Science.gov

Sample records for agents including drugs

  1. Drug therapy reviews: antirheumatic agents.

    PubMed

    Evens, R P

    1979-05-01

    The pathophysiology, symptoms and drug treatment of rheumatic disease are reviewed. Antirheumatic drugs reviewed are salicylates (including aspirin, sodium salicylate, choline salicylate, choline magnesium salicylate, salsalate), phenylpropionic acid derivatives (fenoprofen, ibuprofen, naproxen), indole derivatives (sulindac, tolmetin and indomethacin), pyrazolone derivatives (phenylbutazone, oxyphenbutazone), gold compounds, penicillamine, antimalarials mefenamic acid, corticosteroids and immunosuppressives. Simple analgesic therapy (acetaminophen, aspirin, propoxyphene) is used in the early stage of the disease. As the disease progresses, aspirin remains the drug of choice for antiinflammatory activity but the phenylpropionic acid or indole derivatives may be preferred in patients unable to tolerate salicylates. If such nonsteroidal antiinflammatory agents are not effective, parenteral therapy with gold compounds or oral penicillamine usually is indicated. Indomethacin or phenylbutazone, then antimalarials, are resorted to next. Corticosteroids or immunosuppressives are reserved for patients who are unsuccessfully controlled or who have major side effects with the other drugs. Mefenamic acid occupies a very secondary place in rheumatoid arthritis treatment. PMID:377958

  2. 13 CFR 107.1620 - Functions of agents, including Central Registration Agent, Selling Agent and Fiscal Agent.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false Functions of agents, including Central Registration Agent, Selling Agent and Fiscal Agent. 107.1620 Section 107.1620 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION SMALL BUSINESS INVESTMENT COMPANIES SBA Financial Assistance...

  3. 13 CFR 108.1620 - Functions of agents, including Central Registration Agent, Selling Agent and Fiscal Agent.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false Functions of agents, including Central Registration Agent, Selling Agent and Fiscal Agent. 108.1620 Section 108.1620 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION NEW MARKETS VENTURE CAPITAL (âNMVCâ) PROGRAM SBA...

  4. Antitumor drugs as photochemotherapeutic agents

    NASA Astrophysics Data System (ADS)

    Andreoni, Alessandra; Colasanti, Alberto; Kisslinger, Annamaria; Malatesta, Vincenzo; Mastrocinque, Michele; Roberti, Giuseppe

    1991-11-01

    Irradiation with 86 J/cm2 of cultures of Fisher-rate thyroid cells (FRTL5) in the presence of daunomycin derivatives at wavelengths between 488 and 595 nm i.e., in the visible- absorption bands of these drugs, is shown to enhance their cytotoxicity. Daunomycin, its 4- demethoxy derivative, 5-iminodaunomycin, and two amino-substituted 4-demethoxy derivatives of daunomycin are tested. While a 2-h exposure to the drugs in the dark produces 50 short-term cell mortality at dosages (LD50) in the range 23 to 138 (mu) g/ml, irradiation administered during the cell exposure to the drugs is found to lower the LD50 values down to the range 45 to 289 ng/ml. Furthermore, while the LD50 values for all drugs in the absence of photoactivation are similar, if light is administered those for the 4- demethoxy compounds are lowered by 3 orders of magnitude and those for the other derivatives by 2 orders of magnitude. Microfluorimetric investigations reveal that photoactivation causes fading of the drug fluorescence in the perinuclear cytoplasm. The effect is more pronounced for drugs with higher photosensitizing properties. The nonfluorescent photoproducts which are formed in the cells during photoactivation exhibit a cytotoxic activity that is, at long term, lower than that of the original drug. The authors cannot yet assess which excited-state property of anthracyclines plays the key role in the photosensitized reaction(s) responsible for both short-term cell kill and long-term toxic effects. The show, however, that such property is strongly affected by the removal of the methoxy group from the C4 position.

  5. Crude drugs as anticancer agents

    PubMed Central

    Mou, Xiaoyang; Kesari, Santosh; Wen, Patrick Y; Huang, Xudong

    2011-01-01

    Although tremendous progress has been made in basic cancer biology and in the development of novel cancer treatments, cancer remains a leading cause of death in the world. The etiopathogenesis of cancer is complex. Besides genetic predisposition, known environmental factors associated with cancer are: diet, lifestyle, and environmental toxins. Toxicity of drugs and eventual relapse of cancers contribute to high cancer death rates. Current therapeutic interventions for cancer- surgery, chemotherapy, radiotherapy, thermotherapy, etc. are far from being curative for many forms of cancer. Chemotherapy, in particular, though the most commonly used cancer treatment, is usually associated with side effects with varying degrees of severity. The purpose of this brief review is to assemble current literature on some crude drugs and to focus on their beneficial roles and drug targets in cancer therapy and chemo-prevention. Although their pharmacological mechanisms and biochemical roles in cancer biology and tumor chemo-prevention are not fully understood, crude drugs are believed to have nutriceutical effects upon cancer patients. PMID:21394282

  6. Clinically relevant drug interactions between anticancer drugs and psychotropic agents.

    PubMed

    Yap, K Y-L; Tay, W L; Chui, W K; Chan, A

    2011-01-01

    Drug interactions are commonly seen in the treatment of cancer patients. Psychotropics are often indicated for these patients since they may also suffer from pre-existing psychological disorders or experience insomnia and anxiety associated with cancer therapy. Thus, the risk of anticancer drug (ACD)-psychotropic drug-drug interactions (DDIs) is high. Drug interactions were compiled from the British National Formulary (53rd edn), Lexi-Comp's Drug Information Handbook (15th edn), Micromedex (v5.1), Hansten & Horn's Drug Interactions (2000) and Drug Interaction Facts (2008 edn). Product information of the individual drugs, as well as documented literature on ACD-psychotropic interactions from PubMed and other databases was also incorporated. This paper identifies clinically important ACD-psychotropic DDIs that are frequently observed. Pharmacokinetic DDIs were observed for tyrosine kinase inhibitors, corticosteroids and antimicrotubule agents due to their inhibitory or inductive effects on cytochrome P450 isoenzymes. Pharmacodynamic DDIs were identified for thalidomide with central nervous system depressants, procarbazine with antidepressants, myelosuppressive ACDs with clozapine and anthracyclines with QT-prolonging psychotropics. Clinicians should be vigilant when psychotropics are prescribed concurrently with ACDs. Close monitoring of plasma drug levels should be carried out to avoid toxicity in the patient, as well as to ensure adequate chemotherapeutic and psychotropic coverage. PMID:20030690

  7. The effects of selected drugs, including chlorpromazine and non-steroidal anti-inflammatory agents, on polyclonal IgG synthesis and interleukin 1 production by human peripheral blood mononuclear cells in vitro.

    PubMed

    Martinez, F; Coleman, J W

    1989-05-01

    We tested a range of drugs for their effects on in vitro polyclonal IgG synthesis by human peripheral blood mononuclear cells (PBMC) stimulated with the lectin pokeweed mitogen (PWM). The test drugs were selected on the basis of reported disruptive effects on immune function in vivo. IgG production between day 4 and days 7 or 8 of culture was measured by biotin-streptavidin sandwich ELISA. The anti-psychotic agent chlorpromazine (0.55-1.7 microM) enhanced IgG synthesis to approximately double control levels. In contrast, the non-steroidal anti-inflammatory drugs (NSAIDs) indomethacin, piroxicam, ibuprofen and aspirin inhibited IgG synthesis by up to 50%, with a rank order of potency that reflects their activity as inhibitors of cyclo-oxygenase. Phenytoin, procainamide, propylthiouracil, methimazole, D-penicillamine and D-penicillamine-L-cysteine all failed to modulate IgG synthesis at non-toxic concentrations. The potentiation and inhibition of IgG synthesis by chlorpromazine and indomethacin, respectively, was observed only when the drug was present during the first 24 h of culture. Neither chlorpromazine nor indomethacin, at non-toxic concentrations, affected PHA- and PWM-stimulated proliferation of PBMC. In addition, chlorpromazine, indomethacin and piroxicam, at concentrations which produced maximal modulation of IgG synthesis, and D-penicillamine and D-penicillamine-L-cysteine at 10 microM failed to influence production of interleukin-1-like activity. We conclude that chlorpromazine and NSAIDs, although they exert opposite effects on IgG synthesis, act at an early stage of B cell differentiation that appears to be independent of interleukin 1 synthesis and early proliferative events. PMID:2788047

  8. Agents in Safety Related Systems Including Ubiquitous Networks

    NASA Astrophysics Data System (ADS)

    Strandén, Lars

    The ADM (Autonomous Decision Maker) concept concerns the possibility of including intelligent interfaces, agent like, for supporting the use of ubiquitous networks, such as the Internet, in safety related applications. The need for such interfaces is inevitable if remote surveillance and control shall be supported. The single most important aspect of ADM is its capability of handling limited resources when making intelligent decisions. Intelligence in ADM is manifested in reasoning and learning. This paper outlines the role of ADM and especially in relation to the standard IEC 61508 and presents the overall properties that result. These are exemplified by a presentation of ADM demonstrator.

  9. Recent Advances in Antischistosomal Drugs and Agents.

    PubMed

    Liu, Liang-Xian; Qiong, Chang; Fan, Xiao-Lin

    2013-11-19

    Schistosomiasis is a notable neglected tropical disease caused by trematodes that inflame mainly the intestines, bladder, and liver. Because of the unavailability of a schistosomiasis vaccine, control of the disease depends mainly on chemotherapy. Praziquantel (PZQ), which is active against all schistosome species and the recommended drug by the World Health Organization for schistosomiasis treatment at either the community or individual level, has become the exclusive drug because of its low cost and efficacy against the adult form of all schistosome species. In view of rapid re-infection following treatment and concern about the development of tolerance and/or resistance to praziquantel, there is an urgent need for research and development of novel drugs for the prevention and treatment of schistosomiasis. This comprehensive review shall attempt to briefly review the recent advances in the chemotherapy of schistosomiasis in the literature from 1990s to now, particularly focusing on the context of potential development of antischistosomal agents. Their antischistosomal properties, advantages, and disadvantages as well as structure-activity relationships are reviewed in a simple manner. It shall be of interest for both the synthetic chemist as well as the pharmacologist. PMID:24251801

  10. Recent Advances in Antischistosomal Drugs and Agents.

    PubMed

    Liang-Xian, Liu; Fan, Chang Qiong; Xiao-Lin

    2013-01-31

    Schistosomiasis is a notable neglected tropical disease caused by trematodes that inflame mainly the intestines, bladder, and liver. Because of the unavailability of a schistosomiasis vaccine, control of the disease depends mainly on chemotherapy. Praziquantel (PZQ), which is active against all schistosome species and the recommended drug by the World Health Organization for schistosomiasis treatment at either the community or individual level, has become the exclusive drug because of its low cost and efficacy against the adult form of all schistosome species. In view of rapid re-infection following treatment and concern about the development of tolerance and/or resistance to praziquantel, there is an urgent need for research and development of novel drugs for the prevention and treatment of schistosomiasis. This comprehensive review shall attempt to briefly review the recent advances in the chemotherapy of schistosomiasis in the literature from 1990s to now, particularly focusing on the context of potential development of antischistosomal agents. Their antischistosomal properties, advantages, and disadvantages as well as structure-activity relationships are reviewed in a simple manner. It shall be of interest for both the synthetic chemist as well as the pharmacologist. PMID:23373655

  11. Thalidomide-derived immunomodulatory drugs as therapeutic agents.

    PubMed

    Galustian, Christine; Labarthe, Marie-Christine; Bartlett, J Blake; Dalgleish, Angus G

    2004-12-01

    Thalidomide, a drug originally used to treat morning sickness, was removed from the market place in the early 1960s after it was found to cause serious congenital birth defects. However, thalidomide has recently been investigated in a new light following its activity in a number of chronic diseases. Moreover, like thalidomide itself, its second-generation immunomodulatory drug (IMiD) analogues have been shown to act as powerful anticancer agents and are clearly active in the treatment of patients with relapsed multiple myeloma. These new drugs, in particular the second-generation IMiDs, lenalidomide (CC-5013, REVLIMID; Celgene Corp., NJ, USA) and CC-4047 (ACTIMID; Celgene Corp.), offer improvements over thalidomide (a first-generation IMiD) in terms of efficacy and safety in human studies. The key to the therapeutic potential of IMiDs lies in the fact that the drugs have multiple mechanisms of action, which may produce both anti-inflammatory and antitumour effects. These effects are probably contextual, depending both on the cell type and the stimulus involved. Mechanisms associated with IMiD activity include TNF-alpha-inhibitory, T cell costimulatory and antiangiogenic activities. Studies of the mechanisms of action of these drugs are ongoing and will facilitate the continued development of this class of compound in a number of diseases. PMID:15571458

  12. Biodistribution of gadolinium-based contrast agents, including gadolinium deposition

    PubMed Central

    Aime, Silvio; Caravan, Peter

    2010-01-01

    The biodistribution of approved gadolinium (Gd) based contrast agents (GBCA) is reviewed. After intravenous injection GBCA distribute in the blood and the extracellular space and transiently through the excretory organs. Preclinical animal studies and the available clinical literature indicate that all these compounds are excreted intact. Elimination tends to be rapid and for the most part, complete. In renally insufficient patients the plasma elimination half-life increases substantially from hours to days depending on renal function. In patients with impaired renal function and nephrogenic systemic fibrosis (NSF), the agents gadodiamide, gadoversetamide, and gadopentetate dimeglumine have been shown to result in Gd deposition in the skin and internal organs. In these cases, it is likely that the Gd is no longer present as the GBCA, but this has still not been definitively shown. In preclinical models very small amounts of Gd are retained in the bone and liver, and the amount retained correlates with the kinetic and thermodynamic stability of the GBCA with respect to Gd release in vitro. The pattern of residual Gd deposition in NSF subjects may be different than that observed in preclinical rodent models. GBCA are designed to be used via intravenous administration. Altering the route of administration and/or the formulation of the GBCA can dramatically alter the biodistribution of the GBCA and can increase the likelihood of Gd deposition. PMID:19938038

  13. 28 CFR 552.25 - Use of less-than-lethal weapons, including chemical agents.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ..., including chemical agents. 552.25 Section 552.25 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF... Use of less-than-lethal weapons, including chemical agents. (a) The Warden may authorize the use of less-than-lethal weapons, including those containing chemical agents, only when the situation is...

  14. 28 CFR 552.25 - Use of less-than-lethal weapons, including chemical agents.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ..., including chemical agents. 552.25 Section 552.25 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF... Use of less-than-lethal weapons, including chemical agents. (a) The Warden may authorize the use of less-than-lethal weapons, including those containing chemical agents, only when the situation is...

  15. 28 CFR 552.25 - Use of less-than-lethal weapons, including chemical agents.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ..., including chemical agents. 552.25 Section 552.25 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF... Use of less-than-lethal weapons, including chemical agents. (a) The Warden may authorize the use of less-than-lethal weapons, including those containing chemical agents, only when the situation is...

  16. 28 CFR 552.25 - Use of less-than-lethal weapons, including chemical agents.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ..., including chemical agents. 552.25 Section 552.25 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF... Use of less-than-lethal weapons, including chemical agents. (a) The Warden may authorize the use of less-than-lethal weapons, including those containing chemical agents, only when the situation is...

  17. Statistical Agent Based Modelization of the Phenomenon of Drug Abuse

    NASA Astrophysics Data System (ADS)

    di Clemente, Riccardo; Pietronero, Luciano

    2012-07-01

    We introduce a statistical agent based model to describe the phenomenon of drug abuse and its dynamical evolution at the individual and global level. The agents are heterogeneous with respect to their intrinsic inclination to drugs, to their budget attitude and social environment. The various levels of drug use were inspired by the professional description of the phenomenon and this permits a direct comparison with all available data. We show that certain elements have a great importance to start the use of drugs, for example the rare events in the personal experiences which permit to overcame the barrier of drug use occasionally. The analysis of how the system reacts to perturbations is very important to understand its key elements and it provides strategies for effective policy making. The present model represents the first step of a realistic description of this phenomenon and can be easily generalized in various directions.

  18. Hepatotoxicity by Drugs: The Most Common Implicated Agents

    PubMed Central

    Björnsson, Einar S.

    2016-01-01

    Idiosyncratic drug-induced liver injury (DILI) is an underreported and underestimated adverse drug reaction. Information on the documented hepatotoxicity of drugs has recently been made available by a website that can be accessed in the public domain: LiverTox (http://livertox.nlm.nih.gov). According to critical analysis of the hepatotoxicity of drugs in LiverTox, 53% of drugs had at least one case report of convincing reports of liver injury. Only 48 drugs had more than 50 case reports of DILI. Amoxicillin-clavulanate is the most commonly implicated agent leading to DILI in the prospective series. In a recent prospective study, liver injury due to amoxicillin-clavulanate was found to occur in approximately one out of 2300 users. Drugs with the highest risk of DILI in this study were azathioprine and infliximab. PMID:26861310

  19. Bioengineered Colorectal Cancer Drugs: Orally Delivered Anti-Inflammatory Agents.

    PubMed

    Urbanska, Aleksandra Malgorzata; Zhang, Xiaoying; Prakash, Satya

    2015-07-01

    Intestinal inflammation is one of the major factors that increase colorectal cancer (CRC) incidence worldwide. Inflammation in the gastrointestinal tract is directly linked to tumor development at the early stages of the disease, thus a key issue toward the prevention and the treatment of colonic neoplasia. Thus, the use of anti-inflammatory drugs has emerged first as a strategy to reduce chronic inflammation in case of many inflammatory bowel diseases (IBD), but it has proven its efficacy by reducing the risk of colonic neoplasia. This comprehensive review highlights the role of chronic inflammation, mainly in IBD, in the development of CRC including molecular and immune mechanisms that have tumorigenic effects. Multiple lines of evidence indicate that several bioactive and phytochemical compounds used as anti-inflammatory drugs have also antitumoral attributes. The uses of orally delivered cytokines and small molecules, as well as key dietary supplementation as anti-inflammatory therapeutics are discussed. In addition, comprehensive knowledge about CRC and intestinal inflammation, and the importance of the intestinal mucosal wall as a mucosal immunological barrier that comes into play during interactions with gut microbiota (pathogens and commensal), luminal secretions (bile acids, and bacterial and epithelial metabolites), and ingested chemicals (food components, high fat content, heterocyclic amines, and low intake of dietary fiber) are underscored. The multifunctionality of several anti-inflammatory drugs opens a line for their application in the treatment and prevention not only in IBD but also in CRC. Current bioengineering approaches for oral delivery of anti-inflammatory agents including cytokines, genetically modified bacteria, or small molecule inhibitors of inflammation directly contribute to the early management of CRC. Limitations of the current therapeutics, which stem from the lack of complete understanding of the complex molecular interactions

  20. Stabilizing Agents for Drug Nanocrystals: Effect on Bioavailability.

    PubMed

    Tuomela, Annika; Hirvonen, Jouni; Peltonen, Leena

    2016-01-01

    Drug nanocrystals are a versatile option for drug delivery purposes, and while the number of poorly soluble drug materials is all the time increasing, more research in this area is performed. Drug nanocrystals have a simple structure-a solid drug core is surrounded by a layer of stabilizing agent. However, despite the considerably simple structure, the selection of an appropriate stabilizer for a certain drug can be challenging. Mostly, the stabilizer selection is based purely on the requirement of physical stability, e.g., maintaining the nanosized particle size as long as possible after the formation of drug nanocrystals. However, it is also worth taking into account that stabilizer can affect the bioavailability in the final formulation via interactions with cells and cell layers. In addition, formation of nanocrystals is only one process step, and for the final formulation, more excipients are often added to the composition. The role of the stabilizers in the final formulation can be more than only stabilizing the nanocrystal particle size. A good example is the stabilizer's role as cryoprotectant during freeze drying. In this review, the stabilizing effect, role of stabilizers in final nanocrystalline formulations, challenges in reaching in vitro-in vivo correlation with nanocrystalline products, and stabilizers' effect on higher bioavailability are discussed. PMID:27213435

  1. Stabilizing Agents for Drug Nanocrystals: Effect on Bioavailability

    PubMed Central

    Tuomela, Annika; Hirvonen, Jouni; Peltonen, Leena

    2016-01-01

    Drug nanocrystals are a versatile option for drug delivery purposes, and while the number of poorly soluble drug materials is all the time increasing, more research in this area is performed. Drug nanocrystals have a simple structure—a solid drug core is surrounded by a layer of stabilizing agent. However, despite the considerably simple structure, the selection of an appropriate stabilizer for a certain drug can be challenging. Mostly, the stabilizer selection is based purely on the requirement of physical stability, e.g., maintaining the nanosized particle size as long as possible after the formation of drug nanocrystals. However, it is also worth taking into account that stabilizer can affect the bioavailability in the final formulation via interactions with cells and cell layers. In addition, formation of nanocrystals is only one process step, and for the final formulation, more excipients are often added to the composition. The role of the stabilizers in the final formulation can be more than only stabilizing the nanocrystal particle size. A good example is the stabilizer’s role as cryoprotectant during freeze drying. In this review, the stabilizing effect, role of stabilizers in final nanocrystalline formulations, challenges in reaching in vitro–in vivo correlation with nanocrystalline products, and stabilizers’ effect on higher bioavailability are discussed. PMID:27213435

  2. Novel drug delivery approaches on antiviral and antiretroviral agents

    PubMed Central

    Sharma, Pooja; Chawla, Anuj; Arora, Sandeep; Pawar, Pravin

    2012-01-01

    Viruses have the property to replicate very fast in host cell. It can attack any part of host cell. Therefore, the clinical efficacy of antiviral drugs and its bioavailability is more important concern taken into account to treat viral infections. The oral and parenteral routes of drug administration have several shortcomings, however, which could lead to the search for formulating better delivery systems. Now, a day's novel drug delivery systems (NDDS) proved to be a better approach to enhance the effectiveness of the antivirals and improve the patient compliance and decrease the adverse effect. The NDDS have reduced the dosing frequency and shorten the duration of treatment, thus, which could lead the treatment more cost-effective. The development of NDDS for antiviral and antiretroviral therapy aims to deliver the drug devoid of toxicity, with high compatibility and biodegradability, targeting the drug to specific sites for viral infection and in some instances it also avoid the first pass metabolism effect. This article aims to discuss the usefulness of novel delivery approaches of antiviral agents such as niosomes, microspheres, microemulsions, nanoparticles that are used in the treatment of various Herpes viruses and in human immunodeficiency virus (HIV) infections. PMID:23057001

  3. Mass spectrometry in identification of ecotoxicants including chemical and biological warfare agents.

    PubMed

    Lebedev, Albert T

    2005-09-01

    Mass spectrometry is a unique tool to detect and identify trace levels of organic and bioorganic compounds as well as microorganisms in the environment. The range of potential chemical warfare (CW) and biological warfare (BW) agents is very broad. An important advantage of mass spectrometry over other techniques involves potential for full spectrum detection of chemical and biological agents including mid-spectrum materials (i.e. bioactive peptides, toxins, etc.) for which biological approaches are inadequate. Being very fast (seconds and minutes), extremely sensitive (zeptomoles 10(-21)), and informative (detailed qualitative and quantitative composition of mixtures containing hundreds of chemicals), mass spectrometry is a principal analytical tool at the sites of destruction of CW. Due to its unique features, mass spectrometry is applied not only for the detection of CW agents, but for the analysis of products of metabolism and degradation of these agents in organisms or environment as well. The present paper deals with some examples of successful application of mass spectrometry for the analyses of ecotoxicants, chemical warfare agents, explosives, and microorganisms including biology warfare agents. PMID:16024060

  4. Mass spectrometry in identification of ecotoxicants including chemical and biological warfare agents

    SciTech Connect

    Lebedev, Albert T. . E-mail: lebedev@org.chem.msu.ru

    2005-09-01

    Mass spectrometry is a unique tool to detect and identify trace levels of organic and bioorganic compounds as well as microorganisms in the environment. The range of potential chemical warfare (CW) and biological warfare (BW) agents is very broad. An important advantage of mass spectrometry over other techniques involves potential for full spectrum detection of chemical and biological agents including mid-spectrum materials (i.e. bioactive peptides, toxins, etc.) for which biological approaches are inadequate. Being very fast (seconds and minutes), extremely sensitive (zeptomoles 10{sup -21}), and informative (detailed qualitative and quantitative composition of mixtures containing hundreds of chemicals), mass spectrometry is a principal analytical tool at the sites of destruction of CW. Due to its unique features, mass spectrometry is applied not only for the detection of CW agents, but for the analysis of products of metabolism and degradation of these agents in organisms or environment as well. The present paper deals with some examples of successful application of mass spectrometry for the analyses of ecotoxicants, chemical warfare agents, explosives, and microorganisms including biology warfare agents.

  5. 34 CFR 86.100 - What must the IHE's drug prevention program include?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 34 Education 1 2014-07-01 2014-07-01 false What must the IHE's drug prevention program include? 86.100 Section 86.100 Education Office of the Secretary, Department of Education DRUG AND ALCOHOL ABUSE PREVENTION Institutions of Higher Education § 86.100 What must the IHE's drug prevention program include? The IHE's drug prevention program must,...

  6. 22 CFR 210.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false What must I include in my drug-free awareness... § 210.215 What must I include in my drug-free awareness program? You must establish an ongoing drug-free awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your...

  7. 22 CFR 133.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false What must I include in my drug-free awareness... § 133.215 What must I include in my drug-free awareness program? You must establish an ongoing drug-free awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your...

  8. Neutron capture therapy: a comparison between dose enhancement of various agents, nanoparticles and chemotherapy drugs.

    PubMed

    Khosroabadi, Mohsen; Ghorbani, Mahdi; Rahmani, Faezeh; Knaup, Courtney

    2014-09-01

    The aim of this study is to compare dose enhancement of various agents, nanoparticles and chemotherapy drugs for neutron capture therapy. A (252)Cf source was simulated to obtain its dosimetric parameters, including air kerma strength, dose rate constant, radial dose function and total dose rates. These results were compared with previously published data. Using (252)Cf as a neutron source, the in-tumour dose enhancements in the presence of atomic (10)B, (157)Gd and (33)S agents; (10)B, (157)Gd, (33)S nanoparticles; and Bortezomib and Amifostine chemotherapy drugs were calculated and compared in neutron capture therapy. Monte Carlo code MCNPX was used for simulation of the (252)Cf source, a soft tissue phantom, and a tumour containing each capture agent. Dose enhancement for 100, 200 and 500 ppm of the mentioned media was calculated. Calculated dosimetric parameters of the (252)Cf source were in agreement with previously published values. In comparison to other agents, maximum dose enhancement factor was obtained for 500 ppm of atomic (10)B agent and (10)B nanoparticles, equal to 1.06 and 1.08, respectively. Additionally, Bortezomib showed a considerable dose enhancement level. From a dose enhancement point of view, media containing (10)B are the best agents in neutron capture therapy. Bortezomib is a chemotherapy drug containing boron and can be proposed as an agent in boron neutron capture therapy. However, it should be noted that other physical, chemical and medical criteria should be considered in comparing the mentioned agents before their clinical use in neutron capture therapy. PMID:24961208

  9. Cyclodepsipeptides from marine sponges: natural agents for drug research.

    PubMed

    Andavan, Gowri Shankar Bagavananthem; Lemmens-Gruber, Rosa

    2010-01-01

    A number of natural products from marine sponges, such as cyclodepsipeptides, have been identified. The structural characteristics of this family of cyclic peptides include various unusual amino acid residues and unique N-terminal polyketide-derived moieties. Papuamides are representatives of a class of marine sponge derived cyclic depsipeptides, including callipeltin A, celebesides A and B, homophymine A, mirabamides, microspinosamide, neamphamide A and theopapuamides. They are thought to have cytoprotective activity against HIV-1 in vitro by inhibiting viral entry. Jasplakinolide, a representative member of marine sponge-derived cyclodepsipeptides that include arenastatin A, geodiamolides, homophymines, spongidepsin and theopapuamides, is a potent inducer of actin polymerization in vitro. Although actin dynamics is essential for tumor metasasis, no actin targeting drugs have been used in clinical trials due to their severe cytotoxicity. Nonetheless, the actin cytoskeleton remains a potential target for anti-cancer drug development. These features imply the use of cyclodepsipeptides as molecular models in drug research. PMID:20411126

  10. 45 CFR 630.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any... may impose upon them for drug abuse violations occurring in the workplace. ... 45 Public Welfare 3 2010-10-01 2010-10-01 false What must I include in my drug-free...

  11. 13 CFR 147.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... establish an ongoing drug-free awareness program to inform employees about— (a) The dangers of drug abuse in... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false What must I include in my drug... ADMINISTRATION GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (NONPROCUREMENT) Requirements for...

  12. 21 CFR 1405.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy... assistance programs; and (d) The penalties that you may impose upon them for drug abuse violations occurring... 21 Food and Drugs 9 2010-04-01 2010-04-01 false What must I include in my drug-free...

  13. 29 CFR 1472.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any... may impose upon them for drug abuse violations occurring in the workplace. ... 29 Labor 4 2010-07-01 2010-07-01 false What must I include in my drug-free awareness program?...

  14. 32 CFR 26.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c... that you may impose upon them for drug abuse violations occurring in the workplace. ... 32 National Defense 1 2010-07-01 2010-07-01 false What must I include in my drug-free...

  15. 14 CFR 1267.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... establish an ongoing drug-free awareness program to inform employees about— (a) The dangers of drug abuse in... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false What must I include in my drug-free... ADMINISTRATION GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements...

  16. Polymorphism in the metabolism of drugs, including antidepressant drugs: comments on phenotyping.

    PubMed Central

    Coutts, R T

    1994-01-01

    In neurochemistry there are advantages in determining how patients are likely to react to psychoactive drugs prior to the commencement of drug therapy. Explanations of a patient's nonresponse, or unexpected adverse reactions to drugs are required. In many instances, a knowledge of the drug metabolism status of a patient can be helpful in the selection of a drug and its dosage regimen, and in the prediction of possible drug/drug interactions when two or more drugs have to be administered concomitantly. Important information on these topics may be obtained by phenotyping patients prior to drug therapy. The metabolism of various antidepressant and neuroleptic drugs is catalyzed by CYP2D6, a cytochrome P450 isozyme (also named P450IID6), whereas the metabolism of other drugs may involve different cytochromes P450. The properties of CYP2D6 and four other isozymes (CYP1A1, CYP1A2, CYP2C8/9 and CYP3A4) are described, and substrates identified. Phenotyping of patients for CYP2D6 activity and mephenytoin hydroxylase activity is described. PMID:8148364

  17. 34 CFR 86.100 - What must the IHE's drug prevention program include?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 34 Education 1 2011-07-01 2011-07-01 false What must the IHE's drug prevention program include? 86.100 Section 86.100 Education Office of the Secretary, Department of Education DRUG AND ALCOHOL ABUSE PREVENTION Institutions of Higher Education § 86.100 What must the IHE's drug prevention program include?...

  18. 34 CFR 86.100 - What must the IHE's drug prevention program include?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 1 2010-07-01 2010-07-01 false What must the IHE's drug prevention program include? 86.100 Section 86.100 Education Office of the Secretary, Department of Education DRUG AND ALCOHOL ABUSE PREVENTION Institutions of Higher Education § 86.100 What must the IHE's drug prevention program include?...

  19. 34 CFR 86.100 - What must the IHE's drug prevention program include?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 34 Education 1 2012-07-01 2012-07-01 false What must the IHE's drug prevention program include? 86.100 Section 86.100 Education Office of the Secretary, Department of Education DRUG AND ALCOHOL ABUSE PREVENTION Institutions of Higher Education § 86.100 What must the IHE's drug prevention program include?...

  20. 34 CFR 86.100 - What must the IHE's drug prevention program include?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 34 Education 1 2013-07-01 2013-07-01 false What must the IHE's drug prevention program include? 86.100 Section 86.100 Education Office of the Secretary, Department of Education DRUG AND ALCOHOL ABUSE PREVENTION Institutions of Higher Education § 86.100 What must the IHE's drug prevention program include?...

  1. 45 CFR 1173.205 - What must I include in my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 3 2010-10-01 2010-10-01 false What must I include in my drug-free workplace... REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 1173.205 What must I include in my drug-free workplace statement? You must publish a statement that—...

  2. 45 CFR 1155.205 - What must I include in my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 3 2010-10-01 2010-10-01 false What must I include in my drug-free workplace... REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 1155.205 What must I include in my drug-free workplace statement? You must publish a statement that—...

  3. 29 CFR 1472.205 - What must I include in my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 4 2010-07-01 2010-07-01 false What must I include in my drug-free workplace statement... CONCILIATION SERVICE GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 1472.205 What must I include in my drug-free...

  4. 22 CFR 133.205 - What must I include in my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false What must I include in my drug-free workplace... REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 133.205 What must I include in my drug-free workplace statement? You must publish a statement that—...

  5. 22 CFR 210.205 - What must I include in my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false What must I include in my drug-free workplace... REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 210.205 What must I include in my drug-free workplace statement? You must publish a statement that—...

  6. 49 CFR 32.205 - What must I include in my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 1 2010-10-01 2010-10-01 false What must I include in my drug-free workplace... REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 32.205 What must I include in my drug-free workplace statement? You must publish a statement that—...

  7. New agents for the treatment of drug-resistant Mycobacterium tuberculosis.

    PubMed

    Hoagland, Daniel T; Liu, Jiuyu; Lee, Robin B; Lee, Richard E

    2016-07-01

    Inadequate dosing and incomplete treatment regimens, coupled with the ability of the tuberculosis bacilli to cause latent infections that are tolerant of currently used drugs, have fueled the rise of multidrug-resistant tuberculosis (MDR-TB). Treatment of MDR-TB infections is a major clinical challenge that has few viable or effective solutions; therefore patients face a poor prognosis and years of treatment. This review focuses on emerging drug classes that have the potential for treating MDR-TB and highlights their particular strengths as leads including their mode of action, in vivo efficacy, and key medicinal chemistry properties. Examples include the newly approved drugs bedaquiline and delaminid, and other agents in clinical and late preclinical development pipeline for the treatment of MDR-TB. Herein, we discuss the challenges to developing drugs to treat tuberculosis and how the field has adapted to these difficulties, with an emphasis on drug discovery approaches that might produce more effective agents and treatment regimens. PMID:27151308

  8. Novel antimicrobial peptides that exhibit activity against select agents and other drug resistant bacteria.

    PubMed

    Venugopal, Divakaramenon; Klapper, David; Srouji, Antoine H; Bhonsle, Jayendra B; Borschel, Richard; Mueller, Allen; Russell, Amanda L; Williams, Brittany C; Hicks, Rickey P

    2010-07-15

    One of the greatest challenges facing modern medicine is the evolution of drug resistant strains of bacteria. In addition to traditional methods of exposure to traditional bacterial organisms there is a growing concerned of the use of bacteria as bio-terrorism agents. To counter the evolution of drug resistant and potential bio-terrorism bacterial agents new antibiotic drugs must be developed. One potential source of new therapeutic agents that act via a novel mechanism of action are natural and synthetic antimicrobial peptides (AMPs). In our laboratories we have developed a series of AMPs incorporating the un-natural amino acids Tic-Oic to impart organism selectivity and potency while increasing metabolic stability. Herein the in vitro activity of these peptides, including ten new compounds, against eight potential bio-terrorism bacterial agents and three other bacterial strains is presented and discussed. These peptides exhibit a wide range of organism potency and selectivity. Calcein fluorescence leakage and circular dichroism studies were conducted to confirm that these peptides interact with zwitterionic and anionic liposomes. PMID:20558071

  9. [The actual Russian legislation in sphere of turn-over of drug agents and psychotropic substances].

    PubMed

    Abramov, A Yu; Kosolapova, N V; Mikhaiylova, Yu V

    2014-01-01

    The drug abuse is a social occurrence. Hence, the social economic methods are the first of all means of combating this evil. At the same time, measures of especially juridical character possess significant value since they develop corresponding legal base for applying another measures. In the Russian Federation, during fifteen years the new policy of public regulation and normative legal base in the area of legal turn-over of drug agents, psychotropic substances and their precursors were developed factually from zero ground. However, the current national legislation is not deprived of some flaws and contradictions. Frequently a uniform practice of interpretation and application of legal rules regulating the controlled turn-over is lacking. On the one hand, this circumstance decreases effectiveness of action of such rules and on the other hand favors development of situations for outflow of pharmaceuticals from legal turn-over to illegal traffic. The becoming of the Russian legislation in the area of turn-over of drug agents, precursors and psychotropic substances relates to the period of late 1990s when the Federal Law No 3 FZ "On drug agents and psychotropic substances" of January 8 1998 was developed and passed by the State Duma of the Russian Federation. The given law completely conforms to principles of legal regulation of turn-over of drug agents and psychotropic substances determined by the Constitution of the Russian Federation (provisions 76, 90, 104, 105) and federal laws ("On the government of the Russian Federation" of December 17 1997, "On the ombudsman in the Russian Federation" of February 26 1997). The main characteristic of legal rules included into given group of sources of law is that they contain regulations of general disposition as basic ones for inferior sources of law. The analysis of basic Federal law No 3 FZ "On drug agents and psychotropic substances" of January 8 1998 makes it possible to conclude that in in Russia the international legal

  10. Hydrogels synthesised through photoinitiator-free photopolymerisation technique for delivering drugs including a tumour-tracing porphyrin

    NASA Astrophysics Data System (ADS)

    Ng, Loo-Teck; Swami, Salesh; Gordon-Thomson, Clare

    2006-05-01

    Hydrogels were synthesised using the photoinitiator-free photopolymerisation technique involving interactions between donor/acceptor pairs for delivering drugs of different molecular weights including a porphyrin used as a tumour-tracing agent. N-(5-hydroxy) pentylmaleimide, an acceptor, formed hydrogels with N-vinyl-2-pyrrolidinone, 2-hydroxyethyl methacrylate and N-vinylcaprolactum. Glucosamine, an effective H-donor in enhancing polymerisation as shown by Differential Photocalorimetric results, was found unsuitable for hydrogel preparation. Drugs of different molecular weights releasing at the same rate was discussed. The hydrogels were found to have no toxic effects and were biocompatible with a human keratinocyte cell line.

  11. Drug Abuse Education Program. Drug Abuse Education, Grades 5,7,9. Bibliography Included.

    ERIC Educational Resources Information Center

    Baltimore City Public Schools, MD.

    A drug abuse education program was implemented in grades five, seven, and nine in the Baltimore City Public Schools. Unit plans outline the curriculum content and learning activities for each of the three grades. The major objective in grade five is to familiarize pupils with various medically used drugs and to develop an understanding that they…

  12. Polysaccharide based nanogels in the drug delivery system: Application as the carrier of pharmaceutical agents.

    PubMed

    Debele, Tilahun Ayane; Mekuria, Shewaye Lakew; Tsai, Hsieh-Chih

    2016-11-01

    Polysaccharide-based nanoparticles have fascinated attention as a vesicle of different pharmaceutical agents due to their unique multi-functional groups in addition to their physicochemical properties, including biocompatibility and biodegradability. The existence of multi-functional groups on the polysaccharide backbone permits facile chemical or biochemical modification to synthesize polysaccharide based nanoparticles with miscellaneous structures. Polysaccharide-based nanogels have high water content, large surface area for multivalent bioconjugation, tunable size, and interior network for the incorporation of different pharmaceutical agents. These unique properties offer great potential for the utilization of polysaccharide-based nanogels in the drug delivery systems. Hence, this review describes chemistry of certain common polysaccharides, several methodologies used to synthesize polysaccharide nanoparticles and primarily focused on the polysaccharide (or polysaccharide derivative) based nanogels as the carrier of pharmaceutical agents. PMID:27524098

  13. Metabolic Network Analysis-Based Identification of Antimicrobial Drug Targets in Category A Bioterrorism Agents

    PubMed Central

    Ahn, Yong-Yeol; Lee, Deok-Sun; Burd, Henry; Blank, William; Kapatral, Vinayak

    2014-01-01

    The 2001 anthrax mail attacks in the United States demonstrated the potential threat of bioterrorism, hence driving the need to develop sophisticated treatment and diagnostic protocols to counter biological warfare. Here, by performing flux balance analyses on the fully-annotated metabolic networks of multiple, whole genome-sequenced bacterial strains, we have identified a large number of metabolic enzymes as potential drug targets for each of the three Category A-designated bioterrorism agents including Bacillus anthracis, Francisella tularensis and Yersinia pestis. Nine metabolic enzymes- belonging to the coenzyme A, folate, phosphatidyl-ethanolamine and nucleic acid pathways common to all strains across the three distinct genera were identified as targets. Antimicrobial agents against some of these enzymes are available. Thus, a combination of cross species-specific antibiotics and common antimicrobials against shared targets may represent a useful combinatorial therapeutic approach against all Category A bioterrorism agents. PMID:24454817

  14. 36 CFR 1212.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false What must I include in my drug-free awareness program? 1212.215 Section 1212.215 Parks, Forests, and Public Property NATIONAL... my drug-free awareness program? You must establish an ongoing drug-free awareness program to...

  15. 2 CFR 182.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free... penalties that you may impose upon them for drug abuse violations occurring in the workplace. ... 2 Grants and Agreements 1 2010-01-01 2010-01-01 false What must I include in my...

  16. 29 CFR 94.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a... programs; and (d) The penalties that you may impose upon them for drug abuse violations occurring in the... 29 Labor 1 2010-07-01 2010-07-01 true What must I include in my drug-free awareness program?...

  17. 10 CFR 607.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy... assistance programs; and (d) The penalties that you may impose upon them for drug abuse violations occurring... 10 Energy 4 2010-01-01 2010-01-01 false What must I include in my drug-free awareness program?...

  18. 22 CFR 1008.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy... assistance programs; and (d) The penalties that you may impose upon them for drug abuse violations occurring... 22 Foreign Relations 2 2010-04-01 2010-04-01 true What must I include in my drug-free...

  19. 22 CFR 312.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a... programs; and (d) The penalties that you may impose upon them for drug abuse violations occurring in the... 22 Foreign Relations 2 2010-04-01 2010-04-01 true What must I include in my drug-free...

  20. 40 CFR 36.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any... may impose upon them for drug abuse violations occurring in the workplace. ... 40 Protection of Environment 1 2010-07-01 2010-07-01 false What must I include in my...

  1. 49 CFR 32.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy... assistance programs; and (d) The penalties that you may impose upon them for drug abuse violations occurring... 49 Transportation 1 2010-10-01 2010-10-01 false What must I include in my drug-free...

  2. 24 CFR 21.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any... may impose upon them for drug abuse violations occurring in the workplace. ... 24 Housing and Urban Development 1 2010-04-01 2010-04-01 false What must I include in my...

  3. 22 CFR 1509.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy... assistance programs; and (d) The penalties that you may impose upon them for drug abuse violations occurring... 22 Foreign Relations 2 2010-04-01 2010-04-01 true What must I include in my drug-free...

  4. 45 CFR 1173.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy... assistance programs; and (d) The penalties that you may impose upon them for drug abuse violations occurring... 45 Public Welfare 3 2010-10-01 2010-10-01 false What must I include in my drug-free...

  5. 7 CFR 3021.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a... programs; and (d) The penalties that you may impose upon them for drug abuse violations occurring in the... 7 Agriculture 15 2010-01-01 2010-01-01 false What must I include in my drug-free awareness...

  6. 20 CFR 439.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy... assistance programs; and (d) The penalties that you may impose upon them for drug abuse violations occurring... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false What must I include in my drug-free...

  7. 45 CFR 1155.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy... assistance programs; and (d) The penalties that you may impose upon them for drug abuse violations occurring... 45 Public Welfare 3 2010-10-01 2010-10-01 false What must I include in my drug-free...

  8. Anti-Obesity Agents and the US Food and Drug Administration.

    PubMed

    Casey, Martin F; Mechanick, Jeffrey I

    2014-09-01

    Despite the growing market for obesity care, the US Food and Drug Administration (FDA) has approved only two new pharmaceutical agents-lorcaserin and combination phentermine/topiramate-for weight reduction since 2000, while removing three agents from the market in the same time period. This article explores the FDA's history and role in the approval of anti-obesity medications within the context of a public health model of obesity. Through the review of obesity literature and FDA approval documents, we identified two major barriers preventing fair evaluation of anti-obesity agents including: (1) methodological pitfalls in clinical trials and (2) misaligned values in the assessment of anti-obesity agents. Specific recommendations include the use of adaptive (Bayesian) design protocols, value-based analyses of risks and benefits, and regulatory guidance based on a comprehensive, multi-platform obesity disease model. Positively addressing barriers in the FDA approval process of anti-obesity agents may have many beneficial effects within an obesity disease model. PMID:26626768

  9. Drug Susceptibility Testing of 31 Antimicrobial Agents on Rapidly Growing Mycobacteria Isolates from China

    PubMed Central

    Pang, Hui; Li, Guilian; Zhao, Xiuqin; Liu, Haican; Wan, Kanglin; Yu, Ping

    2015-01-01

    Objectives. Several species of rapidly growing mycobacteria (RGM) are now recognized as human pathogens. However, limited data on effective drug treatments against these organisms exists. Here, we describe the species distribution and drug susceptibility profiles of RGM clinical isolates collected from four southern Chinese provinces from January 2005 to December 2012. Methods. Clinical isolates (73) were subjected to in vitro testing with 31 antimicrobial agents using the cation-adjusted Mueller-Hinton broth microdilution method. The isolates included 55 M. abscessus, 11 M. fortuitum, 3 M. chelonae, 2 M. neoaurum, and 2 M. septicum isolates. Results. M. abscessus (75.34%) and M. fortuitum (15.07%), the most common species, exhibited greater antibiotic resistance than the other three species. The isolates had low resistance to amikacin, linezolid, and tigecycline, and high resistance to first-line antituberculous agents, amoxicillin-clavulanic acid, rifapentine, dapsone, thioacetazone, and pasiniazid. M. abscessus and M. fortuitum were highly resistant to ofloxacin and rifabutin, respectively. The isolates showed moderate resistance to the other antimicrobial agents. Conclusions. Our results suggest that tigecycline, linezolid, clofazimine, and cefmetazole are appropriate choices for M. abscessus infections. Capreomycin, sulfamethoxazole, tigecycline, clofazimine, and cefmetazole are potentially good choices for M. fortuitum infections. Our drug susceptibility data should be useful to clinicians. PMID:26351633

  10. Fluorine-Containing Taxoid Anticancer Agents and Their Tumor-Targeted Drug Delivery.

    PubMed

    Seitz, Joshua; Vineberg, Jacob G; Zuniga, Edison S; Ojima, Iwao

    2013-08-01

    A long-standing problem of conventional chemotherapy is the lack of tumor-specific treatments. Traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects. Consequently, various "molecularly targeted cancer therapies" have been developed for use in specific cancers, including tumor-targeting drug delivery systems. In general, such a drug delivery system consists of a tumor recognition moiety and a cytotoxic "warhead" connected through a "smart" linker to form a conjugate. When a multi-functionalized nanomaterial is used as the vehicle, a "Trojan Horse" approach can be used for mass delivery of cytotoxic "warheads" to maximize the efficacy. Exploitation of the special properties of fluorine has proven successful in the development of new and effective biochemical tools as well as therapeutic agents. Fluorinated congeners can also serve as excellent probes for the investigation of biochemical mechanisms. (19)F-NMR can provide unique and powerful tools for mechanistic investigations in chemical biology. This account presents our recent progress, in perspective, on the molecular approaches to the design and development of novel tumor-targeted drug delivery systems for new generation chemotherapy by exploiting the unique nature of fluorine. PMID:23935213

  11. Selective anti-cancer agents as anti-aging drugs

    PubMed Central

    Blagosklonny, Mikhail V

    2013-01-01

    Recent groundbreaking discoveries have revealed that IGF-1, Ras, MEK, AMPK, TSC1/2, FOXO, PI3K, mTOR, S6K, and NFκB are involved in the aging process. This is remarkable because the same signaling molecules, oncoproteins and tumor suppressors, are well-known targets for cancer therapy. Furthermore, anti-cancer drugs aimed at some of these targets have been already developed. This arsenal could be potentially employed for anti-aging interventions (given that similar signaling molecules are involved in both cancer and aging). In cancer, intrinsic and acquired resistance, tumor heterogeneity, adaptation, and genetic instability of cancer cells all hinder cancer-directed therapy. But for anti-aging applications, these hurdles are irrelevant. For example, since anti-aging interventions should be aimed at normal postmitotic cells, no selection for resistance is expected. At low doses, certain agents may decelerate aging and age-related diseases. Importantly, deceleration of aging can in turn postpone cancer, which is an age-related disease. PMID:24345884

  12. Polymeric protective agents for nanoparticles in drug delivery and targeting.

    PubMed

    Mogoşanu, George Dan; Grumezescu, Alexandru Mihai; Bejenaru, Cornelia; Bejenaru, Ludovic Everard

    2016-08-30

    Surface modification/functionalization of nanoparticles (NPs) using polymeric protective agents is an issue of great importance and actuality for drug delivery and targeting. Improving the blood circulation half-life of surface-protected nanocarriers is closely related to the elimination of main biological barriers and limiting factors (protein absorption and opsonization), due to the phagocytic activity of reticuloendothelial system. For passive or active targeted delivery, in biomedical area, surface-functionalized NPs with tissue-recognition ligands were designed and optimized as a result of modern research techniques. Also, multi-functionalized nanostructures are characterized by enhanced bioavailability, efficacy, targeted localization, active cellular uptake, and low side effects. Surface-protected NPs are obtained from biocompatible, biodegradable and less toxic natural polymers (dextran, β-cyclodextrin, chitosan, hyaluronic acid, heparin, gelatin) or synthetic polymers, such as poly(lactic acid), poly(lactic-co-glycolic) acid, poly(ε-caprolactone) and poly(alkyl cyanoacrylates). PEGylation is one of the most important functionalization methods providing steric stabilization, long circulating and 'stealth' properties for both polymeric and inorganic-based nanosystems. In addition, for their antimicrobial, antiviral and antitumor effects, cutting-edge researches in the field of pharmaceutical nanobiotechnology highlighted the importance of noble metal (platinum, gold, silver) NPs decorated with biopolymers. PMID:26972379

  13. Local drug delivery agents as adjuncts to endodontic and periodontal therapy.

    PubMed

    Puri, K; Puri, N

    2013-01-01

    In the treatment of intracanal and periodontal infections, the local application of antibiotics and other therapeutic agents in the root canal or in periodontal pockets may be a promising approach to achieve sustained/controlled drug release, high antimicrobial activity and low systemic side effects. The conventional method for the elimination of subgingival microbial infection includes mechanical debridement, irrigation with antimicrobial agents or surgical access. But, the effectiveness of conventional nonsurgical treatment is limited by lack of accessibility to bacteria in deeper periodontal pockets, and/or does not completely eliminate intracanal microorganisms. Surgical intervention may be beneficial but cannot be done in all cases, medically compromised cases and also in patients not willing to be subjected to surgical therapy. Development of local drug delivery systems provides an answer to all such difficulties. This comprehensive review tries to cover the detailed information about the latest advances in the various local drug delivery systems, their indications, contraindications and their advantages over systemic drug therapy. PMID:24868252

  14. 7 CFR 3021.205 - What must I include in my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 15 2010-01-01 2010-01-01 false What must I include in my drug-free workplace...-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 3021.205 What must I include in my drug-free workplace statement? You must publish a statement that— (a)...

