro assays indicated anti-angiogenic activity. Compound 3 inhibited the endothelial cell migration at 52 µM, but did not show any endothelial cell antiproliferative effect at 156 µM. The structure of the two new compounds, A (1) and B (2), were elucidated on the basis of extensive spectroscopic analysis, including 1D and 2D NMR experiments. PMID:22910038

  2. 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.

  3. 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.

  4. Twin-to-twin transfusion syndrome: an anti-angiogenic state?

    Science.gov (United States)

    KUSANOVIC, Juan Pedro; ROMERO, Roberto; ESPINOZA, Jimmy; NIEN, Jyh Kae; KIM, Chong Jai; MITTAL, Pooja; EDWIN, Sam; EREZ, Offer; GOTSCH, Francesca; MAZAKI-TOVI, Shali; THAN, Nandor G.; SOTO, Eleazar; CAMACHO, Natalia; GOMEZ, Ricardo; QUINTERO, Ruben; HASSAN, Sonia S.

    2008-01-01

    Objective An imbalanced chronic blood flow between the donor and recipient twin through placental vascular anastomoses is the accepted pathophysiology of twin-to-twin transfusion syndrome (TTTS). Vascular endothelial growth factor receptor-1 (VEGFR-1) mRNA is overexpressed only in the syncytiotrophoblast of the donor twin in some cases of TTTS. This study was conducted to determine maternal plasma concentrations of placental growth factor (PlGF), soluble VEGFR-1, and soluble endoglin (s-Eng) in monochorionic-diamniotic pregnancies with and without TTTS. Study design This case-control study included monochorionic-diamniotic pregnancies between 16–26 weeks with and without TTTS. Maternal plasma concentrations of PlGF, sVEGFR-1 and s-Eng were determined with ELISA. A p-value <.05 was considered statistically significant. Results Patients with TTTS had higher median plasma concentrations of s-Eng [14.8 ng/ml vs. 7.8 ng/ml; p<0.001] and sVEGFR-1 [6383.1 pg/ml vs. 3220.1 pg/ml; p<0.001]; and lower median plasma concentrations of PlGF [115.5 pg/ml vs. 359.3 pg/ml; p=0.002] than those without TTTS. Conclusions We propose that an anti-angiogenic state may be present in some cases of TTTS. PMID:18395032

  5. Antioxidant and antiangiogenic properties of phenolic extract from Pleurotus tuber-regium.

    Science.gov (United States)

    Lin, Shaoling; Lai, Tsz ching; Chen, Lei; Kwok, Hin fai; Lau, Clara Bik-san; Cheung, Peter C K

    2014-10-01

    Pleurotus tuber-regium (Fries) Singer (PTR), both an edible and a medicinal mushroom also known as tiger milk mushroom, has experienced growing popularity and economic importance due to its flavor, nutritive value, and medicinal effects. In this study, the antioxidant and antiangiogenic activities of a 60% ethanol extract (EE) obtained from the sclerotium of PTR were investigated. Typical phenolic compounds including protocatechuic, chlorogenic, syringic, ferulic, and folic acid were identified and quantified in EE by the HPLC-UV-ESI/MS analyses. EE possessed strong antioxidant activity and could dose-dependently inhibit vascular endothelial growth factor (VEGF)-induced human umbilical vein endothelial cells (HUVEC) migration and tube formation. qPCR results showed that VEGF-induced FGF, ANG-Tie, and MMP gene expression as well as VEGFR were down-regulated at the mRNA level after treated with EE, suggesting that multiple molecular targets related to angiogenesis was involved. Furthermore, EE also inhibited the formation of subintestinal vessel plexus (SIVs) in zebrafish embryos in vivo. All of these suggested that EE of PTR could be the source of potential inhibitors to target angiogenesis.

  6. 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

    2015-12-04

    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.

  7. Molecular level interaction of the human acidic fibroblast growth factor with the antiangiogenic agent, inositol hexaphosphate .