  15. 29 CFR 94.205 - What must I include in my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 1 2010-07-01 2010-07-01 true What must I include in my drug-free workplace statement? 94... WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 94.205 What must I include in my drug-free workplace statement? You must publish a statement that— (a) Tells your...

  16. Exploring simvastatin, an antihyperlipidemic drug, as a potential topical antibacterial agent

    PubMed Central

    Thangamani, Shankar; Mohammad, Haroon; Abushahba, Mostafa F. N.; Hamed, Maha I.; Sobreira, Tiago J. P.; Hedrick, Victoria E.; Paul, Lake N.; Seleem, Mohamed N.

    2015-01-01

    The rapid rise of bacterial resistance to traditional antibiotics combined with the decline in discovery of novel antibacterial agents has created a global public health crisis. Repurposing existing drugs presents an alternative strategy to potentially expedite the discovery of new antimicrobial drugs. The present study demonstrates that simvastatin, an antihyperlipidemic drug exhibited broad-spectrum antibacterial activity against important Gram-positive (including methicillin-resistant Staphylococcus aureus (MRSA)) and Gram-negative pathogens (once the barrier imposed by the outer membrane was permeabilized). Proteomics and macromolecular synthesis analyses revealed that simvastatin inhibits multiple biosynthetic pathways and cellular processes in bacteria, including selective interference of bacterial protein synthesis. This property appears to assist in simvastatin’s ability to suppress production of key MRSA toxins (α-hemolysin and Panton-Valentine leucocidin) that impair healing of infected skin wounds. A murine MRSA skin infection experiment confirmed that simvastatin significantly reduces the bacterial burden and inflammatory cytokines in the infected wounds. Additionally, simvastatin exhibits excellent anti-biofilm activity against established staphylococcal biofilms and demonstrates the ability to be combined with topical antimicrobials currently used to treat MRSA skin infections. Collectively the present study lays the foundation for further investigation of repurposing simvastatin as a topical antibacterial agent to treat skin infections. PMID:26553420

  17. Drug treatment of pulmonary arterial hypertension: current and future agents.

    PubMed

    Hoeper, Marius M

    2005-01-01

    During the last decade we have witnessed substantial improvements in the therapeutic options for pulmonary arterial hypertension (PAH), including true innovations targeting some of the mechanisms involved in the pathogenesis of this devastating disease. Intravenous epoprostenol was the first drug to improve symptoms and survival of patients with PAH. Novel prostanoids, including subcutaneous treprostinil and inhaled iloprost, also have beneficial effects in many patients, although their long-term efficacy is less well known. Among the newer treatments for PAH, endothelin receptor antagonists and phosphodiesterase type 5 (PDE5) inhibitors have reshaped clinical practice. The endothelin receptor antagonist bosentan has been approved in many parts of the world and most current guidelines recommend this drug as first-line treatment for patients with PAH in functional class III. Novel endothelin receptor antagonists such as sitaxsentan sodium and ambrisentan are currently being investigated. The PDE5 sildenafil is also being intensively studied in patients with pulmonary hypertension, and most of the available data look promising, although approval for PAH is still pending. Other PDE5 inhibitors have not yet undergone extensive study in PAH. The increasing insight into the pathogenesis of PAH opens several new therapeutic opportunities, which include vasoactive intestinal peptide, selective serotonin reuptake inhibitors, adrenomedullin and HMG-CoA reductase inhibitors (statins). However, PAH is a complex disorder and targeting a single pathway can not be expected to be uniformly successful. Thus, combining substances with different modes of action is expected to improve symptoms, haemodynamics and survival in PAH patients, although combination therapy has yet to undergo the scrutiny of large randomised clinical trials. PMID:15977967

  18. 28 CFR 83.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...-free awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b..., and employee assistance programs; and (d) The penalties that you may impose upon them for drug abuse... 28 Judicial Administration 2 2010-07-01 2010-07-01 false What must I include in my...

  19. 15 CFR 29.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ...-free awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b..., and employee assistance programs; and (d) The penalties that you may impose upon them for drug abuse... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false What must I include in my...

  20. 31 CFR 20.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...-free awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b..., and employee assistance programs; and (d) The penalties that you may impose upon them for drug abuse... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false What must I include in my...

  1. 43 CFR 43.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...-free awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b..., and employee assistance programs; and (d) The penalties that you may impose upon them for drug abuse... 43 Public Lands: Interior 1 2010-10-01 2010-10-01 false What must I include in my...

  2. 10 CFR 607.205 - What must I include in my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false What must I include in my drug-free workplace statement? 607.205 Section 607.205 Energy DEPARTMENT OF ENERGY (CONTINUED) ASSISTANCE REGULATIONS GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than...

  3. 31 CFR 20.205 - What must I include in my drug-free workplace statement?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 31 Money and Finance: Treasury 1 2012-07-01 2012-07-01 false What must I include in my drug-free workplace statement? 20.205 Section 20.205 Money and Finance: Treasury Office of the Secretary of the Treasury GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements...

  4. 31 CFR 20.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 31 Money and Finance: Treasury 1 2014-07-01 2014-07-01 false What must I include in my drug-free awareness program? 20.215 Section 20.215 Money and Finance: Treasury Office of the Secretary of the Treasury GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other...

  5. 31 CFR 20.205 - What must I include in my drug-free workplace statement?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance: Treasury 1 2011-07-01 2011-07-01 false What must I include in my drug-free workplace statement? 20.205 Section 20.205 Money and Finance: Treasury Office of the Secretary of the Treasury GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements...

  6. 31 CFR 20.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 31 Money and Finance: Treasury 1 2013-07-01 2013-07-01 false What must I include in my drug-free awareness program? 20.215 Section 20.215 Money and Finance: Treasury Office of the Secretary of the Treasury GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other...

  7. 31 CFR 20.205 - What must I include in my drug-free workplace statement?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 31 Money and Finance: Treasury 1 2014-07-01 2014-07-01 false What must I include in my drug-free workplace statement? 20.205 Section 20.205 Money and Finance: Treasury Office of the Secretary of the Treasury GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements...

  8. 31 CFR 20.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance: Treasury 1 2011-07-01 2011-07-01 false What must I include in my drug-free awareness program? 20.215 Section 20.215 Money and Finance: Treasury Office of the Secretary of the Treasury GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other...

  9. 31 CFR 20.205 - What must I include in my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false What must I include in my drug-free workplace statement? 20.205 Section 20.205 Money and Finance: Treasury Office of the Secretary of the Treasury GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 20.205...

  10. 31 CFR 20.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 31 Money and Finance: Treasury 1 2012-07-01 2012-07-01 false What must I include in my drug-free awareness program? 20.215 Section 20.215 Money and Finance: Treasury Office of the Secretary of the Treasury GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other...

  11. 31 CFR 20.205 - What must I include in my drug-free workplace statement?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 31 Money and Finance: Treasury 1 2013-07-01 2013-07-01 false What must I include in my drug-free workplace statement? 20.205 Section 20.205 Money and Finance: Treasury Office of the Secretary of the Treasury GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements...

  12. 38 CFR 48.205 - What must I include in my drug-free workplace statement?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2011-07-01 2011-07-01 false What must I include in my drug-free workplace statement? 48.205 Section 48.205 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other...

  13. 38 CFR 48.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2011-07-01 2011-07-01 false What must I include in my drug-free awareness program? 48.215 Section 48.215 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other...

  14. 20 CFR 439.205 - What must I include in my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false What must I include in my drug-free workplace statement? 439.205 Section 439.205 Employees' Benefits SOCIAL SECURITY ADMINISTRATION GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than...

  15. 43 CFR 43.205 - What must I include in my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... workplace statement? 43.205 Section 43.205 Public Lands: Interior Office of the Secretary of the Interior GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 43.205 What must I include in my drug-free workplace statement? You must publish a...

  16. 15 CFR 29.205 - What must I include in my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... workplace statement? 29.205 Section 29.205 Commerce and Foreign Trade Office of the Secretary of Commerce GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 29.205 What must I include in my drug-free workplace statement? You must publish a...

  17. 32 CFR 26.205 - What must I include in my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 1 2010-07-01 2010-07-01 false What must I include in my drug-free workplace... DoD GRANT AND AGREEMENT REGULATIONS GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL... workplace statement? You must publish a statement that— (a) Tells your employees that the...

  18. 40 CFR 36.205 - What must I include in my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... workplace statement? 36.205 Section 36.205 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GRANTS AND OTHER FEDERAL ASSISTANCE GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 36.205 What must I include in my drug-free...

  19. The program of criminal undercover agents sources in the drug trade.

    PubMed

    Hess, Alex; Amir, Menachem

    2002-01-01

    Information and intelligence have always been, and will remain the most essential components of policing, and indeed all law enforcement and security work, including the variety of drug control efforts. Sources of information are many and varied, ranging from everyday interactions of officers of the law with the public, anonymous reports, the use of paid and unpaid informants from the criminal underworld, to the law enforcement and security services' use of agents. This presentation, based on interviews with "handlers" of informants who are offenders and who supply information and evidence against other criminals, who may have been his former "comrades" explores: the dilemmas that the informer, and the handler face at each stage of the "operation" from recruitment to operation in the field, until the agent "fingers" the targets, and becomes a State witness. During each stage of the operation the "agents" motivations, fears, sense of betrayal (being betrayed and betraying others), being a "snitch", the need to protect identity as well as dependency upon the "handler" are the primary issues to be considered and resolved. The "handler" may have to tolerate the agent's commission of crimes during the operation and often may also have to "treat" the informant's spouse. Borrowed identity, which is the main meaning and dynamic of the informant's actions, and of any undercover work, will also be analyzed. PMID:12180575

  20. Should pregnant women be included in phase IV clinical drug trials?

    PubMed

    Briggs, Gerald G; Polifka, Janine E; Wisner, Katherine L; Gervais, Eric; Miller, Richard K; Berard, Anick; Koren, Gideon; Forinash, Alicia; Towers, Craig V

    2015-12-01

    Relatively few drugs, especially those recently approved by the US Food and Drug Administration, have published human pregnancy experience. Although all drugs contain animal reproduction data, these are usually not predictive of human risk. Clinical trials in pregnant women are rarely conducted because of ethical and legal concerns, and it may be many years before sufficient observational data are collected to guide clinical treatment decisions. Because many of these drugs will be used in pregnancy, human data are needed shortly after the drugs come to the market. Lack of human data leads to uncertainty over whether a drug can be safely prescribed for a pregnant patient. Unless there are compelling scientific and ethical reasons to exclude them, pregnant women should be included in phase IV clinical trials (postmarketing studies to obtain additional information, including the risks, benefits, and optimal use of a drug). This paper examines how physicians currently counsel pregnant women when there are no human data and proposes an alternative method in which knowledge regarding risks associated with the use of drugs during pregnancy can be enhanced in a clinical trial setting. PMID:26008178

  1. Genome Sequencing of Four Strains of Rickettsia prowazekii, the Causative Agent of Epidemic Typhus, Including One Flying Squirrel Isolate.

    PubMed

    Bishop-Lilly, Kimberly A; Ge, Hong; Butani, Amy; Osborne, Brian; Verratti, Kathleen; Mokashi, Vishwesh; Nagarajan, Niranjan; Pop, Mihai; Read, Timothy D; Richards, Allen L

    2013-01-01

    Rickettsia prowazekii is a notable intracellular pathogen, the agent of epidemic typhus, and a potential biothreat agent. We present here whole-genome sequence data for four strains of R. prowazekii, including one from a flying squirrel. PMID:23814035

  2. Antiretroviral Drug Interactions: Overview of Interactions Involving New and Investigational Agents and the Role of Therapeutic Drug Monitoring for Management

    PubMed Central

    Rathbun, R. Chris; Liedtke, Michelle D.

    2011-01-01

    Antiretrovirals are prone to drug-drug and drug-food interactions that can result in subtherapeutic or supratherapeutic concentrations. Interactions between antiretrovirals and medications for other diseases are common due to shared metabolism through cytochrome P450 (CYP450) and uridine diphosphate glucuronosyltransferase (UGT) enzymes and transport by membrane proteins (e.g., p-glycoprotein, organic anion-transporting polypeptide). The clinical significance of antiretroviral drug interactions is reviewed, with a focus on new and investigational agents. An overview of the mechanistic basis for drug interactions and the effect of individual antiretrovirals on CYP450 and UGT isoforms are provided. Interactions between antiretrovirals and medications for other co-morbidities are summarized. The role of therapeutic drug monitoring in the detection and management of antiretroviral drug interactions is also briefly discussed. PMID:24309307

  3. Opportunities for Web-based Drug Repositioning: Searching for Potential Antihypertensive Agents with Hypotension Adverse Events

    PubMed Central

    Wang, Kejian; Wan, Mei; Wang, Rui-Sheng

    2016-01-01

    Background Drug repositioning refers to the process of developing new indications for existing drugs. As a phenotypic indicator of drug response in humans, clinical side effects may provide straightforward signals and unique opportunities for drug repositioning. Objective We aimed to identify drugs frequently associated with hypotension adverse reactions (ie, the opposite condition of hypertension), which could be potential candidates as antihypertensive agents. Methods We systematically searched the electronic records of the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) through the openFDA platform to assess the association between hypotension incidence and antihypertensive therapeutic effect regarding a list of 683 drugs. Results Statistical analysis of FAERS data demonstrated that those drugs frequently co-occurring with hypotension events were more likely to have antihypertensive activity. Ranked by the statistical significance of frequent hypotension reporting, the well-known antihypertensive drugs were effectively distinguished from others (with an area under the receiver operating characteristic curve > 0.80 and a normalized discounted cumulative gain of 0.77). In addition, we found a series of antihypertensive agents (particularly drugs originally developed for treating nervous system diseases) among the drugs with top significant reporting, suggesting the good potential of Web-based and data-driven drug repositioning. Conclusions We found several candidate agents among the hypotension-related drugs on our list that may be redirected for lowering blood pressure. More important, we showed that a pharmacovigilance system could alternatively be used to identify antihypertensive agents and sustainably create opportunities for drug repositioning. PMID:27036325

  4. Nanocarrier-mediated co-delivery of chemotherapeutic drugs and gene agents for cancer treatment.

    PubMed

    Kang, Lin; Gao, Zhonggao; Huang, Wei; Jin, Mingji; Wang, Qiming

    2015-05-01

    The efficacy of chemotherapeutic drug in cancer treatment is often hampered by drug resistance of tumor cells, which is usually caused by abnormal gene expression. RNA interference mediated by siRNA and miRNA can selectively knock down the carcinogenic genes by targeting specific mRNAs. Therefore, combining chemotherapeutic drugs with gene agents could be a promising strategy for cancer therapy. Due to poor stability and solubility associated with gene agents and drugs, suitable protective carriers are needed and have been widely researched for the co-delivery. In this review, we summarize the most commonly used nanocarriers for co-delivery of chemotherapeutic drugs and gene agents, as well as the advances in co-delivery systems. PMID:26579443

  5. Nanocarrier-mediated co-delivery of chemotherapeutic drugs and gene agents for cancer treatment

    PubMed Central

    Kang, Lin; Gao, Zhonggao; Huang, Wei; Jin, Mingji; Wang, Qiming

    2015-01-01

    The efficacy of chemotherapeutic drug in cancer treatment is often hampered by drug resistance of tumor cells, which is usually caused by abnormal gene expression. RNA interference mediated by siRNA and miRNA can selectively knock down the carcinogenic genes by targeting specific mRNAs. Therefore, combining chemotherapeutic drugs with gene agents could be a promising strategy for cancer therapy. Due to poor stability and solubility associated with gene agents and drugs, suitable protective carriers are needed and have been widely researched for the co-delivery. In this review, we summarize the most commonly used nanocarriers for co-delivery of chemotherapeutic drugs and gene agents, as well as the advances in co-delivery systems. PMID:26579443

  6. Calixdrugs: calixarene-based clusters of established therapeutic drug agents.

    PubMed

    Nasuhi Pur, Fazel

    2016-08-01

    Calixdrugs are calix[4]arene-based clusters (chaliced shapes) of established therapeutic drugs (e.g., penicillin, cephalosporin, tyrosol, and carboplatin) that are innovatively named calixpenam, calixcephem, calixtyrosol, and calixplatin, respectively. Going over the structures of cluster compounds, the calixarene scaffold lies at the heart of the structure (chaliced shape of drug), and it is an integral part of the cluster. In fact, the monomer drugs contribute as 1/4 of the corresponding cluster. In addition, probably because of the multivalency, spatial preorganization, and synergistic effect of four impacted drug units in the structures of calixdrugs, they are more effective in interactions with the target sites over their corresponding monomers. PMID:27017350

  7. 34 CFR 84.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy... in the workplace. (Authority: E.O.s 12549 and 12689; 20 U.S.C. 1082, 1094, 1221e-3 and 3474; and Sec... 34 Education 1 2012-07-01 2012-07-01 false What must I include in my drug-free awareness...

  8. 34 CFR 84.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy... in the workplace. (Authority: E.O.s 12549 and 12689; 20 U.S.C. 1082, 1094, 1221e-3 and 3474; and Sec... 34 Education 1 2014-07-01 2014-07-01 false What must I include in my drug-free awareness...

  9. 34 CFR 84.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy... in the workplace. (Authority: E.O.s 12549 and 12689; 20 U.S.C. 1082, 1094, 1221e-3 and 3474; and Sec... 34 Education 1 2013-07-01 2013-07-01 false What must I include in my drug-free awareness...

  10. 34 CFR 84.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy... in the workplace. (Authority: E.O.s 12549 and 12689; 20 U.S.C. 1082, 1094, 1221e-3 and 3474; and Sec... 34 Education 1 2010-07-01 2010-07-01 false What must I include in my drug-free awareness...

  11. Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology

    PubMed Central

    Ashbee, H. Ruth; Barnes, Rosemary A.; Johnson, Elizabeth M.; Richardson, Malcolm D.; Gorton, Rebecca; Hope, William W.

    2014-01-01

    The burden of human disease related to medically important fungal pathogens is substantial. An improved understanding of antifungal pharmacology and antifungal pharmacokinetics–pharmacodynamics has resulted in therapeutic drug monitoring (TDM) becoming a valuable adjunct to the routine administration of some antifungal agents. TDM may increase the probability of a successful outcome, prevent drug-related toxicity and potentially prevent the emergence of antifungal drug resistance. Much of the evidence that supports TDM is circumstantial. This document reviews the available literature and provides a series of recommendations for TDM of antifungal agents. PMID:24379304

  12. Development of drug-approval regulations for medical countermeasures against CBRN agents in Japan.

    PubMed

    Shimazawa, Rumiko; Ikeda, Masayuki

    2015-01-01

    To develop approval regulations for drugs against chemical, biological, radiological, or nuclear (CBRN) agents in Japan, and to help inform arguments about the development of anti-CBRN agents, we analyzed documentation describing approval processes and data for drugs against CBRN agents. Sixteen countermeasure products against 10 CBRN agents have been approved in Japan. Approval schemes were grouped into 3 categories: application for off-label uses, expedited review for antiterrorism measures, and expedited review. Ten drug applications were designated "priority reviews," and the median review time was 4.4 months. No application relied exclusively on clinical trials to expose patients to CBRN threats. Clinical experience with drugs in victims of unexpected exposure was not necessarily important for approval. The United States is the most advanced country in terms of developing medical countermeasure products against CBRN agents. Japan has similarities with the US in approved products and application packages, but there were 3 unapproved products or indications that were approved under the Animal Rule in the US. The Animal Rule might encourage development of a novel product by providing efficacy evaluation in animal studies. The US also has regulations that do not exist in Japan that authorize administration of an investigational drug outside a clinical trial for patients. Introduction of the Animal Rule and expanded access of investigational drugs could contribute to development and approvals of novel countermeasure products and improve an emergency response in a crisis in Japan. PMID:25813978

  13. Cross-reactivity of designer drugs, including cathinone derivatives, in commercial enzyme-linked immunosorbent assays.

    PubMed

    Swortwood, Madeleine J; Hearn, W Lee; DeCaprio, Anthony P

    2014-01-01

    Since the introduction of synthetic heroin, designer drugs have been increasing in prevalence in the United States drug market over the past few decades. Recently, 'legal highs' sold as 'bath salts' have become a household term for one such class of designer drugs. While a number of federal and state bans have been enacted, the abuse of these designer drugs still continues. Few assays have been developed for the comprehensive detection of such compounds, so it is important to investigate how they may or may not react in presumptive screens, i.e. pre-existing commercial immunoassays. In this experiment, 16 different ELISA reagents were evaluated to determine the cross-reactivity of 30 designer drugs, including 24 phenylethylamines (including 8 cathinone derivatives), 3 piperazines, and 3 tryptamines. Cross-reactivity towards most drugs was <4% in assays targeting amphetamine or methamphetamine. Compounds such as MDA, MDMA, ethylamphetamine, and α-methyltryptamine demonstrated cross-reactivities in the range of 30-250%, but data were consistent with both manufacturer's inserts and published literature. When tested against the Randox Mephedrone/Methcathinone kit, cathinone derivatives demonstrated cross-reactivity at concentrations as low as 150 ng/ml. Since this same reagent did not cross-react with other amphetamine-like compounds, it opens the possibility to screen post-mortem specimens without the interference of putrefactive amines. All other assays demonstrated essentially no cross-reactivity towards any of the analytes evaluated. Given these results, a great need exists for more broad-range screening techniques to be applied when analyzing biological specimens by immunoassays for drugs of abuse, specifically the more recent designer drugs. PMID:23677923

  14. New hopes from old drugs: revisiting DNA-binding small molecules as anticancer agents

    PubMed Central

    Gurova, Katerina

    2010-01-01

    Most of the anticancer chemotherapeutic drugs that are broadly and successfully used today are DNA-damaging agents. Targeting of DNA has been proven to cause relatively potent and selective destruction of tumor cells. However, the clinical potential of DNA-damaging agents is limited by the adverse side effects and increased risk of secondary cancers that are consequences of the agents' genotoxicity. In this review, we present evidence that those agents capable of targeting DNA without inducing DNA damage would not be limited in these ways, and may be as potent as DNA-damaging agents in the killing of tumor cells. We use as an example literature data and our own research of the well-known antimalarial drug quinacrine, which binds to DNA without inducing DNA damage, yet modulates a number of cellular pathways that impact tumor cell survival. PMID:20001804

  15. Dosage and Dose Schedule Screening of Drug Combinations in Agent-Based Models Reveals Hidden Synergies

    PubMed Central

    Barros de Andrade e Sousa, Lisa C.; Kühn, Clemens; Tyc, Katarzyna M.; Klipp, Edda

    2016-01-01

    The fungus Candida albicans is the most common causative agent of human fungal infections and better drugs or drug combination strategies are urgently needed. Here, we present an agent-based model of the interplay of C. albicans with the host immune system and with the microflora of the host. We took into account the morphological change of C. albicans from the yeast to hyphae form and its dynamics during infection. The model allowed us to follow the dynamics of fungal growth and morphology, of the immune cells and of microflora in different perturbing situations. We specifically focused on the consequences of microflora reduction following antibiotic treatment. Using the agent-based model, different drug types have been tested for their effectiveness, namely drugs that inhibit cell division and drugs that constrain the yeast-to-hyphae transition. Applied individually, the division drug turned out to successfully decrease hyphae while the transition drug leads to a burst in hyphae after the end of the treatment. To evaluate the effect of different drug combinations, doses, and schedules, we introduced a measure for the return to a healthy state, the infection score. Using this measure, we found that the addition of a transition drug to a division drug treatment can improve the treatment reliability while minimizing treatment duration and drug dosage. In this work we present a theoretical study. Although our model has not been calibrated to quantitative experimental data, the technique of computationally identifying synergistic treatment combinations in an agent based model exemplifies the importance of computational techniques in translational research. PMID:26779031

  16. Dosage and Dose Schedule Screening of Drug Combinations in Agent-Based Models Reveals Hidden Synergies.

    PubMed

    Barros de Andrade E Sousa, Lisa C; Kühn, Clemens; Tyc, Katarzyna M; Klipp, Edda

    2015-01-01

    The fungus Candida albicans is the most common causative agent of human fungal infections and better drugs or drug combination strategies are urgently needed. Here, we present an agent-based model of the interplay of C. albicans with the host immune system and with the microflora of the host. We took into account the morphological change of C. albicans from the yeast to hyphae form and its dynamics during infection. The model allowed us to follow the dynamics of fungal growth and morphology, of the immune cells and of microflora in different perturbing situations. We specifically focused on the consequences of microflora reduction following antibiotic treatment. Using the agent-based model, different drug types have been tested for their effectiveness, namely drugs that inhibit cell division and drugs that constrain the yeast-to-hyphae transition. Applied individually, the division drug turned out to successfully decrease hyphae while the transition drug leads to a burst in hyphae after the end of the treatment. To evaluate the effect of different drug combinations, doses, and schedules, we introduced a measure for the return to a healthy state, the infection score. Using this measure, we found that the addition of a transition drug to a division drug treatment can improve the treatment reliability while minimizing treatment duration and drug dosage. In this work we present a theoretical study. Although our model has not been calibrated to quantitative experimental data, the technique of computationally identifying synergistic treatment combinations in an agent based model exemplifies the importance of computational techniques in translational research. PMID:26779031

  17. Anticancer Agent Shikonin Is an Incompetent Inducer of Cancer Drug Resistance

    PubMed Central

    Wu, Hao; Xie, Jiansheng; Pan, Qiangrong; Wang, Beibei; Hu, Danqing; Hu, Xun

    2013-01-01

    Purpose Cancer drug resistance is a major obstacle for the success of chemotherapy. Since most clinical anticancer drugs could induce drug resistance, it is desired to develop candidate drugs that are highly efficacious but incompetent to induce drug resistance. Numerous previous studies have proven that shikonin and its analogs not only are highly tumoricidal but also can bypass drug-transporter and apoptotic defect mediated drug resistance. The purpose of this study is to investigate if or not shikonin is a weak inducer of cancer drug resistance. Experimental Design Different cell lines (K562, MCF-7, and a MDR cell line K562/Adr), after repeatedly treated with shikonin for 18 months, were assayed for drug resistance and gene expression profiling. Results After 18-month treatment, cells only developed a mere 2-fold resistance to shikonin and a marginal resistance to cisplatin and paclitaxel, without cross resistance to shikonin analogs and other anticancer agents. Gene expression profiles demonstrated that cancer cells did strongly respond to shikonin treatment but failed to effectively mobilize drug resistant machineries. Shikonin-induced weak resistance was associated with the up-regulation of βII-tubulin, which physically interacted with shikonin. Conclusion Taken together, apart from potent anticancer activity, shikonin and its analogs are weak inducers of cancer drug resistance and can circumvent cancer drug resistance. These merits make shikonin and its analogs potential candidates for cancer therapy with advantages of avoiding induction of drug resistance and bypassing existing drug resistance. PMID:23300986

  18. A "glucose eater" drug as a therapeutic agent in psychiatry.

    PubMed

    Howland, Robert H

    2013-09-01

    Metformin, currently approved for the treatment of type 2 diabetes, is an interesting drug that has various cellular and molecular mechanisms. These mechanisms have justified other off-label clinical and investigational uses for diabetes prevention in high-risk patients, for polycystic ovary syndrome, non-diabetic obesity, non-alcoholic fatty liver disease, and for prevention or treatment of cancer. A large number of controlled and uncontrolled studies have generally found metformin to be effective, well tolerated, and safe for preventing or treating antipsychotic-related weight gain and for improving metabolic abnormalities in psychiatric patient populations. Metformin has the potential effect of inducing hippocampal neurogenesis, and additional studies of this drug are warranted in patients with mood or cognitive disorders. PMID:23938069

  19. 22 CFR 1008.205 - What must I include in my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 2 2010-04-01 2010-04-01 true What must I include in my drug-free workplace statement? 1008.205 Section 1008.205 Foreign Relations INTER-AMERICAN FOUNDATION GOVERNMENTWIDE REQUIREMENTS... employees for violating that prohibition; and (c) Lets each employee know that, as a condition of...

  20. Double layered hydroxides as potential anti-cancer drug delivery agents.

    PubMed

    Riaz, Ufana; Ashraf, S M

    2013-04-01

    The emergence of nanotechnology has changed the scenario of the medical world by revolutionizing the diagnosis, monitoring and treatment of cancer. This nanotechnology has been proved miraculous in detecting cancer cells, delivering chemotherapeutic agents and monitoring treatment from non-specific to highly targeted killing of tumor cells. In the past few decades, a number of inorganic materials have been investigated such as calcium phosphate, gold, carbon materials, silicon oxide, iron oxide, and layered double hydroxide (LDH) for examining their efficacy in targeting drug delivery. The reason behind the selection of these inorganic materials was their versatile and unique features efficient in drug delivery, such as wide availability, rich surface functionality, good biocompatibility, potential for target delivery, and controlled release of the drug from these inorganic nanomaterials. Although, the drug-LDH hybrids are found to be quite instrumental because of their application as advanced anti-cancer drug delivery systems, there has not been much research on them. This mini review is set to highlight the advancement made in the use of layered double hydroxides (LDHs) as anti-cancer drug delivery agents. Along with the advantages of LDHs as anti-cancer drug delivery agents, the process of interaction of some of the common anti-cancer drugs with LDH has also been discussed. PMID:23170959

  1. Microtubule-stabilizing agents: New drug discovery and cancer therapy.

    PubMed

    Zhao, Ying; Mu, Xin; Du, Guanhua

    2016-06-01

    Microtubule-stabilizing agents (MSAs) have been highly successful in the treatment of cancer in the past 20years. To date, three classes of MSAs have entered the clinical trial stage or have been approved for clinical anticancer chemotherapy, and more than 10 classes of novel structural MSAs have been derived from natural resources. The microtubule typically contains two MSA-binding sites: the taxoid site and the laulimalide/peloruside site. All defined MSAs are known to bind at either of these sites, with subtle but significant differences. MSAs with different binding sites may produce a synergistic effect. Although having been extensively applied in the clinical setting, paclitaxel and other approved MSAs still pose many challenges such as multidrug resistance, low bioavailability, poor solubility, high toxicity, and low passage through the blood-brain barrier. A variety of studies focus on the structure-activity relationship in order to improve the pharmaceutical properties of these agents. Here, the mechanisms of action, advancements in pharmacological research, and clinical developments of defined MSAs during the past decade are discussed. The latest discovered MSAs are also briefly introduced in this review. The increasing number of natural MSAs indicates the potential discovery of more novel, natural MSAs with different structural bases, which will further promote the development of anticancer chemotherapy. PMID:26706241

  2. Human-Persons and the Use of Psychoactive Agents; A Drug Education Curriculum for Modern Youth.

    ERIC Educational Resources Information Center

    Ohio State Dept. of Education, Columbus.

    These two manuals, student's and teacher's, present information to stimulate both dialogue and problem-solving activity on drugs and drug education within the classroom. With a focus on human interaction, the five units include an introduction, a section about people, one about drugs, a section on effects and consequences of drug abuse, and a…

  3. Iron oxide nanoparticles as drug delivery agents in MIA PaCa-2 pancreatic cells

    NASA Astrophysics Data System (ADS)

    Perry, Christopher; Randriamahefa, Alexandrine; Lokko, Carl; Evans, Whitney; Watkins, Julian; Carrell, Holly; King, Natalie; Patel, Darayas

    2007-02-01

    Oleic acid (OA)-Pluronic-coated iron oxide nanoparticles were synthesized and characterized by Fourier Transform Infrared Spectroscopy (FT-IR) and Atomic Force Microscopy (AFM). FT-IR confirmed the bonding of oleic acid and Pluronic (surfactant) to the nanoparticles. AFM measurements on these nanoparticles indicated a root mean square (RMS) roughness, a measure of nanoparticle size of (50 +/- 20) nm. The efficiency of these functionalized nanoparticles was investigated by loading with 5-Fluorouracil (5-FU) in aqueous solution. AFM measurements were used to characterize modified iron oxide nanoparticles and pancreatic MIA PaCa-2 cells, including size distribution, stability and cellular uptake. Nanoparticles were added to MIA PaCa-2 cells and assayed for their cytotoxic effects after 24 and 48 hours. The outcome of this study demonstrated the effectiveness of oleic acid (OA)-Pluronic-coated iron oxide nanoparticles as a non-toxic drug delivery agent for pancreatic cancer.

  4. Drug forecast – the peptide deformylase inhibitors as antibacterial agents

    PubMed Central

    Guay, David R P

    2007-01-01

    The relatively rapid development of microbial resistance after the entry of every new antimicrobial into the marketplace necessitates a constant supply of new agents to maintain effective pharmacotherapy. Despite extensive efforts to identify novel lead compounds from molecular targets, only the peptide deformylase inhibitors (PDIs) have shown any real promise, with some advancing to phase I human trials. Bacterial peptide deformylase, which catalyzes the removal of the N-formyl group from N-terminal methionine following translation, is essential for bacterial protein synthesis, growth, and survival. The majority of PDIs are pseudopeptide hydroxamic acids and two of these (IV BB-83698 and oral NVP LBM-415) entered phase I human trials. However, agents to the present have suffered from major potential liabilities. Their in vitro activity has been limited to gram-positive aerobes and some anaerobes and has been quite modest against the majority of such species (MIC90 values ranging from 1–8 mg/L). They have exerted bacteriostatic, not bacteriocidal, activity, thus reducing their potential usefulness in the management of serious infections in the immunocompromised. The relative ease with which microorganisms have been able to develop resistance and the multiple available mechanisms of resistance (mutations in fmt, defB, folD genes; AcrAB/TolC efflux pump; overexpression of peptide deformylase) are worrisome. These could portend a short timespan of efficacy after marketing. Despite these current liabilities, further pursuit of more potent and broader spectrum PDIs which are less susceptible to bacterial mechanisms of resistance is still warranted. PMID:18472972

  5. Pharmacometrics-guided drug development of antihyperhidrosis agents.

    PubMed

    Mehrotra, Shailly; Schmith, Virginia D; Dumitrescu, Teodora Pene; Gobburu, Jogarao

    2015-11-01

    The objective of the present work was to use modeling and simulation to inform trial design of a proof-of-concept study for agents used in the treatment of hyperhidrosis. Data were available from 36 subjects who received the vehicle, 2% or 4% topical glycopyrrolate wipes daily for 4 weeks, with response (hyperhidrosis disease severity scale [HDSS] and sweat production [SP]) measured weekly. The HDSS and SP time courses were best described using a longitudinal model with maximum response achieved by 1 week. Glycopyrrolate 4% had a higher HDSS responder rate than 2% (50% vs 33%) and placebo (0%) at week 1. Mean change from baseline (mg/5 min [SD]) in SP at week 1 was -90 (220), -185 (214), and -271 (265) for placebo, 2%, and 4% glycopyrrolate, respectively. Subjects with higher baseline SP had higher sweat reduction from baseline. Virtual clinical trials were simulated and analyzed using conventional (at the end of the study) versus model-based methods to determine sample size for achieving 80% power to identify a dose-response relationship. Twenty-seven subjects compared with at least 120 subjects would be needed using model-based and conventional methods, respectively. Thus, the model-based method using longitudinal data required fewer subjects than the conventional single-point method. PMID:25939678

  6. The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

    PubMed Central

    Johnstone, Timothy C.; Suntharalingam, Kogularamanan; Lippard, Stephen J.

    2016-01-01

    The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer,, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing non-classical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore non-classical platinum(II) complexes with trans geometry and with a monofunctional coordination mode, polynuclear platinum(II) compounds, platinum(IV) prodrugs, dual-treat agents, and photoactivatable platinum(IV) complexes. Nanodelivery particles designed to deliver platinum(IV) complexes will also be discussed, including carbon nanotubes, carbon nanoparticles, gold nanoparticles, quantum dots, upconversion nanoparticles, and polymeric micelles. Additional nanoformulations including supramolecular self-assembled structures, proteins, peptides, metal-organic frameworks, and coordination polymers will then be described. Finally, the significant clinical progress made by nanoparticle formulations of platinum(II) agents will be reviewed. We anticipate that such a synthesis of disparate research efforts will not only help to generate new drug development ideas and strategies, but also reflect our optimism that the next generation of platinum cancer drugs is about to arrive. PMID:26865551

  7. The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs.

    PubMed

    Johnstone, Timothy C; Suntharalingam, Kogularamanan; Lippard, Stephen J

    2016-03-01

    The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing nonclassical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown, and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this Review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore nonclassical platinum(II) complexes with trans geometry or with a monofunctional coordination mode, polynuclear platinum(II) compounds, platinum(IV) prodrugs, dual-threat agents, and photoactivatable platinum(IV) complexes. Nanoparticles designed to deliver platinum(IV) complexes will also be discussed, including carbon nanotubes, carbon nanoparticles, gold nanoparticles, quantum dots, upconversion nanoparticles, and polymeric micelles. Additional nanoformulations, including supramolecular self-assembled structures, proteins, peptides, metal-organic frameworks, and coordination polymers, will then be described. Finally, the significant clinical progress made by nanoparticle formulations of platinum(II) agents will be reviewed. We anticipate that such a synthesis of disparate research efforts will not only help to generate new drug development ideas and strategies, but also will reflect our optimism that the next generation of approved platinum cancer drugs is about to arrive. PMID:26865551

  8. Targeted Delivery of Anticancer Agents via a Dual Function Nanocarrier with an Interfacial Drug-Interactive Motif

    PubMed Central

    2015-01-01

    We have developed a dual-function drug carrier, polyethylene glycol (PEG)-derivatized farnesylthiosalicylate (FTS). Here we report that incorporation of a drug-interactive motif (Fmoc) into PEG5k–FTS2 led to further improvement in both drug loading capacity and formulation stability. Doxorubicin (DOX) formulated in PEG5k–Fmoc–FTS2 showed sustained release kinetics slower than those of DOX loaded in PEG5k–FTS2. The maximum tolerated dose of DOX- or paclitaxel (PTX)-loaded PEG5k–Fmoc–FTS2 was significantly higher than that of the free drug. Pharmacokinetics and biodistribution studies showed that DOX/PEG5k–Fmoc–FTS2 mixed micelles were able to retain DOX in the bloodstream for a significant amount of time and efficiently deliver the drug to tumor sites. More importantly, drug (DOX or PTX)-loaded PEG5k–Fmoc–FTS2 led to superior antitumor activity over other treatments including drugs formulated in PEG5k–FTS2 in breast cancer and prostate cancer models. Our improved dual function carrier with a built-in drug-interactive motif represents a simple and effective system for targeted delivery of anticancer agents. PMID:25325795

  9. Molecular Diagnostic and Drug Delivery Agents based on Aptamer-Nanomaterial Conjugates

    PubMed Central

    Lee, Jung Heon; Yigit, Mehmet V.; Mazumdar, Debapriya; Lu, Yi

    2010-01-01

    Recent progress in an emerging area of designing aptamer and nanomaterial conjugates as molecular diagnostic and drug delivery agents in biomedical applications is summarized. Aptamers specific for a wide range of targets are first introduced and compared to antibodies. Methods of integrating these aptamers with a variety of nanomaterials, such as gold nanoparticles, quantum dots, carbon nanotubes, and superparamagnetic iron oxide nanoparticles, each with unique optical, magnetic, and electrochemical properties, are reviewed. Applications of these systems as fluorescent, colorimetric, magnetic resonance imaging, and electrochemical sensors in medical diagnostics are given, along with new applications as smart drug delivery agents. PMID:20338204

  10. Adenine: an important drug scaffold for the design of antiviral agents

    PubMed Central

    Wang, Changyuan; Song, Zhendong; Yu, Haiqing; Liu, Kexin; Ma, Xiaodong

    2015-01-01

    Adenine derivatives, in particular the scaffold bearing the acyclic nucleoside phosphonates (ANPS), possess significant antiviral and cytostatic activity. Till now, several effective adenine derivatives have been marketed for the treatment of HIV, HBV, CMV and other virus-infected diseases. These compounds are represented by tenofovir (PMPA), a medicine for both HIV and HBV, and adefovir as an anti-HBV agent. More than this, other analogs, such as GS9148, GS9131, and GS7340, are also well-known anti-viral agents that have been progressed to the clinical studies for their excellent activity. In general, the structures of these compounds include an adenine nucleobase linked to a phosphonate side chain. Considerable structural modifications on the scaffold itself and the peripheral sections were made. The structure-activity relationships (SARs) of this skeleton will provide valuable clues to identify more effective adenine derivatives as antiviral drugs. Here, we systematically summarized the SARs of the adenine derivatives, and gave important information for further optimizing this template. PMID:26579473

  11. Advances in drug delivery system for platinum agents based combination therapy

    PubMed Central

    Kang, Xiang; Xiao, Hai-Hua; Song, Hai-Qin; Jing, Xia-Bin; Yan, Le-San; Qi, Ruo-Gu

    2015-01-01

    Platinum-based anticancer agents are widely used as first-line drugs in cancer chemotherapy for various solid tumors. However, great side effects and occurrence of resistance remain as the major drawbacks for almost all the platinum drugs developed. To conquer these problems, new strategies should be adopted for platinum drug based chemotherapy. Modern nanotechnology has been widely employed in the delivery of various therapeutics and diagnostic. It provides the possibility of targeted delivery of a certain anticancer drug to the tumor site, which could minimize toxicity and optimize the drug efficacy. Here, in this review, we focused on the recent progress in polymer based drug delivery systems for platinum-based combination therapy. PMID:26779373

  12. Nerve agent hydrolysis activity designed into a human drug metabolism enzyme.

    PubMed

    Hemmert, Andrew C; Otto, Tamara C; Chica, Roberto A; Wierdl, Monika; Edwards, Jonathan S; Lewis, Steven M; Lewis, Steven L; Edwards, Carol C; Tsurkan, Lyudmila; Cadieux, C Linn; Kasten, Shane A; Cashman, John R; Mayo, Stephen L; Potter, Philip M; Cerasoli, Douglas M; Redinbo, Matthew R

    2011-01-01

    Organophosphorus (OP) nerve agents are potent suicide inhibitors of the essential neurotransmitter-regulating enzyme acetylcholinesterase. Due to their acute toxicity, there is significant interest in developing effective countermeasures to OP poisoning. Here we impart nerve agent hydrolysis activity into the human drug metabolism enzyme carboxylesterase 1. Using crystal structures of the target enzyme in complex with nerve agent as a guide, a pair of histidine and glutamic acid residues were designed proximal to the enzyme's native catalytic triad. The resultant variant protein demonstrated significantly increased rates of reactivation following exposure to sarin, soman, and cyclosarin. Importantly, the addition of these residues did not alter the high affinity binding of nerve agents to this protein. Thus, using two amino acid substitutions, a novel enzyme was created that efficiently converted a group of hemisubstrates, compounds that can start but not complete a reaction cycle, into bona fide substrates. Such approaches may lead to novel countermeasures for nerve agent poisoning. PMID:21445272

  13. Nerve Agent Hydrolysis Activity Designed into a Human Drug Metabolism Enzyme

    PubMed Central

    Hemmert, Andrew C.; Otto, Tamara C.; Chica, Roberto A.; Wierdl, Monika; Edwards, Jonathan S.; Lewis, Steven L.; Edwards, Carol C.; Tsurkan, Lyudmila; Cadieux, C. Linn; Kasten, Shane A.; Cashman, John R.; Mayo, Stephen L.; Potter, Philip M.; Cerasoli, Douglas M.; Redinbo, Matthew R.

    2011-01-01

    Organophosphorus (OP) nerve agents are potent suicide inhibitors of the essential neurotransmitter-regulating enzyme acetylcholinesterase. Due to their acute toxicity, there is significant interest in developing effective countermeasures to OP poisoning. Here we impart nerve agent hydrolysis activity into the human drug metabolism enzyme carboxylesterase 1. Using crystal structures of the target enzyme in complex with nerve agent as a guide, a pair of histidine and glutamic acid residues were designed proximal to the enzyme's native catalytic triad. The resultant variant protein demonstrated significantly increased rates of reactivation following exposure to sarin, soman, and cyclosarin. Importantly, the addition of these residues did not alter the high affinity binding of nerve agents to this protein. Thus, using two amino acid substitutions, a novel enzyme was created that efficiently converted a group of hemisubstrates, compounds that can start but not complete a reaction cycle, into bona fide substrates. Such approaches may lead to novel countermeasures for nerve agent poisoning. PMID:21445272

  14. Monitoring temperature-sensitive vaccines and immunologic drugs, including anthrax vaccine.

    PubMed

    Frank, K J

    1999-10-15

    The experience of the U.S. Army Medical Materiel Center, Europe (USAMMCE), in monitoring temperature-sensitive vaccines and immunologic drugs, including anthrax vaccine, during storage and shipment is discussed. USAMMCE uses an electronic monitoring device to monitor and archive the time-temperature history of shipments of various vaccines, immunoglobulins, and other drugs requiring refrigeration. Using these monitors, USAMMCE can track its carriers' performance, reduce product loss, and validate quality. USAMMCE trains people to pack refrigerated items and to activate and place the monitoring device inside the packing container. Over 1200 temperature-monitor readings from 44 U.S. military logistical depots, hospitals, and clinics located outside the United States are evaluated annually by the USAMMCE pharmacist; each reading represents one shipment or packed box. When deactivated during unpacking, the device flashes green for a successful shipment (all temperature readings within the ideal range) or red for a potentially problematic shipment. From January through October 1998, the device was used in 750 temperature-sensitive shipments; 72% of the devices were returned to USAMMCE in green condition and the remainder in red. Of the red-flashing monitors, 15% were determined to signal that the drugs were received in unacceptable condition. USAMMCE successfully shipped more than 26,000 vials of anthrax vaccine from February through October 1998 within the manufacturer's guidelines for storage temperature. Temperature monitoring is essential for proper storage and transport of vaccines and immunologic drugs. PMID:10541032

  15. Measurement of drug facilitated sexual assault agents in simulated sweat by ion mobility spectrometry.

    PubMed

    Demoranville, Leonard T; Verkouteren, Jennifer R

    2013-03-15

    Ion mobility spectrometry has found widespread use for the detection of explosives and illicit drugs. The technique offers rapid results with high sensitivity and little sample preparation. As such, it is well suited for field deployed screening settings. Here the response of ion mobility spectrometers for three drug-facilitated sexual assault (DFSA) agents - flunitrazepam, ketamine, and MDMA - and related metabolites has been studied in the presence of a simulated sweat. While all three DFSA agents present certain challenges for qualitative identification, IMS can provide useful information to guide the early treatment and investigation of sexual assault cases. Used as a presumptive test, the identification of DFSA agents would later require confirmatory analysis by other techniques. PMID:23598140

  16. Drug-resistant tuberculosis in subjects included in the Second National Survey on Antituberculosis Drug Resistance in Porto Alegre, Brazil*, **

    PubMed Central

    Micheletti, Vania Celina Dezoti; Moreira, José da Silva; Ribeiro, Marta Osório; Kritski, Afranio Lineu; Braga, José Ueleres

    2014-01-01

    OBJECTIVE: To describe the prevalence of multidrug-resistant tuberculosis (MDR-TB) among tuberculosis patients in a major Brazilian city, evaluated via the Second National Survey on Antituberculosis Drug Resistance, as well as the social, demographic, and clinical characteristics of those patients. METHODS: Clinical samples were collected from tuberculosis patients seen between 2006 to 2007 at three hospitals and five primary health care clinics participating in the survey in the city of Porto Alegre, Brazil. The samples were subjected to drug susceptibility testing. The species of mycobacteria was confirmed using biochemical methods. RESULTS: Of the 299 patients included, 221 (73.9%) were men and 77 (27.3%) had a history of tuberculosis. The mean age was 36 years. Of the 252 patients who underwent HIV testing, 66 (26.2%) tested positive. The prevalence of MDR-TB in the sample as a whole was 4.7% (95% CI: 2.3-7.1), whereas it was 2.2% (95% CI: 0.3-4.2) among the new cases of tuberculosis and 12.0% (95% CI: 4.5-19.5) among the patients with a history of tuberculosis treatment. The multivariate analysis showed that a history of tuberculosis and a longer time to diagnosis were both associated with MDR-TB. CONCLUSIONS: If our results are corroborated by other studies conducted in Brazil, a history of tuberculosis treatment and a longer time to diagnosis could be used as predictors of MDR-TB. PMID:24831400

  17. 21 CFR 700.13 - Use of mercury compounds in cosmetics including use as skinbleaching agents in cosmetic...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 7 2010-04-01 2010-04-01 false Use of mercury compounds in cosmetics including...) COSMETICS GENERAL Requirements for Specific Cosmetic Products § 700.13 Use of mercury compounds in cosmetics..., mercury compounds have also been widely used as preservatives in cosmetics such as hand and body...

  18. 21 CFR 700.13 - Use of mercury compounds in cosmetics including use as skinbleaching agents in cosmetic...

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 7 2013-04-01 2013-04-01 false Use of mercury compounds in cosmetics including...) COSMETICS GENERAL Requirements for Specific Cosmetic Products § 700.13 Use of mercury compounds in cosmetics..., mercury compounds have also been widely used as preservatives in cosmetics such as hand and body...

  19. 21 CFR 700.13 - Use of mercury compounds in cosmetics including use as skinbleaching agents in cosmetic...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 7 2011-04-01 2010-04-01 true Use of mercury compounds in cosmetics including use... GENERAL Requirements for Specific Cosmetic Products § 700.13 Use of mercury compounds in cosmetics..., mercury compounds have also been widely used as preservatives in cosmetics such as hand and body...

  20. 21 CFR 700.13 - Use of mercury compounds in cosmetics including use as skinbleaching agents in cosmetic...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 7 2014-04-01 2014-04-01 false Use of mercury compounds in cosmetics including...) COSMETICS GENERAL Requirements for Specific Cosmetic Products § 700.13 Use of mercury compounds in cosmetics..., mercury compounds have also been widely used as preservatives in cosmetics such as hand and body...

  1. 21 CFR 700.13 - Use of mercury compounds in cosmetics including use as skinbleaching agents in cosmetic...

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 7 2012-04-01 2012-04-01 false Use of mercury compounds in cosmetics including...) COSMETICS GENERAL Requirements for Specific Cosmetic Products § 700.13 Use of mercury compounds in cosmetics..., mercury compounds have also been widely used as preservatives in cosmetics such as hand and body...

  2. VEGF pathway targeting agents, vessel normalization and tumor drug uptake: from bench to bedside

    PubMed Central

    Arjaans, Marlous; Schröder, Carolina P.; Oosting, Sjoukje F.; Dafni, Urania; Kleibeuker, Josée E.; de Vries, Elisabeth G.E.

    2016-01-01

    Vascular endothelial growth factor (VEGF) pathway targeting agents have been combined with other anticancer drugs, leading to improved efficacy in carcinoma of the cervix, stomach, lung, colon and rectum, ovary, and breast. Vessel normalization induced by VEGF pathway targeting agents influences tumor drug uptake. Following bevacizumab treatment, preclinical and clinical studies have shown a decrease in tumor delivery of radiolabeled antibodies and two chemotherapeutic drugs. The decrease in vessel pore size during vessel normalization might explain the decrease in tumor drug uptake. Moreover, the addition of bevacizumab to cetuximab, or panitumumab in colorectal cancer patients or to trastuzumab in breast cancer patients, did not improve efficacy. However, combining bevacizumab with chemotherapy did increase efficacy in some cancer types. Novel biomarkers to select patients who may benefit from combination therapies, such as the effect of an angiogenesis inhibitor on tumor perfusion, requires innovative trial designs and large clinical trials. Small imaging studies with radiolabeled drugs could be used in the interphase to gain further insight into the interplay between VEGF targeted therapy, vessel normalization and tumor drug delivery. PMID:26789111

  3. 38 CFR 48.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c... that you may impose upon them for drug abuse violations occurring in the workplace. ... drug-free awareness program? 48.215 Section 48.215 Pensions, Bonuses, and Veterans' Relief...

  4. Photophysical characterization of anticancer drug valrubicin in rHDL nanoparticles and its use as an imaging agent.

    PubMed

    Shah, Sunil; Chib, Rahul; Raut, Sangram; Bermudez, Jaclyn; Sabnis, Nirupama; Duggal, Divya; Kimball, Joseph D; Lacko, Andras G; Gryczynski, Zygmunt; Gryczynski, Ignacy

    2016-02-01

    Nanoparticles are target-specific drug delivery agents that are increasingly used in cancer therapy to enhance bioavailability and to reduce off target toxicity of anti-cancer agents. Valrubicin is an anti-cancer drug, currently approved only for vesicular bladder cancer treatment because of its poor water solubility. On the other hand, valrubicin carrying reconstituted high density lipoprotein (rHDL) nanoparticles appear ideally suited for extended applications, including systemic cancer chemotherapy. We determined selected fluorescence properties of the free (unencapsulated) drug vs. valrubicin incorporated into rHDL nanoparticles. We have found that upon encapsulation into rHDL nanoparticles the quantum yield of valrubicin fluorescence increased six fold while its fluorescence lifetime increased about 2 fold. Accordingly, these and potassium iodide (KI) quenching data suggest that upon incorporation, valrubicin is localized deep in the interior of the nanoparticle, inside the lipid matrix. Fluorescence anisotropy of the rHDL valrubicin nanoparticles was also found to be high along with extended rotational correlation time. The fluorescence of valrubicin could also be utilized to assess its distribution upon delivery to prostate cancer (PC3) cells. Overall the fluorescence properties of the rHDL: valrubicin complex reveal valuable novel characteristics of this drug delivery vehicle that may be particularly applicable when used in systemic (intravenous) therapy. PMID:26735001

  5. A Distributed, Collaborative Intelligent Agent System Approach for Proactive Postmarketing Drug Safety Surveillance

    PubMed Central

    Ji, Yanqing; Ying, Hao; Farber, Margo S.; Yen, John; Dews, Peter; Miller, Richard E.; Massanari, R. Michael

    2014-01-01

    Discovering unknown adverse drug reactions (ADRs) in postmarketing surveillance as early as possible is of great importance. The current approach to postmarketing surveillance primarily relies on spontaneous reporting. It is a passive surveillance system and limited by gross underreporting (<10% reporting rate), latency, and inconsistent reporting. We propose a novel team-based intelligent agent software system approach for proactively monitoring and detecting potential ADRs of interest using electronic patient records. We designed such a system and named it ADRMonitor. The intelligent agents, operating on computers located in different places, are capable of continuously and autonomously collaborating with each other and assisting the human users (e.g., the food and drug administration (FDA), drug safety professionals, and physicians). The agents should enhance current systems and accelerate early ADR identification. To evaluate the performance of the ADRMonitor with respect to the current spontaneous reporting approach, we conducted simulation experiments on identification of ADR signal pairs (i.e., potential links between drugs and apparent adverse reactions) under various conditions. The experiments involved over 275 000 simulated patients created on the basis of more than 1000 real patients treated by the drug cisapride that was on the market for seven years until its withdrawal by the FDA in 2000 due to serious ADRs. Healthcare professionals utilizing the spontaneous reporting approach and the ADRMonitor were separately simulated by decision-making models derived from a general cognitive decision model called fuzzy recognition-primed decision (RPD) model that we recently developed. The quantitative simulation results show that 1) the number of true ADR signal pairs detected by the ADRMonitor is 6.6 times higher than that by the spontaneous reporting strategy; 2) the ADR detection rate of the ADRMonitor agents with even moderate decision-making skills is five

  6. A distributed, collaborative intelligent agent system approach for proactive postmarketing drug safety surveillance.

    PubMed

    Ji, Yanqing; Ying, Hao; Farber, Margo S; Yen, John; Dews, Peter; Miller, Richard E; Massanari, R Michael

    2010-05-01

    Discovering unknown adverse drug reactions (ADRs) in postmarketing surveillance as early as possible is of great importance. The current approach to postmarketing surveillance primarily relies on spontaneous reporting. It is a passive surveillance system and limited by gross underreporting (<10% reporting rate), latency, and inconsistent reporting. We propose a novel team-based intelligent agent software system approach for proactively monitoring and detecting potential ADRs of interest using electronic patient records. We designed such a system and named it ADRMonitor. The intelligent agents, operating on computers located in different places, are capable of continuously and autonomously collaborating with each other and assisting the human users (e.g., the food and drug administration (FDA), drug safety professionals, and physicians). The agents should enhance current systems and accelerate early ADR identification. To evaluate the performance of the ADRMonitor with respect to the current spontaneous reporting approach, we conducted simulation experiments on identification of ADR signal pairs (i.e., potential links between drugs and apparent adverse reactions) under various conditions. The experiments involved over 275,000 simulated patients created on the basis of more than 1000 real patients treated by the drug cisapride that was on the market for seven years until its withdrawal by the FDA in 2000 due to serious ADRs. Healthcare professionals utilizing the spontaneous reporting approach and the ADRMonitor were separately simulated by decision-making models derived from a general cognitive decision model called fuzzy recognition-primed decision (RPD) model that we recently developed. The quantitative simulation results show that 1) the number of true ADR signal pairs detected by the ADRMonitor is 6.6 times higher than that by the spontaneous reporting strategy; 2) the ADR detection rate of the ADRMonitor agents with even moderate decision-making skills is five

  7. Histamine, a vasoactive agent with vascular disrupting potential, improves tumour response by enhancing local drug delivery

    PubMed Central

    Brunstein, F; Rens, J; van Tiel, S T; Eggermont, A M M; ten Hagen, T L M

    2006-01-01

    Tumour necrosis factor (TNF)-based isolated limb perfusion (ILP) is an approved and registered treatment for sarcomas confined to the limbs in Europe since 1998, with limb salvage indexes of 76%. TNF improves drug distribution in solid tumours and secondarily destroys the tumour-associated vasculature (TAV). Here we explore the synergistic antitumour effect of another vasoactive agent, histamine (Hi), in doxorubicin (DXR)-based ILP and evaluate its antivascular effects on TAV. We used our well-established rat ILP model for in vivo studies looking at tumour response, drug distribution and effects on tumour vessels. In vitro studies explored drug interactions at cellular level on tumour cells (BN-175) and Human umbilical vein endothelial cells (HUVEC). There was a 17% partial response and a 50% arrest in tumour growth when Hi was combined to DXR, without important side effects, against 100% progressive disease with DXR alone and 29% arrest in tumour growth for Hi alone. Histology documented an increased DXR leakage in tumour tissue combined to a destruction of the TAV, when Hi was added to the ILP. In vitro no synergy between the drugs was observed. In conclusion, Hi is a vasoactive drug, targeting primarily the TAV and synergises with different chemotherapeutic agents. PMID:17106443

  8. Ephrin receptor A10 is a promising drug target potentially useful for breast cancers including triple negative breast cancers.

    PubMed

    Nagano, Kazuya; Maeda, Yuka; Kanasaki, So-Ichiro; Watanabe, Takanobu; Yamashita, Takuya; Inoue, Masaki; Higashisaka, Kazuma; Yoshioka, Yasuo; Abe, Yasuhiro; Mukai, Yohei; Kamada, Haruhiko; Tsutsumi, Yasuo; Tsunoda, Shin-ichi

    2014-09-10

    Ephrin receptor A10 (EphA10) is a relatively uncharacterized protein which is expressed in many breast cancers but not expressed in normal breast tissues. Here, we examined the potential of EphA10 as a drug target in breast cancer. Immunohistochemical staining of clinical tissue sections revealed that EphA10 was expressed in various breast cancer subtypes, including triple negative breast cancers (TNBCs), with no expression observed in normal tissues apart from testis. Ligand-dependent proliferation was observed in EphA10-transfected MDA-MB-435 cells (MDA-MB-435(EphA10)) and native TNBC cells (MDA-MB-436). However, this phenomenon was not observed in parental MDA-MB-435 cells which express a low level of EphA10. Finally, tumor growth was significantly suppressed by administration of an anti-EphA10 monoclonal antibody in a xenograft mouse model. These results suggest that inhibition of EphA10 signaling may be a novel therapeutic option for management of breast cancer, including TNBCs which are currently not treated with molecularly targeted agents. PMID:24946238

  9. Pharmacological exploitation of the phenothiazine antipsychotics to develop novel antitumor agents-A drug repurposing strategy.

    PubMed

    Wu, Chia-Hsien; Bai, Li-Yuan; Tsai, Ming-Hsui; Chu, Po-Chen; Chiu, Chang-Fang; Chen, Michael Yuanchien; Chiu, Shih-Jiuan; Chiang, Jo-Hua; Weng, Jing-Ru

    2016-01-01

    Phenothiazines (PTZs) have been used for the antipsychotic drugs for centuries. However, some of these PTZs have been reported to exhibit antitumor effects by targeting various signaling pathways in vitro and in vivo. Thus, this study was aimed at exploiting trifluoperazine, one of PTZs, to develop potent antitumor agents. This effort culminated in A4 [10-(3-(piperazin-1-yl)propyl)-2-(trifluoromethyl)-10H-phenothiazine] which exhibited multi-fold higher apoptosis-inducing activity than the parent compound in oral cancer cells. Compared to trifluoperazine, A4 demonstrated similar regulation on the phosphorylation or expression of multiple molecular targets including Akt, p38, and ERK. In addition, A4 induced autophagy, as evidenced by increased expression of the autophagy biomarkers LC3B-II and Atg5, and autophagosomes formation. The antitumor activity of A4 also related to production of reactive oxygen species and adenosine monophosphate-activated protein kinase. Importantly, the antitumor utility of A4 was extended in vivo as it, administrated at 10 and 20 mg/kg intraperitoneally, suppressed the growth of Ca922 xenograft tumors. In conclusion, the ability of A4 to target diverse aspects of cancer cell growth suggests its value in oral cancer therapy. PMID:27277973

  10. Display technologies: application for the discovery of drug and gene delivery agents

    PubMed Central

    Sergeeva, Anna; Kolonin, Mikhail G.; Molldrem, Jeffrey J.; Pasqualini, Renata; Arap, Wadih

    2007-01-01

    Recognition of molecular diversity of cell surface proteomes in disease is essential for the development of targeted therapies. Progress in targeted therapeutics requires establishing effective approaches for high-throughput identification of agents specific for clinically relevant cell surface markers. Over the past decade, a number of platform strategies have been developed to screen polypeptide libraries for ligands targeting receptors selectively expressed in the context of various cell surface proteomes. Streamlined procedures for identification of ligand-receptor pairs that could serve as targets in disease diagnosis, profiling, imaging and therapy have relied on the display technologies, in which polypeptides with desired binding profiles can be serially selected, in a process called biopanning, based on their physical linkage with the encoding nucleic acid. These technologies include virus/phage display, cell display, ribosomal display, mRNA display and covalent DNA display (CDT), with phage display being by far the most utilized. The scope of this review is the recent advancements in the display technologies with a particular emphasis on molecular mapping of cell surface proteomes with peptide phage display. Prospective applications of targeted compounds derived from display libraries in the discovery of targeted drugs and gene therapy vectors are discussed. PMID:17123658

  11. Importance of Relating Efficacy Measures to Unbound Drug Concentrations for Anti-Infective Agents

    PubMed Central

    Gonzalez, Daniel; Schmidt, Stephan

    2013-01-01

    SUMMARY For the optimization of dosing regimens of anti-infective agents, it is imperative to have a good understanding of pharmacokinetics (PK) and pharmacodynamics (PD). Whenever possible, drug efficacy needs to be related to unbound concentrations at the site of action. For anti-infective drugs, the infection site is typically located outside plasma, and a drug must diffuse through capillary membranes to reach its target. Disease- and drug-related factors can contribute to differential tissue distribution. As a result, the assumption that the plasma concentration of drugs represents a suitable surrogate of tissue concentrations may lead to erroneous conclusions. Quantifying drug exposure in tissues represents an opportunity to relate the pharmacologically active concentrations to an observed pharmacodynamic parameter, such as the MIC. Selection of an appropriate specimen to sample and the advantages and limitations of the available sampling techniques require careful consideration. Ultimately, the goal will be to assess the appropriateness of a drug and dosing regimen for a specific pathogen and infection. PMID:23554417

  12. Screening of antimicrobial agents for in vitro radiation protection and mitigation capacity, including those used in supportive care regimens for bone marrow transplant recipients.

    PubMed

    Epperly, Michael W; Franicola, Darcy; Shields, Donna; Rwigema, Jean-Claude; Stone, Brandon; Zhang, Xichen; McBride, William; Georges, George; Wipf, Peter; Greenberger, Joel S

    2010-01-01

    Antibiotic and antifungal agents used in supportive care regimens for bone marrow transplantation recipients contribute to a significant dose-modifying effect of otherwise lethal total body irradiation. To determine whether drugs used in supportive care and other commonly used antibiotics such as tetracycline function as radiation protectors or damage mitigators in vitro, 13 drugs were tested for radiation protection and radiation damage mitigation of 32D cl 3 hematopoietic progenitor cells in clonagenic survival curves in vitro. Antibiotic/Antifungal agents including cilastatin, amikacin, ceftazidine, vancomycin, tetracycline, doxycycline, ciprofloxacin, metronidazole, methacycline, minocycline, meclocycline, oxytetracycline and rolitetracycline were added in 1, 10, or 100 micromolar concentrations to murine interleukin-3-dependent hematopoietic progenitor cell line 32D cl 3 cells either before or after irradiation of 0 to 8 Gy. Control irradiated 32D cl 3 cells showed radiosensitivity comparable to freshly explanted mouse marrow hematopoietic progenitor cells (D(0) 1.1+/-0.1 Gy, N 1.5+/-0.4). Positive control GS-nitroxide JP4-039 (known radiation mitigator) treated 32D cl 3 cells were radioresistant (D(0) 1.2+/-0.1, N 5.8+/-2.4 (p=0.009)). Of the 13 drugs tested, tetracycline was found to be a significant radiation mitigator (D(0) 0.9+/-0.1, N 13.9+/-0.4 (p=0.0027)). Thus, the radiation dose-modifying effect of some antibiotics, but not those currently used in the supportive care (antibiotic/antifungal regimens) for marrow transplant patients, may act as radiation damage mitigators for hematopoietic cells as well as decreasing the growth and inflammatory response to microbial pathogens. PMID:20133970

  13. Hallucinogens and Dissociative Drugs, Including LSD, PCP, Ketamine, Dextromethorphan. National Institute on Drug Abuse Research Report Series.

    ERIC Educational Resources Information Center

    National Inst. on Drug Abuse (DHHS/PHS), Rockville, MD.

    Research is developing a clearer picture of the dangers of mind-altering drugs. The goal of this report is to present the latest information to providers to help them strengthen their prevention and treatment efforts. A description is presented of dissociative drugs, and consideration is given as to why people take hallucinogens. The physical…

  14. Anti-platelet agents augment cisplatin nanoparticle cytotoxicity by enhancing tumor vasculature permeability and drug delivery

    NASA Astrophysics Data System (ADS)

    Pandey, Ambarish; Sarangi, Sasmit; Chien, Kelly; Sengupta, Poulomi; Papa, Anne-Laure; Basu, Sudipta; Sengupta, Shiladitya

    2014-11-01

    Tumor vasculature is critically dependent on platelet mediated hemostasis and disruption of the same can augment delivery of nano-formulation based chemotherapeutic agents which depend on enhanced permeability and retention for tumor penetration. Here, we evaluated the role of Clopidogrel, a well-known inhibitor of platelet aggregation, in potentiating the tumor cytotoxicity of cisplatin nano-formulation in a murine breast cancer model. In vivo studies in murine syngeneic 4T1 breast cancer model showed a significant greater penetration of macromolecular fluorescent nanoparticles after clopidogrel pretreatment. Compared to self-assembling cisplatin nanoparticles (SACNs), combination therapy with clopidogrel and SACN was associated with a 4 fold greater delivery of cisplatin to tumor tissue and a greater reduction in tumor growth as well as higher survival rate. Clopidogrel enhances therapeutic efficiency of novel cisplatin based nano-formulations agents by increasing tumor drug delivery and can be used as a potential targeting agent for novel nano-formulation based chemotherapeutics.

  15. Novel Drug Therapies for Fertility Preservation in Men Undergoing Chemotherapy: Clinical Relevance of Protector Agents.

    PubMed

    Rabaça, A; Sousa, M; Alves, M G; Oliveira, P F; Sá, R

    2015-01-01

    Cancer has been affecting a growing number of children, adolescents and adult males in reproductive age. Male reproductive potential is adversely affected by chemotherapeutic drugs and patients are at risk for prolonged infertility. Fertility recovery is related to the chemotherapeutic agent and dosage used, being thus difficult to predict. As a result, there is a strong need to identify a natural or synthetic compound that is able to preserve male fertility without interfering with the efficacy of the chemotherapeutic regimen. New procedures, as well as several drugs, are being investigated to assess their efficiency in protecting male reproductive functions from the chemotherapy side-effects. This review provides an overview of the wide range of chemotherapeutic drugs regularly used in cancer treatment and their detrimental effects on male fertility. In addition, it also assesses the existing protector agents for male fertility and their usefulness in preserving and protecting male reproductive functions exposed to chemotherapeutics. Several protector agents for male fertility are being studied, and results are promising. Nonetheless, further research must be implemented to identify a supplemental therapy that addresses the multiple side effects of chemotherapy on male reproductive function. Until such therapy is discovered, it is fundamental that all fertility preservation options are discussed with patients, before treatment is initiated, to assure parenthood. PMID:26295467

  16. Screening a panel of drugs with diverse mechanisms of action yields potential therapeutic agents against neuroblastoma

    PubMed Central

    Gheeya, Jinesh S.; Chen, Qing-Rong; Benjamin, Christopher D.; Cheuk, Adam T.; Tsang, Patricia; Chung, Joon-Yong; Metaferia, Belhu B.; Badgett, Thomas C.; Johansson, Peter; Wei, Jun S.; Hewitt, Stephen M.

    2009-01-01

    Neuroblastoma (NB) is the most common extracranial solid tumor in children. Despite current aggressive therapy, the survival rate for high risk NB remains less than 40%. To identify novel effective chemo-agents against NB, we screened a panel of 96 drugs against two NB cell lines, SK-N-AS and SH-SY5Y. We found 30 compounds that were active against NB cell lines at ≤ 10 µM concentration. More interestingly, 17 compounds are active at ≤ 1 µM concentration, and they act through a wide spectrum of diverse mechanisms such as mitotic inhibition, topoisomerase inhibition, targeting various biological pathways, and unknown mechanisms. The majority of these active compounds also induced caspase 3/7 by more than 2-fold. Of these 17 active compounds against NB cell lines at sub-micromolar concentration, 11 compounds are not currently used to treat NB. Among them, 9 are FDA approved compounds, and 3 agents are undergoing clinical trials for various malignancies. Furthermore, we identified 4 agents active against these NB cell lines that have not yet been tested in the clinical setting. Finally we demonstrated that Cucurbitacin I inhibits neuroblastoma cell growth through inhibition of STAT3 pathway. These drugs thus represent potential novel therapeutic agents for patients with NB, and further validation studies are needed to translate them to the clinic. PMID:19946221

  17. Development and Optimization of a Doxorubicin Loaded Poly Lactic Acid Contrast Agent for Ultrasound Directed Drug Delivery

    PubMed Central

    Eisenbrey, J.R.; Burstein, O. Mualem; Kambhampati, R.; Forsberg, F.; Liu, J-B.; Wheatley, M.A.

    2010-01-01

    An echogenic, intravenous drug delivery platform is proposed in which an encapsulated chemotherapeutic can travel to a desired location and drug delivery can be triggered using external, focused ultrasound at the area of interest. Three methods of loading poly lactic acid (PLA) shelled ultrasound contrast agents (UCA) with doxorubicin are presented. Effects on encapsulation efficiency, in vitro enhancement, stability, particle size, morphology and release during UCA rupture are compared by loading method and drug concentration. An agent containing doxorubicin within the shell was selected as an ideal candidate for future hepatocellular carcinoma studies. The agent achieved a maximal drug load of 6.2 mg Dox/g PLA with an encapsulation efficiency of 20.5%, showed a smooth surface morphology and tight size distribution (poly dispersity index = 0.309) with a peak size of 1865 nm. Acoustically, the agent provided 19 dB of enhancement in vitro at a dosage of 10 µg/ml, with a half life of over 15 mins. In vivo, the agent provided ultrasound enhancement of 13.4 ± 1.6 dB within the ascending aorta of New Zealand rabbits at a dose of 0.15 ml/kg. While the drug-incorporated agent is thought to be well suited for future drug delivery experiments, this study has shown that agent properties can be tailored for specific applications based on choice of drug loading method. PMID:20060024

  18. Modified agar dilution susceptibility testing method for determining in vitro activities of antifungal agents, including azole compounds.

    PubMed Central

    Yoshida, T; Jono, K; Okonogi, K

    1997-01-01

    In vitro activities of antifungal agents, including azole compounds, against yeasts were easily determined by using RPMI-1640 agar medium and by incubating the plates in the presence of 20% CO2. The end point of inhibition was clear by this method, even in the case of azole compounds, because of the almost complete inhibition of yeast growth at high concentrations which permitted weak growth of some Candida strains by traditional methods. MICs obtained by the agar dilution method were similar to those obtained by the broth dilution method proposed by the National Committee for Clinical Laboratory Standards. PMID:9174197

  19. Channeling agent and drug release from a central core matrix tablet.

    PubMed

    González-Rodríguez, M L; Pérez-Martínez, J I; Merino, S; Fini, A; Rabasco, A M

    2001-05-01

    A new oral dosage form for controlled and complete release of drug after a predetermined lag time is described. The system, designed to exploit the relatively constant small intestine transit time, consists of a drug-containing core coated with a polymeric matrix formed by a channeling agent (NaCl, mannitol, and Emdex) and an inert polymer (Eudragit RS100). The lag time was found to be dependent on type and particle size of the channeling substances used. Also, rheological properties of the binary mixtures (channeling substance--polymer) can affect the lag time periods. On the other hand, the release kinetics were found to be influenced significantly by excipient type and particle size. Results obtained from in vitro dissolution testing demonstrated that this device potentially could be used to deliver drugs orally for up to once-a-day dosing at controllable rates. PMID:11448051

  20. Use of alternative specimens: drugs of abuse in saliva and doping agents in hair.

    PubMed

    Kintz, Pascal; Samyn, Nele

    2002-04-01

    It is generally accepted that chemical testing of biologic fluids is the most objective means of diagnosis of drug use. The presence of a drug analyte in a biologic specimen can be used to document exposure. The standard for drug testing in toxicology is an immunoassay screen conducted on a urine sample, followed by confirmation by gas chromatography with mass spectrometric detection. In recent years, remarkable advances in sensitive analytic techniques have enabled the analysis of drugs in unconventional biologic specimens such as saliva or hair. The aim of this review is to document the current status of drugs of abuse testing in saliva and some doping agents in hair. The influence on drug concentration of the procedure of saliva sampling is described. Screening procedures along with specific methods are reviewed for the determination of amphetamines, cannabis, cocaine, and opiates in saliva. Before an extensive review on the detection of anabolics, corticosteroids, and beta-adrenergic stimulants in hair, the place of this specimen in doping control is discussed, with a focus on the potential problems of this new technology. PMID:11897970

  1. Biodirected synthesis of Miconazole-conjugated bacterial silver nanoparticles and their application as antifungal agents and drug delivery vehicles.

    PubMed

    Kumar, C Ganesh; Poornachandra, Y

    2015-01-01

    The recent strategy to improve the efficacy of drugs is to combine them with metal nanoparticles for the control of microbial infections. Considering this fact, we developed a low cost and eco-friendly method for silver nanoparticles synthesis using the cell free supernatant of Delftia sp. strain KCM-006 and their application as antifungal agents and as a drug carrier. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) analysis revealed the formation of spherical and monodispersed silver nanoparticles with an average size of 9.8 nm. The synthesized nanoparticles were found to be photoluminescent, highly stable and crystalline in nature having a zeta potential of -31 mV. The silver nanoparticles exhibited very good antifungal activity against various pathogenic Candida strains. Furthermore, the efficacy of nanoparticles was increased by conjugating the antifungal drug Miconazole to silver nanoparticles which exhibited significant fungicidal activity, inhibition of ergosterol biosynthesis and biofilm inhibition by increasing ROS levels. In addition, the cell viability and immunocytochemistry analysis against different normal cell lines including Chinese hamster ovary cells (CHO), human lung cell line (MRC5) and human vascular endothelial cells (HUVEC) demonstrated that these nanoparticles were non-toxic up to a concentration of 20 μM. In conclusion, these results suggest that the synthesized nanoparticles find application as both antifungal agents and drug delivery vehicles. This is a first report on the preparation of silver nanoparticles using culture supernatant from Delftia sp. and also on the conjugation of Miconazole, an antifungal drug, to the bacterial silver nanoparticles. PMID:25460601

  2. A Systematic Screen of FDA-Approved Drugs for Inhibitors of Biological Threat Agents

    PubMed Central

    Madrid, Peter B.; Chopra, Sidharth; Manger, Ian D.; Gilfillan, Lynne; Keepers, Tiffany R.; Shurtleff, Amy C.; Green, Carol E.; Iyer, Lalitha V.; Dilks, Holli Hutcheson; Davey, Robert A.; Kolokoltsov, Andrey A.; Carrion, Ricardo; Patterson, Jean L.; Bavari, Sina; Panchal, Rekha G.; Warren, Travis K.; Wells, Jay B.; Moos, Walter H.; Burke, RaeLyn L.; Tanga, Mary J.

    2013-01-01

    Background The rapid development of effective medical countermeasures against potential biological threat agents is vital. Repurposing existing drugs that may have unanticipated activities as potential countermeasures is one way to meet this important goal, since currently approved drugs already have well-established safety and pharmacokinetic profiles in patients, as well as manufacturing and distribution networks. Therefore, approved drugs could rapidly be made available for a new indication in an emergency. Methodology/Principal Findings A large systematic effort to determine whether existing drugs can be used against high containment bacterial and viral pathogens is described. We assembled and screened 1012 FDA-approved drugs for off-label broad-spectrum efficacy against Bacillus anthracis; Francisella tularensis; Coxiella burnetii; and Ebola, Marburg, and Lassa fever viruses using in vitro cell culture assays. We found a variety of hits against two or more of these biological threat pathogens, which were validated in secondary assays. As expected, antibiotic compounds were highly active against bacterial agents, but we did not identify any non-antibiotic compounds with broad-spectrum antibacterial activity. Lomefloxacin and erythromycin were found to be the most potent compounds in vivo protecting mice against Bacillus anthracis challenge. While multiple virus-specific inhibitors were identified, the most noteworthy antiviral compound identified was chloroquine, which disrupted entry and replication of two or more viruses in vitro and protected mice against Ebola virus challenge in vivo. Conclusions/Significance The feasibility of repurposing existing drugs to face novel threats is demonstrated and this represents the first effort to apply this approach to high containment bacteria and viruses. PMID:23577127

  3. Editorial: Current status and perspective on drug targets in tubercle bacilli and drug design of antituberculous agents based on structure-activity relationship.

    PubMed

    Tomioka, Haruaki

    2014-01-01

    Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death. However, the development of new drugs for the treatment and prophylaxis of TB, particularly those truly active against dormant and persistent types of tubercle bacilli, has been slow, although some promising drugs, such as diarylquinoline TMC207, nitroimidazopyran PA-824, nitroimidazo-oxazole Delamanid (OPC-67683), oxazolidinone PNU-100480, ethylene diamine SQ-109, and pyrrole derivative LL3858, are currently under phase 1 to 3 clinical trials. Therefore, novel types of antituberculous drug, which act on unique drug targets in Mycobacterium tuberculosis (MTB) pathogens, particularly drug targets related to the establishment of mycobacterial dormancy in the host's macrophages, are urgently needed. In this context, it should be noted that current anti-TB drugs mostly target the metabolic reactions and proteins which are essential for the growth of MTB in extracellular milieus. It may also be promising to develop another type of drug that exerts an inhibitory action against bacterial virulence factors which cross-talk and interfere with signaling pathways of MTB-infected immunocompetent host cells, such as lymphocytes, macrophages, and NK cells, thereby changing the intracellular milieus that are favorable to intramacrophage survival and the growth of infected bacilli. This special issue contains ten review articles, dealing with recent approaches to identify and establish novel drug targets in MTB for the development of new and unique antitubercular drugs, including those related to mycobacterial dormancy and crosstalk with cellular signaling pathways. In addition, this special issue contains some review papers with special reference to the drug design based on quantitative structure-activity relationship (QSAR) analysis, especially three-dimensional (3D)-QSAR. New, critical information on the entire genome of MTB and mycobacterial virulence genes is

  4. Balancing stealth and echogenic properties in an ultrasound contrast agent with drug delivery potential.

    PubMed

    Jablonowski, Lauren J; Alfego, David; Andorko, James I; Eisenbrey, John R; Teraphongphom, Nutte; Wheatley, Margaret A

    2016-10-01

    Contrast agents are currently being modified to combine diagnostic and therapeutic capabilities. For ultrasound (US) imaging with polymeric contrast agents, it is necessary to modify the shell to create "stealth" microbubbles but without these modifications sacrificing the agent's ability to interact with the focused US beam. We hypothesize that addition of the classic immune shielding molecule polyethylene glycol (PEG) to a polylactide (PLA) microbubble shell will affect the acoustic and physical properties of the resulting agents. In an effort to determine the best formulation to achieve a balance between stealth and acoustic activity, we compared two PEGylation techniques; addition of increasing amounts of PEG-PLA copolymer and employing incorporation of a PEG lipid (LipidPEG) into the shell. Loss of acoustic enhancement occurred in a dose-dependent manner for both types of PEGylated agents (loss of signal occurred at >5 wt% PEG-PLA and >1 wt% LipidPEG), while immune activation was also reduced in a dose-dependent manner for the PEG-PLA agents. This study shows that the balance between acoustic behavior and improved immune avoidance was scalable and successful to different degrees with both PEGylation methods, and was best achieved using for PEG-PLA at 5 wt% and for LipidPEG at 1 wt%. Studies are ongoing to evaluate the best method for the targeting and drug delivery capabilities of these agents for applications in cancer treatment. This study represents the basis for understanding the consequences of making modifications to the native polymeric shell. PMID:27388945

  5. Distribution of drug-resistant bacteria and rational use of clinical antimicrobial agents

    PubMed Central

    ZHOU, CHENLIANG; CHEN, XIAOBING; WU, LIWEN; QU, JING

    2016-01-01

    Open wound may lead to infection in patients. Due to overuse of medication, certain bacteria have become resistant to drugs currently available. The aim of the present study was to provide a guide to ameliorate the appropriate and rational use of clinical antimicrobial agents by analyzing the distribution of drug-resistant pathogenic bacteria in patients. Between October 2013 and January 2015, 126 patients were selected at the Department of Orthopedics. Wound secretion samples were collected, and the pathogen bacteria isolated and identified. Identification was performed using an automated identification instrument and the Kirby-Bauer antibiotic method was used to evaluate the bacterial resistance. Of the 126 patients, 118 patients were infected (infection rate, 93.65%). Additionally, 47 strains of gram-positive pathogenic bacteria (39.83%) and 71 strains of pathogenic-gram negative bacteria (60.17%) were identified. The bacteria were most likely to be resistant to penicillin while sensitive to vancomycin and imipenem. Some bacteria were resistant to several antibacterial agents. The results showed that existing risk factors at the Department of Orthopedics were complex and any non-standard procedures were able to cause bacterial infection. There were obvious dissimilarities among infectious bacteria with regard to their sensitivity to various antibacterial agents. Manipulation techniques during the treatment process were performed in a sterile manner and the use of antibacterial agents was required to be strictly in accordance with the results of drug sensitivity tests to provide effective etiologic information and a treatment plan for clinical trials and to reduce the risk of infection by multi-resistant bacteria. PMID:27313667

  6. Managing potential drug-drug interactions between gastric acid-reducing agents and antiretroviral therapy: experience from a large HIV-positive cohort.

    PubMed

    Lewis, J M; Stott, K E; Monnery, D; Seden, K; Beeching, N J; Chaponda, M; Khoo, S; Beadsworth, M B J

    2016-02-01

    Drug-drug interactions between antiretroviral therapy and other drugs are well described. Gastric acid-reducing agents are one such class. However, few data exist regarding the frequency of and indications for prescription, nor risk assessment in the setting of an HIV cohort receiving antiretroviral therapy. To assess prevalence of prescription of gastric acid-reducing agents and drug-drug interaction within a UK HIV cohort, we reviewed patient records for the whole cohort, assessing demographic data, frequency and reason for prescription of gastric acid-reducing therapy. Furthermore, we noted potential drug-drug interaction and whether risk had been documented and mitigated. Of 701 patients on antiretroviral therapy, 67 (9.6%) were prescribed gastric acid-reducing therapy. Of these, the majority (59/67 [88.1%]) were prescribed proton pump inhibitors. We identified four potential drug-drug interactions, which were appropriately managed by temporally separating the administration of gastric acid-reducing agent and antiretroviral therapy, and all four of these patients remained virally suppressed. Gastric acid-reducing therapy, in particular proton pump inhibitor therapy, appears common in patients prescribed antiretroviral therapy. Whilst there remains a paucity of published data, our findings are comparable to those in other European cohorts. Pharmacovigilance of drug-drug interactions in HIV-positive patients is vital. Education of patients and staff, and accurate data-gathering tools, will enhance patient safety. PMID:25721922

  7. Repositioning drugs for inflammatory disease – fishing for new anti-inflammatory agents

    PubMed Central

    Hall, Christopher J.; Wicker, Sophie M.; Chien, An-Tzu; Tromp, Alisha; Lawrence, Lisa M.; Sun, Xueying; Krissansen, Geoffrey W.; Crosier, Kathryn E.; Crosier, Philip S.

    2014-01-01

    Inflammation is an important and appropriate host response to infection or injury. However, dysregulation of this response, with resulting persistent or inappropriate inflammation, underlies a broad range of pathological processes, from inflammatory dermatoses to type 2 diabetes and cancer. As such, identifying new drugs to suppress inflammation is an area of intense interest. Despite notable successes, there still exists an unmet need for new effective therapeutic approaches to treat inflammation. Traditional drug discovery, including structure-based drug design, have largely fallen short of satisfying this unmet need. With faster development times and reduced safety and pharmacokinetic uncertainty, drug repositioning – the process of finding new uses for existing drugs – is emerging as an alternative strategy to traditional drug design that promises an improved risk-reward trade-off. Using a zebrafish in vivo neutrophil migration assay, we undertook a drug repositioning screen to identify unknown anti-inflammatory activities for known drugs. By interrogating a library of 1280 approved drugs for their ability to suppress the recruitment of neutrophils to tail fin injury, we identified a number of drugs with significant anti-inflammatory activity that have not previously been characterized as general anti-inflammatories. Importantly, we reveal that the ten most potent repositioned drugs from our zebrafish screen displayed conserved anti-inflammatory activity in a mouse model of skin inflammation (atopic dermatitis). This study provides compelling evidence that exploiting the zebrafish as an in vivo drug repositioning platform holds promise as a strategy to reveal new anti-inflammatory activities for existing drugs. PMID:25038060

  8. 38 CFR 48.205 - What must I include in my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... drug-free workplace statement? 48.205 Section 48.205 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL... workplace statement? You must publish a statement that— (a) Tells your employees that the...

  9. The Interactions of P-Glycoprotein with Antimalarial Drugs, Including Substrate Affinity, Inhibition and Regulation

    PubMed Central

    Senarathna, S M D K Ganga; Page-Sharp, Madhu; Crowe, Andrew

    2016-01-01

    The combination of passive drug permeability, affinity for uptake and efflux transporters as well as gastrointestinal metabolism defines net drug absorption. Efflux mechanisms are often overlooked when examining the absorption phase of drug bioavailability. Knowing the affinity of antimalarials for efflux transporters such as P-glycoprotein (P-gp) may assist in the determination of drug absorption and pharmacokinetic drug interactions during oral absorption in drug combination therapies. Concurrent administration of P-gp inhibitors and P-gp substrate drugs may also result in alterations in the bioavailability of some antimalarials. In-vitro Caco-2 cell monolayers were used here as a model for potential drug absorption related problems and P-gp mediated transport of drugs. Artemisone had the highest permeability at around 50 x 10−6 cm/sec, followed by amodiaquine around 20 x 10−6 cm/sec; both mefloquine and artesunate were around 10 x 10−6 cm/sec. Methylene blue was between 2 and 6 x 10−6 cm/sec depending on the direction of transport. This 3 fold difference was able to be halved by use of P-gp inhibition. MRP inhibition also assisted the consolidation of the methylene blue transport. Mefloquine was shown to be a P-gp inhibitor affecting our P-gp substrate, Rhodamine 123, although none of the other drugs impacted upon rhodamine123 transport rates. In conclusion, mefloquine is a P-gp inhibitor and methylene blue is a partial substrate; methylene blue may have increased absorption if co-administered with such P-gp inhibitors. An upregulation of P-gp was observed when artemisone and dihydroartemisinin were co-incubated with mefloquine and amodiaquine. PMID:27045516

  10. The Interactions of P-Glycoprotein with Antimalarial Drugs, Including Substrate Affinity, Inhibition and Regulation.

    PubMed

    Senarathna, S M D K Ganga; Page-Sharp, Madhu; Crowe, Andrew

    2016-01-01

    The combination of passive drug permeability, affinity for uptake and efflux transporters as well as gastrointestinal metabolism defines net drug absorption. Efflux mechanisms are often overlooked when examining the absorption phase of drug bioavailability. Knowing the affinity of antimalarials for efflux transporters such as P-glycoprotein (P-gp) may assist in the determination of drug absorption and pharmacokinetic drug interactions during oral absorption in drug combination therapies. Concurrent administration of P-gp inhibitors and P-gp substrate drugs may also result in alterations in the bioavailability of some antimalarials. In-vitro Caco-2 cell monolayers were used here as a model for potential drug absorption related problems and P-gp mediated transport of drugs. Artemisone had the highest permeability at around 50 x 10(-6) cm/sec, followed by amodiaquine around 20 x 10(-6) cm/sec; both mefloquine and artesunate were around 10 x 10(-6) cm/sec. Methylene blue was between 2 and 6 x 10(-6) cm/sec depending on the direction of transport. This 3 fold difference was able to be halved by use of P-gp inhibition. MRP inhibition also assisted the consolidation of the methylene blue transport. Mefloquine was shown to be a P-gp inhibitor affecting our P-gp substrate, Rhodamine 123, although none of the other drugs impacted upon rhodamine123 transport rates. In conclusion, mefloquine is a P-gp inhibitor and methylene blue is a partial substrate; methylene blue may have increased absorption if co-administered with such P-gp inhibitors. An upregulation of P-gp was observed when artemisone and dihydroartemisinin were co-incubated with mefloquine and amodiaquine. PMID:27045516

  11. Sulphonamides as anti-inflammatory agents: old drugs for new therapeutic strategies in neutrophilic inflammation?

    PubMed

    Ottonello, L; Dapino, P; Scirocco, M C; Balbi, A; Bevilacqua, M; Dallegri, F

    1995-03-01

    1. It is well known that neutrophils act as mediators of tissue injury in a variety of inflammatory diseases. Their histotoxic activity is presently thought to involve proteinases and oxidants, primarily hypochlorous acid (HOCl). This oxidant is also capable of inactivating the specific inhibitor of neutrophil elastase (alpha 1-antitrypsin), thereby favouring digestion of the connective matrix. 2. In the present work, we found that sulphanilamide and some sulphanilamide-related anti-inflammatory drugs such as dapsone, nimesulide and sulphapyridine reduce the availability of HOCl in the extracellular microenvironment of activated neutrophils and prevent the inactivation of alpha 1-antitrypsin by these cells in a dose-dependent manner. The ability of each drug to prevent alpha 1-antitrypsin from inactivation by neutrophils correlates significantly with its capacity to reduce the recovery of HOCl from neutrophils. Five other non-steroidal anti-inflammatory drugs were completely ineffective. 3. Therefore, sulphanilamide-related drugs, i.e. dapsone, nimesulide and sulphapyridine, have the potential to reduce the bioavailability of neutrophil-derived HOCl and, in turn, to favour the alpha 1-antitrypsin-dependent control of neutrophil elastolytic activity. These drugs appear as a well-defined group of agents which are particularly prone to attenuate neutrophil histotoxicity. They can also be viewed as a previously unrecognized starting point for the development of new compounds in order to plan rational therapeutic strategies for controlling tissue injury during neutrophilic inflammation. PMID:7736703

  12. Requirements for Foreign and Domestic Establishment Registration and Listing for Human Drugs, Including Drugs That Are Regulated Under a Biologics License Application, and Animal Drugs. Final rule.

    PubMed

    2016-08-31

    The Food and Drug Administration (FDA) is amending its regulations governing drug establishment registration and drug listing. These amendments reorganize, modify, and clarify current regulations concerning who must register establishments and list human drugs, human drugs that are also biological products, and animal drugs. The final rule requires electronic submission, unless waived in certain circumstances, of registration and listing information. This rulemaking pertains to finished drug products and to active pharmaceutical ingredients (APIs) alone or together with one or more other ingredients. The final rule describes how and when owners or operators of establishments at which drugs are manufactured or processed must register their establishments with FDA and list the drugs they manufacture or process. In addition, the rule makes certain changes to the National Drug Code (NDC) system. We are taking this action to improve management of drug establishment registration and drug listing requirements and make these processes more efficient and effective for industry and for us. This action also supports implementation of the electronic prescribing provisions of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA) and the availability of current drug labeling information through DailyMed, a computerized repository of drug information maintained by the National Library of Medicine. PMID:27580511

  13. Evolution of contrast agents for ultrasound imaging and ultrasound-mediated drug delivery

    PubMed Central

    Paefgen, Vera; Doleschel, Dennis; Kiessling, Fabian

    2015-01-01

    Ultrasound (US) is one of the most frequently used diagnostic methods. It is a non-invasive, comparably inexpensive imaging method with a broad spectrum of applications, which can be increased even more by using bubbles as contrast agents (CAs). There are various different types of bubbles: filled with different gases, composed of soft- or hard-shell materials, and ranging in size from nano- to micrometers. These intravascular CAs enable functional analyses, e.g., to acquire organ perfusion in real-time. Molecular analyses are achieved by coupling specific ligands to the bubbles’ shell, which bind to marker molecules in the area of interest. Bubbles can also be loaded with or attached to drugs, peptides or genes and can be destroyed by US pulses to locally release the entrapped agent. Recent studies show that US CAs are also valuable tools in hyperthermia-induced ablation therapy of tumors, or can increase cellular uptake of locally released drugs by enhancing membrane permeability. This review summarizes important steps in the development of US CAs and introduces the current clinical applications of contrast-enhanced US. Additionally, an overview of the recent developments in US probe design for functional and molecular diagnosis as well as for drug delivery is given. PMID:26441654

  14. Evolution of contrast agents for ultrasound imaging and ultrasound-mediated drug delivery.

    PubMed

    Paefgen, Vera; Doleschel, Dennis; Kiessling, Fabian

    2015-01-01

    Ultrasound (US) is one of the most frequently used diagnostic methods. It is a non-invasive, comparably inexpensive imaging method with a broad spectrum of applications, which can be increased even more by using bubbles as contrast agents (CAs). There are various different types of bubbles: filled with different gases, composed of soft- or hard-shell materials, and ranging in size from nano- to micrometers. These intravascular CAs enable functional analyses, e.g., to acquire organ perfusion in real-time. Molecular analyses are achieved by coupling specific ligands to the bubbles' shell, which bind to marker molecules in the area of interest. Bubbles can also be loaded with or attached to drugs, peptides or genes and can be destroyed by US pulses to locally release the entrapped agent. Recent studies show that US CAs are also valuable tools in hyperthermia-induced ablation therapy of tumors, or can increase cellular uptake of locally released drugs by enhancing membrane permeability. This review summarizes important steps in the development of US CAs and introduces the current clinical applications of contrast-enhanced US. Additionally, an overview of the recent developments in US probe design for functional and molecular diagnosis as well as for drug delivery is given. PMID:26441654

  15. Phytantriol based liquid crystal provide sustained release of anticancer drug as a novel embolic agent.

    PubMed

    Qin, Lingzhen; Mei, Liling; Shan, Ziyun; Huang, Ying; Pan, Xin; Li, Ge; Gu, Yukun; Wu, Chuanbin

    2016-01-01

    Phytantriol has received increasing amount of attention in drug delivery system, however, the ability of the phytantriol based liquid crystal as a novel embolic agent to provide a sustained release delivery system is yet to be comprehensively demonstrated. The purpose of this study was to prepare a phytantriol-based cubic phase precursor solution loaded with anticancer drug hydroxycamptothecine (HCPT) and evaluate its embolization properties, in vitro drug release and cytotoxicity. Phase behavior of the phytantriol-solvent-water system was investigated by visual inspection and polarized light microscopy, and no phase transition was observed in the presence of HCPT within the studied dose range. Water uptake by the phytantriol matrices was determined gravimetrically, suggesting that the swelling complied with the second order kinetics. In vitro evaluation of embolic efficacy indicated that the isotropic solution displayed a satisfactory embolization effect. In vitro drug release results showed a sustained-release up to 30 days and the release behavior was affected by the initial composition and drug loading. Moreover, the in vitro cytotoxicity and anticancer activity were evaluated by MTT assay. No appreciable mortality was observed for NIH 3T3 cells after 48 h exposure to blank formulations, and the anticancer activity of HCPT-loaded formulations to HepG2 and SMMC7721 cells was strongly dependent on the drug loading and treatment time. Taken together, these results indicate that phytantriol-based cubic phase embolic gelling solution is a promising potential carrier for HCPT delivery to achieve a sustained drug release by vascular embolization, and this technology may be potential for clinical applications. PMID:26035332

  16. DNA sequence analyses of blended herbal products including synthetic cannabinoids as designer drugs.

    PubMed

    Ogata, Jun; Uchiyama, Nahoko; Kikura-Hanajiri, Ruri; Goda, Yukihiro

    2013-04-10

    In recent years, various herbal products adulterated with synthetic cannabinoids have been distributed worldwide via the Internet. These herbal products are mostly sold as incense, and advertised as not for human consumption. Although their labels indicate that they contain mixtures of several potentially psychoactive plants, and numerous studies have reported that they contain a variety of synthetic cannabinoids, their exact botanical contents are not always clear. In this study, we investigated the origins of botanical materials in 62 Spice-like herbal products distributed on the illegal drug market in Japan, by DNA sequence analyses and BLAST searches. The nucleotide sequences of four regions were analyzed to identify the origins of each plant species in the herbal mixtures. The sequences of "Damiana" (Turnera diffusa) and Lamiaceae herbs (Mellissa, Mentha and Thymus) were frequently detected in a number of products. However, the sequences of other plant species indicated on the packaging labels were not detected. In a few products, DNA fragments of potent psychotropic plants were found, including marijuana (Cannabis sativa), "Diviner's Sage" (Salvia divinorum) and "Kratom" (Mitragyna speciosa). Their active constituents were also confirmed using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS), although these plant names were never indicated on the labels. Most plant species identified in the products were different from the plants indicated on the labels. The plant materials would be used mainly as diluents for the psychoactive synthetic compounds, because no reliable psychoactive effects have been reported for most of the identified plants, with the exception of the psychotropic plants named above. PMID:23092848

  17. Cyclin-dependent kinase inhibitor drugs as potential novel anti-inflammatory and pro-resolution agents

    PubMed Central

    Leitch, AE; Haslett, C; Rossi, AG

    2009-01-01

    The cyclin-dependent kinase inhibitor (CDKi) drugs such as R-roscovitine have emerged as potential anti-inflammatory, pharmacological agents that can influence the resolution of inflammation. Usually, once an inciting inflammatory stimulus has been eliminated, resolution proceeds by prompt, safe removal of dominant inflammatory cells. This is accomplished by programmed cell death (apoptosis) of prominent effector, inflammatory cells typified by the neutrophil. Apoptosis of neutrophils ensures that toxic neutrophil granule contents are securely packaged in apoptotic bodies and expedites phagocytosis by professional phagocytes such as macrophages. A panel of CDKi drugs have been shown to promote neutrophil apoptosis in a concentration- and time-dependent manner and the archetypal CDKi drug, R-roscovitine, overrides the anti-apoptotic effects of powerful survival factors [including lipopolysaccharide (LPS) and granulocyte macrophage-colony stimulating factor (GM-CSF)]. Inflammatory cell longevity and survival signalling is integral to the inflammatory process and any putative anti-inflammatory agent must unravel a complex web of redundancy in order to be effective. CDKi drugs have also been demonstrated to have significant effects on other cell types including lymphocytes and fibroblasts indicating that they may have pleiotropic anti-inflammatory, pro-resolution activity. In keeping with this, CDKi drugs like R-roscovitine have been reported to be efficacious in resolving established animal models of neutrophil-dominant and lymphocyte-driven inflammation. However, the mechanism of action behind these powerful effects has not yet been fully elucidated. CDKs play an integral role in the regulation of the cell cycle but are also recognized as participants in processes such as apoptosis and transcriptional regulation. Neutrophils have functional CDKs, are transcriptionally active and demonstrate augmented apoptosis in response to CDKi drugs, while lymphocyte proliferation

  18. Natural Products as Tools for Neuroscience: Discovery and Development of Novel Agents to Treat Drug Abuse⊥

    PubMed Central

    Prisinzano, Thomas E.