    Science.gov (United States)

    Kumar, Sriramoju M; Wang, Han-Min; Mohan, Sepuru K; Chou, Ruey-Hwang; Yu, Chin

    2010-12-21

    Acidic fibroblast growth factor (FGF1) regulates a wide array of important biological phenomena such as angiogenesis, cell differentiation, tumor growth, and neurogenesis. Generally, FGFs are known for their strong affinity for the glycosaminoglycan heparin, as a prerequisite for recognition of a specific tyrosine kinase on the cell surface and are responsible for the cell signal transduction cascade. Inositol hexaphosphate (IP6) is a natural antioxidant and is known for its antiangiogenic role, in addition to its ability to control tumor growth. In the present study, we investigated the interaction of IP6 with the acidic fibroblast growth factor (FGF1) using various biophysical techniques including isothermal calorimetry, circular dichroism, and multidimensional NMR spectroscopy. Herein, we have reported the three-dimensional solution structure of the FGF1-IP6 complex. These data show that IP6 binds FGF1 and enhances its thermal stability. In addition, we also demonstrate that IP6 acts as an antagonist to acidic fibroblast growth factor by inhibiting its receptor binding and subsequently decreasing the mitogenic activity. The inhibition likely results in the ability of IP6 to antagonize the angiogenic and mitogenic activity of FGF1.

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

    OpenAIRE

    Ciani O; Jommi C

    2014-01-01

    Oriana Ciani,1,3 Claudio Jommi1,2 1Centre for Research on Health and Social Care Management (CERGAS), Bocconi University, Milan, Italy; 2Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara, Italy; 3University of Exeter Medical School, Exeter, UK Abstract: The use of health technology assessment (HTA) to inform policy-making is established in most developed countries. Compared to licensing agencies, HTA agencies have different interests and, t...

  9. 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?

  10. Substituted phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamides as antimitotics. Antiproliferative, antiangiogenic and antitumoral activity, and quantitative structure-activity relationships.

    Science.gov (United States)

    Fortin, Sébastien; Wei, Lianhu; Moreau, Emmanuel; Lacroix, Jacques; Côté, Marie-France; Petitclerc, Eric; Kotra, Lakshmi P; Gaudreault, René C

    2011-11-01

    The importance of the bridge linking the two phenyl moieties of substituted phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) was assessed using a sulfonamide group, which is a bioisostere of sulfonate and ethenyl groups. Forty one phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamide (PIB-SA) derivatives were prepared and biologically evaluated. PIB-SAs exhibit antiproliferative activities at the nanomolar level against sixteen cancer cell lines, block the cell cycle progression in G(2)/M phase, leading to cytoskeleton disruption and anoikis. These results were subjected to CoMFA and CoMSIA analyses to establish quantitative structure-activity relationships. These results evidence that the sulfonate and sulfonamide moieties are reciprocal bioisosteres and that phenylimidazolidin-2-one could mimic the trimethoxyphenyl moiety found in the structure of numerous potent antimicrotubule agents. Finally, compounds 16 and 17 exhibited potent antitumor and antiangiogenic activities on HT-1080 fibrosarcoma cells grafted onto chick chorioallantoic membrane similar to CA-4 without significant toxicity for the chick embryos, making this class of compounds a promising class of anticancer agents.