    2009-01-01

    Much of what we know about the neurosciences is the direct result of studying psychoactive natural products. Unfortunately, there are many gaps in our understanding of the basic biological processes that contribute to the etiology of many CNS disorders. The investigation of psychoactive natural products offers an excellent approach to identify novel agents to treat CNS disorders and to find new chemical tools to better elucidate their biological mechanisms. This review will detail recent progress in a program directed towards investigating psychoactive natural products with the goal of treating drug abuse by targeting κ opioid receptors. PMID:19099466

  19. Drug Development for Hypertension: Do We Need Another Antihypertensive Agent for Resistant Hypertension?

    PubMed

    Pimenta, Eduardo; Calhoun, David A

    2016-04-01

    The prevalence of resistant hypertension is seemingly much lower than had been reported in early studies. Recent analyses suggest that <5 % of treated hypertensive patients remain uncontrolled if fully adherent to an optimized antihypertensive treatment. However, these patients do have increased cardiovascular risk and need effective therapeutic approaches. Drug development is a high-risk, complex, lengthy, and very expensive process. In this article, we discuss the factors that should be considered in the process of developing a new agent for treatment of resistant hypertension. PMID:26949263

  20. Agents of change: peer mentorship as HIV prevention among HIV-positive injection drug users.

    PubMed

    Mackenzie, Sonja; Pearson, Charles; Frye, Victoria; Gómez, Cynthia A; Latka, Mary H; Purcell, David W; Knowlton, Amy R; Metsch, Lisa R; Tobin, Karin E; Valverde, Eduardo E; Knight, Kelly R

    2012-04-01

    This paper presents a qualitative investigation of peer mentoring among HIV seropositive injection drug users in a randomized controlled trial, the INSPIRE study. Qualitative analyses of 68 in-depth open-ended interviews conducted in 2005 in Baltimore, New York, Miami, and San Francisco revealed that these individuals conceptualized themselves as change agents through the identity of peer mentor at the three related domains of individual, interpersonal, and community-level change. Implications for program development and future research of peer mentoring as a mechanism for HIV prevention are discussed. This study was funded by the Centers for Disease Control and Prevention and Health Resources and Services Administration (HRSA). PMID:22428820

  1. Ferrous iron-dependent drug delivery enables controlled and selective release of therapeutic agents in vivo

    PubMed Central

    Deu, Edgar; Chen, Ingrid T.; Lauterwasser, Erica M. W.; Valderramos, Juan; Li, Hao; Edgington, Laura E.; Renslo, Adam R.; Bogyo, Matthew

    2013-01-01

    The precise targeting of cytotoxic agents to specific cell types or cellular compartments is of significant interest in medicine, with particular relevance for infectious diseases and cancer. Here, we describe a method to exploit aberrant levels of mobile ferrous iron (FeII) for selective drug delivery in vivo. This approach makes use of a 1,2,4-trioxolane moiety, which serves as an FeII-sensitive “trigger,” making drug release contingent on FeII-promoted trioxolane fragmentation. We demonstrate in vivo validation of this approach with the Plasmodium berghei model of murine malaria. Malaria parasites produce high concentrations of mobile ferrous iron as a consequence of their catabolism of host hemoglobin in the infected erythrocyte. Using activity-based probes, we successfully demonstrate the FeII-dependent and parasite-selective delivery of a potent dipeptidyl aminopeptidase inhibitor. We find that delivery of the compound in its FeII-targeted form leads to more sustained target inhibition with greatly reduced off-target inhibition of mammalian cathepsins. This selective drug delivery translates into improved efficacy and tolerability. These findings demonstrate the utility of a purely chemical means to achieve selective drug targeting in vivo. This approach may find useful application in parasitic infections and more broadly in any disease state characterized by aberrant production of reactive ferrous iron. PMID:24145449

  2. Ferrous iron-dependent drug delivery enables controlled and selective release of therapeutic agents in vivo.

    PubMed

    Deu, Edgar; Chen, Ingrid T; Lauterwasser, Erica M W; Valderramos, Juan; Li, Hao; Edgington, Laura E; Renslo, Adam R; Bogyo, Matthew

    2013-11-01

    The precise targeting of cytotoxic agents to specific cell types or cellular compartments is of significant interest in medicine, with particular relevance for infectious diseases and cancer. Here, we describe a method to exploit aberrant levels of mobile ferrous iron (Fe(II)) for selective drug delivery in vivo. This approach makes use of a 1,2,4-trioxolane moiety, which serves as an Fe(II)-sensitive "trigger," making drug release contingent on Fe(II)-promoted trioxolane fragmentation. We demonstrate in vivo validation of this approach with the Plasmodium berghei model of murine malaria. Malaria parasites produce high concentrations of mobile ferrous iron as a consequence of their catabolism of host hemoglobin in the infected erythrocyte. Using activity-based probes, we successfully demonstrate the Fe(II)-dependent and parasite-selective delivery of a potent dipeptidyl aminopeptidase inhibitor. We find that delivery of the compound in its Fe(II)-targeted form leads to more sustained target inhibition with greatly reduced off-target inhibition of mammalian cathepsins. This selective drug delivery translates into improved efficacy and tolerability. These findings demonstrate the utility of a purely chemical means to achieve selective drug targeting in vivo. This approach may find useful application in parasitic infections and more broadly in any disease state characterized by aberrant production of reactive ferrous iron. PMID:24145449

  3. Sonophoresis using ultrasound contrast agents for transdermal drug delivery: an in vivo experimental study.

    PubMed

    Park, Donghee; Ryu, Heungil; Kim, Han Sung; Kim, Young-Sun; Choi, Kyu-Sil; Park, Hyunjin; Seo, Jongbum

    2012-04-01

    Sonophoresis temporally increases skin permeability such that various medications can be delivered noninvasively. Previous sonophoresis studies have suggested that cavitation plays an important role in enhancing transdermal drug delivery (TDD). In this study, the feasibility of controlled cavitation using ultrasound contrast agents (UCAs) at high frequency was explored through in vivo experiments in a rat model. Two commercially available UCAs, SonoVue® and Definity®, were used at 2.47 MHz and 1.12 MHz, respectively. Fluorescein isothiocyanate (FITC)-dextran with 0.1% UCA was used as the drug to be delivered through the skin. Ultrasound with a 10 ms pulse and a 1% duty cycle at 1 MPa acoustic pressure for 30 min was applied in all sonication sessions. The efficacy of sonophoresis with UCAs was quantitatively analyzed using an optical imaging system that was used to count photons emitted from fluorescein. The results showed that the proposed sonophoresis method significantly improved drug penetration compared with the traditional sonophoresis method with 4 kD, 20 kD and 150 kD FITC-dextrans at 1.12 MHz, and with 4 kD and 20 kD FITC-dextrans at 2.47 MHz. Sonophoresis for TDD was performed more effectively with the aid of UCAs. Sonophoresis with UCAs has excellent potential for broad applications in drug delivery for diseases requiring the chronic administration of medications such as diabetes. PMID:22341597

  4. Transdermal Drug Delivery Aided by an Ultrasound Contrast Agent: An In Vitro Experimental Study

    PubMed Central

    Park, Donghee; Yoon, Jinhee; Park, Jingam; Jung, Byungjo; Park, Hyunjin; Seo, Jongbum

    2010-01-01

    Sonophoresis temporarily increases skin permeability such that medicine can be delivered transdermally. Cavitation is believed to be the predominant mechanism in sonophoresis. In this study, an ultrasound contrast agent (UCA) strategy was adopted instead of low frequency ultrasound to assure that cavitation occurred, and the efficacy of sonophoresis with UCA was quantitatively analyzed by optical measurements. The target drug used in this study was 0.1 % Definity® in 70% glycerol, which was delivered into porcine skin samples. Glycerol was used because it is an optical clearing agent, and the efficiency of glycerol delivery could be analyzed with optical measurements. The applied acoustic pressure was approximately 600 kPa at 1 MHz ultrasound with a 10% duty cycle for 60 minutes. Experimental results indicated that the measured relative contrast (RC) after sonophoresis with UCA was approximately 80% higher than RC after sonophoresis without UCA. In addition, the variance of RC was also reduced by more than 50% with the addition of a UCA. The use of a UCA appeared to increase cavitation, demonstrating that the use of a UCA can be effective in transdermal drug delivery (TDD). PMID:20448793

  5. Alternative matrices for therapeutic drug monitoring of immunosuppressive agents using LC–MS/MS

    PubMed Central

    Ghareeb, Mwlod; Akhlaghi, Fatemeh

    2015-01-01

    Immunosuppressive drugs used in solid organ transplants typically have narrow therapeutic windows and high intra- and intersubject variability. To ensure satisfactory exposure, therapeutic drug monitoring (TDM) plays a pivotal role in any successful posttransplant maintenance therapy. Currently, recommendations for optimum immunosuppressant concentrations are based on blood/plasma measurements. However, they introduce many disadvantages, including poor prediction of allograft survival and toxicity, a weak correlation with drug concentrations at the site of action and the invasive nature of the sample collection. Thus, alternative matrices have been investigated. This paper reviews tandem-mass spectrometry (LC–MS/MS) methods used for the quantification of immunosuppressant drugs utilizing nonconventional matrices, namely oral fluids, fingerprick blood and intracellular and intratissue sampling. The advantages, disadvantages and clinical application of such alternative mediums are discussed. Additionally, sample extraction techniques and basic chromatography information regarding these methods are presented in tabulated form. PMID:25966013

  6. A team agent approach to postmarketing surveillance of adverse drug reactions.

    PubMed

    Ji, Yanqing; Ying, Hao; Barth-Jones, Daniel; Yen, John; Zhu, Shizhou; Miller, Richard; Michael Massanari, R

    2005-01-01

    Current postmarketing surveillance methods largely rely on spontaneous reports which suffer from serious underreporting, latency, and inconsistent reporting. Thus they are not ideal for rapidly identifying rare adverse drug reactions (ADRs). We propose an active, multi-agent computer software system, where each agent is empowered with teamwork capabilities such as anticipating information needs, identifying relevant ADR information, and continuously monitoring and proactively sharing such information in a collaborative fashion with other agents. The main purpose of this system is to help regulatory authorities (e.g., FDA in the U.S.) find previously unrecognized ADRs as early as possible. Another objective is to promote increased filing of on-line ADR reports thereby, addressing the severe underreporting problem with the current system. The proposed system has the potential to significantly accelerate the process of ADR discovery and response by utilizing electronic patient data distributed across many different sources and locations more effectively. Our preliminary system design is presented and some issues related to it are discussed. PMID:17281878

  7. Sex-dimorphic adverse drug reactions to immune suppressive agents in inflammatory bowel disease

    PubMed Central

    Zelinkova, Zuzana; Bultman, Evelien; Vogelaar, Lauran; Bouziane, Cheima; Kuipers, Ernst J; van der Woude, C Janneke

    2012-01-01

    AIM: To analyze sex differences in adverse drug reactions (ADR) to the immune suppressive medication in inflammatory bowel disease (IBD) patients. METHODS: All IBD patients attending the IBD outpatient clinic of a referral hospital were identified through the electronic diagnosis registration system. The electronic medical records of IBD patients were reviewed and the files of those patients who have used immune suppressive therapy for IBD, i.e., thiopurines, methotrexate, cyclosporine, tacrolimus and anti-tumor necrosis factor agents (anti-TNF); infliximab (IFX), adalimumab (ADA) and/or certolizumab, were further analyzed. The reported ADR to immune suppressive drugs were noted. The general definition of ADR used in clinical practice comprised the occurrence of the ADR in the temporal relationship with its disappearance upon discontinuation of the medication. Patients for whom the required information on drug use and ADR was not available in the electronic medical record and patients with only one registered contact and no further follow-up at the outpatient clinic were excluded. The difference in the incidence and type of ADR between male and female IBD patients were analyzed statistically by χ2 test. RESULTS: In total, 1009 IBD patients were identified in the electronic diagnosis registration system. Out of these 1009 patients, 843 patients were eligible for further analysis. There were 386 males (46%), mean age 42 years (range: 16-87 years) with a mean duration of the disease of 14 years (range: 0-54 years); 578 patients with Crohn’s disease, 244 with ulcerative colitis and 21 with unclassified colitis. Seventy percent (586 pts) of patients used any kind of immune suppressive agents at a certain point of the disease course, the majority of the patients (546 pts, 65%) used thiopurines, 176 pts (21%) methotrexate, 46 pts (5%) cyclosporine and one patient tacrolimus. One third (240 pts, 28%) of patients were treated with anti-TNF, the majority of patients (227

  8. Plasma sterilization of poly lactic acid ultrasound contrast agents: surface modification and implications for drug delivery.

    PubMed

    Eisenbrey, John R; Hsu, Jennifer; Wheatley, Margaret A

    2009-11-01

    Poly lactic acid (PLA) ultrasound contrast agents (CA) have been developed previously in our laboratory for ultrasound (US) imaging, as well as surface coated with doxorubicin to create a potential targeted platform of chemotherapeutic delivery using focused US. However, we have previously found it impossible to sterilize these agents while at the same time maintaining their acoustic properties, a task that would probably require fabrication within a clean facility. The purpose of this paper is to investigate the feasibility of using plasma to sterilize these CA while maintaining maximum echogenicity, a step that would greatly facilitate in vivo investigations. Effects of plasma exposure time (1, 3 and 6 min) and intensity (low-10 mA, 6.8 W; medium-15 mA, 10.5 W; and high-25 mA, 18 W) on the CAs' acoustic properties, surface morphology, zeta potential, capacity to carry chemotherapeutics and overall sterility are described. Both increases in plasma intensity and exposure time increased CA zeta potential and also significantly increased drug payload. High-intensity plasma exposure for 3 min was found to be an optimal sterilization protocol for maximal (100%) preservation of CA echogenicity. Plasma exposure resulted in sterile samples and maintained original CA enhancement of 20 dB and acoustic half-life over 75 min, while increasing CA zeta potential by 11 mV and doxorubicin loading efficiency by 10%. This study not only shows how a highly temperature- and pressure-sensitive agent can be sterilized using plasma, but also that surface modification can be used to increase surface binding of the drug. PMID:19766380

  9. Responsive Theranostic Systems: Integration of Diagnostic Imaging Agents and Responsive Controlled Release Drug Delivery Carriers

    PubMed Central

    Caldorera-Moore, Mary E.; Liechty, William B.; Peppas, Nicholas A.

    2011-01-01

    CONSPECTUS The ability to non-invasively monitor and treat physiological conditions within the human body has been an aspiration of researchers and medical professionals for decades. The emergences of nanotechnology opened up new possibilities for effective vehicles that could accomplish non-invasive detection of diseases and localized treatment systems to be developed. In turn, extensive research efforts have been spent on the development of imaging moiety that could be used to seek out specific diseased conditions and can be monitored with convention clinical imaging modalities. Nanoscale detection agents like these have the potential to increase early detection of pathophysiological conditions because they have the capability to detect abnormal cells before they even develop into diseased tissue and/or tumors. Once the diseased cells are detected it would be constructive to just be able to treat them simultaneously. From here, the concept of multifunctional carriers that could target, detect, and treat diseased cells emerged. The term “theranostics” has been created to describe this promising area of research that focuses on the combination of diagnostic detection agents with therapeutic drug delivery carriers. Targeted theranostic nanocarriers offer an attractive improvement to disease treatment because of their ability to simultaneously diagnose, image, and treat at targeted diseased sites. Research efforts in the field of theranostics encompass a broad variety of drug delivery vehicles, detection agents, and targeting modalities for the development of an all-in-one, localized, diagnostic and treatment system. Nanotheranostic systems that utilize metallic or magnetic imaging nanoparticles have the added capability to be used as thermal therapeutic systems. This review aims to explore recent advancements in the field of nanotheranostics and the various fundamental components of an effective theranostic carrier. PMID:21932809

  10. Responsive theranostic systems: integration of diagnostic imaging agents and responsive controlled release drug delivery carriers.

    PubMed

    Caldorera-Moore, Mary E; Liechty, William B; Peppas, Nicholas A

    2011-10-18

    For decades, researchers and medical professionals have aspired to develop mechanisms for noninvasive treatment and monitoring of pathological conditions within the human body. The emergence of nanotechnology has spawned new opportunities for novel drug delivery vehicles capable of concomitant detection, monitoring, and localized treatment of specific disease sites. In turn, researchers have endeavored to develop an imaging moiety that could be functionalized to seek out specific diseased conditions and could be monitored with conventional clinical imaging modalities. Such nanoscale detection systems have the potential to increase early detection of pathophysiological conditions because they can detect abnormal cells before they even develop into diseased tissue or tumors. Ideally, once the diseased cells are detected, clinicians would like to treat those cells simultaneously. This idea led to the concept of multifunctional carriers that could target, detect, and treat diseased cells. The term "theranostics" has been created to describe this promising area of research that focuses on the combination of diagnostic detection agents with therapeutic drug delivery carriers. Targeted theranostic nanocarriers offer an attractive improvement to disease treatment because of their ability to execute simultaneous functions at targeted diseased sites. Research efforts in the field of theranostics encompass a broad variety of drug delivery vehicles, imaging contrast agents, and targeting modalities for the development of an all-in-one, localized detection and treatment system. Nanotheranostic systems that utilize metallic or magnetic imaging nanoparticles can also be used as thermal therapeutic systems. This Account explores recent advances in the field of nanotheranostics and the various fundamental components of an effective theranostic carrier. PMID:21932809

  11. Current state of evidence on 'off-label' therapeutic options for systemic lupus erythematosus, including biological immunosuppressive agents, in Germany, Austria and Switzerland--a consensus report.

    PubMed

    Aringer, M; Burkhardt, H; Burmester, G R; Fischer-Betz, R; Fleck, M; Graninger, W; Hiepe, F; Jacobi, A M; Kötter, I; Lakomek, H J; Lorenz, H M; Manger, B; Schett, G; Schmidt, R E; Schneider, M; Schulze-Koops, H; Smolen, J S; Specker, C; Stoll, T; Strangfeld, A; Tony, H P; Villiger, P M; Voll, R; Witte, T; Dörner, T

    2012-04-01

    Systemic lupus erythematosus (SLE) can be a severe and potentially life-threatening disease that often represents a therapeutic challenge because of its heterogeneous organ manifestations. Only glucocorticoids, chloroquine and hydroxychloroquine, azathioprine, cyclophosphamide and very recently belimumab have been approved for SLE therapy in Germany, Austria and Switzerland. Dependence on glucocorticoids and resistance to the approved therapeutic agents, as well as substantial toxicity, are frequent. Therefore, treatment considerations will include 'off-label' use of medication approved for other indications. In this consensus approach, an effort has been undertaken to delineate the limits of the current evidence on therapeutic options for SLE organ disease, and to agree on common practice. This has been based on the best available evidence obtained by a rigorous literature review and the authors' own experience with available drugs derived under very similar health care conditions. Preparation of this consensus document included an initial meeting to agree upon the core agenda, a systematic literature review with subsequent formulation of a consensus and determination of the evidence level followed by collecting the level of agreement from the panel members. In addition to overarching principles, the panel have focused on the treatment of major SLE organ manifestations (lupus nephritis, arthritis, lung disease, neuropsychiatric and haematological manifestations, antiphospholipid syndrome and serositis). This consensus report is intended to support clinicians involved in the care of patients with difficult courses of SLE not responding to standard therapies by providing up-to-date information on the best available evidence. PMID:22072024

  12. Recent progress in the drug development of coumarin derivatives as potent antituberculosis agents.

    PubMed

    Keri, Rangappa S; Sasidhar, B S; Nagaraja, Bhari Mallanna; Santos, M Amélia

    2015-07-15

    Tuberculosis (TB) is still a challenging worldwide health problem and mycobacterium tuberculosis (MTB) remains one of the most deadly human pathogens. TB is the second leading infectious cause of mortality today behind only HIV/AIDS. The impetus for developing new structural classes of antituberculosis drugs comes from the emergence of multi-drug resistant (MDR) strains. The development of MDR strains to commonly used drugs is due to, longer durations of therapy as results of resistance, and the resurgence of the disease in immune compromised patients. Therefore, there is an urgent need to explore new antitubercular (anti-TB) agents. Ironically, the low number of potentially new chemical entities which can act as anti-TB candidates is of great importance at present situation. Considering the severity of the problem, WHO has prepared a strategic plan in Berlin declaration 2007 to stop TB, globally. Among the oxygen heterocycles, coumarin derivatives are important motifs, which can be widely found in many natural products, and many of them displaying diverse biological activities. This spectacular spectrum of applications has intrigued organic and medicinal chemists for decades to explore the natural coumarins or their synthetic analogs for their applicability as anti-TB drugs. To pave the way for the future research, there is a need to collect the latest information in this promising area. In the present review, we collated published reports on coumarin derivatives to shed light on the insights on different types of methods reported for their preparations, characterizations and anti-TB applications, so that its full therapeutic potential class of compounds can be utilized for the treatment of tuberculosis. Therefore, the objective of this review is to focus on important coumarin analogs with anti-TB activities, and structure-activity relationships (SAR) for designing the better anti-TB agents. It is hoped that, this review will be helpful for new thoughts in the

  13. Repurposing Drugs in Oncology (ReDO)—diclofenac as an anti-cancer agent

    PubMed Central

    Pantziarka, Pan; Sukhatme, Vidula; Bouche, Gauthier; Meheus, Lydie; Sukhatme, Vikas P

    2016-01-01

    Diclofenac (DCF) is a well-known and widely used non-steroidal anti-inflammatory drug (NSAID), with a range of actions which are of interest in an oncological context. While there has long been an interest in the use of NSAIDs in chemoprevention, there is now emerging evidence that such drugs may have activity in a treatment setting. DCF, which is a potent inhibitor of COX-2 and prostaglandin E2 synthesis, displays a range of effects on the immune system, the angiogenic cascade, chemo- and radio-sensitivity and tumour metabolism. Both pre-clinical and clinical evidence of these effects, in multiple cancer types, is assessed and summarised and relevant mechanisms of action outlined. Based on this evidence the case is made for further clinical investigation of the anticancer effects of DCF, particularly in combination with other agents - with a range of possible multi-drug and multi-modality combinations outlined in the supplementary materials accompanying the main paper. PMID:26823679

  14. Progressive development in experimental models of transungual drug delivery of anti-fungal agents.

    PubMed

    Thatai, P; Tiwary, A K; Sapra, B

    2016-02-01

    Pre-clinical development comprises of different procedures that relate drug discovery in the laboratory for commencement of human clinical trials. Pre-clinical studies can be designed to recognize a lead candidate from a list to develop the procedure for scale-up, to choose the unsurpassed formulation, to determine the frequency, and duration of exposure; and eventually make the foundation of the anticipated clinical trial design. The foremost aim in the pharmaceutical research and industry is the claim of drug product quality throughout a drug's life cycle. The particulars of the pre-clinical development process for different candidates may vary; however, all have some common features. Typically in vitro, in vivo or ex vivo studies are elements of pre-clinical studies. Human pharmacokinetic in vivo studies are often supposed to serve as the 'gold standard' to assess product performance. On the other hand, when this general assumption is revisited, it appears that in vitro studies are occasionally better than in vivo studies in assessing dosage forms. The present review is compendious of different such models or approaches that can be used for designing and evaluation of formulations for nail delivery with special reference to anti-fungal agents. PMID:25919363

  15. Repurposing Drugs in Oncology (ReDO)-diclofenac as an anti-cancer agent.

    PubMed

    Pantziarka, Pan; Sukhatme, Vidula; Bouche, Gauthier; Meheus, Lydie; Sukhatme, Vikas P

    2016-01-01

    Diclofenac (DCF) is a well-known and widely used non-steroidal anti-inflammatory drug (NSAID), with a range of actions which are of interest in an oncological context. While there has long been an interest in the use of NSAIDs in chemoprevention, there is now emerging evidence that such drugs may have activity in a treatment setting. DCF, which is a potent inhibitor of COX-2 and prostaglandin E2 synthesis, displays a range of effects on the immune system, the angiogenic cascade, chemo- and radio-sensitivity and tumour metabolism. Both pre-clinical and clinical evidence of these effects, in multiple cancer types, is assessed and summarised and relevant mechanisms of action outlined. Based on this evidence the case is made for further clinical investigation of the anticancer effects of DCF, particularly in combination with other agents - with a range of possible multi-drug and multi-modality combinations outlined in the supplementary materials accompanying the main paper. PMID:26823679

  16. Buoyancy-generating agents for stomach-specific drug delivery: an overview with special emphasis on floating behavior.

    PubMed

    Ishak, Rania A H

    2015-01-01

    Gastric retentive drug delivery provides a promising technology exhibiting an extended gastric residence and a drug release independent of patient related variables. It is usually useful in improving local gastric treatment as well as overcoming drug-related problems .i.e. drugs having narrow absorption window, short half-life or low intestinal solubility. Buoyancy is considered one of the most promising approaches for gastro-retention of dosage forms. Floating drug delivery systems have a bulk density lower than gastric fluids and thus remain buoyant in the stomach causing an increase in gastric residence time. The buoyancy of these systems is attained by the aid of substances responsible to generate the low density. Various agents with different mechanisms were adopted either gas-generating agents, air entrapping swellable polymers, inherent low density substances, porous excipients, hollow/porous particles inducing preparation techniques or sublimating agents. Therefore, this review gives an exclusive descriptive classification of the different categories of these buoyancy-generating agents while representing the related research works. An overview is also conducted to describe relevant techniques assessing the floating behavior of such dosage forms either in vitro or in vivo. Finally, a collection representing FDA-approved floating pharmaceutical products is adopted with emphasis on the buoyancy-generating agent type used in each product. PMID:25877444

  17. Update on medical and regulatory issues pertaining to compounded and FDA-approved drugs, including hormone therapy

    PubMed Central

    Pinkerton, JoAnn V.; Pickar, James H.

    2016-01-01

    Abstract Objective: We review the historical regulation of drug compounding, concerns about widespread use of non-Food and Drug Admiistration (FDA)-approved compounded bioidentical hormone therapies (CBHTs), which do not have proper labeling and warnings, and anticipated impact of the 2013 Drug Quality and Security Act (DQSA) on compounding. Methods: US government websites were searched for documents concerning drug compounding regulation and oversight from 1938 (passage of Federal Food, Drug, and Cosmetic Act [FDCA]) through 2014, including chronologies, Congressional testimony, FDA guidelines and enforcements, and reports. The FDCA and DQSA were reviewed. PubMed and Google were searched for articles on compounded drugs, including CBHT. Results: Congress explicitly granted the FDA limited oversight of compounded drugs in a 1997 amendment to the FDCA, but the FDA has encountered obstacles in exercising that authority. After 64 patient deaths and 750 adversely affected patients from the 2012 meningitis outbreak due to contaminated compounded steroid injections, Congress passed the DQSA, authorizing the FDA to create a voluntary registration for facilities that manufacture and distribute sterile compounded drugs in bulk and reinforcing FDCA regulations for traditional compounding. Given history and current environment, concerns remain about CBHT product regulation and their lack of safety and efficacy data. Conclusions: The DQSA and its reinforcement of §503A of the FDCA solidifies FDA authority to enforce FDCA provisions against compounders of CBHT. The new law may improve compliance and accreditation by the compounding industry; support state and FDA oversight; and prevent the distribution of misbranded, adulterated, or inconsistently compounded medications, and false and misleading claims, thus reducing public health risk. PMID:26418479

  18. Effects of anti-inflammatory agents and some other drugs on prostaglandin biotransport.

    PubMed

    Bito, L Z; Salvador, E V

    1976-08-01

    The inhibitory effects of drugs on prostaglandin biotransport were studied by measuring the concentrative accumulation of 3H by rabbit choroid plexuses, segments of anterior uvea and kidney cortex slices after incubation in tissue culture medium containing 3H-prostaglandin F2 alpha. After 10 minutes of incubation in the absence of an inhibitor, the choroid plexus showed a tissue/medium 3H accumulation ratio of 14 +/- 0.7; after 30 minutes of incubation, the anterior uvea and the kidney cortex slices showed accumulation ratios of 6.4 +/- 0.5 and 5.6 +/- 0.1, respectively. The I50 values for inhibition of 3H accumulation by indomethacin were 10, 8 and 12 muM for the three tissues, respectively. Some related drugs-oxyphenbutazone, D-naproxen, l-naproxen, ibuprofen, phenylbutazone and pirprofen-were also found to be effective inhibitors of 3H accumulation (I50 for anterior uvea, 6-28 muM) whereas aspirin, dexamethasone phosphate and penicillin had an inhibitory effect only at much higher concentrations (I50 0.1-2.0 mM). Papaverine, fursemide and probenecid were approximately as effective as the anti-inflammatory organic acids (I50 0.01-0.1 mM), whereas bromcresol green was at least 10-fold more effective. Diphenhydramine and the nonacidic prostaglandin synthesis inhibitors, phenelzine and paracetamol, showed little (I50 greater than 1 mM) or no inhibitory effect. The inhibition of this transport system by some drugs, most notably nonsteroidal anti-inflammatory organic acids, and consequent alterations in the distribution and disposition of prostaglandins must be taken into account in the development of new anti-inflammatory agents and in the interpretation of the mechansim of action and side effects of such drugs. PMID:948038

  19. Mitomycin Resistance in Streptomyces lavendulae Includes a Novel Drug-Binding-Protein-Dependent Export System

    PubMed Central

    Sheldon, Paul J.; Mao, Yingqing; He, Min; Sherman, David H.

    1999-01-01

    Sequence analysis of Streptomyces lavendulae NRRL 2564 chromosomal DNA adjacent to the mitomycin resistance locus mrd (encoding a previously described mitomycin-binding protein [P. Sheldon, D. A. Johnson, P. R. August, H.-W. Liu, and D. H. Sherman, J. Bacteriol. 179:1796–1804, 1997]) revealed a putative mitomycin C (MC) transport gene (mct) encoding a hydrophobic polypeptide that has significant amino acid sequence similarity with several actinomycete antibiotic export proteins. Disruption of mct by insertional inactivation resulted in an S. lavendulae mutant strain that was considerably more sensitive to MC. Expression of mct in Escherichia coli conferred a fivefold increase in cellular resistance to MC, led to the synthesis of a membrane-associated protein, and correlated with reduced intracellular accumulation of the drug. Coexpression of mct and mrd in E. coli resulted in a 150-fold increase in resistance, as well as reduced intracellular accumulation of MC. Taken together, these data provide evidence that MRD and Mct function as components of a novel drug export system specific to the mitomycins. PMID:10198016

  20. Cancer morbidity in British military veterans included in chemical warfare agent experiments at Porton Down: cohort study

    PubMed Central

    Linsell, L; Brooks, C; Keegan, T J; Langdon, T; Doyle, P; Maconochie, N E S; Fletcher, T; Nieuwenhuijsen, M J; Beral, V

    2009-01-01

    Objective To determine cancer morbidity in members of the armed forces who took part in tests of chemical warfare agents from 1941 to 1989. Design Historical cohort study, with cohort members followed up to December 2004. Data source Archive of UK government research facility at Porton Down, UK military personnel records, and national death and cancer records. Participants All veterans included in the cohort study of mortality, excluding those known to have died or been lost to follow-up before 1 January 1971 when the UK cancer registration system commenced: 17 013 male members of the UK armed forces who took part in tests (Porton Down veterans) and a similar group of 16 520 men who did not (non-Porton Down veterans). Main outcome measures Cancer morbidity in each group of veterans; rate ratios, with 95% confidence intervals, adjusted for age group and calendar period. Results 3457 cancers were reported in the Porton Down veterans compared with 3380 cancers in the non-Porton Down veterans. While overall cancer morbidity was the same in both groups (rate ratio 1.00, 95% confidence interval 0.95 to 1.05), Porton Down veterans had higher rates of ill defined malignant neoplasms (1.12, 1.02 to 1.22), in situ neoplasms (1.45, 1.06 to 2.00), and those of uncertain or unknown behaviour (1.32, 1.01 to 1.73). Conclusion Overall cancer morbidity in Porton Down veterans was no different from that in non-Porton Down veterans. PMID:19318700

  1. A Strategy for assessing potential drug-drug interactions of a concomitant agent against a drug absorbed via an intestinal transporter in humans.

    PubMed

    Mizuno-Yasuhira, Akiko; Nakai, Yasuhiro; Gunji, Emi; Uchida, Saeko; Takahashi, Teisuke; Kinoshita, Kohnosuke; Jingu, Shigeji; Sakai, Soichi; Samukawa, Yoshishige; Yamaguchi, Jun-Ichi

    2014-09-01

    A strategy for assessing potential drug-drug interactions (DDIs) based on a simulated intestinal concentration is described. The proposed prediction method was applied to the DDI assessment of luseogliflozin, a novel antidiabetic drug, against miglitol absorbed via the intestinal sodium-glucose cotransporter 1 (SGLT1). The method involves four steps: collection of physicochemical and pharmacokinetic parameters of luseogliflozin for use in a computer simulation; evaluation of the validity of these parameters by verifying the goodness of fit between simulated and observed plasma profiles; simulation of the intestinal luseogliflozin concentration-time profile using the Advanced Compartment Absorption and Transit (ACAT) model in a computer program and estimation of the time spent above a value 10-fold higher than the IC50 value (TAIC) for SGLT1; and evaluation of the DDI potential of luseogliflozin by considering the percentage of TAIC against the miglitol Tmax (time for Cmax) value (TAIC/Tmax). An initial attempt to prove the validity of this method was performed in rats. The resulting TAIC/Tmax in rats was 32%, suggesting a low DDI potential of luseogliflozin against miglitol absorption. The validity was then confirmed using an in vivo interaction study in rats. In humans, luseogliflozin was expected to have no DDI potential against miglitol absorption, since the TAIC/Tmax in humans was lower than that in rats. This prediction was proven, as expected, in a clinical interaction study. In conclusion, the present strategy based on a simulation of the intestinal concentration-time profile using dynamic modeling would be useful for assessing the clinical DDI potential of a concomitant agent against drugs absorbed via an intestinal transporter. PMID:25005603

  2. Identification of drugs as single agents or in combination to prevent carcinoma dissemination in a microfluidic 3D environment.

    PubMed

    Bai, Jing; Tu, Ting-Yuan; Kim, Choong; Thiery, Jean Paul; Kamm, Roger D

    2015-11-01

    Experiments were performed in a modified microfluidic platform recapitulating part of the in vivo tumor microenvironment by co-culturing carcinoma cell aggregates embedded in a three-dimensional (3D) collagen scaffold with human umbilical vein endothelial cells (HUVECs). HUVECs were seeded in one channel of the device to initiate vessel-like structures in vitro prior to introducing the aggregates. The lung adenocarcinoma cell line A549 and the bladder carcinoma cell line T24 were tested. Dose-response assays of four drugs known to interfere with Epithelial Mesenchymal Transition (EMT) signaling pathways were quantified using relative dispersion as a metric of EMT progression. The presence of HUVECs in one channel induces cell dispersal in A549 which then can be inhibited by each of the four drugs. Complete inhibition of T24 aggregate dispersal, however, is not achieved with any single agent, although partial inhibition was observed with 10 μM of the Src inhibitor, AZD-0530. Almost complete inhibition of T24 dispersal in monoculture was achieved only when the four drugs were added in combination, each at 10 μM concentration. Coculture of T24 with HUVECs forfeits the almost-complete inhibition. The enhanced dispersal observed in the presence of HUVECs is a consequence of secretion of growth factors, including HGF and FGF-2, by endothelial cells. This 3D microfluidic co-culture platform provides an in vivo-like surrogate for anti-invasive and anti-metastatic drug screening. It will be particularly useful for defining combination therapies for aggressive tumors such as invasive bladder carcinoma. PMID:26474384

  3. Identification of drugs as single agents or in combination to prevent carcinoma dissemination in a microfluidic 3D environment

    PubMed Central

    Kim, Choong; Thiery, Jean Paul; Kamm, Roger D.

    2015-01-01

    Experiments were performed in a modified microfluidic platform recapitulating part of the in vivo tumor microenvironment by co-culturing carcinoma cell aggregates embedded in a three-dimensional (3D) collagen scaffold with human umbilical vein endothelial cells (HUVECs). HUVECs were seeded in one channel of the device to initiate vessel-like structures in vitro prior to introducing the aggregates. The lung adenocarcinoma cell line A549 and the bladder carcinoma cell line T24 were tested. Dose-response assays of four drugs known to interfere with Epithelial Mesenchymal Transition (EMT) signaling pathways were quantified using relative dispersion as a metric of EMT progression. The presence of HUVECs in one channel induces cell dispersal in A549 which then can be inhibited by each of the four drugs. Complete inhibition of T24 aggregate dispersal, however, is not achieved with any single agent, although partial inhibition was observed with 10 μM of the Src inhibitor, AZD-0530. Almost complete inhibition of T24 dispersal in monoculture was achieved only when the four drugs were added in combination, each at 10 μM concentration. Coculture of T24 with HUVECs forfeits the almost-complete inhibition. The enhanced dispersal observed in the presence of HUVECs is a consequence of secretion of growth factors, including HGF and FGF-2, by endothelial cells. This 3D microfluidic co-culture platform provides an in vivo-like surrogate for anti-invasive and anti-metastatic drug screening. It will be particularly useful for defining combination therapies for aggressive tumors such as invasive bladder carcinoma. PMID:26474384

  4. 'Genipin' - the natural water soluble cross-linking agent and its importance in the modified drug delivery systems: an overview.

    PubMed

    Manickam, Balamurugan; Sreedharan, Rajesh; Elumalai, Manogaran

    2014-01-01

    One of the popular approaches in controlling drug delivery from the polymeric carriers is suitably achieved by the inclusion of crosslinking agents into the formulations at different concentrations. Nevertheless, addition of the chemical crosslinkers such as glutaraldehyde, formaldehyde etc, used in the drug delivery systems causes very serious cytotoxic reactions. These chemical crosslinking agents did not offer any significant advantageous effects when compared to the natural crosslinking agents for instance genipin, which is quite less toxic, biocompatible and offers very stable crosslinked products. Based on the earlier reports the safety of this particular natural crosslinker is very well established, since it has been widely used as a Chinese traditional medicine for long-time, isolated from fruits of the plant Gardenia jasminoides Ellis. This concise article largely portrayed the value of this unique natural crosslinker, utilized in controlling the drug delivery from the various formulations. PMID:24041312

  5. In vitro drug susceptibility of 40 international reference rapidly growing mycobacteria to 20 antimicrobial agents

    PubMed Central

    Pang, Hui; Li, Guilian; Wan, Li; Jiang, Yi; Liu, Haican; Zhao, Xiuqin; Zhao, Zhongfu; Wan, Kanglin

    2015-01-01

    Rapidly growing mycobacteria (RGM) are human pathogens that are relatively easily identified by acid-fast staining but are proving difficult to treat in the clinic. In this study, we performed susceptibility testing of 40 international reference RGM species against 20 antimicrobial agents using the cation-adjusted Mueller-Hinton (CAMH) broth microdilution based on the minimum inhibitory concentration (MIC) assay recommended by the guidelines of the Clinical and Laboratory Standards Institute (CLSI). The results demonstrated that RGM organisms were resistant to the majority of first-line antituberculous agents but not to second-line fluoroquinolones or aminoglycosides. Three drugs (amikacin, tigecycline and linezolid) displayed potent antimycobacterial activity against all tested strains. Capreomycin, levofloxacin and moxifloxacin emerged as promising candidates for the treatment of RGM infections, and cefoxitin and meropenem were active against most strains. Mycobacterium chelonae (M. chelonae), M. abscessus, M. bolletii, M. fortuitum, M. boenickei, M. conceptionense, M. pseudoshottsii, M. septicum and M. setense were the most resistant RGM species. These results provide significant insight into the treatment of RGM species and will assist optimization of clinical criteria. PMID:26629031

  6. Experimental design and instability analysis of coaxial electrospray process for microencapsulation of drugs and imaging agents

    PubMed Central

    Si, Ting; Zhang, Leilei; Li, Guangbin; Roberts, Cynthia J.; Yin, Xiezhen

    2013-01-01

    Abstract. Recent developments in multimodal imaging and image-guided therapy requires multilayered microparticles that encapsulate several imaging and therapeutic agents in the same carrier. However, commonly used microencapsulation processes have multiple limitations such as low encapsulation efficiency and loss of bioactivity for the encapsulated biological cargos. To overcome these limitations, we have carried out both experimental and theoretical studies on coaxial electrospray of multilayered microparticles. On the experimental side, an improved coaxial electrospray setup has been developed. A customized coaxial needle assembly combined with two ring electrodes has been used to enhance the stability of the cone and widen the process parameter range of the stable cone-jet mode. With this assembly, we have obtained poly(lactide-co-glycolide) microparticles with fine morphology and uniform size distribution. On the theoretical side, an instability analysis of the coaxial electrified jet has been performed based on the experimental parameters. The effects of process parameters on the formation of different unstable modes have been studied. The reported experimental and theoretical research represents a significant step toward quantitative control and optimization of the coaxial electrospray process for microencapsulation of multiple drugs and imaging agents in multimodal imaging and image-guided therapy. PMID:23864011

  7. In Vitro Activities of Five Antifungal Drugs Against Opportunistic Agents of Aspergillus Nigri Complex.

    PubMed

    Badali, Hamid; Fakhim, Hamed; Zarei, Fereshteh; Nabili, Mojtaba; Vaezi, Afsane; Poorzad, Nafiseh; Dolatabadi, Somayeh; Mirhendi, Hossein

    2016-04-01

    Black aspergilli, particularly Aspergillus niger and A. tubingensis, are the most common etiological agents of otomycosis followed by onychomycosis, pulmonary aspergillosis and aspergilloma. However, so far there is no systematic study on their antifungal susceptibility profiles. A collection of 124 clinical and environmental species of black aspergilli consisted of A. niger, A. tubingensis, A. uvarum. A. acidus and A. sydowii were verified by DNA sequencing of the partial β-tubulin gene. MICs of amphotericin B, itraconazole, voriconazole, posaconazole, and MECs of caspofungin were performed based on CLSI M38-A2. Posaconazole and caspofungin had the lowest MIC range (0.016-0.125 µg/ml and 0.008-0.031 µg/ml, respectively), followed by amphotericin B (0.25-4 µg/ml), voriconazole (0.125-16 µg/ml) and itraconazole (0.25 to >16) in an increasing order. Some strains of A. niger showed high MIC value for itraconazole and voriconazole (>16 µg/ml), in contrast only environmental isolates of A. tubingensis had high itraconazole MICs (>16 µg/ml). These results confirm that posaconazole and caspofungin are potential drugs for treatment of aspergillosis due to opportunistic agents of Aspergillus Nigri complex. However, in vivo efficacy remains to be determined. PMID:26615417

  8. Absorption-enhancing effects of gemini surfactant on the intestinal absorption of poorly absorbed hydrophilic drugs including peptide and protein drugs in rats.

    PubMed

    Alama, Tammam; Kusamori, Kosuke; Katsumi, Hidemasa; Sakane, Toshiyasu; Yamamoto, Akira

    2016-02-29

    In general, the intestinal absorption of small hydrophilic molecules and macromolecules like peptides, after oral administration is very poor. Absorption enhancers are considered to be one of the most promising agents to enhance the intestinal absorption of drugs. In this research, we focused on a gemini surfactant, a new type of absorption enhancer. The intestinal absorption of drugs, with or without sodium dilauramidoglutamide lysine (SLG-30), a gemini surfactant, was examined by an in situ closed-loop method in rats. The intestinal absorption of 5(6)-carboxyfluorescein (CF) and fluorescein isothiocyanate-dextrans (FDs) was significantly enhanced in the presence of SLG-30, such effect being reversible. Furthermore, the calcium levels in the plasma significantly decreased when calcitonin was co-administered with SLG-30, suggestive of the increased intestinal absorption of calcitonin. In addition, no significant increase in the of lactate dehydrogenase (LDH) activity or in protein release from the intestinal epithelium was observed in the presence of SLG-30, suggestive of the safety of this compound. These findings indicate that SLG-30 is an effective absorption-enhancer for improving the intestinal absorption of poorly absorbed drugs, without causing serious damage to the intestinal epithelium. PMID:26707414

  9. STAT3 Inhibition by Microtubule-Targeted Drugs: Dual Molecular Effects of Chemotherapeutic Agents

    PubMed Central

    Walker, Sarah R.; Chaudhury, Mousumi; Frank, David A.

    2011-01-01

    To improve the effectiveness of anti-cancer therapies, it is necessary to identify molecular targets that are essential to a tumor cell but dispensable in a normal cell. Increasing evidence indicates that the transcription factor STAT3, which regulates the expression of genes controlling proliferation, survival, and self-renewal, constitutes such a target. Recently it has been found that STAT3 can associate with the cytoskeleton. Since many of the tumors in which STAT3 is activated, such as breast cancer and ovarian cancer, are responsive to drugs that target microtubules, we examined the effect of these compounds on STAT3. We found that microtubule stabilizers, such as paclitaxel, or microtubule inhibitors, such as vinorelbine, decrease the activating tyrosine phosphorylation of STAT3 in tumor cells and inhibit the expression of STAT3 target genes. Paclitaxel decreases the association between STAT3 and microtubules, and appears to decrease STAT3 phosphorylation through induction of a negative feedback regulator. The cytotoxic activity of paclitaxel in breast cancer cell lines correlates with its ability to decrease STAT3 phosphorylation. However, consistent with the necessity for expression of a negative regulator, treatment of resistant MDA-MB-231 cells with the DNA demethylating agent 5-azacytidine restores the ability of paclitaxel to block STAT3-dependent gene expression. Finally, the combination of paclitaxel and agents that directly target STAT3 has beneficial effects in killing STAT3-dependent cell lines. Thus, microtubule-targeted agents may exert some of their effects by inhibiting STAT3, and understanding this interaction may be important for optimizing rational targeted cancer therapies. PMID:21949561

  10. Repurposing Drugs in Oncology (ReDO)—nitroglycerin as an anti-cancer agent

    PubMed Central

    Sukhatme, Vidula; Bouche, Gauthier; Meheus, Lydie; Sukhatme, Vikas P; Pantziarka, Pan

    2015-01-01

    Nitroglycerin (NTG), a drug that has been in clinical use for more than a century, has a range of actions which make it of particular interest in an oncological setting. It is generally accepted that the main mechanism of action of NTG is via the production of nitric oxide (NO), which improves cardiac oxygenation via multiple mechanisms including improved blood flow (vasodilation), decreased platelet aggregation, increased erythrocyte O2 release and decreased mitochondrial utilization of oxygen. Its vasoactive properties mean that it has the potential to exploit more fully the enhanced permeability and retention effect in delivering anti-cancer drugs to tumour tissues. Moreover NTG can reduce HIF-1α levels in hypoxic tumour tissues and this may have anti-angiogenic, pro-apoptotic and anti-efflux effects. Additionally NTG may enhance anti-tumour immunity. Pre-clinical and clinical data on these anti-cancer properties of NTG are summarised and discussed. While there is evidence of a positive action as a monotherapy in prostate cancer, there are mixed results in NSCLC where initially positive results have yet to be fully replicated. Based on the evidence presented, a case is made that further exploration of the clinical benefits that may accrue to cancer patients is warranted. Additionally, it is proposed that NTG may synergise with a number of other drugs, including other repurposed drugs, and these are discussed in the supplementary material appended to this paper. PMID:26435741

  11. Novel uses for anti-platelet agents as anti-inflammatory drugs

    PubMed Central

    Pitchford, S C

    2007-01-01

    An alteration in the character and function of platelets is manifested in patients with inflammatory diseases, and these alterations have been dissociated from the well-characterized involvement of platelets in thrombosis and haemostasis. Recent evidence reveals platelet activation is sometimes critical in the development of inflammation. The mechanisms by which platelets participate in inflammation are diverse, and offer numerous opportunities for future drug intervention. There is now acceptance that platelets act as innate inflammatory cells in immune responses, with roles as sentinel cells undergoing surveillance, responding to microbial invasion, orchestrating leukocyte recruitment, and migrating through tissue, causing damage and influencing repair processes in chronic disease. Some of these processes are targeted by drugs that are being developed to target platelet participation in atherosclerosis. The actions of platelets therefore influence the pathogenesis of diverse inflammatory diseases in various body compartments, encompassing parasitic and bacterial infection, allergic inflammation (especially asthma and rhinitis), and non-atopic inflammatory conditions, for example, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and atherosclerosis. This review will first discuss the evidence for platelet activation in these various inflammatory diseases, and secondly discuss the mechanisms by which this pathogenesis occurs and the various anti-platelet agents which have been developed to combat platelet activation in atherosclerosis and their potential future use for the treatment of other inflammatory diseases. PMID:17603547

  12. Using ultrasound to steer ultrasound contrast agents: Implications for targeted drug delivery

    NASA Astrophysics Data System (ADS)

    Clark, Alicia; Aliseda, Alberto

    2013-11-01

    Ultrasound can be used to manipulate ultrasound contrast agents (UCAs), micron-sized bubbles used in ultrasound imaging to increase image contrast. The Bjerknes force, resulting from the lagged response of the microbubbles to the oscillatory ultrasound pressure field, can be utilized to steer the microbubbles to a targeted area in the vasculature, with the microbubbles serving as drug delivery vectors and injectors. The response of microbubbles to ultrasound in a sheared flow has shown a complex coupling of ultrasound-induced volume oscillations with hydrodynamic forces: Saffman lift and the Bjerknes force. In this work, the relative influence of these two forces acting in the across-streamlines direction is determined as a function of the Reynolds and Womersley and the excitation to bubble natural frequency ratio. We use in-vitro experiments to study the behavior of microbubbles in physiologically-realistic pulsatile flows. Quantitative information about microbubble trajectories in physiological conditions is necessary to develop models in order to control ultrasound steering of bubble-based drug delivery vectors in the human vasculature.

  13. Recent Development of Multifunctional Agents as Potential Drug Candidates for the Treatment of Alzheimer's Disease

    PubMed Central

    Guzior, Natalia; ckowska,, Anna Wię; Panek, Dawid; Malawska, Barbara

    2015-01-01

    Alzheimer’s disease (AD) is a complex and progressive neurodegenerative disorder. The available therapy is limited to the symptomatic treatment and its efficacy remains unsatisfactory. In view of the prevalence and expected increase in the incidence of AD, the development of an effective therapy is crucial for public health. Due to the multifactorial aetiology of this disease, the multi-target-directed ligand (MTDL) approach is a promising method in search for new drugs for AD. This review updates information on the development of multifunctional potential anti-AD agents published within the last three years. The majority of the recently reported structures are acetylcholinesterase inhibitors, often endowed with some additional properties. These properties enrich the pharmacological profile of the compounds giving hope for not only symptomatic but also causal treatment of the disease. Among these advantageous properties, the most often reported are an amyloid-β anti-aggregation activity, inhibition of β-secretase and monoamine oxidase, an antioxidant and metal chelating activity, NO-releasing ability and interaction with cannabinoid, NMDA or histamine H3 receptors. The majority of novel molecules possess heterodimeric structures, able to interact with multiple targets by combining different pharmacophores, original or derived from natural products or existing therapeutics (tacrine, donepezil, galantamine, memantine). Among the described compounds, several seem to be promising drug candidates, while others may serve as a valuable inspiration in the search for new effective therapies for AD. PMID:25386820

  14. Repurposing Drugs in Oncology (ReDO)—itraconazole as an anti-cancer agent

    PubMed Central

    Pantziarka, Pan; Sukhatme, Vidula; Bouche, Gauthier; Meheus, Lydie; Sukhatme, Vikas P

    2015-01-01

    Itraconazole, a common triazole anti-fungal drug in widespread clinical use, has evidence of clinical activity that is of interest in oncology. There is evidence that at the clinically relevant doses, itraconazole has potent anti-angiogenic activity, and that it can inhibit the Hedgehog signalling pathway and may also induce autophagic growth arrest. The evidence for these anticancer effects, in vitro, in vivo, and clinical are summarised, and the putative mechanisms of their action outlined. Clinical trials have shown that patients with prostate, lung, and basal cell carcinoma have benefited from treatment with itraconazole, and there are additional reports of activity in leukaemia, ovarian, breast, and pancreatic cancers. Given the evidence presented, a case is made that itraconazole warrants further clinical investigation as an anti- cancer agent. Additionally, based on the properties summarised previously, it is proposed that itraconazole may synergise with a range of other drugs to enhance the anti-cancer effect, and some of these possible combinations are presented in the supplementary materials accompanying this paper. PMID:25932045

  15. Recent development of multifunctional agents as potential drug candidates for the treatment of Alzheimer's disease.

    PubMed

    Guzior, Natalia; Wieckowska, Anna; Panek, Dawid; Malawska, Barbara

    2015-01-01

    Alzheimer's disease (AD) is a complex and progressive neurodegenerative disorder. The available therapy is limited to the symptomatic treatment and its efficacy remains unsatisfactory. In view of the prevalence and expected increase in the incidence of AD, the development of an effective therapy is crucial for public health. Due to the multifactorial aetiology of this disease, the multi-target-directed ligand (MTDL) approach is a promising method in search for new drugs for AD. This review updates information on the development of multifunctional potential anti-AD agents published within the last three years. The majority of the recently reported structures are acetylcholinesterase inhibitors, often endowed with some additional properties. These properties enrich the pharmacological profile of the compounds giving hope for not only symptomatic but also causal treatment of the disease. Among these advantageous properties, the most often reported are an amyloid-β antiaggregation activity, inhibition of β-secretase and monoamine oxidase, an antioxidant and metal chelating activity, NOreleasing ability and interaction with cannabinoid, NMDA or histamine H3 receptors. The majority of novel molecules possess heterodimeric structures, able to interact with multiple targets by combining different pharmacophores, original or derived from natural products or existing therapeutics (tacrine, donepezil, galantamine, memantine). Among the described compounds, several seem to be promising drug candidates, while others may serve as a valuable inspiration in the search for new effective therapies for AD. PMID:25386820

  16. An overview of anthrax infection including the recently identified form of disease in injection drug users

    PubMed Central

    Hicks, Caitlin W.; Sweeney, Daniel A.; Cui, Xizhong; Li, Yan

    2012-01-01

    Purpose Bacillus anthracis infection (anthrax) can be highly lethal. Two recent outbreaks related to contaminated mail in the USA and heroin in the UK and Europe and its potential as a bioterrorist weapon have greatly increased concerns over anthrax in the developed world. Methods This review summarizes the microbiology, pathogenesis, diagnosis, and management of anthrax. Results and conclusions Anthrax, a gram-positive bacterium, has typically been associated with three forms of infection: cutaneous, gastrointestinal, and inhalational. However, the anthrax outbreak among injection drug users has emphasized the importance of what is now considered a fourth disease form (i.e., injectional anthrax) that is characterized by severe soft tissue infection. While cutaneous anthrax is most common, its early stages are distinct and prompt appropriate treatment commonly produces a good outcome. However, early symptoms with the other three disease forms can be nonspecific and mistaken for less lethal conditions. As a result, patients with gastrointestinal, inhalational, or injectional anthrax may have advanced infection at presentation that can be highly lethal. Once anthrax is suspected, the diagnosis can usually be made with gram stain and culture from blood or tissue followed by confirmatory testing (e.g., PCR). While antibiotics are the mainstay of anthrax treatment, use of adjunctive therapies such as anthrax toxin antagonists are a consideration. Prompt surgical therapy appears to be important for successful management of injectional anthrax. PMID:22527064

  17. DMSO inhibits human platelet activation through cyclooxygenase-1 inhibition. A novel agent for drug eluting stents?

    SciTech Connect

    Asmis, Lars; Tanner, Felix C.; Sudano, Isabella; Luescher, Thomas F.; Camici, Giovanni G.

    2010-01-22

    Background: DMSO is routinely infused together with hematopoietic cells in patients undergoing myeloablative therapy and was recently found to inhibit smooth muscle cells proliferation and arterial thrombus formation in the mouse by preventing tissue factor (TF), a key activator of the coagulation cascade. This study was designed to investigate whether DMSO prevents platelet activation and thus, whether it may represent an interesting agent to be used on drug eluting stents. Methods and results: Human venous blood from healthy volunteers was collected in citrated tubes and platelet activation was studied by cone and platelet analyzer (CPA) and rapid-platelet-function-assay (RPFA). CPA analysis showed that DMSO-treated platelets exhibit a lower adherence in response to shear stress (-15.54 {+-} 0.9427%, n = 5, P < 0.0001 versus control). Additionally, aggregometry studies revealed that DMSO-treated, arachidonate-stimulated platelets had an increased lag phase (18.0% {+-} 4.031, n = 9, P = 0.0004 versus control) as well as a decreased maximal aggregation (-6.388 {+-} 2.212%, n = 6, P = 0.0162 versus control). Inhibitory action of DMSO could be rescued by exogenous thromboxane A2 and was mediated, at least in part, by COX-1 inhibition. Conclusions: Clinically relevant concentrations of DMSO impair platelet activation by a thromboxane A2-dependent, COX-1-mediated effect. This finding may be crucial for the previously reported anti-thrombotic property displayed by DMSO. Our findings support a role for DMSO as a novel drug to prevent not only proliferation, but also thrombotic complications of drug eluting stents.

  18. In Vitro Metabolism and Drug-Drug Interaction Potential of UTL-5g, a Novel Chemo- and Radioprotective Agent

    PubMed Central

    Wu, Jianmei; Shaw, Jiajiu; Dubaisi, Sarah; Valeriote, Frederick

    2014-01-01

    N-(2,4-dichlorophenyl)-5-methyl-1,2-oxazole-3-carboxamide (UTL-5g), a potential chemo- and radioprotective agent, acts as a prodrug requiring bioactivation to the active metabolite 5-methylisoxazole-3-carboxylic acid (ISOX). UTL-5g hydrolysis to ISOX and 2,4-dichloroaniline (DCA) has been identified in porcine and rabbit liver esterases. The purpose of this study was to provide insights on the metabolism and drug interaction potential of UTL-5g in humans. The kinetics of UTL-5g hydrolysis was determined in human liver microsomes (HLM) and recombinant human carboxylesterases (hCE1b and hCE2). The potential of UTL-5g and its metabolites for competitive inhibition and time-dependent inhibition of microsomal cytochrome P450 (P450) was examined in HLM. UTL-5g hydrolysis to ISOX and DCA in HLM were NADPH-independent, with a maximum rate of reaction (Vmax) of 11.1 nmol/min per mg and substrate affinity (Km) of 41.6 µM. Both hCE1b and hCE2 effectively catalyzed UTL-5g hydrolysis, but hCE2 exhibited ∼30-fold higher catalytic efficiency (Vmax/Km) than hCE1b. UTL-5g and DCA competitively inhibited microsomal CYP1A2, CYP2B6, and CYP2C19 (IC50 values <50 µM), and exhibited time-dependent inhibition of microsomal CYP1A2 with the inactivation efficiency (kinact/KI) of 0.68 and 0.51 minute−1·mM−1, respectively. ISOX did not inhibit or inactivate any tested microsomal P450. In conclusion, hCE1b and hCE2 play a key role in the bioactivation of UTL-5g. Factors influencing carboxylesterase activities may have a significant impact on the pharmacological and therapeutic effects of UTL-5g. UTL-5g has the potential to inhibit P450-mediated metabolism through competitive inhibition or time-dependent inhibition. Caution is particularly needed for potential drug interactions involving competitive inhibition or time-dependent inhibition of CYP1A2 in the future clinical development of UTL-5g. PMID:25249693

  19. Biomedical effects of chemical-threat-agent antidote and pretreatment drugs. An abstracted bibliography. Volume 1. Interim report

    SciTech Connect

    Lentz, J.M.; Reams, G.G.; DeJohn, C.A.

    1986-04-01

    The bibliographic abstracts in this report are part of a project to assess biomedical effects of chemical-warfare antidote agents and related pre-treatment drugs. Specific attention is focused on the biomedical effects in the following general areas: vision, auditory, spatial orientation, musculoskeletal, cardipulmonary, cognitive performance, pharmacology, cutaneous stimuli, and cortical effects. In some cases, the bibliography addresses other therapeutic drugs that may be used simultaneously with chemical-warfare antidotes.

  20. Applicability of bioanalysis of multiple analytes in drug discovery and development: review of select case studies including assay development considerations.

    PubMed

    Srinivas, Nuggehally R

    2006-05-01

    The development of sound bioanalytical method(s) is of paramount importance during the process of drug discovery and development culminating in a marketing approval. Although the bioanalytical procedure(s) originally developed during the discovery stage may not necessarily be fit to support the drug development scenario, they may be suitably modified and validated, as deemed necessary. Several reviews have appeared over the years describing analytical approaches including various techniques, detection systems, automation tools that are available for an effective separation, enhanced selectivity and sensitivity for quantitation of many analytes. The intention of this review is to cover various key areas where analytical method development becomes necessary during different stages of drug discovery research and development process. The key areas covered in this article with relevant case studies include: (a) simultaneous assay for parent compound and metabolites that are purported to display pharmacological activity; (b) bioanalytical procedures for determination of multiple drugs in combating a disease; (c) analytical measurement of chirality aspects in the pharmacokinetics, metabolism and biotransformation investigations; (d) drug monitoring for therapeutic benefits and/or occupational hazard; (e) analysis of drugs from complex and/or less frequently used matrices; (f) analytical determination during in vitro experiments (metabolism and permeability related) and in situ intestinal perfusion experiments; (g) determination of a major metabolite as a surrogate for the parent molecule; (h) analytical approaches for universal determination of CYP450 probe substrates and metabolites; (i) analytical applicability to prodrug evaluations-simultaneous determination of prodrug, parent and metabolites; (j) quantitative determination of parent compound and/or phase II metabolite(s) via direct or indirect approaches; (k) applicability in analysis of multiple compounds in select

  1. Transgenic Mice that Express the Human Multidrug-Resistance Gene in Bone Marrow Enable a Rapid Identification of Agents that Reverse Drug Resistance

    NASA Astrophysics Data System (ADS)

    Mickisch, Gerald H.; Merlino, Glenn T.; Galski, Hanan; Gottesman, Michael M.; Pastan, Ira

    1991-01-01

    The development of preclinical models for the rapid testing of agents that circumvent multidrug resistance in cancer is a high priority of research on drug resistance. A common form of multidrug resistance in human cancer results from expression of the MDR1 gene, which encodes a M_r 170,000 glycoprotein that functions as a plasma membrane energy-dependent multidrug efflux pump. We have engineered transgenic mice that express this multidrug transporter in their bone marrow and demonstrated that these animals are resistant to leukopenia by a panel of anticancer drugs including anthracyclines, vinca alkaloids, etoposide, taxol, and actinomycin D. Differential leukocyte counts indicate that both neutrophils and lymphocytes are protected. Drugs such as cisplatin, methotrexate, and 5-fluorouracil, which are not handled by the multidrug transporter, produce bone marrow suppression in both normal and transgenic mice. The resistance conferred by the MDR1 gene can be circumvented in a dose-dependent manner by simultaneous administration of agents previously shown to be inhibitors of the multidrug transporter in vitro, including verapamil isomers, quinidine, and quinine. Verapamil and quinine, both at levels suitable for human trials that produced only partial sensitization of the MDR1-transgenic mice, were fully sensitizing when used in combination. We conclude that MDR1-transgenic mice provide a rapid and reliable system to determine the bioactivity of agents that reverse multidrug resistance in animals.

  2. Transgenic mice that express the human multidrug-resistance gene in bone marrow enable a rapid identification of agents that reverse drug resistance

    SciTech Connect

    Mickisch, G.H.; Merlino, G.T.; Galski, H.; Gottesman, M.M.; Pastan, I. )

    1991-01-15

    The development of preclinical models for the rapid testing of agents that circumvent multidrug resistance in cancer is a high priority of research on drug resistance. A common form of multidrug resistance in human cancer results from expression of the MDR1 gene, which encodes a M{sub r} 170,000 glycoprotein that functions as a plasma membrane energy-dependent multidrug efflux pump. The authors have engineered transgenic mice that express this multidrug transporter in their bone marrow and demonstrated that these animals are resistant to leukopenia by a panel of anticancer drugs including anthracyclines, vinca alkaloids, etoposide, taxol, and actinomycin D. Differential leukocyte counts indicate that both neutrophils and lympohcytes are pretected. Drugs such as cisplatin, methotrexate, and 5-fluorouracil, which are not handled by the multidrug transporter, produce bone marrow suppression in both normal and transgenic mice. The resistance conferred by the MDR1 gene can be circumvented in a dose-dependent manner by simultaneous administration of agents previously shown to be inhibitors of the multidrug transporter in vitro, including verapamil isomers, quinidine, and quinine. They conclude that MDR1-transgenic mice provide a rapid and reliable system to determine the bioactivity of agents that reverse multidrug resistance in animals.

  3. Xanthones from Mangosteen Extracts as Natural Chemopreventive Agents: Potential Anticancer Drugs

    PubMed Central

    Shan, T.; Ma, Q.; Guo, K.; Liu, J.; Li, W.; Wang, F.; Wu, E.

    2011-01-01

    Despite decades of research, the treatment and management of malignant tumors still remain a formidable challenge for public health. New strategies for cancer treatment are being developed, and one of the most promising treatment strategies involves the application of chemopreventive agents. The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds. Xanthones, from the pericarp, whole fruit, heartwood, and leaf of mangosteen (Garcinia mangostana Linn., GML), are known to possess a wide spectrum of pharmacologic properties, including anti-oxidant, anti-tumor, anti-allergic, anti-inflammatory, anti-bacterial, anti-fungal, and anti-viral activities. The potential chemopreventive and chemotherapeutic activities of xanthones have been demonstrated in different stages of carcinogenesis (initiation, promotion, and progression) and are known to control cell division and growth, apoptosis, inflammation, and metastasis. Multiple lines of evidence from numerous in vitro and in vivo studies have confirmed that xanthones inhibit proliferation of a wide range of human tumor cell types by modulating various targets and signaling transduction pathways. Here we provide a concise and comprehensive review of preclinical data and assess the observed anticancer effects of xanthones, supporting its remarkable potential as an anticancer agent. PMID:21902651

  4. Borrelia burgdorferi, the Causative Agent of Lyme Disease, Forms Drug-Tolerant Persister Cells.

    PubMed

    Sharma, Bijaya; Brown, Autumn V; Matluck, Nicole E; Hu, Linden T; Lewis, Kim

    2015-08-01

    Borrelia burgdorferi is the causative agent of Lyme disease, which affects an estimated 300,000 people annually in the United States. When treated early, the disease usually resolves, but when left untreated, it can result in symptoms such as arthritis and encephalopathy. Treatment of the late-stage disease may require multiple courses of antibiotic therapy. Given that antibiotic resistance has not been observed for B. burgdorferi, the reason for the recalcitrance of late-stage disease to antibiotics is unclear. In other chronic infections, the presence of drug-tolerant persisters has been linked to recalcitrance of the disease. In this study, we examined the ability of B. burgdorferi to form persisters. Killing growing cultures of B. burgdorferi with antibiotics used to treat the disease was distinctly biphasic, with a small subpopulation of surviving cells. Upon regrowth, these cells formed a new subpopulation of antibiotic-tolerant cells, indicating that these are persisters rather than resistant mutants. The level of persisters increased sharply as the culture transitioned from the exponential to stationary phase. Combinations of antibiotics did not improve killing. Daptomycin, a membrane-active bactericidal antibiotic, killed stationary-phase cells but not persisters. Mitomycin C, an anticancer agent that forms adducts with DNA, killed persisters and eradicated growing and stationary cultures of B. burgdorferi. Finally, we examined the ability of pulse dosing an antibiotic to eliminate persisters. After addition of ceftriaxone, the antibiotic was washed away, surviving persisters were allowed to resuscitate, and the antibiotic was added again. Four pulse doses of ceftriaxone killed persisters, eradicating all live bacteria in the culture. PMID:26014929

  5. Borrelia burgdorferi, the Causative Agent of Lyme Disease, Forms Drug-Tolerant Persister Cells

    PubMed Central

    Sharma, Bijaya; Brown, Autumn V.; Matluck, Nicole E.; Hu, Linden T.

    2015-01-01

    Borrelia burgdorferi is the causative agent of Lyme disease, which affects an estimated 300,000 people annually in the United States. When treated early, the disease usually resolves, but when left untreated, it can result in symptoms such as arthritis and encephalopathy. Treatment of the late-stage disease may require multiple courses of antibiotic therapy. Given that antibiotic resistance has not been observed for B. burgdorferi, the reason for the recalcitrance of late-stage disease to antibiotics is unclear. In other chronic infections, the presence of drug-tolerant persisters has been linked to recalcitrance of the disease. In this study, we examined the ability of B. burgdorferi to form persisters. Killing growing cultures of B. burgdorferi with antibiotics used to treat the disease was distinctly biphasic, with a small subpopulation of surviving cells. Upon regrowth, these cells formed a new subpopulation of antibiotic-tolerant cells, indicating that these are persisters rather than resistant mutants. The level of persisters increased sharply as the culture transitioned from the exponential to stationary phase. Combinations of antibiotics did not improve killing. Daptomycin, a membrane-active bactericidal antibiotic, killed stationary-phase cells but not persisters. Mitomycin C, an anticancer agent that forms adducts with DNA, killed persisters and eradicated growing and stationary cultures of B. burgdorferi. Finally, we examined the ability of pulse dosing an antibiotic to eliminate persisters. After addition of ceftriaxone, the antibiotic was washed away, surviving persisters were allowed to resuscitate, and the antibiotic was added again. Four pulse doses of ceftriaxone killed persisters, eradicating all live bacteria in the culture. PMID:26014929

  6. Evaluation of kappa carrageenan as potential carrier for floating drug delivery system: Effect of pore forming agents.

    PubMed

    Selvakumaran, Suguna; Muhamad, Ida Idayu; Abd Razak, Saiful Izwan

    2016-01-01

    Floating hydrogels were prepared from kappa carrageenan containing CaCO3 and NaHCO3 as pore forming agents. The effects of CaCO3 and NaHCO3 on hydrogel characterizations were investigated and compared. Amoxicillin trihydrate was used as a model drug. Characterizations of the hydrogels were carried out using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and field emission scanning electron microscope (FESEM). As pore forming agents concentration increases, the porosity (%) and floating properties increased. NaHCO3 incorporated hydrogels showed higher porosity with shorter floating lag time (FLT) than CaCO3. Hydrogel which contained CaCO3 exhibited better gel stability over the control and NaHCO3 containing gel. Incorporation of CaCO3 into kappa carrageenan hydrogel showed smoother surface gels compared to those produced with NaHCO3. CaCO3 also showed higher drug entrapment efficiency and sustained drug release profile than NaHCO3. The results of these studies showed that, CaCO3 is an effective pore forming agents in κC hydrogels preparation as compare to NaHCO3. Thus, CaCO3 can be an excellent pore forming agent for an effective floating drug delivery system. PMID:26453870

  7. Clostridium difficile Drug Pipeline: Challenges in Discovery and Development of New Agents

    PubMed Central

    2015-01-01

    In the past decade Clostridium difficile has become a bacterial pathogen of global significance. Epidemic strains have spread throughout hospitals, while community acquired infections and other sources ensure a constant inoculation of spores into hospitals. In response to the increasing medical burden, a new C. difficile antibiotic, fidaxomicin, was approved in 2011 for the treatment of C. difficile-associated diarrhea. Rudimentary fecal transplants are also being trialed as effective treatments. Despite these advances, therapies that are more effective against C. difficile spores and less damaging to the resident gastrointestinal microbiome and that reduce recurrent disease are still desperately needed. However, bringing a new treatment for C. difficile infection to market involves particular challenges. This review covers the current drug discovery pipeline, including both small molecule and biologic therapies, and highlights the challenges associated with in vitro and in vivo models of C. difficile infection for drug screening and lead optimization. PMID:25760275

  8. Repurposing drugs in oncology (ReDO)—cimetidine as an anti-cancer agent

    PubMed Central

    Pantziarka, Pan; Bouche, Gauthier; Meheus, Lydie; Sukhatme, Vidula; Sukhatme, Vikas P

    2014-01-01

    Cimetidine, the first H2 receptor antagonist in widespread clinical use, has anti-cancer properties that have been elucidated in a broad range of pre-clinical and clinical studies for a number of different cancer types. These data are summarised and discussed in relation to a number of distinct mechanisms of action. Based on the evidence presented, it is proposed that cimetidine would synergise with a range of other drugs, including existing chemotherapeutics, and that further exploration of the potential of cimetidine as an anti-cancer therapeutic is warranted. Furthermore, there is compelling evidence that cimetidine administration during the peri-operative period may provide a survival benefit in some cancers. A number of possible combinations with other drugs are discussed in the supplementary material accompanying this paper. PMID:25525463

  9. Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents

    PubMed Central

    Shaked, Yuval; Henke, Erik; Roodhart, Jeanine; Mancuso, Patrizia; Langenberg, Marlies; Colleoni, Marco; Daenen, Laura G.; Man, Shan; Xu, Ping; Emmenegger, Urban; Tang, Terence; Zhu, Zhenping; Witte, Larry; Strieter, Robert M.; Bertolini, Francesco; Voest, Emile; Benezra, Robert; Kerbel, Robert S.

    2008-01-01

    SUMMARY Several hypotheses have been proposed to explain how antiangiogenic drugs enhance the treatment efficacy of cytotoxic chemotherapy including impairing the ability of chemotherapy-responsive tumors to regrow after therapy. With respect to the latter, we show that certain chemotherapy drugs, e.g. paclitaxel, can rapidly induce pro-angiogenic bone marrow derived circulating endothelial cell (CEP) mobilization, and subsequent tumor homing, whereas others, e.g. gemcitabine, did not. Acute CEP mobilization was mediated, at least in part, by systemic induction of SDF-1α and could be prevented by various procedures such as treatment with anti-VEGFR2 blocking antibodies or by paclitaxel treatment in CEP-deficient Id-mutant mice, both of which resulted in enhanced anti-tumor effects mediated by paclitaxel, but not gemcitabine. PMID:18772115

  10. Drug interactions between antihypertensive drugs and non-steroidal anti-inflammatory agents: a descriptive study using the French Pharmacovigilance database.

    PubMed

    Fournier, Jean-Pascal; Sommet, Agnès; Durrieu, Geneviève; Poutrain, Jean-Christophe; Lapeyre-Mestre, Maryse; Montastruc, Jean-Louis

    2014-04-01

    Drug-drug interactions (DDIs) between antihypertensive drugs and non-steroidal anti-inflammatory drugs (NSAIDs) can lead to adverse drug reactions (ADRs). Guidelines are available to help prescribers deal with these drug associations, but their implementation is not well evaluated. The aims of this study were to assess the prevalence of NSAIDs exposure in patients treated with antihypertensive drugs, using the French Pharmacovigilance database, and explore the ADRs related to DDIs between antihypertensive drugs and NSAIDs. Over the 11, 442 notifications of ADRs recorded in this database in patients treated with oral antihypertensive drugs between 2008 and 2010, 517 (4.5 and 95% CI: 4.1-4.9) also included exposure to NSAIDs. These subjects were more frequently women, took more drugs in general, and were younger and less frequently treated with antiplatelet drugs. In 24.2% of them (125 patients), a DDI between NSAIDs and antihypertensive drugs was potentially the cause of the reported ADR. Acute renal failure caused by DDIs between NSAIDs and angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), or diuretics was the most frequently reported ADR (20.7%). Finally, in the French Pharmacovigilance database, around one-fourth of associations NSAIDs  +  antihypertensive drugs are associated with a 'serious' ADR (mainly acute renal failure), suggesting that this well-known DDI is not enough taken into account by prescribers. PMID:23190210

  11. Cyclin-dependent protein kinase inhibitors including palbociclib as anticancer drugs.

    PubMed

    Roskoski, Robert

    2016-05-01

    Cyclins and cyclin-dependent protein kinases (CDKs) are important regulatory components that are required for cell cycle progression. The levels of the cell cycle CDKs are generally constant and their activities are controlled by cyclins, proteins whose levels oscillate during each cell cycle. Additional CDK family members were subsequently discovered that play significant roles in a wide range of activities including the control of gene transcription, metabolism, and neuronal function. In response to mitogenic stimuli, cells in the G1 phase of the cell cycle produce cyclins of the D type that activate CDK4/6. These activated enzymes catalyze the monophosphorylation of the retinoblastoma protein. Then CDK2-cyclin E catalyzes the hyperphosphorylation of Rb that promotes the release and activation of the E2F transcription factors, which in turn lead to the generation of several proteins required for cell cycle progression. As a result, cells pass through the G1-restriction point and are committed to complete cell division. CDK2-cyclin A, CDK1-cyclin A, and CDK1-cyclin B are required for S, G2, and M-phase progression. Increased cyclin or CDK expression or decreased levels of endogenous CDK inhibitors such as INK4 or CIP/KIP have been observed in various cancers. In contrast to the mutational activation of EGFR, Kit, or B-Raf in the pathogenesis of malignancies, mutations in the CDKs that cause cancers are rare. Owing to their role in cell proliferation, CDKs represent natural targets for anticancer therapies. Abemaciclib (LY2835219), ribociclib (Lee011), and palbociclib (Ibrance(®) or PD0332991) target CDK4/6 with IC50 values in the low nanomolar range. Palbociclib and other CDK inhibitors bind in the cleft between the small and large lobes of the CDKs and inhibit the binding of ATP. Like ATP, palbociclib forms hydrogen bonds with residues in the hinge segment of the cleft. Like the adenine base of ATP, palbociclib interacts with catalytic spine residues CS6 and CS7

  12. Graphene nanoribbons as a drug delivery agent for lucanthone mediated therapy of glioblastoma multiforme

    SciTech Connect

    Chowdhury, Sayan Mullick; Surhland, Cassandra; Sanchez, Zina; Chaudhary, Pankaj; Suresh Kumar, M. A.; Lee, Stephen; Peña, Louis A.; Waring, Michael; Sitharaman, Balaji; Naidu, Mamta

    2014-08-13

    We report use of PEG-DSPE coated oxidized graphene nanoribbons (O-GNR-PEG-DSPE) as agent for delivery of anti-tumor drug Lucanthone (Luc) into Glioblastoma Multiformae (GBM) cells targeting base excision repair enzyme APE-1 (Apurinic endonuclease-1). Lucanthone, an endonuclease inhibitor of APE-1, was loaded onto O-GNR-PEG-DSPEs using a simple non-covalent method. We found its uptake by GBM cell line U251 exceeding 67% and 60% in APE-1-overexpressing U251, post 24 hours (h). However, their uptake was ~38% and 29% by MCF-7 and rat glial progenitor cells (CG-4), respectively. TEM analysis of U251 showed large aggregates of O-GNR-PEG-DSPE in vesicles. Luc-O-GNR-PEG-DSPE was significantly toxic to U251 but showed little / no toxicity when exposed to MCF-7/CG-4 cells. This differential uptake effect can be exploited to use O-GNR-PEG-DSPEs as a vehicle for Luc delivery to GBM, while reducing nonspecific cytotoxicity to the surrounding healthy tissue. In conclusion, cell death in U251 was necrotic, probably due to oxidative degradation of APE-1.

  13. Graphene nanoribbons as a drug delivery agent for lucanthone mediated therapy of glioblastoma multiforme

    DOE PAGESBeta

    Chowdhury, Sayan Mullick; Surhland, Cassandra; Sanchez, Zina; Chaudhary, Pankaj; Suresh Kumar, M. A.; Lee, Stephen; Peña, Louis A.; Waring, Michael; Sitharaman, Balaji; Naidu, Mamta

    2014-08-13

    We report use of PEG-DSPE coated oxidized graphene nanoribbons (O-GNR-PEG-DSPE) as agent for delivery of anti-tumor drug Lucanthone (Luc) into Glioblastoma Multiformae (GBM) cells targeting base excision repair enzyme APE-1 (Apurinic endonuclease-1). Lucanthone, an endonuclease inhibitor of APE-1, was loaded onto O-GNR-PEG-DSPEs using a simple non-covalent method. We found its uptake by GBM cell line U251 exceeding 67% and 60% in APE-1-overexpressing U251, post 24 hours (h). However, their uptake was ~38% and 29% by MCF-7 and rat glial progenitor cells (CG-4), respectively. TEM analysis of U251 showed large aggregates of O-GNR-PEG-DSPE in vesicles. Luc-O-GNR-PEG-DSPE was significantly toxic to U251more » but showed little / no toxicity when exposed to MCF-7/CG-4 cells. This differential uptake effect can be exploited to use O-GNR-PEG-DSPEs as a vehicle for Luc delivery to GBM, while reducing nonspecific cytotoxicity to the surrounding healthy tissue. In conclusion, cell death in U251 was necrotic, probably due to oxidative degradation of APE-1.« less

  14. One-step fabrication of agent-loaded biodegradable microspheroids for drug delivery and imaging applications.

    PubMed

    Heslinga, Michael J; Willis, Gabriella M; Sobczynski, Daniel J; Thompson, Alex J; Eniola-Adefeso, Omolola

    2014-04-01

    Non-spherical particles may offer advantages over conventional spherical systems for drug delivery applications. This work describes the fabrication of agent-loaded poly(lactic-co-glycolic acid) (PLGA) spheroids via the emulsion solvent evaporation (ESE) method. The versatility of this technique for loading a variety of therapeutics is demonstrated via loading of paclitaxel, bovine serum albumin, and cadmium sulfide nanoparticles into PLGA spheroids. The encapsulation efficiency for spheroids fabricated via oil-in-water (O/W) emulsions is highest at low aqueous phase surfactant concentrations while the encapsulation efficiency for spheroids made via water-in-oil-in-water (W/O/W) is highest at high aqueous phase surfactant concentrations and basic aqueous phase pH values. Particle aspect ratio polydispersity can be minimized via the use of high aqueous phase PVA concentration and pH. The ESE technique is an attractive alternative to recently described methods for fabrication of non-spherical particles due to its simplicity in setup, high particle yield and adaptability to a variety of biodegradable polymers and therapeutics. PMID:24441181

  15. Re-Directing an Alkylating Agent to Mitochondria Alters Drug Target and Cell Death Mechanism

    PubMed Central

    Wisnovsky, Simon P.; Pereira, Mark P.; Wang, Xiaoming; Hurren, Rose; Parfitt, Jeremy; Larsen, Lesley; Smith, Robin A. J.; Murphy, Michael P.; Schimmer, Aaron D.; Kelley, Shana O.

    2013-01-01

    We have successfully delivered a reactive alkylating agent, chlorambucil (Cbl), to the mitochondria of mammalian cells. Here, we characterize the mechanism of cell death for mitochondria-targeted chlorambucil (mt-Cbl) in vitro and assess its efficacy in a xenograft mouse model of leukemia. Using a ρ° cell model, we show that mt-Cbl toxicity is not dependent on mitochondrial DNA damage. We also illustrate that re-targeting Cbl to mitochondria results in a shift in the cell death mechanism from apoptosis to necrosis, and that this behavior is a general feature of mitochondria-targeted Cbl. Despite the change in cell death mechanisms, we show that mt-Cbl is still effective in vivo and has an improved pharmacokinetic profile compared to the parent drug. These findings illustrate that mitochondrial rerouting changes the site of action of Cbl and also alters the cell death mechanism drastically without compromising in vivo efficacy. Thus, mitochondrial delivery allows the exploitation of Cbl as a promiscuous mitochondrial protein inhibitor with promising therapeutic potential. PMID:23585833

  16. Graphene Nanoribbons as a Drug Delivery Agent for Lucanthone Mediated Therapy of Glioblastoma Multiforme

    PubMed Central

    Chowdhury, Sayan Mullick; Surhland, Cassandra; Sanchez, Zina; Chaudhary, Pankaj; Kumar, M.A. Suresh; Lee, Stephen; Peña, Louis A.; Waring, Michael; Sitharaman, Balaji; Naidu, Mamta

    2014-01-01

    We report use of PEG-DSPE coated oxidized graphene nanoribbons (O-GNR-PEG-DSPE) as agent for delivery of anti-tumor drug Lucanthone (Luc) into Glioblastoma Multiformae (GBM) cells targeting base excision repair enzyme APE-1 (Apurinic endonuclease-1). Lucanthone, an endonuclease inhibitor of APE-1, was loaded onto O-GNR-PEG-DSPEs using a simple non-covalent method. We found its uptake by GBM cell line U251 exceeding 67% and 60% in APE-1-overexpressing U251, post 24 hours (h). However, their uptake was ~38% and 29% by MCF-7 and rat glial progenitor cells (CG-4), respectively. TEM analysis of U251 showed large aggregates of O-GNR-PEG-DSPE in vesicles. Luc-O-GNR-PEG-DSPE was significantly toxic to U251 but showed little / no toxicity when exposed to MCF-7/CG-4 cells. This differential uptake effect can be exploited to use O-GNR-PEG-DSPEs as a vehicle for Luc delivery to GBM, while reducing nonspecific cytotoxicity to the surrounding healthy tissue. Cell death in U251 was necrotic, probably due to oxidative degradation of APE-1. PMID:25131339

  17. Intestinal transport of gentamicin with a novel, glycosteroid drug transport agent

    NASA Technical Reports Server (NTRS)

    Axelrod, H. R.; Kim, J. S.; Longley, C. B.; Lipka, E.; Amidon, G. L.; Kakarla, R.; Hui, Y. W.; Weber, S. J.; Choe, S.; Sofia, M. J.

    1998-01-01

    PURPOSE: The objective was to investigate the ability of a glycosteroid (TC002) to increase the oral bioavailability of gentamicin. METHODS: Admixtures of gentamicin and TC002 were administered to the rat ileum by injection and to dogs by ileal or jejunal externalized ports, or PO. Bioavailability of gentamicin was determined by HPLC. 3H-TC002 was injected via externalized cannulas into rat ileum or jejunum, or PO and its distribution and elimination was determined. The metabolism of TC002 in rats was evaluated by solid phase extraction and HPLC analysis of plasma, urine and feces following oral or intestinal administration. RESULTS: The bioavailability of gentamicin was substantially increased in the presence of TC002 in both rats and dogs. The level of absorption was dependent on the concentration of TC002 and site of administration. Greatest absorption occurred following ileal orjejunal administration. TC002 was significantly more efficacious than sodium taurocholate, but similar in cytotoxicity. TC002 remained primarily in the GI tract following oral or intestinal administration and cleared rapidly from the body. It was only partly metabolized in the GI tract, but was rapidly and completely converted to its metabolite in plasma and urine. CONCLUSIONS: TC002 shows promise as a new drug transport agent for promoting intestinal absorption of polar molecules such as gentamicin.

  18. Mithramycin, an agent for developing new therapeutic drugs for neurodegenerative diseases.

    PubMed

    Osada, Nobuhiro; Kosuge, Yasuhiro; Ishige, Kumiko; Ito, Yoshihisa

    2013-01-01

    Mithramycin A (MTM) has been shown to inhibit cancer growth by blocking the binding of Sp-family transcription factors to gene regulatory elements and is used for the treatment of leukemia and testicular cancer in the United States. In contrast, MTM has also been shown to exert neuroprotective effects in normal cells. An earlier study showed that MTM protected primary cortical neurons against oxidative stress-induced cell death. Recently, we demonstrated that MTM suppressed endoplasmic reticulum (ER) stress-induced neuronal death in organotypic hippocampal slice cultures and cultured hippocampal cells through attenuation of ER stress-associated signal proteins. We also found that MTM decreased neuronal death in area CA1 of the hippocampus after transient global ischemia/reperfusion in mice and restored the ischemia/reperfusion-induced impairment of long-term potentiation in this area. MTM has been shown to prolong the survival of Huntington's disease model mice and to attenuate dopaminergic neurotoxicity in mice after repeated administration of methamphetamine. In this review, we provide an up to date overview of neuroprotective effects of MTM and less toxic MTM analogs, MTM SK and MTM SDK, on some of the neurodegenerative diseases and discuss the promise of MTM as an agent for developing new therapeutic drugs for such diseases. PMID:23902990

  19. Huperzine a as a pretreatment candidate drug against nerve agent toxicity. (Reannouncement with new availability information)

    SciTech Connect

    Grunwald, J.; Raveh, L.; Doctor, B.P.; Ashani, Y.

    1994-12-31

    Huperzine A (HUP) is a naturally-occurring, potent, reversible inhibitor of acetylcholinesterase (AChE) that crosses the blood-brain barrier. To examine its ability to protect against nerve agent poisoning, HUP was administered i.p. to mice, and the s.c. LD50 of soman was determined at various time intervals after pretreatment. Results were compared to those obtained for animals treated with physostigmine. A protective ratio of approximately 2 was maintained for at least 6 hr after a single injection of HUP, without the need for any post-challenge drug therapy. By contrast, pretreatment with physostigmine increased the LD50 of soman by 1.4- to 1.5-fold for only up to 90 min. The long-lasting antidotal efficacy displayed by HUP correlated with the time course of the blood-AChE inhibition. The results suggest that the protection of animals by HUP from soman poisoning was achieved by temporarily sequestering the active site region of the physiologically important AChE.

  20. Connectivity mapping using a combined gene signature from multiple colorectal cancer datasets identified candidate drugs including existing chemotherapies

    PubMed Central

    2015-01-01

    Background While the discovery of new drugs is a complex, lengthy and costly process, identifying new uses for existing drugs is a cost-effective approach to therapeutic discovery. Connectivity mapping integrates gene expression profiling with advanced algorithms to connect genes, diseases and small molecule compounds and has been applied in a large number of studies to identify potential drugs, particularly to facilitate drug repurposing. Colorectal cancer (CRC) is a commonly diagnosed cancer with high mortality rates, presenting a worldwide health problem. With the advancement of high throughput omics technologies, a number of large scale gene expression profiling studies have been conducted on CRCs, providing multiple datasets in gene expression data repositories. In this work, we systematically apply gene expression connectivity mapping to multiple CRC datasets to identify candidate therapeutics to this disease. Results We developed a robust method to compile a combined gene signature for colorectal cancer across multiple datasets. Connectivity mapping analysis with this signature of 148 genes identified 10 candidate compounds, including irinotecan and etoposide, which are chemotherapy drugs currently used to treat CRCs. These results indicate that we have discovered high quality connections between the CRC disease state and the candidate compounds, and that the gene signature we created may be used as a potential therapeutic target in treating the disease. The method we proposed is highly effective in generating quality gene signature through multiple datasets; the publication of the combined CRC gene signature and the list of candidate compounds from this work will benefit both cancer and systems biology research communities for further development and investigations. PMID:26356760

  1. New Pyrrole Derivatives with Potent Tubulin Polymerization Inhibiting Activity As Anticancer Agents Including Hedgehog-Dependent Cancer

    PubMed Central

    La Regina, Giuseppe; Bai, Ruoli; Coluccia, Antonio; Famiglini, Valeria; Pelliccia, Sveva; Passacantilli, Sara; Mazzoccoli, Carmela; Ruggieri, Vitalba; Sisinni, Lorenza; Bolognesi, Alessio; Rensen, Whilelmina Maria; Miele, Andrea; Nalli, Marianna; Alfonsi, Romina; Di Marcotullio, Lucia; Gulino, Alberto; Brancale, Andrea; Novellino, Ettore; Dondio, Giulio; Vultaggio, Stefania; Varasi, Mario; Mercurio, Ciro; Hamel, Ernest; Lavia, Patrizia; Silvestri, Romano

    2014-01-01

    We synthesized 3-aroyl-1-arylpyrrole (ARAP) derivatives as potential anticancer agents having different substituents at the pendant 1-phenyl ring. Both the 1-phenyl ring and 3-(3,4,5-trimethoxyphenyl)carbonyl moieties were mandatory to achieve potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARAP 22 showed strong inhibition of the P-glycoprotein-overexpressing NCI-ADR-RES and Messa/Dx5MDR cell lines. Compounds 22 and 27 suppressed in vitro the Hedgehog signaling pathway, strongly reducing luciferase activity in SAG treated NIH3T3 Shh-Light II cells, and inhibited the growth of medulloblastoma D283 cells at nanomolar concentrations. ARAPs 22 and 27 represent a new potent class of tubulin polymerization and cancer cell growth inhibitors with the potential to inhibit the Hedgehog signaling pathway. PMID:25025991

  2. The study of photoacoustic imaging without nanoparticles as a contrast agent for anti-body drug monitoring

    NASA Astrophysics Data System (ADS)

    Han, Seung Hee; Kang, Jeeun; Wilson, Brian; Song, Tai-Kyong; Kim, Young Il

    2015-03-01

    As an emerging hybrid Imaging, Photoacoustic became a powerful tool that can scan disease at the deeper site in tissue and monitor of drug delivery in vivo. PAI system used nano-particle as contrast agent to enhance the PA signal in deeper site in tissue. So this makes that PAI's application have some limitation for monitoring of all kinds of anti-body drug, because of various anti-body's absorption excitation. In this study, we designed a PAI system with a tunable pulse OPO laser (from 450~700nm excitation wavelength) to show the optimal wavelength for monitoring of the antibody drug; doxorubicin having peak absorption at near 500nm excitation without any nano-particle combine. We made a gelatin phantoms having 4 different concentration doxorubicin as an anti-body drug; Doxorubicin concentration were in- 0mg/ml, 0.5mg/ml, 1mg/ml, and 2mg/ml. We found that 500nm is optimization wavelength to produce PA peak signal and PAI can be tool to monitor of anti-body drug without contrast agent.

  3. Quantitative analysis of the anti-proliferative activity of combinations of selected iron-chelating agents and clinically used anti-neoplastic drugs.

    PubMed

    Potuckova, Eliska; Jansova, Hana; Machacek, Miloslav; Vavrova, Anna; Haskova, Pavlina; Tichotova, Lucie; Richardson, Vera; Kalinowski, Danuta S; Richardson, Des R; Simunek, Tomas

    2014-01-01

    Recent studies have demonstrated that several chelators possess marked potential as potent anti-neoplastic drugs and as agents that can ameliorate some of the adverse effects associated with standard chemotherapy. Anti-cancer treatment employs combinations of several drugs that have different mechanisms of action. However, data regarding the potential interactions between iron chelators and established chemotherapeutics are lacking. Using estrogen receptor-positive MCF-7 breast cancer cells, we explored the combined anti-proliferative potential of four iron chelators, namely: desferrioxamine (DFO), salicylaldehyde isonicotinoyl hydrazone (SIH), (E)-N'-[1-(2-hydroxy-5-nitrophenyl)ethyliden] isonicotinoyl hydrazone (NHAPI), and di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), plus six selected anti-neoplastic drugs. These six agents are used for breast cancer treatment and include: paclitaxel, 5-fluorouracil, doxorubicin, methotrexate, tamoxifen and 4-hydroperoxycyclophosphamide (an active metabolite of cyclophosphamide). Our quantitative chelator-drug analyses were designed according to the Chou-Talalay method for drug combination assessment. All combinations of these agents yielded concentration-dependent, anti-proliferative effects. The hydrophilic siderophore, DFO, imposed antagonism when used in combination with all six anti-tumor agents and this antagonistic effect increased with increasing dose. Conversely, synergistic interactions were observed with combinations of the lipophilic chelators, NHAPI or Dp44mT, with doxorubicin and also the combinations of SIH, NHAPI or Dp44mT with tamoxifen. The combination of Dp44mT with anti-neoplastic agents was further enhanced following formation of its redox-active iron and especially copper complexes. The most potent combinations of Dp44mT and NHAPI with tamoxifen were confirmed as synergistic using another estrogen receptor-expressing breast cancer cell line, T47D, but not estrogen receptor-negative MDA

  4. Drugs targeting the mitochondrial pore act as citotoxic and cytostatic agents in temozolomide-resistant glioma cells

    PubMed Central

    Lena, Annalisa; Rechichi, Mariarosa; Salvetti, Alessandra; Bartoli, Barbara; Vecchio, Donatella; Scarcelli, Vittoria; Amoroso, Rosina; Benvenuti, Lucia; Gagliardi, Rolando; Gremigni, Vittorio; Rossi, Leonardo

    2009-01-01

    Background High grade gliomas are one of the most difficult cancers to treat and despite surgery, radiotherapy and temozolomide-based chemotherapy, the prognosis of glioma patients is poor. Resistance to temozolomide is the major barrier to effective therapy. Alternative therapeutic approaches have been shown to be ineffective for the treatment of genetically unselected glioma patients. Thus, novel therapies are needed. Mitochondria-directed chemotherapy is an emerging tool to combat cancer, and inner mitochondrial permeability transition (MPT) represents a target for the development of cytotoxic drugs. A number of agents are able to induce MPT and some of them target MPT-pore (MPTP) components that are selectively up-regulated in cancer, making these agents putative cancer cell-specific drugs. Objective The aim of this paper is to report a comprehensive analysis of the effects produced by selected MPT-inducing drugs (Betulinic Acid, Lonidamine, CD437) in a temozolomide-resistant glioblastoma cell line (ADF cells). Methods EGFRvIII expression has been assayed by RT-PCR. EGFR amplification and PTEN deletion have been assayed by differential-PCR. Drugs effect on cell viability has been tested by crystal violet assay. MPT has been tested by JC1 staining. Drug cytostatic effect has been tested by mitotic index analysis. Drug cytotoxic effect has been tested by calcein AM staining. Apoptosis has been assayed by Hoechst incorporation and Annexine V binding assay. Authophagy has been tested by acridine orange staining. Results We performed a molecular and genetic characterization of ADF cells and demonstrated that this line does not express the EGFRvIII and does not show EGFR amplification. ADF cells do not show PTEN mutation but differential PCR data indicate a hemizygous deletion of PTEN gene. We analyzed the response of ADF cells to Betulinic Acid, Lonidamine, and CD437. Our data demonstrate that MPT-inducing agents produce concentration-dependent cytostatic and

  5. 41 CFR 105-74.215 - What must I include in my drug-free awareness program?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free... penalties that you may impose upon them for drug abuse violations occurring in the workplace. ... my drug-free awareness program? 105-74.215 Section 105-74.215 Public Contracts and...

  6. Survey of antiinflammatory agents and related drugs as inhibitors of ovulation in the rabbit.

    PubMed

    Espey, L L; Stein, V I; Dumitrescu, J

    1982-08-01

    A wide variety of antiinflammatory agents and related compounds were administered to rabbits so that their ability to inhibit ovulation could be evaluated. In order of decreasing effectiveness, ovulation was inhibited by the nonsteroidal antiinflammatory agents diclofenac, indomethacin, fenoprofen, niflumate, tolmetin, phenylbutazone, naproxen, meclofenamate, ibuprofen, and flufenamate. Ovulation was not inhibited by aspirin, salicylate, or mefenamate, nor by the steroidal antiinflammatory agents dexamethasone (DEX) and prednisolone. The antineoplastic agents colchicine and vinblastine inhibited ovulation, but not azathioprine, 6-mercaptopurine, or cyclophosphamide. Contrary to previous reports, ovulation was not inhibited by the antihistamines chlorpheniramine, diphenhydramine, or cimetidine. Among the miscellaneous agents tested, ovulation was strongly inhibited by cycloheximide and slightly by acetaminophen but not by clomiphene, quinacrine, allopurinol, diethylstilbestrol (DES), heparin, melatonin, papaverine, chloroquine, D-penicillamine, or levamisole. These results show that ovulation can be inhibited by agents that inhibit acute inflammatory reactions. PMID:6125417

  7. Therapeutic drug monitoring: antiarrhythmic drugs

    PubMed Central

    Campbell, T J; Williams, K M

    2001-01-01

    Antiarrhythmic agents are traditionally classified according to Vaughan Williams into four classes of action. Class I antiarrhythmic agents include most of the drugs traditionally thought of as antiarrhythmics, and have as a common action, blockade of the fast-inward sodium channel on myocardium. These agents have a very significant toxicity, and while they are being used less, therapeutic drug monitoring (TDM) does significantly increase the safety with which they can be administered. Class II agents are antisympathetic drugs, particularly the b-adrenoceptor blockers. These are generally safe agents which do not normally require TDM. Class III antiarrhythmic agents include sotalol and amiodarone. TDM can be useful in the case of amiodarone to monitor compliance and toxicity but is generally of little value for sotalol. Class IV antiarrhythmic drugs are the calcium channel blockers verapamil and diltiazem. These are normally monitored by haemodynamic effects, rather than using TDM. Other agents which do not fall neatly into the Vaughan Williams classification include digoxin and perhexiline. TDM is very useful for monitoring the administration (and particularly the safety) of both of these agents. PMID:11564050

  8. Mechanical and dynamic characteristics of encapsulated microbubbles coupled by magnetic nanoparticles as multifunctional imaging and drug delivery agents

    NASA Astrophysics Data System (ADS)

    Guo, Gepu; Lu, Lu; Yin, Leilei; Tu, Juan; Guo, Xiasheng; Wu, Junru; Xu, Di; Zhang, Dong

    2014-11-01

    Development of magnetic encapsulated microbubble agents that can integrate multiple diagnostic and therapeutic functions is a key focus in both biomedical engineering and nanotechnology and one which will have far-reaching impact on medical diagnosis and therapies. However, properly designing multifunctional agents that can satisfy particular diagnostic/therapeutic requirements has been recognized as rather challenging, because there is a lack of comprehensive understanding of how the integration of magnetic nanoparticles to microbubble encapsulating shells affects their mechanical properties and dynamic performance in ultrasound imaging and drug delivery. Here, a multifunctional imaging contrast and in-situ gene/drug delivery agent was synthesized by coupling super paramagnetic iron oxide nanoparticles (SPIOs) into albumin-shelled microbubbles. Systematical studies were performed to investigate the SPIO-concentration-dependence of microbubble mechanical properties, acoustic scattering response, inertial cavitation activity and ultrasound-facilitated gene transfection effect. These demonstrated that, with the increasing SPIO concentration, the microbubble mean diameter and shell stiffness increased and ultrasound scattering response and inertial cavitation activity could be significantly enhanced. However, an optimized ultrasound-facilitated vascular endothelial growth factor transfection outcome would be achieved by adopting magnetic albumin-shelled microbubbles with an appropriate SPIO concentration of 114.7 µg ml-1. The current results would provide helpful guidance for future development of multifunctional agents and further optimization of their diagnostic/therapeutic performance in clinic.