  11. Multiparametric Monitoring of Early Response to Antiangiogenic Therapy: A Sequential Perfusion CT and PET/CT Study in a Rabbit VX2 Tumor Model

    Directory of Open Access Journals (Sweden)

    Jung Im Kim

    2014-01-01

    Full Text Available Objectives. To perform dual analysis of tumor perfusion and glucose metabolism using perfusion CT and FDG-PET/CT for the purpose of monitoring the early response to bevacizumab therapy in rabbit VX2 tumor models and to assess added value of FDG-PET to perfusion CT. Methods. Twenty-four VX2 carcinoma tumors implanted in bilateral back muscles of 12 rabbits were evaluated. Serial concurrent perfusion CT and FDG-PET/CT were performed before and 3, 7, and 14 days after bevacizumab therapy (treatment group or saline infusion (control group. Perfusion CT was analyzed to calculate blood flow (BF, blood volume (BV, and permeability surface area product (PS; FDG-PET was analyzed to calculate SUVmax, SUVmean, total lesion glycolysis (TLG, entropy, and homogeneity. The flow-metabolic ratio (FMR was also calculated and immunohistochemical analysis of microvessel density (MVD was performed. Results. On day 14, BF and BV in the treatment group were significantly lower than in the control group. There were no significant differences in all FDG-PET-derived parameters between both groups. In the treatment group, FMR prominently decreased after therapy and was positively correlated with MVD. Conclusions. In VX2 tumors, FMR could provide further insight into the early antiangiogenic effect reflecting a mismatch in intratumor blood flow and metabolism.

  12. 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.

  13. Sunitinib treatment enhances metastasis of innately drug resistant breast tumors

    Science.gov (United States)

    Wragg, Joseph W; Heath, Victoria L; Bicknell, Roy

    2017-01-01

    Anti-angiogenic therapies have failed to confer survival benefits in patients with metastatic breast cancer (mBC). However, to date there has not been an inquiry into roles for acquired versus innate drug resistance in this setting. In this study, we report roles for these distinct phenotypes in determining therapeutic response in a murine model of mBC resistance to the anti-angiogenic tyrosine kinase inhibitor sunitinib. Using tumor measurement and vascular patterning approaches, we differentiated tumors displaying innate versus acquired resistance. Bioluminescent imaging of tumor metastases to the liver, lungs and spleen revealed that sunitinib administration enhances metastasis, but only in tumors displaying innate resistance to therapy. Transcriptomic analysis of tumors displaying acquired versus innate resistance allowed the identification of specific biomarkers, many of which have a role in angiogenesis. In particular, aquaporin-1 upregulation occurred in acquired resistance, mTOR in innate resistance, and pleiotrophin in both settings, suggesting their utility as candidate diagnostics to predict drug response or to design tactics to circumvent resistance. Our results unravel specific features of antiangiogenic resistance, with potential therapeutic implications. PMID:28011623

  14. 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.

  15. 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.

  16. Evaluación positiva de medicamentos: 2º Trimestre 2012 Positive assessment of drugs: 2nd quarter 2012

    Directory of Open Access Journals (Sweden)

    A. García Luque

    2012-09-01

    Full Text Available Se reseñan los medicamentos ya evaluados por la Agencia Española de Medicamentos y Productos Sanitarios hechos públicos en el segundo trimestre de 2012, y considerados de mayor interés para el profesional sanitario. 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 second quarter of 2012, and considered of interest to the healthcare professional, are reviewed. These are positive technical reports prior to the authorization and placing on the market of the product.

  17. The effect of roxatidine acetate and cimetidine on hepatic drug clearance assessed by simultaneous administration of three model substrates.

    Science.gov (United States)

    Tanaka, E; Nakamura, K

    1989-08-01

    The effect of pretreatment for 7 days with either roxatidine acetate 75 mg twice daily or cimetidine 200 mg four times daily on the kinetics of antipyrine (AP), trimethadione (TMO) and indocyanine green (ICG) was studied in seven healthy, male, nonsmoking subjects. After pretreatment with cimetidine, the plasma clearances (CL) of AP and TMO were significantly lower and the elimination half-life (t1/2) of AP was significantly increased. The volumes of distribution (V) of AP and TMO were not affected. After roxatidine acetate, the pharmacokinetics of AP and TMO were unchanged. The cumulative renal excretion (% dose) and formation clearance of 3-hydroxymethyl-3-nor-antipyrine (NORA) were lowered by cimetidine treatment, but not following the administration of roxatidine acetate. ICG clearance was not changed significantly by either pretreatment. The results of this study show that roxatidine acetate does not impair the metabolism of three model substrates used to assess hepatic drug clearance.