  9. Mechanical and dynamic characteristics of encapsulated microbubbles coupled by magnetic nanoparticles as multifunctional imaging and drug delivery agents.

    PubMed

    Guo, Gepu; Lu, Lu; Yin, Leilei; Tu, Juan; Guo, Xiasheng; Wu, Junru; Xu, Di; Zhang, Dong

    2014-11-21

    Development of magnetic encapsulated microbubble agents that can integrate multiple diagnostic and therapeutic functions is a key focus in both biomedical engineering and nanotechnology and one which will have far-reaching impact on medical diagnosis and therapies. However, properly designing multifunctional agents that can satisfy particular diagnostic/therapeutic requirements has been recognized as rather challenging, because there is a lack of comprehensive understanding of how the integration of magnetic nanoparticles to microbubble encapsulating shells affects their mechanical properties and dynamic performance in ultrasound imaging and drug delivery. Here, a multifunctional imaging contrast and in-situ gene/drug delivery agent was synthesized by coupling super paramagnetic iron oxide nanoparticles (SPIOs) into albumin-shelled microbubbles. Systematical studies were performed to investigate the SPIO-concentration-dependence of microbubble mechanical properties, acoustic scattering response, inertial cavitation activity and ultrasound-facilitated gene transfection effect. These demonstrated that, with the increasing SPIO concentration, the microbubble mean diameter and shell stiffness increased and ultrasound scattering response and inertial cavitation activity could be significantly enhanced. However, an optimized ultrasound-facilitated vascular endothelial growth factor transfection outcome would be achieved by adopting magnetic albumin-shelled microbubbles with an appropriate SPIO concentration of 114.7 µg ml(-1). The current results would provide helpful guidance for future development of multifunctional agents and further optimization of their diagnostic/therapeutic performance in clinic. PMID:25327566

  10. Studies in Multifunctional Drug Development: Preparation and Evaluation of 11beta-Substituted Estradiol-Drug Conjugates, Cell Membrane Targeting Imaging Agents, and Target Multifunctional Nanoparticles

    NASA Astrophysics Data System (ADS)

    Dao, KinhLuan Lenny D.

    Cancer is the second leading cause of death after cardiovascular disease in the United State. Despite extensive research in development of antitumor drugs, most of these therapeutic entities often possess nonspecific toxicity, thus they can only be used to treat tumors in higher doses or more frequently. Because of the cytotoxicity and severe side effects, the drug therapeutic window normally is limited. Beside the toxicity issue, antitumor drug are also not selectively taken up by tumor cells, thus the necessitating concentrations that would eradicate the tumor can often not be used. In addition, tumor cells tend to develop resistance against the anticancer drugs after prolonged treatment. Therefore, alleviating the systemic cytotoxicity and side effects, improving in tumor selectivity, high potency, and therapeutic efficacy are still major obstacles in the area of anticancer drug development. A more promising approach for developing a selective agent for cancer is to conjugate a potent therapeutic drug, or an imaging agent with a targeting group, such as antibody or a high binding-specificity small molecule, that selectively recognize the overexpressed antigens or proteins on tumor cells. My research combines several approaches to describe this strategy via using different targeting molecules to different diseases, as well as different potent cytotoxic drugs for different therapies. Three studies related to the preparation and biological evaluation of new therapeutic agents, such as estradiol-drug hybrids, cell membrane targeted molecular imaging agents, and multifunctional NPs will be discussed. The preliminary results of these studies indicated that our new reagents achieved their initial objectives and can be further improved for optimized synthesis and in vivo experiments. The first study describes the method in which we employed a modular assembly approach to synthesize a novel 11beta-substituted steroidal anti-estrogen. The key intermediate was synthesized

  11. Drug-Drug Interaction of Omeprazole With the HCV Direct-Acting Antiviral Agents Paritaprevir/Ritonavir and Ombitasvir With and Without Dasabuvir.

    PubMed

    Polepally, Akshanth R; Dutta, Sandeep; Hu, Beibei; Podsadecki, Thomas J; Awni, Walid M; Menon, Rajeev M

    2016-07-01

    Paritaprevir (administered with low-dose ritonavir), ombitasvir, and dasabuvir are direct-acting antiviral agents administered as combination regimens for the treatment of chronic hepatitis C virus infection. Drug-drug interactions between 2D (ombitasvir/paritaprevir/ritonavir) or 3D (ombitasvir/paritaprevir/ritonavir and dasabuvir) regimens and omeprazole, a CYP2C19 substrate and acid-reducing agent, were evaluated in 24 healthy volunteers. Subjects received omeprazole (40 mg once daily) on day 1 and days 20-24 and the 2D or 3D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily ± dasabuvir 250 mg twice daily) on days 6-24. Compared with omeprazole alone, coadministration with the 2D or 3D regimen decreased omeprazole geometric mean Cmax and AUCt values by 40% to 50%. Ombitasvir, dasabuvir, and ritonavir mean exposures showed <10% change, and paritaprevir mean exposures showed <20% change when the 2D or 3D regimen was administered with omeprazole compared with administration without omeprazole. Although no a priori dose adjustment is needed, a higher omeprazole dose should be considered if clinically indicated when coadministered with the 2D or 3D regimen. No dose adjustment is required for the 2D or 3D regimen when administered with omeprazole, other acid-reducing agents, or CYP2C19 inhibitors. PMID:27310328

  12. Cysteine-modifying agents: a possible approach for effective anticancer and antiviral drugs.

    PubMed Central

    Casini, Angela; Scozzafava, Andrea; Supuran, Claudiu T

    2002-01-01

    Modification of cysteine residues in proteins, due to a) the participation of the thiol moiety of this amino acid in oxido-reduction reactions, b) its ability to strongly coordinate transition metal ions, or c) its nucleophilic nature and facile reaction with electrophiles, may be critically important for the design of novel types of pharmacological agents. Application of such procedures recently led to the design of novel antivirals, mainly based on the reaction of zinc finger proteins with disulfides and related derivatives. This approach was particularly successful for developing novel antiviral agents for human immunodeficiency virus and human papilloma virus. Several new anticancer therapeutic approaches, mainly targeting tubulin, have also been reported. Thus, this unique amino acid offers very interesting possibilities for developing particularly useful pharmacological agents, which generally possess a completely different mechanism of action compared with classic agents in clinical use, thus avoiding major problems such as multidrug resistance (for antiviral and anticancer agents) or high toxicity. PMID:12426135

  13. Nephrogenic systemic fibrosis and class labeling of gadolinium-based contrast agents by the Food and Drug Administration.

    PubMed

    Yang, Lucie; Krefting, Ira; Gorovets, Alex; Marzella, Louis; Kaiser, James; Boucher, Robert; Rieves, Dwaine

    2012-10-01

    In 2007, the Food and Drug Administration requested that manufacturers of all approved gadolinium-based contrast agents (GBCAs), drugs widely used in magnetic resonance imaging, use nearly identical text in their product labeling to describe the risk of nephrogenic systemic fibrosis (NSF). Accumulating information about NSF risks led to revision of the labeling text for all of these drugs in 2010. The present report summarizes the basis and purpose of this class-labeling approach and describes some of the related challenges, given the evolutionary nature of the NSF risk evidence. The class-labeling approach for presentation of product risk is designed to decrease the occurrence of NSF and to enhance the safe use of GBCAs in radiologic practice. PMID:22923714

  14. Small-Molecule Anticonvulsant Agents with Potent in vitro Neuroprotection and Favorable Drug-like Properties

    PubMed Central

    Smith, Garry R.; Brenneman, Douglas E.; Zhang, Yan; Du, Yanming; Reitz, Allen B.

    2014-01-01

    Severe seizure activity is associated with reoccurring cycles of excitotoxicity and oxidative stress that result in progressive neuronal damage and death. Intervention with these pathological processes is a compelling disease-modifying strategy for the treatment of seizure disorders. We have optimized a series of small molecules for neuroprotective and anticonvulsant activity as well as altered their physical properties to address potential metabolic liabilities, to improve CNS penetration and to prolong the duration of action in vivo. Utilizing phenotypic screening of hippocampal cultures with nutrient medium depleted of antioxidants as a disease model, cell death and decreased neuronal viability produced by acute treatment with glutamate or hydrogen peroxide were prevented. Modifications to our previously reported proof of concept compounds have resulted in a lead which has full neuroprotective action at < 1 nM and antiseizure activity across six animal models, including the kindled rat, and displays excellent pharmacokinetics including high exposure to the brain. These modifications have also eliminated the requirement for a chiral molecule, removing the possibility of racemization and making large scale synthesis more easily accessible. These studies strengthen our earlier findings which indicate that potent, multifunctional neuroprotective anticonvulsants are feasible within a single molecular entity which also possesses favorable CNS-active drug properties in vitro and in vivo. PMID:24277343

  15. Delivery of antifibroblast agents as adjuncts to filtration surgery. Part I--Periocular clearance of cobalt-57 bleomycin in experimental drug delivery: pilot study in the rabbit

    SciTech Connect

    Kay, J.S.; Litin, B.S.; Woolfenden, J.M.; Chvapil, M.; Herschler, J.

    1986-10-01

    Antitumor and antifibroblast agents show promise as adjuncts after glaucoma filtration surgery in reducing postoperative scarring and failure. We used nuclear imaging in rabbits to investigate periocular clearance of one such agent (/sup 57/Co-bleomycin). Sub-Tenon injection was compared to other delivery techniques. Our results showed that a collagen sponge and a silastic disc implant with a microhole prolonged drug delivery when compared to sub-Tenon injection alone or injection with a viscosity enhancing agent (0.5% sodium hyaluronate). We theorize that if an antifibroblast agent can be delivered in small and sustained amounts after filtration surgery, this may prolong bleb longevity and avoid unnecessary drug toxicity.

  16. Cationic albumin-conjugated chelating agent as a novel brain drug delivery system in neurodegeneration.

    PubMed

    Kamalinia, Golnaz; Khodagholi, Fariba; Shaerzadeh, Fatemeh; Tavssolian, Faranak; Chaharband, Farkhondeh; Atyabi, Fatemeh; Sharifzadeh, Mohammad; Amini, Mohsen; Dinarvand, Rassoul

    2015-11-01

    The critical role of metal ions and in particular iron in oxidative stress and protein aggregation offers chelation therapy as a sensible pharmaceutical strategy in oxidative stress-induced neuronal damages. In this research, we conjugated an iron-chelating agent, deferasirox, to cationized human serum albumin molecules in order to develop a novel brain delivery system for the management of neurodegenerative disorders due to the significant role of oxidative stress-induced neuronal injury in such diseases. Cationized albumin is known to be able to transport to brain tissue via adsorptive-mediated transcytosis. The developed structures were molecularly characterized, and their conjugation ratio was determined. PC12 cell line was utilized to evaluate the neuroprotective features of these newly developed molecules in the presence of hydrogen peroxide neuronal damage and to identify the mechanisms behind the observed neuronal protection including apoptotic and autophagic pathways. Furthermore, a rat model of Alzheimer's disease was utilized to evaluate the impact of conjugated structures in vivo. Data analysis revealed that the conjugated species were able to hinder apoptotic cell death while enhancing autophagic process. The developed conjugated species were also able to attenuate amyloid beta-induced learning deficits when administered peripherally. PMID:25976552

  17. Anti-biofilm agents: recent breakthrough against multi-drug resistant Staphylococcus aureus.

    PubMed

    Chung, Pooi Y; Toh, Yien S

    2014-04-01

    Staphylococcus aureus is a Gram-positive pathogen that causes potentially life-threatening nosocomial- and community-acquired infections, such as osteomyelitis and endocarditis. Staphylococcus aureus has the ability to form multicellular, surface-adherent communities called biofilms, which enables it to survive in various sources of stress, including antibiotics, nutrient limitations, heat shock, and immune responses. Biofilm-forming capacity is now recognized as an important virulence determinant in the development of staphylococcal device-related infections. In light of the projected increase in the numbers of elderly patients who will require semi-permanent indwelling medical devices such as artificial knees and hips, we can anticipate an expanded need for new agents and treatment options to manage biofilm-associated infections in an expanding at-risk population. With better understanding of staphylococcal biofilm formation and growth, novel strategies that target biofilm-associated infections caused by S. aureus have recently been described and seem promising as future anti-biofilm therapies. PMID:24453168

  18. 41 CFR 105-74.205 - What must I include in my drug-free workplace statement?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... my drug-free workplace statement? 105-74.205 Section 105-74.205 Public Contracts and Property... Regional Offices-General Services Administration 74-GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE... my drug-free workplace statement? You must publish a statement that— (a) Tells your employees...

  19. Engineered reversal of drug resistance in cancer cells—metastases suppressor factors as change agents

    PubMed Central

    Yadav, Vinod Kumar; Kumar, Akinchan; Mann, Anita; Aggarwal, Suruchi; Kumar, Maneesh; Roy, Sumitabho Deb; Pore, Subrata Kumar; Banerjee, Rajkumar; Mahesh Kumar, Jerald; Thakur, Ram Krishna; Chowdhury, Shantanu

    2014-01-01

    Building molecular correlates of drug resistance in cancer and exploiting them for therapeutic intervention remains a pressing clinical need. To identify factors that impact drug resistance herein we built a model that couples inherent cell-based response toward drugs with transcriptomes of resistant/sensitive cells. To test this model, we focused on a group of genes called metastasis suppressor genes (MSGs) that influence aggressiveness and metastatic potential of cancers. Interestingly, modeling of 84 000 drug response transcriptome combinations predicted multiple MSGs to be associated with resistance of different cell types and drugs. As a case study, on inducing MSG levels in a drug resistant breast cancer line resistance to anticancer drugs caerulomycin, camptothecin and topotecan decreased by more than 50–60%, in both culture conditions and also in tumors generated in mice, in contrast to control un-induced cells. To our knowledge, this is the first demonstration of engineered reversal of drug resistance in cancer cells based on a model that exploits inherent cellular response profiles. PMID:24157835

  20. Repurposing Drugs in Oncology (ReDO)-clarithromycin as an anti-cancer agent.

    PubMed

    Van Nuffel, An Mt; Sukhatme, Vidula; Pantziarka, Pan; Meheus, Lydie; Sukhatme, Vikas P; Bouche, Gauthier

    2015-01-01

    Clarithromycin (CAM) is a well-known macrolide antibiotic available as a generic drug. CAM is traditionally used for many types of bacterial infections, treatment of Lyme disease and eradication of gastric infection with Helicobacter pylori. Extensive preclinical and clinical data demonstrate a potential role for CAM to treat various tumours in combination with conventional treatment. The mechanisms of action underlying the anti-tumour activity of CAM are multiple and include prolonged reduction of pro-inflammatory cytokines, autophagy inhibition, and anti-angiogenesis. Here, we present an overview of the current preclinical (in vitro and in vivo) and clinical evidence supporting the role of CAM in cancer. Overall these findings justify further research with CAM in many tumour types, with multiple myeloma, lymphoma, chronic myeloid leukaemia (CML), and lung cancer having the highest level of evidence. Finally, a series of proposals are being made to further investigate the use of CAM in clinical trials which offer the greatest prospect of clinical benefit to patients. PMID:25729426

  1. Repurposing Drugs in Oncology (ReDO)—clarithromycin as an anti-cancer agent

    PubMed Central

    Van Nuffel, An MT; Sukhatme, Vidula; Pantziarka, Pan; Meheus, Lydie; Sukhatme, Vikas P; Bouche, Gauthier

    2015-01-01

    Clarithromycin (CAM) is a well-known macrolide antibiotic available as a generic drug. CAM is traditionally used for many types of bacterial infections, treatment of Lyme disease and eradication of gastric infection with Helicobacter pylori. Extensive preclinical and clinical data demonstrate a potential role for CAM to treat various tumours in combination with conventional treatment. The mechanisms of action underlying the anti-tumour activity of CAM are multiple and include prolonged reduction of pro-inflammatory cytokines, autophagy inhibition, and anti-angiogenesis. Here, we present an overview of the current preclinical (in vitro and in vivo) and clinical evidence supporting the role of CAM in cancer. Overall these findings justify further research with CAM in many tumour types, with multiple myeloma, lymphoma, chronic myeloid leukaemia (CML), and lung cancer having the highest level of evidence. Finally, a series of proposals are being made to further investigate the use of CAM in clinical trials which offer the greatest prospect of clinical benefit to patients. PMID:25729426

  2. Study of anti-angiogenic drugs by fluorescence imaging and spectroscopy of a contrast agent in mice

    NASA Astrophysics Data System (ADS)

    Valentini, G.; D'Andrea, C.; Ferrari, R.; Pifferi, A.; Cubeddu, R.; Caronia, D.; Martinelli, M.; Giavazzi, R.

    2007-07-01

    We used two fluorescence techniques based on the Indocyanine Green contrast agent to study the effectiveness of antiangionenic drugs in mice. To this purpose, the volume of the active vasculature in different tumor models implanted in mice was assessed by means of a low noise fluorescence imaging setup and by a photon counting system working in transmittance geometry. Using a first tumor model (carcinoma MDA-MB-435) we observed that mice treated with a Vascular Disrupting Agent (ZD6126) showed a reduction in fluorescence emission of the contrast agent with respect to control mice. This was a clear indication of the vascular shutdown that took place in tumors. The effectiveness of the treatment was also confirmed by histological sections. Then, in a second experiment we considered a second tumor model (carcinoma 1A9-VS1) overexpressing the Vascular Endotelial Growth Factor (VEGF121), which is used by tumor cells to promote angiogenesis. We measured the Indocyanine Green fluorescence in mice treated with an antioangiogenic drug (Avastin TM) and in control mice. In tumors of treated mice we observed an ICG emission lower than the one detected in control mice. This demonstrated that VEGF activity was effectively blocked by the treatment with Avastin. In conclusion, ICG fluorescence provides a simple and reliable way to assess the effectiveness of vascular targeting therapies. Measurements of the fluorescence signal can be repeated every 24 hours, thus allowing oncologists to perform longitudinal studies on the same animals.

  3. QuBiLs-MAS method in early drug discovery and rational drug identification of antifungal agents.

    PubMed

    Medina Marrero, R; Marrero-Ponce, Y; Barigye, S J; Echeverría Díaz, Y; Acevedo-Barrios, R; Casañola-Martín, G M; García Bernal, M; Torrens, F; Pérez-Giménez, F

    2015-01-01

    The QuBiLs-MAS approach is used for the in silico modelling of the antifungal activity of organic molecules. To this effect, non-stochastic (NS) and simple-stochastic (SS) atom-based quadratic indices are used to codify chemical information for a comprehensive dataset of 2478 compounds having a great structural variability, with 1087 of them being antifungal agents, covering the broadest antifungal mechanisms of action known so far. The NS and SS index-based antifungal activity classification models obtained using linear discriminant analysis (LDA) yield correct classification percentages of 90.73% and 92.47%, respectively, for the training set. Additionally, these models are able to correctly classify 92.16% and 87.56% of 706 compounds in an external test set. A comparison of the statistical parameters of the QuBiLs-MAS LDA-based models with those for models reported in the literature reveals comparable to superior performance, although the latter were built over much smaller and less diverse datasets, representing fewer mechanisms of action. It may therefore be inferred that the QuBiLs-MAS method constitutes a valuable tool useful in the design and/or selection of new and broad spectrum agents against life-threatening fungal infections. PMID:26567876

  4. ZnO nanoparticles as drug delivery agent for photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Fakhar-e-Alam, M.; Rahim, S.; Atif, M.; Hammad Aziz, M.; Imran Malick, M.; Zaidi, S. S. Z.; Suleman, R.; Majid, A.

    2014-02-01

    Multidrug resistance (MDR) limits the success of many tumoricidal drugs. Non-significant accumulation of the drug into the target site is one major problem in photodynamic therapy. Nanoparticles are extensively used as efficient drug carriers in various local infectious and premalignant biological tissues. Due to their unique physical and chemical properties, PEGylated zinc oxide nanoparticles (ZnO NPs) exhibit high drug loading capacities, sustained drug release profiles and long-term anticancer efficacy. (Polyethylene glycol) PEG-zinc oxide nanoparticles were synthesized using the aquis chemical technique. Morphology/structural analysis of the said nanoparticles was confirmed by applying many techniques, e.g. scanning electron microscopy (SEM) and XRD. Average grain size of the nanoparticles, which was ≈100 nm, was calculated by applying the Scherrer formula. The PEGylated ZnO NPs were loaded with protoporphyrin IX (PpIX) to enhance the capability of drug carrying potency. Current work focused on the comparison of the cell killing effect (apoptosis/necrosis) by functionalizing different nanostructures via PEGylated ZnO NPs and bare ZnO NPs using the free-standing drug delivery procedure. ZnO NPs were used as anticancer drug vehicles because of their biocompatibility and bio-safety profile. The apoptotic effect of PEGylated tumoricidal drugs has been studied in human muscle carcinoma (RD cell line) in the dark as well as under laser exposure. It was concluded that PpIX localization was a significant time greater using encapsulation as compared to a conventional drug delivery system. This new technique may find excellent opportunities in the field of nanomedicine, especially in a multidrug delivery system.

  5. Assessment of global reporting of adverse drug reactions for anti-malarials, including artemisinin-based combination therapy, to the WHO Programme for International Drug Monitoring

    PubMed Central

    2011-01-01

    Background In spite of enhanced control efforts, malaria remains a major public health problem causing close to a million deaths annually. With support from several donors, large amounts of artemisinin-based combination therapy (ACT) are being deployed in endemic countries raising safety concerns as little is known about the use of ACT in several of the settings where they are deployed. This project was undertaken to profile the provenance of the pharmacovigilance reporting of all anti-malarials, including ACT to the WHO adverse drug reaction (ADR) database (Vigibase™) over the past 40 years. Methods The WHO Programme for International Drug Monitoring, the Uppsala Monitoring Centre (UMC) provided anonymized extracts of Vigibase™ covering the period 1968-2008. All countries in the programme were clustered according to their malaria control phase and income status. The number of individual case safety reports (ICSRs) of anti-malarials was analyzed according to those clusters. Results From 1968 to 2008, 21,312 ICSRs suspecting anti-malarials were received from 64 countries. Low-income countries, that are also malaria-endemic (categorized as priority 1 countries) submitted only 1.2% of the ICSRs. Only 60 out of 21,312 ICSRs were related to ACT, 51 of which were coming from four sub-Saharan African countries. Although very few ICSRs involved artemisinin-based compounds, many of the adverse events reported were potentially serious. Conclusions This paper illustrates the low reporting of ADRs to anti-malarials in general and ACT in particular. Most reports were submitted by non-endemic and/or high-income countries. Given the current mix of large donor funding, the insufficient information on safety of these drugs, increasing availability of ACT and artemisinin-based monotherapies in public and private sector channels, associated potential for inappropriate use and finally a pipeline of more than 10 new novel anti-malarials in various stages of development, the

  6. Synthesis, biological evaluation, drug-likeness, and in silico screening of novel benzylidene-hydrazone analogues as small molecule anticancer agents.

    PubMed

    Alam, Mohammad Sayed; Lee, Dong-Ung

    2016-02-01

    A series of fifteen benzylidene-hydrazone analogues (3a-o), including eight new compounds, were synthesized and evaluated for their cytotoxic activities in four human cancer cell lines and for their antioxidant activities using DPPH. Of the tested compounds 3e, which possesses two methoxy substituents in its benzylidene phenyl ring, was found to be potently cytotoxic to all cancer cell lines tested with IC50 values of 0.12 (lung), 0.024 (ovarian), 0.097 (melanoma), and 0.05 μM (colon), and these IC50 values were comparable to those of the doxorubicin standard (IC50 = 0.021, 0.074, 0.001, and 0.872 μM, respectively). DPPH assay showed compounds 3f, 3i, and 3g had IC50 values of 0.60, 0.99, and 1.30 μM, respectively, which were comparable to that of ascorbic acid (IC50 = 0.87 μM). Computational parameters such as, drug-likeness, ADME properties, toxicity effects, and drug scores were evaluated, and none of the fifteen compounds violated Lipinski's rule of five or Veber's rule, and thus they demonstrated good drug-likeness properties. In addition, all fifteen compounds had a higher drug score than the doxorubicin and BIBR1532. In silico screening was also conducted by docking of the active compounds on the active site of telomerase reverse transcriptase catalytic subunit, an important therapeutic target of anticancer agents, to determine the probable binding properties. The total binding energies of docked compounds are correlated well with cytotoxic potencies (pIC50) against lung, ovarian, melanoma, and colon cancer cell lines indicating that the benzylidene-hydrazones could use for the development of new anticancer agents as a telomerase inhibitor. PMID:26694484

  7. Dynamic Contrast-Enhanced MRI Using a Macromolecular MR Contrast Agent (P792): Evaluation of Antivascular Drug Effect in a Rabbit VX2 Liver Tumor Model

    PubMed Central

    Park, Hee Sun; Lee, Jeong Min; Kim, Young Il; Woo, Sungmin; Yoon, Jung Hwan; Choi, Jin-Young; Choi, Byung Ihn

    2015-01-01

    Objective To evaluate the utility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using macromolecular contrast agent (P792) for assessment of vascular disrupting drug effect in rabbit VX2 liver tumor models. Materials and Methods This study was approved by our Institutional Animal Care and Use Committee. DCE-MRI was performed with 3-T scanner in 13 VX2 liver tumor-bearing rabbits, before, 4 hours after, and 24 hours after administration of vascular disrupting agent (VDA), using gadomelitol (P792, n = 7) or low molecular weight contrast agent (gadoterate meglumine [Gd-DOTA], n = 6). P792 was injected at a of dose 0.05 mmol/kg, while that of Gd-DOTA was 0.2 mmol/kg. DCE-MRI parameters including volume transfer coefficient (Ktrans) and initial area under the gadolinium concentration-time curve until 60 seconds (iAUC) of tumors were compared between the 2 groups at each time point. DCE-MRI parameters were correlated with tumor histopathology. Reproducibility in measurement of DCE-MRI parameters and image quality of source MR were compared between groups. Results P792 group showed a more prominent decrease in Ktrans and iAUC at 4 hours and 24 hours, as compared to the Gd-DOTA group. Changes in DCE-MRI parameters showed a weak correlation with histologic parameters (necrotic fraction and microvessel density) in both groups. Reproducibility of DCE-MRI parameters and overall image quality was not significantly better in the P792 group, as compared to the Gd-DOTA group. Conclusion Dynamic contrast-enhanced magnetic resonance imaging using a macromolecular contrast agent shows changes of hepatic perfusion more clearly after administration of the VDA. Gadolinium was required at smaller doses than a low molecular contrast agent. PMID:26357497

  8. A High-Throughput In Vitro Drug Screen in a Genetically Engineered Mouse Model of Diffuse Intrinsic Pontine Glioma Identifies BMS-754807 as a Promising Therapeutic Agent

    PubMed Central

    Halvorson, Kyle G.; Barton, Kelly L.; Schroeder, Kristin; Misuraca, Katherine L.; Hoeman, Christine; Chung, Alex; Crabtree, Donna M.; Cordero, Francisco J.; Singh, Raj; Spasojevic, Ivan; Berlow, Noah; Pal, Ranadip; Becher, Oren J.

    2015-01-01

    Diffuse intrinsic pontine gliomas (DIPGs) represent a particularly lethal type of pediatric brain cancer with no effective therapeutic options. Our laboratory has previously reported the development of genetically engineered DIPG mouse models using the RCAS/tv-a system, including a model driven by PDGF-B, H3.3K27M, and p53 loss. These models can serve as a platform in which to test novel therapeutics prior to the initiation of human clinical trials. In this study, an in vitro high-throughput drug screen as part of the DIPG preclinical consortium using cell-lines derived from our DIPG models identified BMS-754807 as a drug of interest in DIPG. BMS-754807 is a potent and reversible small molecule multi-kinase inhibitor with many targets including IGF-1R, IR, MET, TRKA, TRKB, AURKA, AURKB. In vitro evaluation showed significant cytotoxic effects with an IC50 of 0.13 μM, significant inhibition of proliferation at a concentration of 1.5 μM, as well as inhibition of AKT activation. Interestingly, IGF-1R signaling was absent in serum-free cultures from the PDGF-B; H3.3K27M; p53 deficient model suggesting that the antitumor activity of BMS-754807 in this model is independent of IGF-1R. In vivo, systemic administration of BMS-754807 to DIPG-bearing mice did not prolong survival. Pharmacokinetic analysis demonstrated that tumor tissue drug concentrations of BMS-754807 were well below the identified IC50, suggesting that inadequate drug delivery may limit in vivo efficacy. In summary, an unbiased in vitro drug screen identified BMS-754807 as a potential therapeutic agent in DIPG, but BMS-754807 treatment in vivo by systemic delivery did not significantly prolong survival of DIPG-bearing mice. PMID:25748921

  9. Studies in Multifunctional Drug Development: Preparation and Evaluation of 11beta-Substituted Estradiol-Drug Conjugates, Cell Membrane Targeting Imaging Agents, and Target Multifunctional Nanoparticles

    NASA Astrophysics Data System (ADS)

    Dao, KinhLuan Lenny D.

    Cancer is the second leading cause of death after cardiovascular disease in the United State. Despite extensive research in development of antitumor drugs, most of these therapeutic entities often possess nonspecific toxicity, thus they can only be used to treat tumors in higher doses or more frequently. Because of the cytotoxicity and severe side effects, the drug therapeutic window normally is limited. Beside the toxicity issue, antitumor drug are also not selectively taken up by tumor cells, thus the necessitating concentrations that would eradicate the tumor can often not be used. In addition, tumor cells tend to develop resistance against the anticancer drugs after prolonged treatment. Therefore, alleviating the systemic cytotoxicity and side effects, improving in tumor selectivity, high potency, and therapeutic efficacy are still major obstacles in the area of anticancer drug development. A more promising approach for developing a selective agent for cancer is to conjugate a potent therapeutic drug, or an imaging agent with a targeting group, such as antibody or a high binding-specificity small molecule, that selectively recognize the overexpressed antigens or proteins on tumor cells. My research combines several approaches to describe this strategy via using different targeting molecules to different diseases, as well as different potent cytotoxic drugs for different therapies. Three studies related to the preparation and biological evaluation of new therapeutic agents, such as estradiol-drug hybrids, cell membrane targeted molecular imaging agents, and multifunctional NPs will be discussed. The preliminary results of these studies indicated that our new reagents achieved their initial objectives and can be further improved for optimized synthesis and in vivo experiments. The first study describes the method in which we employed a modular assembly approach to synthesize a novel 11beta-substituted steroidal anti-estrogen. The key intermediate was synthesized

  10. Production of limit size nanoliposomal systems with potential utility as ultra-small drug delivery agents.

    PubMed

    Zhigaltsev, Igor V; Tam, Ying K; Leung, Alex K K; Cullis, Pieter R

    2016-06-01

    Previous studies from this group have shown that limit size lipid-based systems - defined as the smallest achievable aggregates compatible with the packing properties of their molecular constituents - can be efficiently produced using rapid microfluidic mixing technique. In this work, it is shown that similar procedures can be employed for the production of homogeneously sized unilamellar vesicular systems of 30-40 nm size range. These vesicles can be remotely loaded with the protonable drug doxorubicin and exhibit adequate drug retention properties in vitro and in vivo. In particular, it is demonstrated that whereas sub-40 nm lipid nanoparticle (LNP) systems consisting entirely of long-chain saturated phosphatidylcholines cannot be produced, the presence of such lipids may have a beneficial effect on the retention properties of limit size systems consisting of mixed lipid components. Specifically, a 33-nm diameter doxorubicin-loaded LNP system composed of 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), 1,2-dipalmitoyl phosphatidylcholine (DPPC), cholesterol, and PEGylated lipid (DSPE-PEG2000) demonstrated adequate, stable drug retention in the circulation, with a half-life for drug release of ∼12 h. These results indicate that microfluidic mixing is the technique of choice for the production of bilayer LNP systems with sizes less than 50 nm that could lead to development of a novel class of ultra-small drug delivery vehicles. PMID:25856305

  11. Engineering Design and Molecular Dynamics of Mucoadhesive Drug Delivery Systems as Targeting Agents

    PubMed Central

    Serra, Laura; Doménech, Josep; Peppas, Nicholas

    2009-01-01

    The goal of this critical review is to provide a critical analysis of the chain dynamics responsible for the action of micro- and nanoparticles of mucoadhesive biomaterials. The objective of using bioadhesive controlled drug delivery devices is to prolong their residence at a specific site of delivery, thus enhancing the drug absorption process. These mucoadhesive devices can protect the drug during the absorption process in addition to protecting it on its route to the delivery site. The major emphasis of recent research on mucoadhesive biomaterials has been on the use of adhesion promoters, which would enhance the adhesion between synthetic polymers and mucus. The use of adhesion promoters such as linear or tethered polymer chains is a natural result of the diffusional characteristics of adhesion. Mucoadhesion depends largely on the structure of the synthetic polymer gels used in controlled release applications. PMID:18976706

  12. Composite fiber structures with antiproliferative agents exhibit advantageous drug delivery and cell growth inhibition in vitro.

    PubMed

    Kraitzer, Amir; Kloog, Yoel; Haklai, Roni; Zilberman, Meital

    2011-01-01

    Composite core/shell fiber structures loaded with the antiproliferative drugs paclitaxel or farnesylthiosalicylate (FTS) were developed and studied. The latter is a specific nontoxic Ras inhibitor with a mild hydrophobic nature, which can also be used for local cancer treatment and stent applications. The fibers were composed of a dense polyglyconate core and a porous drug-loaded poly(D,L-lactic-glycolic acid) shell, prepared using freeze drying of inverted emulsions. Our study focused on the release profile of the antiproliferative drugs from the fibers, the shell morphology and its degradation and erosion. The postfabrication antiproliferative effect of the drugs was tested in a cell culture. The process parameters were found to affect the drug-release profile via two routes: (1) direct, through water uptake and swelling of the structure leading to FTS release, or through degradation of the host polymer leading to paclitaxel release at a later stage; (2) indirect effect of the microstructure on the release profile. The fabrication process did not reduce the pharmacological activity of either paclitaxel or FTS. FTS-eluting composite fibers proved to effectively induce growth inhibition or cell death by a gradient effect and dose-dependent manner. The combined effect of the targeted mechanism of FTS as a Ras inhibitor together with the localized and controlled release characteristics of the fiber is an advantageous antiproliferative quality. It is therefore suggested that our drug-eluting fibers may be used in biomedical applications that require short release (restenosis) or prolonged release (cancer therapy). PMID:20623695

  13. Novel drug delivery systems for actinides (uranium and plutonium) decontamination agents.

    PubMed

    Fattal, Elias; Tsapis, Nicolas; Phan, Guillaume

    2015-08-01

    The possibility of accidents in the nuclear industry or of nuclear terrorist attacks makes the development of new decontamination strategies crucial. Among radionuclides, actinides such as uranium and plutonium and their different isotopes are considered as the most dangerous contaminants, plutonium displaying mostly a radiological toxicity whereas uranium exhibits mainly a chemical toxicity. Contamination occurs through ingestion, skin or lung exposure with subsequent absorption and distribution of the radionuclides to different tissues where they induce damaging effects. Different chelating agents have been synthesized but their efficacy is limited by their low tissue specificity and high toxicity. For these reasons, several groups have developed smart delivery systems to increase the local concentration of the chelating agent or to improve its biodistribution. The aim of this review is to highlight these strategies. PMID:26144994

  14. Role of anti-diabetic drugs as therapeutic agents in Alzheimer's disease

    PubMed Central

    Rizvi, Syed Mohd. Danish; Shaikh, Sibhghatulla; Waseem, Shah Mohammad Abbas; Shakil, Shazi; Abuzenadah, Adel M.; Biswas, Deboshree; Tabrez, Shams; Ashraf, Ghulam Md.; Kamal, Mohammad Amjad

    2015-01-01

    Recent data have suggested a strong possible link between Type 2 Diabetes Mellitus and Alzheimer's disease (AD), although exact mechanisms linking the two are still a matter of research and debate. Interestingly, both are diseases with high incidence and prevalence in later years of life. The link appears so strong that some scientists use Alzheimer's and Type 3 Diabetes interchangeably. In depth study of recent data suggests that the anti diabetic drugs not only have possible role in treatment of Alzheimer's but may also arrest the declining cognitive functions associated with it. The present review gives an insight into the possible links, existing therapeutics and clinical trials of anti diabetic drugs in patients suffering from AD primarily or as co-morbidity. It may be concluded that the possible beneficial effects and usefulness of the current anti diabetic drugs in AD cannot be neglected and further research is required to achieve positive results. Currently, several drug trials are in progress to give conclusive evidence based data. PMID:27152105

  15. Fabrication of biodendrimeric β-cyclodextrin via click reaction with potency of anticancer drug delivery agent.

    PubMed

    Toomari, Yousef; Namazi, Hassan; Entezami, Ali Akbar

    2015-08-01

    The aim of this work was the synthesis of biodendrimeric β-cyclodextrin (β-CD) on the secondary face with encapsulation efficacy, with β-CDs moiety to preserve the biocompatibility properties, also particularly growth their loading capacity for drugs with certain size. The new dendrimer, having 14 β-CD residues attached to the core β-CD in secondary face (11), was prepared through click reaction. The encapsulation property of the prepared compound was evaluated by methotrexate (MTX) drug molecule. Characterization of compound 11 was performed with (1)H NMR, (13)C NMR and FTIR and its supramolecular inclusion complex structure was determined using FTIR, DLS, DSC and SEM techniques. In vitro cytotoxicity test results showed that compound 11 has very low or no cytotoxic effect on T47D cancer cells. In vitro drug release study at pHs 3, 5 and 7.4 showed that the release process was noticeably pH dependent and the dendrimer could be used as an appropriate controlled drug delivery system (DDS) for cancer treatment. PMID:26056989

  16. Discovery and basic pharmacology of erythropoiesis-stimulating agents (ESAs), including the hyperglycosylated ESA, darbepoetin alfa: an update of the rationale and clinical impact.

    PubMed

    Kiss, Zoltán; Elliott, Steven; Jedynasty, Kinga; Tesar, Vladimír; Szegedi, János

    2010-04-01

    Cloning of the human erythropoietin (EPO) gene and development of the first recombinant human erythropoietin (rHuEPO) drug were truly breakthroughs. This allowed a deeper understanding of the structure and pharmacology of rHuEpo, which in turn inspired the discovery and development of additional erythropoiesis-stimulating agents (ESAs). In vivo specific activity and serum half-life of rHuEPO are influenced by the amount and structure of the attached carbohydrate. Increased numbers of sialic acids on carbohydrate attached to rHuEPO correlated with a relative increase in in-vivo-specific activity and increased serum half-life. The effect of increasing the number of sialic-acid-containing carbohydrates on in-vivo-specific activity was explored. Initial research focused on solving the problem of how the protein backbone could be engineered so a cell would add more carbohydrate to it. Additional work resulted in darbepoetin alfa, a longer-acting molecule with two additional carbohydrate chains. PMID:20127232

  17. Potentiation of cytotoxicity by 3-aminobenzamide in DNA repair-deficient human tumor cell lines following exposure to methylating agents or anti-neoplastic drugs.

    PubMed

    Babich, M A; Day, R S

    1988-04-01

    We studied the potentiation by 3-aminobenzamide (3AB) of killing of nine human cell lines exposed to alkylating agents. Cell lines included normal, transformed and DNA repair-proficient and -deficient phenotypes. 3AB potentiated cell killing by the methylating agents methylmethanesulfonate (MMS) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in all lines tested. The degree of potentiation ranged from 1.7- to 3.8-fold, based on the LD99. The average potentiation observed with MMS (2.7-fold) was greater than with MNNG (2.2-fold). On average the potentiation of MMS and MNNG killing of repair-deficient Mer- lines (2.4-fold) was similar to that of repair-proficient Mer+ lines. The degree of 3AB potentiation of MNNG killing (2.0-fold) was similar in Mer+ Rem- lines and in Mer+ Rem+ lines. Mer+ Rem+, Mer+ Rem-, Mer- Rem+, and Mer- Rem- strains all appeared proficient in a 3AB-sensitive DNA repair pathway. Within experimental error, 20 mM 3AB did not inhibit the removal of the MNNG-induced methylpurines 7-methylguanine, O6-methylguanine and 3-methyladenine from the DNA of repair-proficient Mer+ Rem+ HT29 cells, consistent with evidence that 3AB inhibits the ligation step of excision repair. 3AB potentiated cell killing by the bifunctional alkylating agents 1-(2-chlorethyl)-1-nitrosourea or busulfan, two anti-neoplastic drugs, by only 0.9- to 1.5-fold. These drugs therefore produce DNA damage which is not efficiently repaired by the pathways that repair methylated bases. PMID:3356063

  18. Sarcoma Cell Line Screen of Oncology Drugs and Investigational Agents Identifies Patterns Associated with Gene and microRNA Expression.

    PubMed

    Teicher, Beverly A; Polley, Eric; Kunkel, Mark; Evans, David; Silvers, Thomas; Delosh, Rene; Laudeman, Julie; Ogle, Chad; Reinhart, Russell; Selby, Michael; Connelly, John; Harris, Erik; Monks, Anne; Morris, Joel

    2015-11-01

    The diversity in sarcoma phenotype and genotype make treatment of this family of diseases exceptionally challenging. Sixty-three human adult and pediatric sarcoma lines were screened with 100 FDA-approved oncology agents and 345 investigational agents. The investigational agents' library enabled comparison of several compounds targeting the same molecular entity allowing comparison of target specificity and heterogeneity of cell line response. Gene expression was derived from exon array data and microRNA expression was derived from direct digital detection assays. The compounds were screened against each cell line at nine concentrations in triplicate with an exposure time of 96 hours using Alamar blue as the endpoint. Results are presented for inhibitors of the following targets: aurora kinase, IGF-1R, MEK, BET bromodomain, and PARP1. Chemical structures, IC50 heat maps, concentration response curves, gene expression, and miR expression heat maps are presented for selected examples. In addition, two cases of exceptional responders are presented. The drug and compound response, gene expression, and microRNA expression data are publicly available at http://sarcoma.cancer.gov. These data provide a unique resource to the cancer research community. PMID:26351324

  19. Investigations on nanoconfinement of low-molecular antineoplastic agents into biocompatible magnetic matrices for drug targeting.

    PubMed

    Tomoiaga, Alina Maria; Cioroiu, Bogdan Ionel; Nica, Valentin; Vasile, Aurelia

    2013-11-01

    Magnetic mesoporous silica nanoparticles are employed as biocompatible matrices to host low-molecular antineoplastic drugs. 5-Fluorouracil is a well-known antimetabolite drug used to treat many malignancies: colon, rectal, breast, head and neck, pancreatic, gastric, esophageal, liver and G-U (bladder, penile, vulva, prostate), skin cancers (basal cell and keratosis). Unfortunately severe gastrointestinal, hematological, neural, cardiac and dermatological toxic effects are often registered due to its cytotoxicity. Thus, this work focuses on development of a magnetic silica nanosystem, capable of hosting high amounts of 5-fluorouracil and delivers it in a targeted manner, under the influence of external magnetic field. There are few reports on nanoconfinement of this particular small molecule antimetabolite on mesoporous silica hosts. Therefore we have investigated different ways to confine high amounts of 5-FU within amino-modified and non-modified mesopores of the silica shell, from water and ethanol, under magnetic stirring and ultrasound irradiation. Also, we have studied the adsorption process from water as a function of pH in order to rationalize drug-support interactions. It is shown that nature of the solvent has great influence on diffusion of small molecules into mesopores, which is slower from alcoholic solutions. More importantly, sonication is proven as an excellent alternative to long adsorption tests, since the time necessary to reach equilibrium is drastically reduced to 1h and higher amounts of drug may be immobilized within the mesopores of amino-modified magnetic silica nanoparticles. These results are highly important for optimization of drug immobilization process in order to attain desired release profile. PMID:23777792

  20. Synthesis and Characterization of Curcumin-Functionalized HP-β-CD-Modified GoldMag Nanoparticles as Drug Delivery Agents.

    PubMed

    Lian, Ting; Peng, Mingli; Vermorken, Alphons J M; Jin, Yanyan; Luo, Zhiyi; Van de Ven, Wim J M; Wan, Yinsheng; Hou, Peng; Cui, Yali

    2016-06-01

    Curcumin, a polyphenol extracted from turmeric (Curcuma longa), has emerged as a potent multimodal cancer-preventing agent. It may attenuate the spread of cancer and render chemotherapy more effective. However, curcumin is neither well absorbed nor well retained in the blood, resulting in low efficacy. In an attempt to enhance the potency and to improve the bioavailability of curcumin, new delivery agents, hydroxypropyl-beta-cyclodextrin (HP-β-CD)-modified GoldMag nanoparticles (CD-GMNs) were designed and synthesized to incorporate curcumin. The CD-GMNs were characterized by Fourier Transform Infrared Spectroscopy (FT-IR), Thermo-gravimetric Analysis (TGA), X-ray Diffraction (XRD), Dynamic Light Scattering measurements (DLS), Transmission Electron Microscopy (TEM) and Vibrating Sample Magnetometer (VSM) analyses. For the magnetic carrier of CD-GMNs, the content of HP-β-CD was 26.9 wt%. CD-GMNs have a saturation magnetization of 22.7 emu/g with an average hydrodynamic diameter of 80 nm. The curcumin loading, encapsulation efficiency and releasing properties in vitro were also investigated. The results showed that the drug encapsulation ratio was 88% and the maximum curcumin loading capacity of CD-GMNs was 660 μg/5 mg. In vitro drug release studies showed a controlled and pH-sensitive curcumin release over a period of one week. Collectively, our data suggest that HP-β-CD-modified GoldMag nanoparticles can be considered to form a promising delivery system for curcumin to tumor sites. Targeting can be achieved by the combined effects of the application of an external magnetic field and the effect on drug release of lower pH values often found in the tumor microenvironment. PMID:27427699

  1. The investigational agent MLN2238 induces apoptosis and is cytotoxic to CLL cells in vitro, as a single agent and in combination with other drugs.

    PubMed

    Paulus, Aneel; Masood, Aisha; Miller, Kena C; Khan, A N M Nazmul H; Akhtar, Drusilla; Advani, Pooja; Foran, James; Rivera, Candido; Roy, Vivek; Colon-Otero, Gerardo; Chitta, Kasyapa; Chanan-Khan, Asher

    2014-04-01

    Chronic lymphocytic leukaemia (CLL) is the most common haematological malignancy in the U.S. The course of the disease has been shown to be negatively impacted by increased levels of BCL2. Strategies to downregulate BCL2 and shift the balance towards cellular demise are actively being explored. Therefore, we examined whether the investigational agent MLN2238 could inhibit the proteasomal machinery and induce CLL cell death while also downregulating BCL2. MLN2238-induced cell death was studied in peripheral blood mononuclear cells from 28 CLL patients. MLN2238 produced a dose-dependent reduction in BCL2 and CLL cell viability with maximum cell death observed at a 50 nmol/l concentration by 48 h. Annexin-V staining, PARP1 and caspase-3 cleavage along with an increase in mitochondrial membrane permeability were noted after cells were treated with MLN2238; however, apoptosis was only partially blocked by the pan-caspase inhibitor z-VAD.fmk. Furthermore, we observed enhanced anti-CLL effects in tumour cells treated with either a combination of MLN2238 and the BH3 mimetic AT-101 or MLN2238 and fludarabine. Together, our data suggest the potential for proteasome inhibitor based therapy in CLL and the rationale design of drug combination strategies based on CLL biology. PMID:24467634

  2. Rasayana drugs from the Ayurvedic system of medicine as possible radioprotective agents in cancer treatment.

    PubMed

    Baliga, Manjeshwar Shrinath; Meera, Sharake; Vaishnav, Lalit Kumar; Rao, Suresh; Palatty, Princy Louis

    2013-11-01

    The use of ionizing radiation, which is the cornerstone of cancer treatment, is compromised by the radiosensitivity of normal tissues. A chemical that can give selective benefit to the normal cells against the deleterious effects of ionizing radiation has been a long-sought goal. However, most of the compounds studied have shown inadequate clinical application owing to their inherent toxicity, undesirable side effects, and high cost. Studies carried out in the past 2 decades have shown that some of the classical Indian Ayurvedic drugs (Amritaprasham, Ashwagandha Rasayana, Brahma Rasayana, Chyavanprasha, Narasimha Rasayana, and Triphala Churna) possess radioprotective effects. In the current review, an attempt is made to summarize the radioprotective observations of these Ayurvedic drugs and the mechanisms responsible for the radioprotective effects. PMID:23737641

  3. Interspecies pharmacokinetics as applied to the hard drug photosensitizing agent meta(tetrahydroxphenyl)chlorin

    NASA Astrophysics Data System (ADS)

    Ronn, Avigdor M.; Lofgren, Lennart A.; Westerborn, Anders

    1996-01-01

    Having successfully completed an extensive three year study of the pharmacokinetics and efficacy of m-THPC as a photosensitizer in three different animal models (rabbit, dog and nude rats) we began a phase one human trial in two centers. At the Orebro Medical Center Hospital, Sweden ten patients were selected for the treatment of bronchial, prostate, skin, laryngeal and nasopharyngeal tumors while at Long Island Jewish Medical Center Hospital four patients were treated for laryngeal cancers. These studies were designed to study the optimal parameters for human treatment and as such relied on data from the animal studies mentioned above. De-escalating drug doses of 0.3, 0.15, 0.075 and 0.0375 mg/kg were chosen and the pharmacokinetics of the patients plasma, tumor and adjacent healthy tissues were measured spectrofluorometrically following chemical extraction of the drug. The half life of the drug in our Cotton tail rabbit model was measured as 24.7 hours as opposed to the human half life of 44.5 hours within the studied dosing range. This illustrates the extreme care that must be exercised before translating animal pharmacokinetics data to human dosing decision.