  18. Evaluación positiva de medicamentos: 4.º Trimestre 2012 Positive assessment of drugs: 4th quarter 2012

    Directory of Open Access Journals (Sweden)

    M. Puerro Vicente

    2013-03-01

    Full Text Available Se reseñan los medicamentos ya evaluados por la Agencia Española de Medicamentos y Productos Sanitarios hechos públicos en el último trimestre de 2012, y considerados de mayor interés para el profesional sanitario. 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 last quarter of 2012, and considered of interest to the healthcare professional, are reviewed. These are positive technical reports prior to the authorization and placing on the market of the product.

  19. A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Mintun, M.A.; Raichle, M.E.; Kilbourn, M.R.; Wooten, G.F.; Welch, M.J.

    1984-03-01

    We propose an in vivo method for use with positron emission tomography (PET) that results in a quantitative characterization of neuroleptic binding sites using radiolabeled spiperone. The data are analyzed using a mathematical model that describes transport, nonspecific binding, and specific binding in the brain. The model demonstrates that the receptor quantities Bmax (i.e., the number of binding sites) and KD-1 (i.e., the binding affinity) are not separably ascertainable with tracer methodology in human subjects. We have, therefore, introduced a new term, the binding potential, equivalent to the product BmaxKD-1, which reflects the capacity of a given tissue, or region of a tissue, for ligand-binding site interaction. The procedure for obtaining these measurements is illustrated with data from sequential PET scans of baboons after intravenous injection of carrier-added (18F)spiperone. From these data we estimate the brain tissue nonspecific binding of spiperone to be in the range of 94.2 to 95.3%, and the regional brain spiperone permeability (measured as the permeability-surface area product) to be in the range of 0.025 to 0.036 cm3/(s X ml). The binding potential of the striatum ranged from 17.4 to 21.6; these in vivo estimates compare favorably to in vitro values in the literature. To our knowledge this represents the first direct evidence that PET can be used to characterize quantitatively, locally and in vivo, drug binding sites in brain. The ability to make such measurements with PET should permit the detailed investigation of diseases thought to result from disorders of receptor function.

  20. 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.

  1. 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

  2. Novel 3D Culture Systems for Studies of Human Liver Function and Assessments of the Hepatotoxicity of Drugs and Drug Candidates.

    Science.gov (United States)

    Lauschke, Volker M; Hendriks, Delilah F G; Bell, Catherine C; Andersson, Tommy B; Ingelman-Sundberg, Magnus

    2016-12-19

    The liver is an organ with critical importance for drug treatment as the disposition and response to a given drug is often determined by its hepatic metabolism. Patient-specific factors can entail increased susceptibility to drug-induced liver injury, which constitutes a major risk for drug development programs causing attrition of promising drug candidates or costly withdrawals in postmarketing stages. Hitherto, mainly animal studies and 2D hepatocyte systems have been used for the examination of human drug metabolism and toxicity. Yet, these models are far from satisfactory due to extensive species differences and because hepatocytes in 2D cultures rapidly dedifferentiate resulting in the loss of their hepatic phenotype and functionality. With the increasing comprehension that 3D cell culture systems more accurately reflect in vivo physiology, in the recent decade more and more research has focused on the development and optimization of various 3D culture strategies in an attempt to preserve liver properties in vitro. In this contribution, we critically review these developments, which have resulted in an arsenal of different static and perfused 3D models. These systems include sandwich-cultured hepatocytes, spheroid culture platforms, and various microfluidic liver or multiorgan biochips. Importantly, in many of these models hepatocytes maintain their phenotype for prolonged times, which allows probing the potential of newly developed chemical entities to cause chronic hepatotoxicity. Moreover, some platforms permit the investigation of drug action in specific genetic backgrounds or diseased hepatocytes, thereby significantly expanding the repertoire of tools to detect drug-induced liver injuries. It is concluded that the development of 3D liver models has hitherto been fruitful and that systems are now at hand whose sensitivity and specificity in detecting hepatotoxicity are superior to those of classical 2D culture systems. For the future, we highlight the

  3. Prescription factors associated with medication non-adherence in Japan assessed from leftover drugs in the SETSUYAKU-BAG campaign: Focus on oral antidiabetic drugs

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    Kaori Koyanagi

    2016-07-01

    Full Text Available Background: Medication adherence has an important influence on health outcomes in patients with chronic diseases. However, few studies have been performed in Japan to determine factors related to medication non-adherence. Objective: The aim of this study was to identify prescription factors related to medication non-adherence by investigating patient characteristics, all prescriptions, and prescriptions for oral antidiabetic drugs (OADs.Methods: A retrospective cross-sectional survey of prescription data about implementation of dosing regimen was performed at community pharmacies engaged in appropriate use of leftover drugs. We evaluated the amount of drugs originally prescribed and the reduced amount after use of leftover drugs, and then calculated prescription reduction ratio (PRR. We analyzed prescription factors contributing to non-adherence based on the PRR.Results: Prescription information for 1,207 patients was reviewed, revealing that patients were non-adherent to 58% of prescriptions. Lack of a drug copayment, fewer concurrent drugs, and drugs not in single-dose packaging were associated with non-adherence. Among the 1,207 patients, 234 prescriptions for diabetes and 452 OAD formulations were included. Forty-seven percent of prescriptions and 29% of the formulations were non-adherent. A higher dosing frequency and preprandial administration were associated with non-adherence. Among the OADs, adherence was lower for α-glucosidase inhibitors and biguanides than for sulfonylureas. Conclusions: Several factors related to patient characteristics, general drug prescriptions, and OAD prescriptions were associated with non-adherence. Further consideration will be needed to improve adherence to medication in Japan. Health care providers should perform more careful monitoring of adherence in patients with the factors identified by this study.

  4. ENMD-2076 is an orally active kinase inhibitor with antiangiogenic and antiproliferative mechanisms of action.

    Science.gov (United States)

    Fletcher, Graham C; Brokx, Richard D; Denny, Trisha A; Hembrough, Todd A; Plum, Stacy M; Fogler, William E; Sidor, Carolyn F; Bray, Mark R

    2011-01-01

    ENMD-2076 is a novel orally active, small molecule kinase inhibitor with a mechanism of action involving several pathways key to tumor growth and survival: angiogenesis, proliferation, and the cell cycle. ENMD-2076 has selective activity against the mitotic kinase Aurora A, as well as kinases involved in angiogenesis (VEGFRs, FGFRs). ENMD-2076 inhibited the growth in vitro of a wide range of human solid tumor and hematopoietic cancer cell lines with IC(50) values ranging from 0.025 to 0.7 μmol/L. ENMD-2076 was also shown to induce regression or complete inhibition of tumor growth in vivo at well-tolerated doses in tumor xenograft models derived from breast, colon, melanoma, leukemia, and multiple myeloma cell lines. Pharmacodynamic experiments in vivo showed that in addition to inhibiting Aurora A, single doses of ENMD-2076 had sustained inhibitory effects on the activation of Flt3 as well as the angiogenic tyrosine kinases, VEGFR2/KDR and FGFR1 and 2. ENMD-2076 was shown to prevent the formation of new blood vessels and regress formed vessels in vivo at doses equivalent to those that gave substantial activity in tumor xenograft models. These results indicate that ENMD-2076 is a well-tolerated, orally active multitarget kinase inhibitor with a unique antiangiogenic/antiproliferative profile and provides strong preclinical support for use as a therapeutic for human cancers. Several phase 1 studies involving ENMD-2076 have been recently completed, and the compound is currently being evaluated in a phase 2 clinical trial in patients with platinum-resistant ovarian cancer.