  4. Aptamer-functionalized hydrogel as effective anti-cancer drugs delivery agents.

    PubMed

    Wang, Zonghua; Xia, Jianfei; Cai, Feng; Zhang, Feifei; Yang, Min; Bi, Sai; Gui, Rijun; Li, Yanhui; Xia, Yanzhi

    2015-10-01

    An aptamer-functionalized hydrogel has been developed, which can be regulated by the AS1411 aptamer with the sol-gel conversion. Also the hydrogel can be further utilized for the controlled encapsulation and release of the cancer drugs. Specially, the AS1411 initiates the hybridization of acrydite-modified oligonucleotides to form the hydrogels and the presence of the target protein nucleolin leads the gel to dissolve as a result of reducing the cross-linking density by competitive target-aptamer binding. Based on the rheology of hydrogels, it is possible to utilize this material for storing and releasing molecules. In this research, the cancer drug doxorubicin is encapsulated inside the gel during the formation of the hydrogel and then released in the presence of nucleolin. Further experiments are carried out to prove the specific recognition of target matter. In vitro researches confirm that the aptamer-functionalized hydrogels can be used as drug carriers in targeted therapy and other biotechnological applications. PMID:26142627

  5. SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions

    PubMed Central

    Preissner, Saskia; Kroll, Katharina; Dunkel, Mathias; Senger, Christian; Goldsobel, Gady; Kuzman, Daniel; Guenther, Stefan; Winnenburg, Rainer; Schroeder, Michael; Preissner, Robert

    2010-01-01

    Much of the information on the Cytochrome P450 enzymes (CYPs) is spread across literature and the internet. Aggregating knowledge about CYPs into one database makes the search more efficient. Text mining on 57 CYPs and drugs led to a mass of papers, which were screened manually for facts about metabolism, SNPs and their effects on drug degradation. Information was put into a database, which enables the user not only to look up a particular CYP and all metabolized drugs, but also to check tolerability of drug-cocktails and to find alternative combinations, to use metabolic pathways more efficiently. The SuperCYP database contains 1170 drugs with more than 3800 interactions including references. Approximately 2000 SNPs and mutations are listed and ordered according to their effect on expression and/or activity. SuperCYP (http://bioinformatics.charite.de/supercyp) is a comprehensive resource focused on CYPs and drug metabolism. Homology-modeled structures of the CYPs can be downloaded in PDB format and related drugs are available as MOL-files. Within the resource, CYPs can be aligned with each other, drug-cocktails can be ‘mixed’, SNPs, protein point mutations, and their effects can be viewed and corresponding PubMed IDs are given. SuperCYP is meant to be a platform and a starting point for scientists and health professionals for furthering their research. PMID:19934256

  6. Colonic drug delivery: influence of cross-linking agent on pectin beads properties and role of the shell capsule type.

    PubMed

    Dupuis, G; Chambin, O; Génelot, C; Champion, D; Pourcelot, Y

    2006-08-01

    For colonic delivery, pectin beads obtained by ionotropic gelation method have been already reported as an interesting approach. This study investigated the influence of the cross-linking agent (calcium or zinc) and the type of shell capsule used (classical or enteric capsules) on pectin beads properties and on their performance to target the colon (in vitro dissolution studies with subsequent pH change to mimic overall gastro-intestinal tract). Zinc pectinate beads seemed to be relatively similar to calcium's ones in morphological point, except on the surface aspect. When beads were introduced in classical hard capsules, ketoprofen release was not significantly different between CPG and ZPG beads, and it was too premature and too quick due to a chemical erosion of the pectinate matrix (acid + basic attacks). However, zinc pectinate beads showed slower ketoprofen release compared with calcium pectinate beads when enteric hard capsules were used. This interesting finding could be due to the strength of the network formed during the process between the zinc cations and the LM-pectin following the "egg-box" model. This network was stronger and induced a reduction of swelling and hydration when contact with dissolution medium, then subsequently a decrease of drug release. Thus, the zinc pectinate beads could protect sufficiently drug entrapped from the upper gastro-intestinal conditions and drug release will be controlled by pectin degradation with colonic microflora. Finally, these zinc pectinate beads in enteric hard capsules are promising as a carrier for specific colonic delivery of drugs after oral administration. PMID:16908422

  7. Repurposing the FDA-Approved Pinworm Drug Pyrvinium as a Novel Chemotherapeutic Agent for Intestinal Polyposis

    PubMed Central

    Giambelli, Camilla; Fei, Dennis Liang; Han, Lu; Hang, Brian I.; Bai, Feng; Pei, Xin-Hai; Nose, Vania; Burlingame, Oname; Capobianco, Anthony J.; Orton, Darren; Lee, Ethan; Robbins, David J.

    2014-01-01

    Mutations in the WNT-pathway regulator ADENOMATOUS POLYPOSIS COLI (APC) promote aberrant activation of the WNT pathway that is responsible for APC-associated diseases such as Familial Adenomatous Polyposis (FAP) and 85% of spontaneous colorectal cancers (CRC). FAP is characterized by multiple intestinal adenomas, which inexorably result in CRC. Surprisingly, given their common occurrence, there are few effective chemotherapeutic drugs for FAP. Here we show that the FDA-approved, anti-helminthic drug Pyrvinium attenuates the growth of WNT-dependent CRC cells and does so via activation of CK1α. Furthermore, we show that Pyrvinium can function as an in vivo inhibitor of WNT-signaling and polyposis in a mouse model of FAP: APCmin mice. Oral administration of Pyrvinium, a CK1α agonist, attenuated the levels of WNT-driven biomarkers and inhibited adenoma formation in APCmin mice. Considering its well-documented safe use for treating enterobiasis in humans, our findings suggest that Pyrvinium could be repurposed for the clinical treatment of APC-associated polyposes. PMID:25003333

  8. Wittig derivatization of sesquiterpenoid polygodial leads to cytostatic agents with activity against drug resistant cancer cells and capable of pyrrolylation of primary amines.

    PubMed

    Dasari, Ramesh; De Carvalho, Annelise; Medellin, Derek C; Middleton, Kelsey N; Hague, Frédéric; Volmar, Marie N M; Frolova, Liliya V; Rossato, Mateus F; De La Chapa, Jorge J; Dybdal-Hargreaves, Nicholas F; Pillai, Akshita; Kälin, Roland E; Mathieu, Véronique; Rogelj, Snezna; Gonzales, Cara B; Calixto, João B; Evidente, Antonio; Gautier, Mathieu; Munirathinam, Gnanasekar; Glass, Rainer; Burth, Patricia; Pelly, Stephen C; van Otterlo, Willem A L; Kiss, Robert; Kornienko, Alexander

    2015-10-20

    Many types of cancer, including glioma, melanoma, non-small cell lung cancer (NSCLC), among others, are resistant to proapoptotic stimuli and thus poorly responsive to current therapies based on the induction of apoptosis in cancer cells. The current investigation describes the synthesis and anticancer evaluation of unique C12-Wittig derivatives of polygodial, a sesquiterpenoid dialdehyde isolated from Persicaria hydropiper (L.) Delabre. These compounds were found to undergo an unprecedented pyrrole formation with primary amines in a chemical model system, a reaction that could be relevant in the biological environment and lead to the pyrrolation of lysine residues in the target proteins. The anticancer evaluation of these compounds revealed their promising activity against cancer cells displaying various forms of drug resistance, including resistance to proapoptotic agents. Mechanistic studies indicated that compared to the parent polygodial, which displays fixative general cytotoxic action against human cells, the C12-Wittig derivatives exerted their antiproliferative action mainly through cytostatic effects explaining their activity against apoptosis-resistant cancer cells. The possibility for an intriguing covalent modification of proteins through a novel pyrrole formation reaction, as well as useful activities against drug resistant cancer cells, make the described polygodial-derived chemical scaffold an interesting new chemotype warranting thorough investigation. PMID:26360047

  9. Tumor vascular-targeted co-delivery of anti-angiogenesis and chemotherapeutic agents by mesoporous silica nanoparticle-based drug delivery system for synergetic therapy of tumor

    PubMed Central

    Li, Xiaoyu; Wu, Meiying; Pan, Limin; Shi, Jianlin

    2016-01-01

    To overcome the drawback of drug non-selectivity in traditional chemotherapy, the construction of multifunctional targeting drug delivery systems is one of the most effective and prevailing approaches. The intratumoral anti-angiogenesis and the tumor cell-killing are two basic approaches in fighting tumors. Herein we report a novel tumor vascular-targeting multidrug delivery system using mesoporous silica nanoparticles as carrier to co-load an antiangiogenic agent (combretastatin A4) and a chemotherapeutic drug (doxorubicin) and conjugate with targeting molecules (iRGD peptide) for combined anti-angiogenesis and chemotherapy. Such a dual-loaded drug delivery system is capable of delivering the two agents at tumor vasculature and then within tumors through a differentiated drug release strategy, which consequently results in greatly improved antitumor efficacy at a very low doxorubicin dose of 1.5 mg/kg. The fast release of the antiangiogenic agent at tumor vasculatures led to the disruption of vascular structure and had a synergetic effect with the chemotherapeutic drug slowly released in the following delivery of chemotherapeutic drug into tumors. PMID:26766908

  10. Holarrhena antidysenterica Extract and Its Steroidal Alkaloid, Conessine, as Resistance-Modifying Agents Against Extensively Drug-Resistant Acinetobacter baumannii.

    PubMed

    Siriyong, Thanyaluck; Chusri, Sasitorn; Srimanote, Potjanee; Tipmanee, Varomyalin; Voravuthikunchai, Supayang Piyawan

    2016-06-01

    Emergence and spread of antibiotic-resistant Acinetobacter baumannii have become a major public health concern. This study was designed to investigate the efficacy of Holarrhena antidysenterica extract and its major steroidal alkaloid conessine as resistance-modifying agents (RMAs) on the susceptibility of A. baumannii to novobiocin and rifampicin. A significant synergistic activity of both the extract and conessine in combination with either novobiocin or rifampicin with fractional inhibitory concentration index ≤0.5 was demonstrated. Fluorescent dyes and different efflux pump inhibitors were used to further investigate the synergism. Increase in the uptake of 1-N-phenylnaphthylamine in the bacterial cells treated with the extract and conessine was not observed indicating that both substances did not act as permeabilizers. With regard to efflux pump inhibition, no accumulation in ethidium bromide (EtBr) was noticed suggesting that the AdeABC pump was not involved. In contrast, accumulation in Pyronin Y was significantly increased (p < 0.05) demonstrating that the synergism was due to interference with the AdeIJK pump. Study on frequencies of the spontaneous mutational resistance to the extract in combination with antibiotics demonstrated attenuation in drug-resistant organisms. Thus, H. antidysenterica extract and conessine as RMAs may offer a combinatory therapy to restore antibiotic susceptibility in the extensively drug-resistant A. baumannii. PMID:26745443

  11. Semi-synthetic ocotillol analogues as selective ABCB1-mediated drug resistance reversal agents.

    PubMed

    Zhang, Yun-Kai; Zhang, Hengyuan; Zhang, Guan-Nan; Wang, Yi-Jun; Kathawala, Rishil J; Si, Rui; Patel, Bhargav A; Xu, Jinyi; Chen, Zhe-Sheng

    2015-09-15

    Overexpression of ATP-Binding Cassette transporters leads to multidrug resistance in cancer cells and results in the failure of chemotherapy. In this in-vitro study, we investigated whether or not (20S, 24R/S)-epoxy-12β, 25-dihydroxy-dommarane-3β-amine (ORA and OSA), a pair of semi-synthetic ocotillol analogue epimers, could inhibit the ABCB1 transporter. ORA (1 μM and 3 μM) significantly reversed the resistance to paclitaxel and vincristine in ABCB1-overexpressing SW620/Ad300 and HEK/ABCB1 cells, whereas OSA had no significant effects. In addition, ORA (3 μM) significantly increased the intracellular accumulation of [3H]-paclitaxel by suppressing the efflux function of ABCB1. Meanwhile, both ORA (3 μM) and OSA (3 μM) did not significantly alter the expression level or the subcellular location of ABCB1 protein. Moreover, the ABCB1 ATPase study suggested that ORA had a stronger stimulatory effect on the ATPase activity than OSA. ORA also exhibited a higher docking score as compared with OSA inside transmembrane domain of ABCB1. Overall, we concluded that ORA reverse ABCB1-mediated MDR by competitively inhibiting the ABCB1 drug efflux function. PMID:26296969

  12. Semi-synthetic ocotillol analogues as selective ABCB1-mediated drug resistance reversal agents

    PubMed Central

    Zhang, Guan-Nan; Wang, Yi-Jun; Kathawala, Rishil J.; Si, Rui; Patel, Bhargav A.; Xu, Jinyi; Chen, Zhe-Sheng

    2015-01-01

    Overexpression of ATP-Binding Cassette transporters leads to multidrug resistance in cancer cells and results in the failure of chemotherapy. In this in-vitro study, we investigated whether or not (20S, 24R/S)-epoxy-12β, 25-dihydroxy-dommarane-3β-amine (ORA and OSA), a pair of semi-synthetic ocotillol analogue epimers, could inhibit the ABCB1 transporter. ORA (1 μM and 3 μM) significantly reversed the resistance to paclitaxel and vincristine in ABCB1-overexpressing SW620/Ad300 and HEK/ABCB1 cells, whereas OSA had no significant effects. In addition, ORA (3 μM) significantly increased the intracellular accumulation of [3H]-paclitaxel by suppressing the efflux function of ABCB1. Meanwhile, both ORA (3 μM) and OSA (3 μM) did not significantly alter the expression level or the subcellular location of ABCB1 protein. Moreover, the ABCB1 ATPase study suggested that ORA had a stronger stimulatory effect on the ATPase activity than OSA. ORA also exhibited a higher docking score as compared with OSA inside transmembrane domain of ABCB1. Overall, we concluded that ORA reverse ABCB1-mediated MDR by competitively inhibiting the ABCB1 drug efflux function. PMID:26296969

  13. Drug leads agents from methanol extract of Nigerian bee (Apis mellifera) propolis

    PubMed Central

    Lawal, Bashir; Shittu, Oluwatosin Kudirat; Abubakar, Asmau Niwoye; Olalekan, Ibrahim Azeez; Jimoh, Adisa Mohammed; Abdulazeez, Adeniyi Kamoru

    2016-01-01

    Background: Propolis is a bee (Apis mellifera) product of plant origin with varied chemical composition depending on the ecology of the botanical origin. It has been reported in literature to possess various therapeutic effects both traditionally, clinical trial, and animal study. Objectives: In the present study bioactive principle in methanol extract of Nigerian bee (A. mellifera) propolis was determined by gas chromatography-mass spectrometry (GC/MS) study. Materials and Methods: The methanol extract of Nigerian bee (A. mellifera) propolis was characterized for its chemical composition by preliminary phytochemicals screening and GC/MS analysis using standard procedures and methods. Results: Phytochemical screening revealed the presence of flavonoids, saponins, alkaloids, tannins, cardiac glycosides, anthraquinones phlobatannins, and steroids while GC/MS chromatogram revealed nineteen peaks representing 60 different chemical compounds. The first compounds identified with less retention time (RT) (13.33s) were methyl tetradecanoate, tridecanoic acid, methyl ester, decanoic acid, methyl ester while squalene, all-trans-squalene, 2,6,10-dodecatrien-1-ol, 3,7,11-trimethyl-, (E,E)- and farnesol isomer a took longest RT (23.647s) to identify. Methyl 14-methylpentadecanoate, hexadecanoic acid methyl ester, methyl isoheptadecanoate, and methyl tridecanoate were the most concentrated constituent as revealed by there peak height (26.01%) while eicosanoic acid was the least concentrated (peak height 0.81%) constituent of Nigerian bee propolis. Conclusion: The presence of these chemical principles is an indication that methanol extract of Nigeria bee propolis, if properly screened could yield a drug of pharmaceutical importance. PMID:27069724

  14. Applications of docking and molecular dynamic studies on the search for new drugs against the biological warfare agents Bacillus anthracis and Yersinia pestis.

    PubMed

    França, Tanos Celmar Costa; Guimarães, Ana Paula; Cortopassi, Wilian Augusto; Oliveira, Aline Alves; Ramalho, Teodorico Castro

    2013-12-01

    The fear of biological warfare agents (BWA) use by terrorists is the major concern of the security agencies and health authorities worldwide today. The non-existence of vaccines or drugs against most BWA and the possibility of genetic modified strains has turned the search for new drugs to a state of urgency. Fast in silico techniques are, therefore, perfect tools for this task once they can quickly provide structures of several new lead compounds for further experimental work. Here we try to present a mini-review on docking and molecular dynamics simulations studies applied to the drug design against the BWA Bacillus anthracis and Yersinia pestis. PMID:24341424

  15. Second annual progress report on introduction and use of investigational anticancer agents in Australia, 1984-1985. Anticancer Subcommittee of the Australian Drug Evaluation Committee.

    PubMed

    1986-03-31

    Since the publication of its first report, the Anticancer Subcommittee of the Australian Drug Evaluation Committee (ADEC) has provided advice to ADEC and to the Commonwealth Department of Health on investigational anticancer agents in all stages of development. This second report outlines the progress in 1984-1985. PMID:3515139

  16. Biological Agents

    MedlinePlus

    ... to Z Index Contact Us FAQs What's New Biological Agents This page requires that javascript be enabled ... and Health Topics A-Z Index What's New Biological agents include bacteria, viruses, fungi, other microorganisms and ...

  17. Preparation and performance of a colorimetric biosensor using acetylcholinesterase and indoxylacetate for assay of nerve agents and drugs

    PubMed Central

    Vlcek, Vitezslav

    2014-01-01

    Different toxic compounds can target the cholinergic nervous system. Acetylcholinesterase (AChE; EC 3.1.1.7) is one of the most crucial components of the cholinergic nervous system and thus many of the toxins interact with this enzyme. As to inhibitors, nerve agents used as chemical warfare, some insecticides, and drugs influencing the cholinergic system are common examples of AChE inhibitors. Once inhibited by a neurotoxic compound, a serious cholinergic crisis can occur. On the other hand, sensitivity of AChE to the inhibition can be used for analytical purposes. In this study, a simple disposable biosensor with AChE as a recognition element was devised. AChE was immobilized onto a cellulose matrix and indoxylacetate was used as a chromogenic substrate. The enzyme reaction was assessed by the naked eye using arbitrary units and pyridostigmine, tacrine, paraoxon, carbofuran, soman and VX were assayed as selected inhibitors. A good stability of the biosensors was found, with no aging over a quarter of a year and minimal sensitivity to the interference of organic solvents. The limit of detection ranged from 10 to 100 nmol/L for the compounds tested with a sample volume of 40 µL. PMID:26109903

  18. Preparation and performance of a colorimetric biosensor using acetylcholinesterase and indoxylacetate for assay of nerve agents and drugs.

    PubMed

    Pohanka, Miroslav; Vlcek, Vitezslav

    2014-12-01

    Different toxic compounds can target the cholinergic nervous system. Acetylcholinesterase (AChE; EC 3.1.1.7) is one of the most crucial components of the cholinergic nervous system and thus many of the toxins interact with this enzyme. As to inhibitors, nerve agents used as chemical warfare, some insecticides, and drugs influencing the cholinergic system are common examples of AChE inhibitors. Once inhibited by a neurotoxic compound, a serious cholinergic crisis can occur. On the other hand, sensitivity of AChE to the inhibition can be used for analytical purposes. In this study, a simple disposable biosensor with AChE as a recognition element was devised. AChE was immobilized onto a cellulose matrix and indoxylacetate was used as a chromogenic substrate. The enzyme reaction was assessed by the naked eye using arbitrary units and pyridostigmine, tacrine, paraoxon, carbofuran, soman and VX were assayed as selected inhibitors. A good stability of the biosensors was found, with no aging over a quarter of a year and minimal sensitivity to the interference of organic solvents. The limit of detection ranged from 10 to 100 nmol/L for the compounds tested with a sample volume of 40 µL. PMID:26109903

  19. Express analysis of explosives, chemical warfare agents and drugs with multicapillary column gas chromatography and ion mobility increment spectrometry.

    PubMed

    Buryakov, Igor A

    2004-02-01

    Description of a gas chromatograph designed for express analysis of explosives (2,4-dinitrotoluene, 2,4,6-trinitrotoluene, pentaerythritol tetranitrate), chemical warfare agents (mustard gas, lewisite, sarin) and drugs (heroin, cocaine hydrochloride, crack) is given. The devices comprises a multicapillary chromatographic column and an ion mobility increment spectrometer (MCC-IMIS). The main analytical characteristics of an IMIS (estimated detection limit (DL), linear dynamic range (LDR), speed of response) and a chromatographic column (separation power, degree of separation, a number of possible peaks at a chromatogram section, divided by analysis time) are determined. The maximum value of DL equal to 5 pg/ml was registered for cis-alpha-LW, and the lowest one of 0.001 pg/ml was for cocaine. The maximum value of LDR equal to 1000 was registered for sarin and the lowest one of 150 was for the ions of lewisite. Speed of response of one compound detection with the IMIS was 0.7 s. PMID:14698239

  20. Agent-Based Model Forecasts Aging of the Population of People Who Inject Drugs in Metropolitan Chicago and Changing Prevalence of Hepatitis C Infections.

    PubMed

    Gutfraind, Alexander; Boodram, Basmattee; Prachand, Nikhil; Hailegiorgis, Atesmachew; Dahari, Harel; Major, Marian E

    2015-01-01

    People who inject drugs (PWID) are at high risk for blood-borne pathogens transmitted during the sharing of contaminated injection equipment, particularly hepatitis C virus (HCV). HCV prevalence is influenced by a complex interplay of drug-use behaviors, social networks, and geography, as well as the availability of interventions, such as needle exchange programs. To adequately address this complexity in HCV epidemic forecasting, we have developed a computational model, the Agent-based Pathogen Kinetics model (APK). APK simulates the PWID population in metropolitan Chicago, including the social interactions that result in HCV infection. We used multiple empirical data sources on Chicago PWID to build a spatial distribution of an in silico PWID population and modeled networks among the PWID by considering the geography of the city and its suburbs. APK was validated against 2012 empirical data (the latest available) and shown to agree with network and epidemiological surveys to within 1%. For the period 2010-2020, APK forecasts a decline in HCV prevalence of 0.8% per year from 44(± 2)% to 36(± 5)%, although some sub-populations would continue to have relatively high prevalence, including Non-Hispanic Blacks, 48(± 5)%. The rate of decline will be lowest in Non-Hispanic Whites and we find, in a reversal of historical trends, that incidence among non-Hispanic Whites would exceed incidence among Non-Hispanic Blacks (0.66 per 100 per years vs 0.17 per 100 person years). APK also forecasts an increase in PWID mean age from 35(± 1) to 40(± 2) with a corresponding increase from 59(± 2)% to 80(± 6)% in the proportion of the population >30 years old. Our studies highlight the importance of analyzing subpopulations in disease predictions, the utility of computer simulation for analyzing demographic and health trends among PWID and serve as a tool for guiding intervention and prevention strategies in Chicago, and other major cities. PMID:26421722

  1. Agent-Based Model Forecasts Aging of the Population of People Who Inject Drugs in Metropolitan Chicago and Changing Prevalence of Hepatitis C Infections

    PubMed Central

    Prachand, Nikhil; Hailegiorgis, Atesmachew; Dahari, Harel; Major, Marian E.

    2015-01-01

    People who inject drugs (PWID) are at high risk for blood-borne pathogens transmitted during the sharing of contaminated injection equipment, particularly hepatitis C virus (HCV). HCV prevalence is influenced by a complex interplay of drug-use behaviors, social networks, and geography, as well as the availability of interventions, such as needle exchange programs. To adequately address this complexity in HCV epidemic forecasting, we have developed a computational model, the Agent-based Pathogen Kinetics model (APK). APK simulates the PWID population in metropolitan Chicago, including the social interactions that result in HCV infection. We used multiple empirical data sources on Chicago PWID to build a spatial distribution of an in silico PWID population and modeled networks among the PWID by considering the geography of the city and its suburbs. APK was validated against 2012 empirical data (the latest available) and shown to agree with network and epidemiological surveys to within 1%. For the period 2010–2020, APK forecasts a decline in HCV prevalence of 0.8% per year from 44(±2)% to 36(±5)%, although some sub-populations would continue to have relatively high prevalence, including Non-Hispanic Blacks, 48(±5)%. The rate of decline will be lowest in Non-Hispanic Whites and we find, in a reversal of historical trends, that incidence among non-Hispanic Whites would exceed incidence among Non-Hispanic Blacks (0.66 per 100 per years vs 0.17 per 100 person years). APK also forecasts an increase in PWID mean age from 35(±1) to 40(±2) with a corresponding increase from 59(±2)% to 80(±6)% in the proportion of the population >30 years old. Our studies highlight the importance of analyzing subpopulations in disease predictions, the utility of computer simulation for analyzing demographic and health trends among PWID and serve as a tool for guiding intervention and prevention strategies in Chicago, and other major cities. PMID:26421722

  2. Antibiotic-loaded, silver core-embedded mesoporous silica nanovehicles as a synergistic antibacterial agent for the treatment of drug-resistant infections.

    PubMed

    Wang, Yao; Ding, Xiali; Chen, Yuan; Guo, Mingquan; Zhang, Yan; Guo, Xiaokui; Gu, Hongchen

    2016-09-01

    Drug-resistant bacterial infections have become one of the most serious risks in public health as they make the conventional antibiotics less efficient. There is an urgent need for developing new generations of antibacterial agents in this field. In this work, a nanoplatform of LEVO-loaded and silver core-embedded mesoporous silica nanovehicles (Ag@MSNs@LEVO) is demonstrated as a synergistic antibacterial agent for the treatment of drug-resistant infections both in vitro and in vivo. The combination of the inner Ag core and the loaded antibiotic drug in mesopores endows the single-particle nanoplatform with a synergistic effect on killing the drug-resistant bacteria. The nanoplatform of Ag@MSNs@LEVO exhibits superior antibacterial activity to LEVO-loaded MSNs (MSNs@LEVO) and silver core-embedded MSNs (Ag@MSNs) in vitro. In the in vivo acute peritonitis model, the infected drug-resistant Escherichia coli GN102 in peritoneal cavity of the mice is reduced by nearly three orders of magnitude and the aberrant pathological feature of spleen and peritoneum disappears after treatment with Ag@MSNs@LEVO. Importantly, this nanopaltform renders no obvious toxic side effect to the mice during the tested time. There is no doubt that this study strongly indicates a promising potential of Ag@MSNs@LEVO as a synergistic and safety therapy tool for the clinical drug-resistant infections. PMID:27294538

  3. Comparison of inhibition kinetics of several organophosphates, including some nerve agent surrogates, using human erythrocyte and rat and mouse brain acetylcholinesterase.

    PubMed

    Coban, Alper; Carr, Russell L; Chambers, Howard W; Willeford, Kenneth O; Chambers, Janice E

    2016-04-25

    Because testing of nerve agents is limited to only authorized facilities, our laboratory developed several surrogates that resemble nerve agents because they phosphylate the acetylcholinesterase (AChE) with the same moiety as the actual nerve agents. The inhibition kinetic parameters were determined for AChE by surrogates of cyclosarin (NCMP), sarin (NIMP, PIMP and TIMP) and VX (NEMP and TEMP) and other organophosphorus compounds derived from insecticides. All compounds were tested with rat brain and a subset was tested with mouse brain and purified human erythrocyte AChE. Within the compounds tested on all AChE sources, chlorpyrifos-oxon had the highest molecular rate constant followed by NCMP and NEMP. This was followed by NIMP then paraoxon and DFP with rat and mouse brain AChE but DFP was a more potent inhibitor than NIMP and paraoxon with human AChE. With the additional compounds tested only in rat brain, TEMP was slightly less potent than NEMP but more potent than PIMP which was more potent than NIMP. Methyl paraoxon was slightly less potent than paraoxon but more potent than TIMP which was more potent than DFP. Overall, this study validates that the pattern of inhibitory potencies of our surrogates is comparable to the pattern of inhibitory potencies of actual nerve agents (i.e., cyclosarin>VX>sarin), and that these are more potent than insecticidal organophosphates. PMID:26965078

  4. Acylation of SC4 dodecapeptide increases bactericidal potency against Gram-positive bacteria, including drug-resistant strains.

    PubMed Central

    Lockwood, Nathan A; Haseman, Judith R; Tirrell, Matthew V; Mayo, Kevin H

    2004-01-01

    We have conjugated dodecyl and octadecyl fatty acids to the N-terminus of SC4, a potently bactericidal, helix-forming peptide 12-mer (KLFKRHLKWKII), and examined the bactericidal activities of the resultant SC4 'peptide-amphiphile' molecules. SC4 peptide-amphiphiles showed up to a 30-fold increase in bactericidal activity against Gram-positive strains (Staphylococcus aureus, Streptococcus pyogenes and Bacillus anthracis), including S. aureus strains resistant to conventional antibiotics, but little or no increase in bactericidal activity against Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa). Fatty acid conjugation improved endotoxin (lipopolysaccharide) neutralization by 3- to 6-fold. Although acylation somewhat increased lysis of human erythrocytes, it did not increase lysis of endothelial cells, and the haemolytic effects occurred at concentrations 10- to 100-fold higher than those required for bacterial cell lysis. For insight into the mechanism of action of SC4 peptide-amphiphiles, CD, NMR and fluorescence spectroscopy studies were performed in micelle and liposome models of eukaryotic and bacterial cell membranes. CD indicated that SC4 peptide-amphiphiles had the strongest helical tendencies in liposomes mimicking bacterial membranes, and strong membrane integration of the SC4 peptide-amphiphiles was observed using tryptophan fluorescence spectroscopy under these conditions; results that correlated with the increased bactericidal activities of SC4 peptide-amphiphiles. NMR structural analysis in micelles demonstrated that the two-thirds of the peptide closest to the fatty acid tail exhibited a helical conformation, with the positively-charged side of the amphipathic helix interacting more with the model membrane surface. These results indicate that conjugation of a fatty acid chain to the SC4 peptide enhances membrane interactions, stabilizes helical structure in the membrane-bound state and increases bactericidal potency. PMID:14609430

  5. Electrodes for high-definition transcutaneous DC stimulation for applications in drug-delivery and electrotherapy, including tDCS

    PubMed Central

    Minhas, Preet; Bansal, Varun; Patel, Jinal; Ho, Johnson S.; Diaz, Julian; Datta, Abhishek; Bikson, Marom

    2010-01-01

    Transcutaneous electrical stimulation is applied in a range of biomedical applications including Transcranial Direct Current Stimulation (tDCS). tDCS is a non-invasive procedure where a weak direct current (<2 mA) is applied across the scalp to modulate brain function. High-Definition tDCS (HD-tDCS) is a technique used to increase the spatial focality of tDCS by passing current across the scalp using <12 mm diameter electrodes. The purpose of this study was to design and optimize “high-definition” electrode-gel parameters for electrode durability, skin safety, and subjective pain. Anode and cathode electrode potential, temperature, pH, and subjective sensation over time were assessed during application of 2 mA direct current, for up to 22 minutes on agar gel or subject forearms. A selection of 5 types of solid-conductors (Ag pellet, Ag/AgCl pellet, Rubber pellet, Ag/AgCl ring, and Ag/AgCl disc) and 7 conductive gels (Signa, Spectra, Tensive, Redux, BioGel, Lectron, and CCNY-4) were investigated. The Ag/AgCl ring in combination with CCNY-4 gel resulted in the most favorable outcomes. Under anode stimulations, electrode potential and temperature rises were generally observed in all electrode-gel combinations except for Ag/AgCl ring and disc electrodes. pH remained constant for all solid-conductors except for both Ag and Rubber pellet electrodes with Signa and CCNY-4 gels. Sensation ratings were independent of stimulation polarity. Ag/AgCl ring electrodes were found to be the most comfortable followed by Ag, Rubber, and Ag/AgCl pellet electrodes across all gels. PMID:20488204

  6. Exploration of the Parameter Space in AN Agent-Based Model of Tuberculosis Spread: Emergence of Drug Resistance in Developing VS Developed Countries

    NASA Astrophysics Data System (ADS)

    Espindola, Aquino L.; Girardi, Daniel; Penna, Thadeu J. P.; Bauch, Chris T.; Martinez, Alexandre S.; Cabella, Brenno C. T.

    2012-06-01

    In this work we present an agent-based model for the spread of tuberculosis where the individuals can be infected with either drug-susceptible or drug-resistant strains and can also receive a treatment. The dynamics of the model and the role of each one of the parameters are explained. The whole set of parameters is explored to check their importance in the numerical simulation results. The model captures the beneficial impact of the adequate treatment on the prevalence of tuberculosis. Nevertheless, depending on the treatment parameters range, it also captures the emergence of drug resistance. Drug resistance emergence is particularly likely to occur for parameter values corresponding to less efficacious treatment, as usually found in developing countries.

  7. Biomedical HIV prevention including pre-exposure prophylaxis and opiate agonist therapy for women who inject drugs: State of research and future directions

    PubMed Central

    Page, Kimberly; Tsui, Judith; Maher, Lisa; Choopanya, Kachit; Vanichseni, Suphak; Mock, Philip A.; Celum, Connie; Martin, Michael

    2015-01-01

    Women who inject drugs are at higher risk of HIV compared to their male counterparts as a result of multiple factors including biological, behavioral and socio-structural, yet comparatively little effort has been invested in testing and delivering prevention methods that directly target this group. In this paper, we discuss the need for expanded prevention interventions for women who inject drugs, focusing on two safe, effective, and approved, yet underutilized biomedical prevention methods: opiate agonist therapy (OAT) and oral pre-exposure prophylaxis (PrEP). While both interventions are well researched they have not been well examined in the context of gender. We discuss the drivers of women injectors’ higher HIV risk, review the effectiveness of OAT and PrEP interventions among women, and explain why these new HIV prevention tools should be prioritized for women who inject drugs. There is substantial potential for impact of OAT and PrEP programs for women who inject drugs in the context of broader gender-responsive HIV prevention initiatives. While awaiting efficacy data on other biomedical approaches in the HIV prevention research ‘pipeline’, we propose that the scale up and implementation of these proven, safe, and effective interventions are needed now. PMID:25978484

  8. Decontamination methods for cytotoxic drugs. 1. Use of a bioluminescent technique to monitor the inactivation of methotrexate with chlorine-based agents.

    PubMed

    Wren, A E; Melia, C D; Garner, S T; Denyer, S P

    1993-04-01

    A new microbial bioluminescence assay has been used to monitor the loss of mutagenicity on inactivation of methotrexate by active chlorine-based agents. The drug was degraded to products that were non-active in this mutagen detection system, in agreement with previously described work. Presept granules appear to be a suitable alternative to sodium hypochlorite for inactivating solutions and surface spills of methotrexate. The bioluminescence assay appears to have potential for monitoring clean-up and decontamination procedures in areas where cytotoxic agents are used. PMID:8458881

  9. Drug Retention Rates and Treatment Discontinuation among Anti-TNF-α Agents in Psoriatic Arthritis and Ankylosing Spondylitis in Clinical Practice

    PubMed Central

    Fabbroni, Marta; Costa, Luisa; Pagano, Veronica Anna; Frediani, Bruno; Manganelli, Stefania; Galeazzi, Mauro

    2014-01-01

    Objective. The study aim was to determine treatment persistence rates and to identify causes of discontinuation in psoriatic arthritis (PsA) and ankylosing spondylitis (AS) patients in clinical practice. Methods. Patients treated with adalimumab (ADA), etanercept (ETA), or infliximab (INF) were retrospectively included. Treatment persistence rates were analyzed by means of a stepwise logistic regression. Differences between therapy duration were assessed by means of an analysis of variance model (ANOVA), while a chi-square test was used to evaluate relationships between therapies and causes of treatment discontinuation and the administration of concomitant disease-modifying antirheumatic drugs (DMARDs) among therapies and types of disease considering completed courses of therapy versus courses that were discontinued. Results. 268 patients received a total of 353 anti-TNF treatment courses (97 ADA, 180 ETA, and 76 INF). Comparison among therapies showed significant difference regarding the treatment persistence rates due to the contrast between ETA and INF (P = 0.0062). We observed that 84.7% of patients were still responding after 6 months of follow-up. Comparison among diseases showed that there were significant differences between PsA and AS (P = 0.0073) and PsA and PsA with predominant axial involvement (P = 0.0467) in terms of duration of the therapy, while there were no significant differences with regard to the persistence rate. Conclusions. In this cohort, anti-TNF-α therapy was associated with high drug persistence rates. As in rheumatoid arthritis, switching to another anti-TNF-α agent can be an effective option when, during the treatment of AS or PsA, therapy is suspended because of inefficacy or an adverse event. Combination therapy with DMARDs was associated with a better persistence rate. PMID:25110401

  10. Determination of drugs in surface water and wastewater samples by liquid chromatography-mass spectrometry: Methods and preliminary results including toxicity studies with Vibrio fischeri

    USGS Publications Warehouse

    Farre, M.; Ferrer, I.; Ginebreda, A.; Figueras, M.; Olivella, L.; Tirapu, L.; Vilanova, M.; Barcelo, D.

    2001-01-01

    In the present work a combined analytical method involving toxicity and liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) was developed for the determination of pharmaceutical compounds in water samples. The drugs investigated were the analgesics: ibuprofen, ketoprofen, naproxen, and diclofenac, the decomposition product of the acetyl salicylic acid: salicylic acid and one lipid lowering agent, gemfibrozil. The selected compounds are acidic substances, very polar and all of them are analgesic compounds that can be purchased without medical prescription. The developed protocol consisted, first of all, on the use Microtox?? and ToxAlert??100 toxicity tests with Vibrio fischeri for the different pharmaceutical drugs. The 50% effective concentration (EC50) values and the toxicity units (TU) were determined for every compound using both systems. Sample enrichment of water samples was achieved by solid-phase extraction procedure (SPE), using the Merck LiChrolut?? EN cartridges followed by LC-ESI-MS. Average recoveries loading 1 l of samples with pH=2 varied from 69 to 91% and the detection limits in the range of 15-56 ng/l. The developed method was applied to real samples from wastewater and surface-river waters of Catalonia (north-east of Spain). One batch of samples was analyzed in parallel also by High Resolution Gas Chromatography coupled with Mass Spectrometry (HRGC-MS) and the results have been compared with the LC-ESI-MS method developed in this work. ?? 2001 Elsevier Science B.V. All rights reserved.

  11. Nano carriers that enable co-delivery of chemotherapy and RNAi agents for treatment of drug-resistant cancers.

    PubMed

    Tsouris, Vasilios; Joo, Min Kyung; Kim, Sun Hwa; Kwon, Ick Chan; Won, You-Yeon

    2014-01-01

    Tumor cells exhibit drug resistant phenotypes that decrease the efficacy of chemotherapeutic treatments. The drug resistance has a genetic basis that is caused by an abnormal gene expression. There are several types of drug resistance: efflux pumps reducing the cellular concentration of the drug, alterations in membrane lipids that reduce cellular uptake, increased or altered drug targets, metabolic alteration of the drug, inhibition of apoptosis, repair of the damaged DNA, and alteration of the cell cycle checkpoints (Gottesman et al., 2002; Holohan et al., 2013). siRNA is used to silence the drug resistant phenotype and prevent this drug resistance response. Of the listed types of drug resistance, pump-type resistance (e.g., high expression of ATP-binding cassette transporter proteins such as P-glycoproteins (Pgp; also known as multi-drug resistance protein 1 or MDR1, encoded by the ATP-Binding Cassette Sub-Family B Member 1 (ABCB1) gene)) and apoptosis inhibition (e.g., expression of anti-apoptotic proteins such as Bcl-2) are the most frequently targeted for gene silencing. The co-delivery of siRNA and chemotherapeutic drugs has a synergistic effect, but many of the current projects do not control the drug release from the nanocarrier. This means that the drug payload is released before the drug resistance proteins have degraded and the drug resistance phenotype has been silenced. Current research focuses on cross-linking the carrier's polymers to prevent premature drug release, but these carriers still rely on environmental cues to release the drug payload, and the drug may be released too early. In this review, we studied the release kinetics of siRNA and chemotherapeutic drugs from a broad range of carriers. We also give examples of carriers used to co-deliver siRNA and drugs to drug-resistant tumor cells, and we examine how modifications to the carrier affect the delivery. Lastly, we give our recommendations for the future directions of the co-delivery of si

  12. Parenteral patent drug S/GSK1265744 has the potential to be an effective agent in pre-exposure prophylaxis against HIV infection.

    PubMed

    Taha, Huda; Morgan, James; Das, Archik; Das, Satyajit

    2013-12-01

    The continuing HIV epidemic has driven advancements in antiretroviral therapy. New therapeutic targets have been identified over the past years, one of which has been the Integrase enzyme. This is responsible for integrating HIV pro-DNA into the host cell genome and has proved a successful drug target. Efforts have also been made to improve the pharmacokinetic parameters of current drug therapy and utilise these techniques in maximising drug therapeutic effect whilst minimising adverse events. An exciting example of new technologies is that of nanotechnology where drugs can be specifically targeted to certain tissues and drug delivery can be improved by utilising biological molecules and structures. Pre-exposure prophylaxis is also an area of much interest currently both on an individual and population level. Compliance is however a major issue with daily medication to prevent HIV acquisition as has been demonstrated with contraceptive agents. However if long acting compounds can be developed, compliance can be improved. The patent drug currently being developed through nanotechnology as an analogue of Dolutegravir, GSK1265744 LAP (Long Acting Parenteral) has shown promise as a Long Acting Integrase Inhibitor with potential action both as a therapeutic agent but also in pre-exposure prophylaxis. The favourable pharmacokinetic profile and therapeutic efficacy in comparison to other compounds of the same class demonstrate it to be a promising advance. However given current limitations in study material, further randomised studies with long term follow up are required to fully evaluate the value of the patent drug GSK1265744 LAP in action in both seropositive and seronegative individuals. PMID:24738551

  13. Facile solvothermal synthesis of mesostructured Fe3O4/chitosan nanoparticles as delivery vehicles for pH-responsive drug delivery and magnetic resonance imaging contrast agents.

    PubMed

    Zhao, Guanghui; Wang, Jianzhi; Peng, Xiaomen; Li, Yanfeng; Yuan, Xuemei; Ma, Yingxia

    2014-02-01

    We report a facile fabrication of a host-metal-guest coordination-bonding system in a mesostructured Fe3O4/chitosan nanoparticle that can act as a pH-responsive drug-delivery system. The mesostructured Fe3O4/chitosan was synthesized by a solvothermal approach with iron(III) chloride hexahydrate as a precursor, ethylene glycol as a reducing agent, ammonium acetate as a porogen, and chitosan as a surface-modification agent. Subsequently, doxorubicin (DOX), acting as a model drug (guest), was loaded onto the mesostructured Fe3O4/chitosan nanoparticles, with chitosan acting as a host molecule to form the NH2-Zn(II)-DOX coordination architecture. The release of DOX can be achieved through the cleavage of coordination bonds that are sensitive to variations in external pH under weakly acidic conditions. The pH-responsive nature of the nanoparticles was confirmed by in vitro releases and cell assay tests. Furthermore, the relaxation efficiency of the nanoparticles as high-performance magnetic resonance imaging contrast agents was also investigated. Experimental results confirm that the synthesized mesostructured Fe3O4/chitosan is a smart nanovehicle for drug delivery owing to both its pH-responsive nature and relaxation efficiency. PMID:24259489

  14. Pharmacokinetics and pharmacodynamics of phase II drug metabolizing/antioxidant enzymes gene response by anticancer agent sulforaphane in rat lymphocytes.

    PubMed

    Wang, Hu; Khor, Tin Oo; Yang, Qian; Huang, Ying; Wu, Tien-Yuan; Saw, Constance Lay-Lay; Lin, Wen; Androulakis, Ioannis P; Kong, Ah-Ng Tony

    2012-10-01

    This study assesses the pharmacokinetics (PK) and pharmacodynamics (PD) of Nrf2-mediated increased expression of phase II drug metabolizing enzymes (DME) and antioxidant enzymes which represents an important component of cancer chemoprevention in rat lymphocytes following intravenous (iv) administration of an anticancer phytochemical sulforaphane (SFN). SFN was administered intravenously to four groups of male Sprague-Dawley JVC rats each group comprising four animals. Blood samples were drawn at selected time points. Plasma were obtained from half of each of the blood samples and analyzed using a validated LC-MS/MS method. Lymphocytes were collected from the remaining blood samples using Ficoll-Paque Plus centrifuge medium. Lymphocyte RNAs were extracted and converted to cDNA, quantitative real-time PCR analyses were performed, and fold changes were calculated against those at time zero for the relative expression of Nrf2-target genes of phase II DME/antioxidant enzymes. PK-PD modeling was conducted based on Jusko's indirect response model (IDR) using GastroPlus and bootstrap method. SFN plasma concentration declined biexponentially and the pharmacokinetic parameters were generated. Rat lymphocyte mRNA expression levels showed no change for GSTM1, SOD, NF-κB, UGT1A1, or UGT1A6. Moderate increases (2-5-fold) over the time zero were seen for HO-1, Nrf2, and NQO1, and significant increases (>5-fold) for GSTT1, GPx1, and Maf. PK-PD analyses using GastroPlus and the bootstrap method provided reasonable fitting for the PK and PD profiles and parameter estimates. Our present study shows that SFN could induce Nrf2-mediated phase II DME/antioxidant mRNA expression for NQO1, GSTT1, Nrf2, GPx, Maf, and HO-1 in rat lymphocytes after iv administration, suggesting that Nrf2-mediated mRNA expression in lymphocytes may serve as surrogate biomarkers. The PK-PD IDR model simultaneously linking the plasma concentrations of SFN and the PD response of lymphocyte mRNA expression is

  15. Continuous exposure of pancreatic cancer cells to dietary bioactive agents does not induce drug resistance unlike chemotherapy.

    PubMed

    Fan, P; Zhang, Y; Liu, L; Zhao, Z; Yin, Y; Xiao, X; Bauer, N; Gladkich, J; Mattern, J; Gao, C; Schemmer, P; Gross, W; Herr, I

    2016-01-01

    The repeated treatment of cancer cells with chemo- or radiotherapy induces therapy resistance, but it was previously unknown whether the same effect occurs upon continuous exposure of cancer cells to diet-derived chemopreventive agents. We elucidated this interesting question in pancreatic ductal adenocarcinoma, which is a highly aggressive cancer entity with a marked resistance toward gemcitabine and other cytotoxic drugs. The isothiocyanate sulforaphane, present in cruciferous vegetables, and the polyphenol quercetin, present in many fruits and vegetables induced apoptosis and reduced viability in gemcitabine-sensitive BxPC-3 cells but not in non-malignant ductal pancreas cells and mesenchymal stromal cells. In turn, BxPC-3 cells were treated with increasing concentrations of gemcitabine, sulforaphane or quercetin for more than 1 year and the surviving subclones Bx-GEM, Bx-SF and Bx-Q were selected, respectively. While Bx-GEM cells acquired a total resistance, Bx-SF or Bx-Q cells largely kept their sensitivity as proved by MTT assay, annexin staining and FACS analysis. The evaluation of the self-renewal-, differentiation- and migration-potential by colony formation, differentiation or migration assays demonstrated that cancer stem cell features were enriched in gemcitabine-resistant cells, but decreased in sulforaphane- and quercetin-long time-treated cells. These results were confirmed by orthotopic xenotransplantation of cancer cells to the mouse pancreas, where Bx-GEM formed large, Bx-Q small and Bx-SF cells almost undetectable tumors. An mRNA expression profiling array and subsequent gene set enrichment analysis and qRT-PCR confirmed that tumor progression markers were enriched in Bx-GEM, but reduced in Bx-SF and Bx-Q cells. This study demonstrates that the continuous exposure of pancreatic cancer cells to sulforaphane or quercetin does not induce resistance in surviving cells but reduces tumorigenicity by inhibition of tumor progression markers. These

  16. Clinical Comparison of Two Contrast Agents for Oral Cholecystography: Radiologic Efficacy and Drug Safety of Iopanoic Acid and Iopronic Acid 1

    PubMed Central

    Hedlund, Laurence; Putman, Charles E.; Burrell, Morton

    1979-01-01

    Oral doses of either iopronic acid (4.5 g Oravue, Squibb) or iopanoic acid (3 g Telepaque, Winthrop) were given to 98 patients requiring cholecystography. Radiographs were taken 13 to 16 hours after treatment showed good to excellent gallbladder opacification in 44 percent of patients after the first dose of iopronic acid and in an additional 29 percent after a second dose. Similar opacification occurred in 42 percent of patients after the first dose of iopanoic acid and in 34 percent after a second dose. Drug-related abnormalities in blood and urine tests occurred about equally in both groups and one patient in each group exhibited a clinically adverse reaction (diarrhea). Thus, the performance (radiographic efficacy and drug safety) of the new contrast agent, iopronic acid, was similar to a widely used drug, iopanoic acid. PMID:380184

  17. Drug-induced panniculitides.

    PubMed

    Borroni, G; Torti, S; D'Ospina, R M; Pezzini, C

    2014-04-01

    A substantial number of all panniculitides fails to recognize a specific etiology, and that is true also for a relatively frequent type of panniculitis, such as erythema nodosum (EN). Between the recognized causative factors of panniculitides, infectious, physical agents, autoimmune mechanisms and neoplastic disorders are well known. On the contrary, the role of drugs as inducers of panniculitides is marginally considered, and their report limited to anecdotal observations, often without due histopathological support. Since the clinical and histopathological features of drug-induced panniculitides are indistinguishable from those caused by other agents, the causative relationship may be demonstrated by the history of previous drug intake and by clinical improvement after drug discontinuation. We reviewed the currently reported descriptions of drug-induced panniculitis, including a few exemplificative original observations. EN results as the most frequently reported drug-induced panniculitis. Among the causative drugs of EN a variety of medications, with disparate, or even opposite, mechanisms of action are reported, thus limiting the understanding of the pathogenesis. Common causative drugs include oral contraceptives, nonsteroidal anti-inflammatory drugs, antiobiotics and leukotriene-modifying agents. Unfortunately, in several cases, the diagnosis of drug-induced EN is done on clinical findings alone. In those cases, the lack of histopathological support does not allow to define a precise clinicopathological correlation on etiologic grounds. Drug-induced lobular and mixed panniculitides, including eosinophilic panniculitis, are even more rarely described. Reported causative agents are glatiramer acetate, interferon beta and heparin (at sites of injections), and systemic steroids, tyrosine kinase inhibitors and BRAF with subcutaneous fat involvement at distance. In view of the recent introduction of new classes of drugs, attention should be paid to disclose their

  18. Antifungal agents.

    PubMed

    Ryder, N S

    1999-12-01

    At this year's ICAAC Meeting, new data on approximately 20 different antifungal agents were presented, while no new agents were disclosed. Drugs in late development include the triazoles, voriconazole (Pfizer Ltd) and Sch-56592 (Schering-Plough Corp), and the echinocandins, caspofungin (Merck & Co Inc) and FK-463 (Fujisawa Pharmaceutical Co Ltd). In contrast to previous years, presentations on these and earlier developmental compounds were relatively modest in scope, with few significant new data. Little new information appeared on the most recent novel class of agents, the sordarins (Glaxo Wellcome plc). Early clinical results were presented for FK-463, showing acceptable tolerability and dose-dependent efficacy in AIDS-associated esophageal candidiasis. A new liposomal formulation of nystatin (Nyotran; Aronex Pharmaceuticals Inc) was shown to be equivalent to conventional amphotericin B in empiric therapy of presumed fungal infection in neutropenic patients, but with reduced toxicity. Intravenous itraconazole (Janssen Pharmaceutica NV) was an effective prophylactic therapy in invasive pulmonary aspergillosis, while oral itraconazole was discussed as a treatment for fungal infection in heart and liver transplant patients. The allylamine compound, terbinafine (Novartis AG), showed good clinical efficacy against fungal mycetoma, a serious tropical infection. A major highlight was the first presentation of inhibitors of fungal efflux pumps as a strategy for overcoming resistance. MC-510027 (milbemycin alpha-9; Microcide Pharmaceuticals Inc) and its derivatives, potentiated the antifungal activity of triazoles and terbinafine in a number of Candida spp. Another pump inhibitor, MC-005172 (Microcide Pharmaceuticals Inc) showed in vivo potentiation of fluconazole in a mouse kidney infection model. Microcide Pharmaceuticals Inc also presented inhibitors of bacterial efflux pumps. PMID:16113946

  19. [Clinical pharmacology of anticancer agents. (Part 1) Introduction, alkylating agents and platinum compounds].