  5. Recurrence or metastasis of HCC: predictors, early detection and experimental antiangiogenic therapy

    Institute of Scientific and Technical Information of China (English)

    Yang Fu Jiang; Zhi Hua Yang; Jin Qun Hu

    2000-01-01

    AIM To investigate the predictors for recurrence or metastasis of HCC, and to evaluate the effect of antiangiogenic therapy on the growth of transplantable human HCC in nude mice. METHODS RT-PCR was used to measure the expression of matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) in 56 pairs of nontumorous liver and tumor samples. Sixty blood samples from human HCC were examined by nested RT-PCR to find out AFP mRNA. Recombinant human endostatin and polyclonal antibody against VEGF were administered to treat human HCC transplanted in nude mice. RESULTS Thirty of 56 HCC samples showed stronger expression of MMP-9 in tumorous tissues than in nontumorous tissues. Fifteen of the 26 patients with relative expression level of MMP-9 more than 0.34 developed tumor recurrence or metastasis, whereas only 7 of 30 patients with relative expression level less than 0.34 developed tumor recurrence (P<0.05).There was no significant difference in the relative expression level of VEGF between patients with postoperative recurrence or metastasis and those without recurrence. AFP mRNA was detectable in 53.3% of patients with HCC. The sensitivity and specificity of AFP mRNA as a marker to detect hematogenous dissemination of HCC cells was 81.8% and 84.4%, respectively. Recombinant human endostatin and polyclonal antibody against VEGF inhibited the growth of transplantable HCC in nude mice by 52.2% and 45.7%, respectively.CONCLUSION MMP-9 expression in HCC correlates with the postoperative recurrence or metastasis of HCC. Patients with high level of MMP-9 expression in HCC are susceptible to metastasis. AFP mRNA could serve as an indicator of hematogenous spreading of HCC cells in circulation and a predictor of recurrence or metastasis of HCC. Antiangiogenesis may be an adjuvant therapy for HCC.

  6. Vascular CXCR4 expression - a novel antiangiogenic target in gastric cancer?

    Directory of Open Access Journals (Sweden)

    Barbara Ingold

    antiangiogenic target for the treatment of gastric carcinomas.

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

    Energy Technology Data Exchange (ETDEWEB)

    Narayana, Ashwatha, E-mail: ashwatha.narayana@nyumc.org [Department of Radiation Oncology, New York University Langone Medical Center, New York, NY (United States); Department of Neurosurgery, New York University Langone Medical Center, New York, NY (United States); Kunnakkat, Saroj D. [Department of Radiation Oncology, New York University Langone Medical Center, New York, NY (United States); Medabalmi, Praveen [Department of Biostatistics, New York University Langone Medical Center, New York, NY (United States); Golfinos, John; Parker, Erik [Department of Neurosurgery, New York University Langone Medical Center, New York, NY (United States); Knopp, Edmond [Department of Radiology, New York University Langone Medical Center, New York, NY (United States); Zagzag, David [Department of Pathology, New York University Langone Medical Center, New York, NY (United States); Eagan, Patricia [Department of Neuro-Oncology, New York University Langone Medical Center, New York, NY (United States); Atlantic Health System, Overlook Hospital, Summit, NJ (United States); Gruber, Deborah [Department of Neuro-Oncology, New York University Langone Medical Center, New York, NY (United States); Gruber, Michael L. [Department of Neurosurgery, New York University Langone Medical Center, New York, NY (United States); Department of Neuro-Oncology, New York University Langone Medical Center, New York, NY (United States); Atlantic Health System, Overlook Hospital, Summit, NJ (United States)

    2012-01-01

    Purpose: Local recurrence is the dominant pattern of relapse in high-grade glioma (HGG) after conventional therapy. The recent use of antiangiogenic therapy has shown impressive radiologic and clinical responses in adult HGG. The preclinical data suggesting increased invasiveness after angiogenic blockade have necessitated a detailed analysis of the pattern of recurrence after therapy. Methods and Materials: A total of 162 consecutive patients with HGG, either newly diagnosed (n = 58) or with recurrent disease (n = 104) underwent therapy with bevacizumab at 10 mg/kg every 2 weeks and conventional chemotherapy with or without involved field radiotherapy until disease progression. The pattern of recurrence and interval to progression were the primary aims of the present study. Diffuse invasive recurrence (DIR) was defined as the involvement of multiple lobes with or without crossing the midline. Results: At a median follow-up of 7 months (range, 1-37), 105 patients had recurrence, and 79 patients ultimately developed DIR. The interval to progression was similar in the DIR and local recurrence groups (6.5 and 6.3 months, p = .296). The hazard risk of DIR increased exponentially with time and was similar in those with newly diagnosed and recurrent HGG (R{sup 2} = 0.957). The duration of bevacizumab therapy increased the interval to recurrence (p < .0001) and improved overall survival (p < .0001). However, the pattern of relapse did not affect overall survival (p = .253). Conclusion: Along with an increase in median progression-free survival, bevacizumab therapy increased the risk of DIR in HGG patients. The risk of increased invasion with prolonged angiogenic blockade should be addressed in future clinical trials.

  8. Assessment of the degree of adherence to health facility indicators related to rational drug use in Selected Health Facilities of Amhara Region, Northwest Ethiopia

    Directory of Open Access Journals (Sweden)

    Wubante Demilew Nigussie

    2014-04-01

    Full Text Available Purpose: The purpose of this study was to assess the degree of adherence of health care facility to World Health Organization health facility indicators in selected health care facilities of Amhara Region, Northwest Ethiopia. Methods: A cross sectional study was conducted among randomly selected health care facilities of Amhara region from March 01 to 15, 2014. Data was collected by interview and observation using structured questionnaire and check list respectively. Ethical clearance was obtained from the ethics review committee of Amhara regional state health bureau. The data was checked for completeness and consistency, cleared, coded, and entry and analysis was done by using SPSS (version 16. Results: The percentage availability of key essential drugs was found to be 73.05%, availability of Essential Drug List (EDL, Standard Treatment Guidelines (STG, drug formulary and average stock out duration were 75%, 87.5% 75% and 34 days respectively. Conclusion: The study revealed that evaluation of the patterns of drug use based on World Health Organization (WHO facility indicators was not satisfactory. So there is a need for managerial and educational intervention to improve rational drug use and thereby need to improve’ availability of essential drug list, standard treatment guidelines, drug formulary in order to access unbiased information for health care providers and also to prevent stock out of key essential drugs.

  9. Fluorescent Trimethoprim Conjugate Probes To Assess Drug Accumulation in Wild Type and Mutant Escherichia coli

    Science.gov (United States)

    2016-01-01

    Reduced susceptibility to antimicrobials in Gram-negative bacteria may result from multiple resistance mechanisms, including increased efflux pump activity or reduced porin protein expression. Up-regulation of the efflux pump system is closely associated with multidrug resistance (MDR). To help investigate the role of efflux pumps on compound accumulation, a fluorescence-based assay was developed using fluorescent derivatives of trimethoprim (TMP), a broad-spectrum synthetic antibiotic that inhibits an intracellular target, dihydrofolate reductase (DHFR). Novel fluorescent TMP probes inhibited eDHFR activity with comparable potency to TMP, but did not kill or inhibit growth of wild type Escherichia coli. However, bactericidal activity was observed against an efflux pump deficient E. coli mutant strain (ΔtolC). A simple and quick fluorescence assay was developed to measure cellular accumulation of the TMP probe using either fluorescence spectroscopy or flow cytometry, with validation by LC-MS/MS. This fluorescence assay may provide a simple method to assess efflux pump activity with standard laboratory equipment. PMID:27737551

  10. 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

  11. 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

  12. 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.

  13. 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

  14. 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.

  15. Nanomedicine-nanoemulsion formulation improves safety and efficacy of the anti-cancer drug paclitaxel according to preclinical assessment.

    Science.gov (United States)

    Lee, King C; Maturo, Claudia; Rodriguez, Robert; Nguyen, Hoang-Lan; Shorr, Robert

    2011-08-01

    Paclitaxel is an important anticancer drug and is currently used to treat a variety of cancers, including ovarian carcinomas, breast cancer, non-small cell lung cancer, and AIDS-related Kaposi's sarcoma. The objectives of the studies were to assess and compare the safety and efficacy of EmPAC (a newly developed nanoemulsion formulation of paclitaxel) versus Taxol (the injectable formulation of paclitaxel involving the use of polyethylated or polyoxyl castor oil currently used in the clinic). The objectives were also to investigate the mechanism for the improved safety and efficacy of EmPAC over Taxol. These results showed that EmPAC had better anti-tumor efficacy than Taxol, according to in vitro cell culture studies and studies in animal tumor models. EmPAC had improved anti-tumor efficacy even in tumor cell lines that are known to be multi-drug resistant. Part of the mechanism of action for the improved efficacy may be related to EmPAC inducing greater cellular uptake of paclitaxel into tumor cells than Taxol did, according to the in vitro cell culture radioactive-labeled studies and in vitro cell culture antibody studies. It may also partly be because EmPAC delivered more paclitaxel to the tumor mass than Taxol, while the delivery of paclitaxel to other tissues (e.g., blood, muscle, liver, spleen, kidney and lung) were similar between the two formulations of paclitaxel, according to studies in animals with tumor xenograft. EmPAC also had better safety than Taxol according to toxicology studies in rabbits. This may be because EmPAC does not contain the toxic ingredients used in formulating Taxol (such as polyethylated or polyoxyl castor oil). These results support the clinical development of the nanoemulsion formulation of paclitaxel.

  16. 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.

  17. Rat granulocyte colony-forming unit (CFU-G) assay for the assessment of drug-induced hematotoxicity.

    Science.gov (United States)

    Matsumura-Takeda, K; Kotosai, K; Ozaki, A; Hara, H; Yamashita, S

    2002-06-01

    To assess the drug-induced hematotoxicity to granulocyte progenitors, we established a modified colony-forming assay using rat bone marrow cells (BMCs). In the presence of various colony-stimulating factors (CSFs), rat BMCs were disseminated on methylcellulose at a concentration of 1.3 x 10(4) cells/cm(2) (5 x 10(4) cells/0.5 ml/well in a 12-well plate). Mouse granulocyte-macrophage colony-stimulating factor (mGM-CSF) stimulated the formation of almost all macrophage colonies. Human granulocyte colony-stimulating factor (hG-CSF) alone or in combination with mouse interleukin-3 (mIL-3) did not significantly effect on the number of rat colony-forming units in culture (CFU-C). When BMCs were seeded at 5.2 x 10(4) cells/cm(2) (5 x 10(5) cells/1 ml/dish in a 35-mm dish), hG-CSF increased the number of the colonies in a dose-dependent manner, and resulted in about 50 colonies at 50 ng/ml. The constituent cells of the colonies were identified as neutrophils. Under these conditions, the effects of 5-fluorouracil (5-FU) on granulocyte colony-forming units (CFU-G) were examined in rats and mice. The inhibitory effect of 5-FU on rat CFU-G was similar to the effect on mouse CFU-G. These results indicate that the rat CFU-G induced by hG-CSF is capable of being used for the evaluation of drug-induced hematotoxicity.

  18. 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

  19. 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