    PubMed

    Fujita, H

    1991-11-01

    Pharmacokinetic concepts as to absorption, distribution, metabolism and excretion of anticancer agents, and how drugs reach to the site of action were reviewed. Then, roles of the liver and kidney to the excretion and metabolism, intracellular pharmacokinetics, and relationships between drug response and cell proliferation kinetics or cell cycle phase were explained. Drug development, mode of action and pharmacokinetics of alkylating agents and platinum compounds were reviewed. This includes: alkylating agents: nitrogen mustard, phenylalanine mustard, estracyte, cyclophosphamide, carboquone, busulfan, nitrosourea, etc., and platinum compounds: cisplatin, carboplatin, 254-S, DWA-2114 R, NK-121. PMID:1952967

  20. Agent-based model forecasts aging of the population of people who inject drugs in metropolitan Chicago and changing prevalence of hepatitis C infections

    SciTech Connect

    Gutfraind, Alexander; Boodram, Basmattee; Prachand, Nikhil; Hailegiorgis, Atesmachew; Dahari, Harel; Major, Marian E.; Kaderali, Lars

    2015-09-30

    People who inject drugs (PWID) are at high risk for blood-borne pathogens transmitted during the sharing of contaminated injection equipment, particularly hepatitis C virus (HCV). HCV prevalence is influenced by a complex interplay of drug-use behaviors, social networks, and geography, as well as the availability of interventions, such as needle exchange programs. To adequately address this complexity in HCV epidemic forecasting, we have developed a computational model, the Agent-based Pathogen Kinetics model (APK). APK simulates the PWID population in metropolitan Chicago, including the social interactions that result in HCV infection. We used multiple empirical data sources on Chicago PWID to build a spatial distribution of an in silico PWID population and modeled networks among the PWID by considering the geography of the city and its suburbs. APK was validated against 2012 empirical data (the latest available) and shown to agree with network and epidemiological surveys to within 1%. For the period 2010–2020, APK forecasts a decline in HCV prevalence of 0.8% per year from 44(±2)% to 36(±5)%, although some sub-populations would continue to have relatively high prevalence, including Non-Hispanic Blacks, 48(±5)%. The rate of decline will be lowest in Non-Hispanic Whites and we find, in a reversal of historical trends, that incidence among non-Hispanic Whites would exceed incidence among Non-Hispanic Blacks (0.66 per 100 per years vs 0.17 per 100 person years). APK also forecasts an increase in PWID mean age from 35(±1) to 40(±2) with a corresponding increase from 59(±2)% to 80(±6)% in the proportion of the population >30 years old. Our research highlight the importance of analyzing sub-populations in disease predictions, the utility of computer simulation for analyzing demographic and health trends among PWID and serve as a tool for guiding intervention and prevention strategies in Chicago, and other major cities.

  1. Agent-based model forecasts aging of the population of people who inject drugs in metropolitan Chicago and changing prevalence of hepatitis C infections

    DOE PAGESBeta

    Gutfraind, Alexander; Boodram, Basmattee; Prachand, Nikhil; Hailegiorgis, Atesmachew; Dahari, Harel; Major, Marian E.; Kaderali, Lars

    2015-09-30

    People who inject drugs (PWID) are at high risk for blood-borne pathogens transmitted during the sharing of contaminated injection equipment, particularly hepatitis C virus (HCV). HCV prevalence is influenced by a complex interplay of drug-use behaviors, social networks, and geography, as well as the availability of interventions, such as needle exchange programs. To adequately address this complexity in HCV epidemic forecasting, we have developed a computational model, the Agent-based Pathogen Kinetics model (APK). APK simulates the PWID population in metropolitan Chicago, including the social interactions that result in HCV infection. We used multiple empirical data sources on Chicago PWID tomore » build a spatial distribution of an in silico PWID population and modeled networks among the PWID by considering the geography of the city and its suburbs. APK was validated against 2012 empirical data (the latest available) and shown to agree with network and epidemiological surveys to within 1%. For the period 2010–2020, APK forecasts a decline in HCV prevalence of 0.8% per year from 44(±2)% to 36(±5)%, although some sub-populations would continue to have relatively high prevalence, including Non-Hispanic Blacks, 48(±5)%. The rate of decline will be lowest in Non-Hispanic Whites and we find, in a reversal of historical trends, that incidence among non-Hispanic Whites would exceed incidence among Non-Hispanic Blacks (0.66 per 100 per years vs 0.17 per 100 person years). APK also forecasts an increase in PWID mean age from 35(±1) to 40(±2) with a corresponding increase from 59(±2)% to 80(±6)% in the proportion of the population >30 years old. Our research highlight the importance of analyzing sub-populations in disease predictions, the utility of computer simulation for analyzing demographic and health trends among PWID and serve as a tool for guiding intervention and prevention strategies in Chicago, and other major cities.« less

  2. The enhanced inhibitory effect of different antitumor agents in self-microemulsifying drug delivery systems on human cervical cancer HeLa cells.

    PubMed

    Ujhelyi, Zoltán; Kalantari, Azin; Vecsernyés, Miklós; Róka, Eszter; Fenyvesi, Ferenc; Póka, Róbert; Kozma, Bence; Bácskay, Ildikó

    2015-01-01

    The aim of this study was to develop topical self-microemulsifying drug delivery systems (SMEDDS) containing antitumor agents (bleomycin, cisplatin and ifosfamide) and to investigate their inhibitory potential in SMEDDS on human cervical cancer HeLa cells. The physicochemical properties of cytostatic drug loaded SMEDDS were characterized. The cytotoxicity of main components of SMEDDS was also investigated. Their IC50 values were determined. HeLa cells were treated by different concentrations of cisplatin, bleomycin and ifosfamide alone and in various SMEDDS. The inhibitory effect on cell growth was analyzed by MTT cell viability assay. Inflammation is a driving force that accelerates cancer development. The inhibitory effect of these antitumor agents has also been tested on HeLa cells in the presence of inflammatory mediators (IL-1-β, TNF-α) as an in vitro model of inflamed human cervix. Significant differences in the cytotoxicity of cytostatic drugs alone and in SMEDDS have been found in a concentration-dependent manner. The self-micro emulsifying system may potentiate the effectiveness of bleomycin, cisplatin and ifosfamide topically. The effect of SMEDDS containing antitumor agents was decreased significantly in the presence of inflammatory mediators. According to our experiments, the optimal SMEDDS formulation is 1:1:2:6:2 ratios of Isopropyl myristate, Capryol 90, Kolliphor RH 40, Cremophor RH40, Transcutol HP and Labrasol. It can be concluded that SMEDDS may increase the inhibitory effect of bleomycin, ifosfamide and cisplatin on human cervical cancer HeLa cells. Inflammation on HeLa cells hinders the effectiveness of SMEDDS containing antitumor agents. Our results might ensure useful data for development of optimal antitumor formulations. PMID:26197311

  3. Suspected nosocomial infections with multi-drug resistant E. coli, including extended-spectrum beta-lactamase (ESBL)-producing strains, in an equine clinic.

    PubMed

    Walther, Birgit; Lübke-Becker, Antina; Stamm, Ivonne; Gehlen, Heidrun; Barton, Ann Kristin; Janssen, Traute; Wieler, Lothar H; Guenther, Sebastian

    2014-01-01

    Enterobacteriaceae such as Escherichia coli are common commensals as well as opportunistic and obligate pathogens. They cause a broad spectrum of infectious diseases in various hosts, including hospital-associated infections. In recent years, the rise of extended spectrum beta-lactamase (ESBL)-producing E. coli in companion animals (dogs, cats and horses) has been striking. However, reports on nosocomial infections are mostly anecdotic. Here we report on the suspected nosocomial spread of both ESBL-producing and non-ESBL-producing multi-drug resistant E. coli isolates in three equine patients within an equine clinic. Unlike easy-to-clean hospitalization opportunities available for small animal settings like boxes and cages made of ceramic floor tiles or stainless steel, clinical settings for horses are challenging environments for infection control programs due to unavoidable extraneous material including at least hay and materials used for horse bedding. The development of practice-orientated recommendations is needed to improve the possibilities for infection control to prevent nosocomial infections with multi-drug resistant and other transmissible pathogens in equine clinical settings. PMID:25872251

  4. Getting Acquainted: An Induction Training Guide for First-Year Extension Agents. Suggestions for Completing Certain Learning Experiences Included in the Induction Training Guide; a Supplement to "Getting Acquainted."

    ERIC Educational Resources Information Center

    Collings, Mary Louise; Gassie, Edward W.

    An induction guide to help the extension agent get acquainted with his role and suggestions for completing learning experiences that are included in the guide comprise this two-part publication. The training guide learning experiences, a total of 25, are made up of: Objectives of the New Worker; When Completed; Learning Experiences; Person(s)…

  5. Albumin-based micro-composite drug carriers with dual chemo-agents for targeted breast cancer treatment.

    PubMed

    Abedin, Farhana; Anwar, Md R; Asmatulu, Ramazan; Yang, Shang-You

    2015-07-01

    Albumin-based drug-carrying micro-composite spheres were fabricated and studied to evaluate their potentials for breast cancer treatment. Magnetic nanoparticles and albumin were incorporated within poly(D l-lactide-co-glycolide) microspheres to increase accumulation of the microspheres at the target site. Two chemotherapeutics, cyclophosphamide and 5-fluorouracil, were encapsulated into the microspheres. The drug-release study revealed an initial burst of drug and then sustained release by diffusion. A Fourier transform infrared spectroscopy study confirmed the presence of all components of the drug delivery system. An in vitro study using fibroblast cells (3T3) and breast cancer cells (MDA-486) exhibited an effective cytotoxicity behavior when exposed to the drug delivery system in a dose- and time-dependent manner. The therapeutic influence of the drug delivery system was evaluated in vivo using a nude mouse breast cancer model. A continuous decrease in tumor size was observed in groups treated with microspheres containing the chemotherapeutics, whereas mice treated with direct chemotherapy without drug delivery system showed less efficacy and suggested tumor relapse after cessation of treatment. The enhanced therapeutic influence of the drug delivery system may be attributed to the increased uptake of the microspheres by malignant cells due to the presence of albumin and magnetic force. The bioavailability of chemotherapeutics at the target site was further increased due to the sustained release of the drugs by diffusion following the burst release. Continuous investigations will optimize the size of the drug delivery system and portions of the target driving-force components (magnetic nanoparticles and albumin) in the drug delivery system to maximize its therapeutic efficacy and minimize potential long-term side effects. PMID:25638169

  6. A magnetic mesoporous silica nanoparticle-based drug delivery system for photosensitive cooperative treatment of cancer with a mesopore-capping agent and mesopore-loaded drug

    NASA Astrophysics Data System (ADS)

    Knežević, Nikola Ž.; Lin, Victor S.-Y.

    2013-01-01

    Lately, there has been a growing interest in anticancer therapy with a combination of different drugs that work by different mechanisms of action, which decreases the possibility that resistant cancer cells will develop. Herein we report on the development of a drug delivery system for photosensitive delivery of a known anticancer drug camptothecin along with cytotoxic cadmium sulfide nanoparticles from a magnetic drug nanocarrier. Core-shell nanoparticles consisting of magnetic iron-oxide-cores and mesoporous silica shells are synthesized with a high surface area (859 m2 g-1) and hexagonal packing of mesopores, which are 2.6 nm in diameter. The mesopores are loaded with anticancer drug camptothecin while entrances of the mesopores are blocked with 2-nitro-5-mercaptobenzyl alcohol functionalized CdS nanoparticles through a photocleavable carbamate linkage. Camptothecin release from this magnetic drug delivery system is successfully triggered upon irradiation with UV light, as measured by fluorescence spectroscopy. Photosensitive anticancer activity of the drug delivery system is monitored by viability studies on Chinese hamster ovarian cells. The treatment of cancer cells with drug loaded magnetic material leads to a decrease in viability of the cells due to the activity of capping CdS nanoparticles. Upon exposure to low power UV light (365 nm) the loaded camptothecin is released which induces additional decrease in viability of CHO cells. Hence, the capping CdS nanoparticles and loaded camptothecin exert a cooperative anticancer activity. Responsiveness to light irradiation and magnetic activity of the nanocarrier enable its potential application for selective targeted treatment of cancer.

  7. In vitro susceptibility of dermatomycoses agents to six antifungal drugs and evaluation by fractional inhibitory concentration index of combined effects of amorolfine and itraconazole in dermatophytes.

    PubMed

    Tamura, Takashi; Asahara, Miwa; Yamamoto, Mikachi; Yamaura, Mariko; Matsumura, Mitsuru; Goto, Kazuo; Rezaei-Matehkolaei, Ali; Mirhendi, Hossein; Makimura, Miho; Makimura, Koichi

    2014-01-01

    To investigate the antifungal drug susceptibility of fungi responsible for dermatomycoses, minimum inhibition concentration (MIC) tests were performed in 44 strains of dermatophytes, including Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton verrucosum, Trichophyton tonsurans, Microsporum canis, Microsporum gypseum and Epidermophyton floccosum, with six antifungal drugs (amorolfine, terbinafine, butenafine, ketoconazole, itraconazole and bifonazole) by broth microdilution assay according to Clinical Laboratory Standard Institute protocols. Six possible dermatomycosis-causing non-dermatophytic fungi were also tested. The two major causes of tinea, T. rubrum and T. mentagrophytes, showed significantly different sensitivities to ketoconazole and bifonazole. Clinically derived dermatophytes were sensitive to the six antifungal drugs tested. However, non-dermatophytes, especially Fusarium spp., tended to be resistant to these antifungal drugs. In Trichophyton spp., the MICs of non-azole drugs had narrower distributions than those of azoles. To evaluate the effects of antifungal drug combinations, the fractional inhibitory concentration index was calculated for the combination of amorolfine and itraconazole as representative external and internal drugs for dermatophytes. It was found that this combination had synergistic or additive effects on most dermatophytes, and had no antagonistic effects. The variation in susceptibility of clinically derived fungal isolates indicates that identification of causative fungi is indispensable for appropriately choosing effective antifungal drugs in the early stages of infection. The results of combination assay suggest that multiple drugs with different antifungal mechanisms against growth of dermatophytes should be used to treat refractory dermatomycoses, especially onychomycosis. PMID:24215461

  8. Evaluation of Drug-Drug Interactions between Direct-Acting Anti-Hepatitis C Virus Combination Regimens and the HIV-1 Antiretroviral Agents Raltegravir, Tenofovir, Emtricitabine, Efavirenz, and Rilpivirine.

    PubMed

    Khatri, Amit; Dutta, Sandeep; Dunbar, Martin; Podsadecki, Thomas; Trinh, Roger; Awni, Walid; Menon, Rajeev

    2016-05-01

    The three direct-acting antiviral agent (3D) regimen is a novel combination of direct-acting antiviral agents (DAAs) that has proven effective for the treatment of hepatitis C virus (HCV) infection. Given the potential for coadministration in patients with human immunodeficiency virus infection, possible drug interactions with antiretroviral drugs must be carefully considered. Four phase 1, multiple-dose pharmacokinetic studies were conducted in healthy volunteers (n = 66). The 3D regimen of 150/100 mg daily paritaprevir/ritonavir, 25 mg daily ombitasvir, and 400 mg twice-daily dasabuvir was administered alone or in combination with 200 mg daily of emtricitabine and 300 mg daily of tenofovir disoproxil fumarate (tenofovir DF), 25 mg daily of rilpivirine, or 400 mg of raltegravir twice daily. A 2-DAA regimen of 150/100 mg daily paritaprevir/ritonavir and 400 mg of dasabuvir twice daily was also studied in combination with efavirenz/emtricitabine/tenofovir DF at 600/200/300 mg daily, respectively (Atripla; Bristol-Myers Squibb). Pharmacokinetic parameters were determined from plasma drug concentrations. No clinically significant drug interactions were observed (≤32% change in exposure) between the 3D regimen and that of emtricitabine plus tenofovir DF. Raltegravir exposure was increased up to 134% when the drug was coadministered with the 3D regimen. Although coadministration with rilpivirine was well tolerated in healthy volunteers, observed elevations in rilpivirine exposures may increase the potential for adverse drug reactions. Concomitant use of the 2-DAA regimen and efavirenz/emtricitabine/tenofovir DF was discontinued owing to poor tolerability and adverse events. No dose adjustment is required during coadministration of raltegravir, tenofovir DF, or emtricitabine with the 3D regimen. Rilpivirine is not recommended and efavirenz is contraindicated for coadministration with the 3D regimen. PMID:26953200

  9. Sucrose esters with various hydrophilic-lipophilic properties: novel controlled release agents for oral drug delivery matrix tablets prepared by direct compaction.

    PubMed

    Chansanroj, K; Betz, G

    2010-08-01

    Sucrose esters (SE) are esters of sucrose and fatty acids with various hydrophilic-lipophilic properties which have attracted interest from being used in pharmaceutical applications. This study aimed to gain insight into the use of SE as controlled release agents for direct compacted matrix tablets. The study focused on the effect of hydrophilic-lipophilic properties on tableting properties and drug release. Sucrose stearate with hydrophilic-lipophilic balance (HLB) values ranging from 0 to 16 was systematically tested. Tablet formulations contained SE, metoprolol tartrate as a highly soluble model drug and dibasic calcium phosphate dihydrate as a tablet formulation filler in the ratio 1:1:2. The compaction behaviour of matrix tablets was compared with the compacts of individual starting materials as reference. SE incorporation improved the plasticity, compressibility and lubricating property of powder mixtures. The hydrophilic-lipophilic properties of SE affected tableting properties, drug release rate and release mechanism. Increasing hydrophilicity corresponding to the increased monoesters in SE composition increased the relative porosity, elastic recovery and tensile strength of the tablets due to the increased hydrogen bonding between the monoesters. This also facilitated the swelling behaviour of SE, which sustained the drug release rate. A sustained release effect prevailed in tablets containing SE with HLB values of 3-16. The ability to improve the tableting properties as well as sustain the drug release rate of the highly soluble model drug via gelation of SE highlights SE as promising controlled release regulators for direct compacted matrix tablets comprising drugs with various solubilities according to the Biopharmaceutics Classification System. PMID:20132913

  10. The effectiveness and cost-effectiveness of erythropoiesis-stimulating agents (epoetin and darbepoetin) for treating cancer treatment-induced anaemia (including review of technology appraisal no. 142): a systematic review and economic model.

    PubMed Central

    Crathorne, Louise; Huxley, Nicola; Haasova, Marcela; Snowsill, Tristan; Jones-Hughes, Tracey; Hoyle, Martin; Briscoe, Simon; Coelho, Helen; Long, Linda; Medina-Lara, Antonieta; Mujica-Mota, Ruben; Napier, Mark; Hyde, Chris

    2016-01-01

    BACKGROUND Anaemia is a common side effect of cancer treatments and can lead to a reduction in quality of life. Erythropoiesis-stimulating agents (ESAs) are licensed for use in conjunction with red blood cell transfusions to improve cancer treatment-induced anaemia (CIA). OBJECTIVE To investigate the effectiveness and cost-effectiveness of ESAs in anaemia associated with cancer treatment (specifically chemotherapy). DATA SOURCES The following databases were searched from 2004 to 2013: The Cochrane Library, MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Web of Science, Cumulative Index to Nursing and Allied Health Literature, British Nursing Index, Health Management Information Consortium, Current Controlled Trials and ClinicalTrials.gov. The US Food and Drug Administration and European Medicines Agency websites were also searched. Bibliographies of included papers were scrutinised for further potentially includable studies. REVIEW METHODS The clinical effectiveness review followed principles published by the NHS Centre for Reviews and Dissemination. Randomised controlled trials (RCTs), or systematic reviews of RCTs, of ESAs (epoetin or darbepoetin) for treating people with CIA were eligible for inclusion in the review. Comparators were best supportive care, placebo or other ESAs. Anaemia- and malignancy-related outcomes, health-related quality of life (HRQoL) and adverse events (AEs) were evaluated. When appropriate, data were pooled using meta-analysis. An empirical health economic model was developed comparing ESA treatment with no ESA treatment. The model comprised two components: one evaluating short-term costs and quality-adjusted life-years (QALYs) (while patients are anaemic) and one evaluating long-term QALYs. Costs and benefits were discounted at 3.5% per annum. Probabilistic and univariate deterministic sensitivity analyses were performed. RESULTS Of 1457 titles and abstracts screened, 23 studies assessing ESAs within their licensed

  11. Cryptolepis sanguinolenta: an ethnobotanical approach to drug discovery and the isolation of a potentially useful new antihyperglycaemic agent.

    PubMed

    Luo, J; Fort, D M; Carlson, T J; Noamesi, B K; nii-Amon-Kotei, D; King, S R; Tsai, J; Quan, J; Hobensack, C; Lapresca, P; Waldeck, N; Mendez, C D; Jolad, S D; Bierer, D E; Reaven, G M

    1998-05-01

    Evidence has been published that a wide array of plant-derived active principles, representing numerous classes of chemical compounds, demonstrate activity consistent with their possible use in the treatment of patients with Type 2 diabetes mellitus (DM). Despite these interesting observations, to date, metformin is the only ethical drug approved for treatment of Type 2 DM derived from a medicinal plant. Why is this so, given the fact that higher plants are such a potential source of new drugs? The answer to this rhetorical question may lie in the reliance of most pharmaceutical companies on random, in vitro, mechanism-based, high throughput screening in the initial phases of plant drug research. In this article we describe an alternative pathway to discovery of drugs for the treatment of Type 2 DM: on based on an ethnomedical approach, involving ethnobotany and traditional medicine. In particular, we present evidence that cryptolepine, an indoloquinolone alkaloid isolated from Cryptolepis sanguinolenta, significantly lowers glucose when given orally to a mouse model of diabetes. The antihyperglycaemic effect of cryptolepine leads to a significant decline in plasma insulin concentration, associated with evidence of an enhancement in insulin-mediated glucose disposal. Finally, cryptolepine increases glucose uptake by 3T3-L1 cells. These data permit us to conclude that an ethnobotanical approach to drug discovery can identify a potentially useful drug for the treatment of Type 2 DM. PMID:9609357

  12. Bioanalytical procedures for detection of chemical agents in hair in the case of drug-facilitated crimes.

    PubMed

    Kintz, Pascal

    2007-08-01

    The use of a drug to modify a person's behavior for criminal gain is not a recent phenomenon. However, the recent increase in reports of drug-facilitated crimes (sexual assault, robbery) has caused alarm in the general public. The drugs involved can be pharmaceuticals, such as benzodiazepines (flunitrazepam, lorazepam, etc.), hypnotics (zopiclone, zolpidem), sedatives (neuroleptics, some anti-H1) or anaesthetics (gamma-hydroxybutyrate, ketamine), drugs of abuse, such as cannabis, ecstasy or LSD, or more often ethanol. To perform successful toxicological examinations, the analyst must follow some important rules: (1) obtain as soon as possible the corresponding biological specimens (blood and urine); (2) collect hair about 1 month after the alleged event; (3) use sophisticated analytical techniques (gas or liquid chromatography coupled to tandem mass spectrometry, MS/MS, headspace gas chromatography); and (4) take care in the interpretation of the findings. Drugs used to facilitate sexual assaults can be difficult to detect (active products at low doses, chemical instability), possess amnesic properties and can be rapidly cleared from the body (short half-life). In these situations, blood or even urine can be of low interest. This is the reason why some laboratories have developed an original approach based on hair testing. Hair was suggested as a valuable specimen in situations where, as a result of a delay in reporting the crime, natural processes have eliminated the drug from typical biological specimens. While there are a lot of papers that have focused on the identification of drugs in hair following chronic drug use, those dealing with a single dose are very scarce. The experience of the author and a review of the existing literature will be presented for cases involving benzodiazepines, hypnotics, gamma-hydroxybutyrate and various sedatives or chemical weapons. The expected concentrations in hair are in the low picogram/milligram range for most compounds

  13. [Decorporation agents for internal radioactive contamination].

    PubMed

    Ohmachi, Yasushi

    2015-01-01

    When radionuclides are accidentally ingested or inhaled, blood circulation or tissue/organ deposition of the radionuclides causes systemic or local radiation effects. In such cases, decorporation therapy is used to reduce the health risks due to their intake. Decorporation therapy includes reduction and/or inhibition of absorption from the gastrointestinal tract, isotopic dilution, and the use of diuretics, adsorbents, and chelating agents. For example, penicillamine is recommended as a chelating agent for copper contamination, and diethylene triamine pentaacetic acid is approved for the treatment of internal contamination with plutonium. During chelation therapy, the removal effect of the drugs should be monitored using a whole-body counter and/or bioassay. Some authorities, such as the National Council on Radiation Protection and Measurements and International Atomic Energy Agency, have reported recommended decorporation agents for each radionuclide. However, few drugs are approved by the US Food and Drug Administration, and many are off-label-use agents. Because many decontamination agents are drugs that have been available for a long time and have limited efficacy, the development of new, higher-efficacy drugs has been carried out mainly in the USA and France. In this article, in addition to an outline of decorporation agents for internal radioactive contamination, an outline of our research on decorporation agents for actinide (uranium and plutonium) contamination and for radio-cesium contamination is also presented. PMID:25832835

  14. A fatal case of poisoning related to new cathinone designer drugs, 4-methoxy PV8, PV9, and 4-methoxy PV9, and a dissociative agent, diphenidine.

    PubMed

    Kudo, Keiko; Usumoto, Yosuke; Kikura-Hanajiri, Ruri; Sameshima, Naomi; Tsuji, Akiko; Ikeda, Noriaki

    2015-09-01

    A woman in her thirties was found dead on a bed. Considerable amounts of "aroma liquid" and "bath salt" products and hypnotic drug tablets were scattered beside the bed. Autopsy showed pulmonary congestion and edema. Gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) analyses of "aroma liquid" and "bath salt" products showed the presence of new cathinone designer drugs, 4-methoxy PV8 (4-methoxy PHPP), PV9 (α-POP), and 4-methoxy PV9 (4-methoxy α-POP), and a dissociative agent, diphenidine. Drug screening in stomach contents, blood and hydrolyzed urine of the woman by GC-MS and liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed the presence of the above 4 types of drugs and 3 types of benzodiazepines, triazolam, flunitrazepam, and nitrazepam, and their metabolites. The above 7 drugs and 3 benzodiazepine metabolites were simultaneously determined by LC-MS/MS after modified QuEChERS (Quick, Easy, Cheap, Effective, Rugged, Safe) extraction using diazepam-d5 as the internal standard. The concentrations of 4-methoxy PV8, PV9, 4-methoxy PV9, and diphenidine in the femoral blood were 2.69, 0.743, 0.261, and 1.38μg/ml, respectively, which were significantly higher than concentrations reported in previous cases. Alcohol concentration in the femoral blood was 1.52mg/ml. Based on the pathological and toxicological findings, the cause of death was determined to be 3 types of cathinone drugs, 4-methoxy PV8, PV9, and 4-methoxy PV9, and diphenidine poisoning under the influence of 3 benzodiazepines and alcohol. PMID:26162997

  15. Investigating the influence of drug aggregation on the percutaneous penetration rate of tetracaine when applying low doses of the agent topically to the skin.

    PubMed

    Cai, X J; Patel, T; Woods, A; Mesquida, P; Jones, S A

    2016-04-11

    Understanding the molecular aggregation of therapeutic agents is particularly important when applying low doses of a drug to the surface of the skin. The aim of this study was to understand how the concentration of a drug influenced its molecular aggregation and its subsequent percutaneous penetration after topical application. A model drug tetracaine was shown to form a series of different aggregates across the μM (fluorescence spectroscopy) to mM (light scattering analysis) concentration range. The aggregate formation process was sensitive to the pH of the vehicle in which the drug was dissolved (pH 4, critical aggregation concentration (CAC) - 11μM; pH 8, CAC - 7μM) and it appeared to have an impact upon the drug's percutaneous penetration. At pH 4, increasing the concentration of the drug in the donor solution decreased the skin permeability coefficient (Kp) of tetracaine (13.7±4.3×10(-3)cm/h to0.06±0.02×10(-3)cm/h), whilst at pH 8, it increased the Kp (29.9±9.9×10(-3)cm/h to 75.1±41.7×10(-3)cm/h). These data trends were reproduced in a silicone membrane and this supported the notion that the more polar aggregates formed at pH 4 acted to decrease the proportion of species available to pass through the skin, whilst the more hydrophobic aggregates formed in pH 8 increased the membrane diffusing species. PMID:26854427

  16. Controlled nail delivery of a novel lipophilic antifungal agent using various modern drug carrier systems as well as in vitro and ex vivo model systems.

    PubMed

    Naumann, Sandy; Meyer, Jean-Philippe; Kiesow, Andreas; Mrestani, Yahya; Wohlrab, Johannes; Neubert, Reinhard H H

    2014-04-28

    The penetration behavior into human nails and animal hoof membranes of a novel antifungal agent (EV-086K) for the treatment of onychomycosis was investigated in this study. The new drug provides a high lipophilicity which is adverse for penetration into nails. Therefore, four different formulations were developed, with particular focus on a colloidal carrier system (CCS) due to its penetration enhancing properties. On the one hand, ex vivo penetration experiments on human nails were performed. Afterwards the human nail plates were cut by cryomicrotome in order to quantify the drug concentration in the dorsal, intermediate and ventral nail layer using high-performance liquid chromatography (HPLC) with UV detection. On the other hand, equine and bovine hoof membranes were used to determine the in vitro penetration of the drug into the acceptor compartment of an online diffusion cell coupled with Fourier transform infrared attenuated total reflectance (FTIR-ATR) spectroscopy. In combination, both results should exhibit a correlation between the EV-086K penetration behavior in human nail plates and animal hoof membranes. The investigations showed that the developed CCS could increase drug delivery through the human nail most compared to other formulations (nail lacquer, solution and hydrogel). Using animal hooves in the online diffusion cell, we were able to calculate pharmacokinetic data of the penetration process, especially diffusion and permeability coefficients. Finally, a qualitative correlation between the penetration results of human nails and equine hooves was established. PMID:24560884

  17. Amorphous calcium phosphate nanoparticles could function as a novel cancer therapeutic agent by employing a suitable targeted drug delivery platform

    PubMed Central

    2013-01-01

    Employment of nanovehicular system for delivering apoptogenic agent to cancer cells for inducing apoptosis has widely been investigated. Loading efficacy and controlled release of the agents are of the inseparable obstacles that hamper the efforts in reaching an efficacious targeted cancer therapy method. When the carrier itself is apoptogenic, then there is no need to load the carrier with apoptogenic agent and just delivering of the particle to the specific location matters. Hence, we hypothesize that amorphous calcium phosphate nanoparticle (ACPN) is a potent candidate for apoptosis induction, although encapsulation in liposome shell, and surface decoration with targeting ligand (TL), and cell-penetrating peptide (CPP) plays a pivotal role in the employment of this agent. It is well understood that elevation in cytosolic Ca2+ ([Ca2+]c) would result in the induction of apoptosis. ACPN has the potential to cause imbalance in this medium by elevating [Ca2+]c. Owning to the fact that the nanoparticles should be delivered into cytosol, it is necessary to trap them in a liposomal shell for evading endocytosis. It was demonstrated that employment of the trans-activator of transcription (TAT) as CPP eminently enhances the efficacy of endosomal escape; therefore, the platform is designed in a way that TAT is positioned on the surface of the liposome. Due to the fact that the apoptosis should be induced in sole cancer cells, Folate as TL is also attached on the surface of the liposome. This hypothesis heralds the new generation of chemotherapeutic agents and platforms which could have less side effect than the most common ones, in addition to other advantages they have. PMID:24172080

  18. Discovery of BC-01, a novel mutual prodrug (hybrid drug) of ubenimex and fluorouracil as anticancer agent.

    PubMed

    Jiang, Yuqi; Li, Xiaoyang; Hou, Jinning; Huang, Yongxue; Jia, Yuping; Zou, Mingming; Zhang, Jian; Wang, Xuejian; Xu, Wenfang; Zhang, Yingjie

    2016-10-01

    We designed and synthesized a novel mutual prodrug, named BC-01 (3), by integrating ubenimex and Fluorouracil (5-FU) into one molecule based on prior research results that showed that a combination of the aminopeptidase N (CD13) inhibitor, ubenimex, and the cytotoxic antitumor agent, 5-FU, exhibited improved in vitro and in vivo antitumor efficiency. 3 showed potent inhibitory activity against CD13 enzymatic activity. Compared with ubenimex, 3 exhibited more potent anti-angiogenesis effects, and compared with the approved 5-FU prodrug, capecitabine, 3 exhibited more potent tumor growth inhibitory and anti-metastasis effects. Additionally, compared with 5-FU or 5-FU plus ubenimex, 3 also exhibited a superior antitumor efficiency even in our 5-FU-resistant mice model. Other antitumor agents could be conjugated with ubenimex using this strategy to obtain novel mutual prodrugs with promising antitumor potency. PMID:27322756

  19. Nonsteroidal anti-inflammatory drug activated gene-1 (NAG-1) modulators from natural products as anti-cancer agents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Natural products are rich source of gene modulators for prevention and treatment of cancer. In recent days, nonsteroidal anti-inflammatory drug (NSAID) activated gene-1 (NAG-1) has been focused as a new target of diverse cancers like colorectal, pancreatic, prostate, and breast. A variety of natural...

  20. Magnetic nanoscale metal organic frameworks for potential targeted anticancer drug delivery, imaging and as an MRI contrast agent.

    PubMed

    Ray Chowdhuri, Angshuman; Bhattacharya, Dipsikha; Sahu, Sumanta Kumar

    2016-02-21

    The development of a novel multifunctional porous nanoplatform for targeted anticancer drug delivery with cell imaging and magnetic resonance imaging has been realised in the current work. Here we have developed a magnetic nanoscale metal organic frameworks (NMOF) for potential targeted drug delivery. These magnetic NMOFs were fabricated by incorporation of Fe3O4 nanoparticles into porous isoreticular metal organic frameworks (IRMOF-3). To achieve targeted drug delivery towards cancer cells specifically, folic acid was conjugated to the NMOF surface. Then, the fluorescent molecule rhodamine B isothiocyanate (RITC) was conjugated to the NMOFs for biological imaging applications. The synthesized magnetic NMOFs were fully characterised by FTIR, powder XRD, XPS, SQUID, TGA, TEM, FESEM, and DLS. The synthesized magnetic NMOFs were observed to be smaller than 100 nm and were found to be nontoxic towards human cervix adenocarcinoma (HeLa) and murine fibroblast (NIH3T3) cells according to cell viability assays. The cancer chemotherapy drug paclitaxel was conjugated to the magnetic NMOFs through hydrophobic interactions with a relatively high loading capacity. Moreover, these folic acid-conjugated magnetic NMOFs showed stronger T2-weighted MRI contrast towards the cancer cells, justifying their possible significance in imaging. PMID:26754449

  1. Recent approaches for reducing hemolytic activity of chemotherapeutic agents.

    PubMed

    Jeswani, Gunjan; Alexander, Amit; Saraf, Shailendra; Saraf, Swarnlata; Qureshi, Azra; Ajazuddin

    2015-08-10

    Drug induced hemolysis is a frequent complication associated with chemotherapy. It results from interaction of drug with erythrocyte membrane and leads to cell lysis. In recent past, various approaches were made to reduce drug-induced hemolysis, which includes drug polymer conjugation, drug delivery via colloidal carriers and hydrogels, co-administration of botanical agents and modification in molecular chemistry of drug molecules. The basic concept behind these strategies is to protect the red blood cells from membrane damaging effects of drugs. There are several examples of drug polymer conjugate that either are approved by Food and Drug Administration or are under clinical trial for delivering drugs with reduced toxicities. Likewise, colloidal carriers are also used successfully nowadays for the delivery of various chemotherapeutic agents like gemcitabine and amphotericin B with remarkable decrease in their hemolytic activity. Similarly, co-administration of botanical agents with drugs works as secondary system proving protection and strength to erythrocyte membranes. In addition to the above statement, interaction hindrance between RBC and drug molecule by molecular modification plays an important role in reducing hemolysis. This review predominantly describes the above recent approaches explored to achieve the reduced hemolytic activity of drugs especially chemotherapeutic agents. PMID:26047758

  2. Synthetic agents in the context of metabolic/bariatric surgery: expanding the scope and impact of diabetes drug discovery.

    PubMed

    Janero, David R

    2014-03-01

    Type 2 diabetes (T2D) - particularly with concurrent obesity ('diabesity') - is an intensifying global public-health problem. Medical needs and market opportunities in the T2D space have propelled discovery efforts aimed at inventing new synthetic T2D drugs differentiable by improved safety and efficacy and/or the ability to modulate emerging T2D targets. Particularly for moderately and severely obese individuals, weight-loss (bariatric) surgery offers an effective means of reducing obesity-driven T2D that is superior in many respects to medical T2D management. Yet, not all overweight or obese individuals with T2D qualify for bariatric surgery, and current healthcare resources are inadequate for applying surgical T2D control to more than a very small segment of qualified patients. Bariatric surgery is no guarantee of 'curative' T2D abrogation, significant rates of T2D non-remission or re-emergence having been observed in diabesity patients following bariatric procedures. Preoperative glucose control by oral hypoglycemic drugs reduces the chance of T2D recurrence post-surgery, and diabesity patients in whom glycemic indices have been improved by bariatric surgery may still require some level of T2D pharmacotherapy. Laboratory and clinical data indicate that synthetic T2D drugs can improve T2D-related outcomes following bariatric procedures, and current T2D drug-discovery efforts are being informed by the metabolic advantages associated with bariatric surgery. These circumstances intensify the need for and extend the impact of T2D drug discovery by demonstrating multiple levels of interplay between medical and surgical approaches to improve the health of individuals with diabesity and, perhaps, approach the overarching goal of decreasing long-term cardiovascular mortality. PMID:24397872

  3. Screening for phenotype selective activity in multidrug resistant cells identifies a novel tubulin active agent insensitive to common forms of cancer drug resistance

    PubMed Central

    2013-01-01

    Background Drug resistance is a common cause of treatment failure in cancer patients and encompasses a multitude of different mechanisms. The aim of the present study was to identify drugs effective on multidrug resistant cells. Methods The RPMI 8226 myeloma cell line and its multidrug resistant subline 8226/Dox40 was screened for cytotoxicity in response to 3,000 chemically diverse compounds using a fluorometric cytotoxicity assay (FMCA). Follow-up profiling was subsequently performed using various cellular and biochemical assays. Results One compound, designated VLX40, demonstrated a higher activity against 8226/Dox40 cells compared to its parental counterpart. VLX40 induced delayed cell death with apoptotic features. Mechanistic exploration was performed using gene expression analysis of drug exposed tumor cells to generate a drug-specific signature. Strong connections to tubulin inhibitors and microtubule cytoskeleton were retrieved. The mechanistic hypothesis of VLX40 acting as a tubulin inhibitor was confirmed by direct measurements of interaction with tubulin polymerization using a biochemical assay and supported by demonstration of G2/M cell cycle arrest. When tested against a broad panel of primary cultures of patient tumor cells (PCPTC) representing different forms of leukemia and solid tumors, VLX40 displayed high activity against both myeloid and lymphoid leukemias in contrast to the reference compound vincristine to which myeloid blast cells are often insensitive. Significant in vivo activity was confirmed in myeloid U-937 cells implanted subcutaneously in mice using the hollow fiber model. Conclusions The results indicate that VLX40 may be a useful prototype for development of novel tubulin active agents that are insensitive to common mechanisms of cancer drug resistance. PMID:23919498

  4. Repurposing Drugs to Target the Diabetes Epidemic.

    PubMed

    Turner, Nigel; Zeng, Xiao-Yi; Osborne, Brenna; Rogers, Suzanne; Ye, Ji-Ming

    2016-05-01

    Despite major investment by pharmaceutical companies in conventional drug discovery pipelines, development of new drugs has failed to keep up with the increasing incidence of many diseases, including type 2 diabetes (T2D). Drug repurposing, where existing drugs are applied to a new indication, is gaining momentum as a successful approach to overcome the bottlenecks commonly encountered with conventional approaches. Repurposing takes advantage of available information on the molecular pharmacology of clinical agents to drastically shorten drug development timelines. This review discusses recent advances in the discovery of new antidiabetic agents using repurposing strategies. PMID:26900045

  5. 21 CFR 316.20 - Content and format of a request for orphan-drug designation.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... agent including title, address, and telephone number; the generic and trade name, if any, of the drug or... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Content and format of a request for orphan-drug designation. 316.20 Section 316.20 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND...

  6. 21 CFR 316.20 - Content and format of a request for orphan-drug designation.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... agent including title, address, and telephone number; the generic and trade name, if any, of the drug or... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Content and format of a request for orphan-drug designation. 316.20 Section 316.20 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND...

  7. Simultaneous determination in hair of multiclass drugs of abuse (including THC) by ultra-high performance liquid chromatography-tandem mass spectrometry.

    PubMed

    Di Corcia, D; D'Urso, F; Gerace, E; Salomone, A; Vincenti, M

    2012-06-15

    A simple procedure for the quantitative determination in hair samples of 13 common drugs of abuse or metabolites (morphine, 6-acetylmorphine, codeine, amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyethylamphetamine, benzoylecgonine, cocaine, buprenorphine, methadone and Δ(9)-tetrahydrocannabinol) has been developed and fully validated. The analytes were extracted from the matrix by a simple overnight incubation with methanol at 55 °C. An aliquot of the extract was directly injected into an ultra-high performance liquid chromatography system equipped with Waters Acquity UHPLC BEH C18 column (100 mm × 2.1mm, 1.7 μm). The mobile phase eluted with a linear gradient (water/formic acid 5 mM:acetonitrile; v:v) from 98:2 to 0:100 in 4.5 min, followed by isocratic elution at 100% B for 1.0 min. The flow rate was 0.6 mL/min and the total run time was 8.0 min including re-equilibration at the initial conditions. The compounds were revealed by a triple quadrupole mass spectrometer operating in the selected reaction monitoring mode. The absence of matrix interferents, together with excellent repeatability of both retention times and relative abundances of diagnostic transitions, allowed the correct identification of all analytes tested. The method proved linear in the interval from the limit of quantification to 5.0 ng/mg (1.0 ng/mg for Δ⁹-tetrahydrocannabinol) with correlation coefficient values ranging from 0.9970 to 0.9997. Quantitation limits were below the cut-off values recommended by the Society of Hair Testing and ranged from 0.02 to 0.08 ng/mg. Application of the present UHPLC-MS/MS procedure and instrumentation to hair analysis allows high sample-throughput, together with excellent sensitivity and selectivity, in workplace drug-screening controls and forensic investigations. These qualities, combined with minimal sample workup, make the cost of this screening affordable for most private and

  8. A New Application of Lipid Nanoemulsions as Coating Agent, Providing Zero-Order Hydrophilic Drug Release from Tablets

    PubMed Central

    Anton, Nicolas; de Crevoisier, Astrid; Schmitt, Sabrina; Vandamme, Thierry

    2012-01-01

    The objective of the present investigation was to evaluate potential of nanoemulsions as a coating material for the tablets. The nanoemulsion of size less than 100 nm was prepared using a simple and low-energy spontaneous emulsification method. Conventional tablets containing theophylline as a model hydrophilic drug were prepared. The theophylline tablets were coated with the nanoemulsion using a fluid bed coater. The effect of different levels of the nanoemulsion coating on the theophylline release was evaluated. The theophylline tablets containing different levels of the nanoemulsion coating could be successfully prepared. Interestingly, the coating of tablet with the nanoemulsion resulted in zero-order release of theophylline from the tablets. The noncoated theophylline tablets release the entire drug in less than 2 minutes, whereas nanoemulsion coating delayed the release of theophylline from tablets. This investigation establishes the proof of concept for the potential of nanoemulsions as a coating material for tablets. PMID:22272376

  9. Peptide-Decorated Gold Nanoparticles as Functional Nano-Capping Agent of Mesoporous Silica Container for Targeting Drug Delivery.

    PubMed

    Chen, Ganchao; Xie, Yusheng; Peltier, Raoul; Lei, Haipeng; Wang, Ping; Chen, Jun; Hu, Yi; Wang, Feng; Yao, Xi; Sun, Hongyan

    2016-05-11

    A stimuli-responsive drug delivery system (DDS) with bioactive surface is constructed by end-capping mesoporous silica nanoparticles (MSNs) with functional peptide-coated gold nanoparticles (GNPs). MSNs are first functionalized with acid-labile α-amide-β-carboxyl groups to carry negative charges, and then capped with positively charged GNPs that are decorated with oligo-lysine-containing peptide. The resulting hybrid delivery system exhibits endo/lysosomal pH triggered drug release, and the incorporation of RGD peptide facilitates targeting delivery to αvβ3 integrin overexpressing cancer cells. The system can serve as a platform for preparing diversified multifunctional nanocomposites using various functional inorganic nanoparticles and bioactive peptides. PMID:27102225

  10. Influence of cross-linking agent type and chitosan content on the performance of pectinate-chitosan beads aimed for colon-specific drug delivery.

    PubMed

    Maestrelli, F; Cirri, M; Mennini, N; Bragagni, M; Zerrouk, N; Mura, P

    2012-09-01

    Pectinate-chitosan-beads aimed for colon theophylline delivery have been developed. The effect of zinc or calcium ions as cross-linking agent, and of chitosan concentration on the properties and colon-targeting performance of beads was investigated. Beads were characterized for morphology, entrapment efficiency and mucoadhesion properties. Zn-pectinate-chitosan beads formed a stronger gel network than the Ca-containing ones, enabling a greater entrapment efficiency, which further increased with chitosan content, probably due to polyelectrolyte complexes formation. Transport studies across Caco-2 cells evidenced a significant (p > 0.05) drug permeation increase from all beads with respect to drug alone, attributable to the enhancer and/or mucoadhesion properties of the polymers, and Ca-pectinate-chitosan beads were more effective than the Zn-containing ones. Beads formulated as enteric-coated tablets demonstrated good colon-targeting properties, and no differences were observed in drug-release profiles from Zn- or Ca-pectinate-chitosan beads. Therefore, Ca-pectinate-chitosan beads emerged as the choice formulation, joining colon-targeting specificity with better permeation enhancer power. PMID:22191551

  11. [Comparison of antimicrobial use density (AUD) of carbapenem antibacterial agents and investigation of the drug susceptibility of Pseudomonas aeruginosa in 3 hospitals in southern Ibaraki Prefecture, Japan].

    PubMed

    Oishi, Tsuyoshi; Hitomi, Shigemi; Kamoshita, Masaharu; Fukue, Hidetaka; Kawahata, Daisuke; Fukutake, Katsuyuki

    2008-07-01

    The optimal use of anti-Pseudomonas agents is an important issue in the prevention of a tolerance against Pseudomonas aeruginosa. We evaluated the effect of antimicrobial use density (AUD) of carbapenem on drug susceptibility. The AUD of the four carbapenems, imipenem (IPM/CS), panipenem (PAPM/BP), meropenem (MEPM), and biapenem (BIPM), was examined at three hospitals in Ibaraki Prefecture, between April and September 2004. The AUD was calculated using the Defined Daily Doses (DDD) methodology developed by the WHO. A drug susceptibility test was conducted on the 306 Pseudomonas aeruginosa strains randomly collected from clinical specimens at the three hospitals between September and December 2004. In accordance with the standards set by the Clinical and Laboratory Standards Institute (CLSI), minimal inhibitory concentration (MIC) was measured using the broth microdilution method. The results showed that the AUD of carbapenem at the three hospitals tended to be higher than that in other research results in Japan. At one of the three hospitals, the AUD of the PAPM was remarkably high compared to the other carbapenems. Furthermore, P. aeruginosa strains collected at this hospital showed a low susceptibility to carbapenem, and many highly tolerant strains were also observed in this hospital. In order to maintain the susceptibility of Pseudomonas aeruginosa to carbapenem, the overall extent of carbapenem use must be optimal. The use of antimicrobial drugs should be controlled properly at each hospital, in order to prevent excessive use of PAPM/BP from being used over a long period of time. PMID:18709988

  12. Localized sequence-specific release of a chemopreventive agent and an anticancer drug in a time-controllable manner to enhance therapeutic efficacy.

    PubMed

    Pan, Wen-Yu; Lin, Kun-Ju; Huang, Chieh-Cheng; Chiang, Wei-Lun; Lin, Yu-Jung; Lin, Wei-Chih; Chuang, Er-Yuan; Chang, Yen; Sung, Hsing-Wen

    2016-09-01

    Combination chemotherapy with multiple drugs commonly requires several injections on various schedules, and the probability that the drug molecules reach the diseased tissues at the proper time and effective therapeutic concentrations is very low. This work elucidates an injectable co-delivery system that is based on cationic liposomes that are adsorbed on anionic hollow microspheres (Lipos-HMs) via electrostatic interaction, from which the localized sequence-specific release of a chemopreventive agent (1,25(OH)2D3) and an anticancer drug (doxorubicin; DOX) can be thermally driven in a time-controllable manner by an externally applied high-frequency magnetic field (HFMF). Lipos-HMs can greatly promote the accumulation of reactive oxygen species (ROS) in tumor cells by reducing their cytoplasmic expression of an antioxidant enzyme (superoxide dismutase) by 1,25(OH)2D3, increasing the susceptibility of cancer cells to the cytotoxic action of DOX. In nude mice that bear xenograft tumors, treatment with Lipos-HMs under exposure to HFMF effectively inhibits tumor growth and is the most effective therapeutic intervention among all the investigated. These empirical results demonstrate that the synergistic anticancer effects of sequential release of 1,25(OH)2D3 and DOX from the Lipos-HMs may have potential for maximizing DOX cytotoxicity, supporting more effective cancer treatment. PMID:27294541

  13. In Vitro Interactions between Non-Steroidal Anti-Inflammatory Drugs and Antifungal Agents against Planktonic and Biofilm Forms of Trichosporon asahii

    PubMed Central

    Cong, Lin; Lu, Xuelian

    2016-01-01

    Increasing drug resistance has brought enormous challenges to the management of Trichosporon spp. infections. The in vitro antifungal activities of non-steroidal anti-inflammatory drugs (NSAIDs) against Candida spp. and Cryptococcus spp. were recently discovered. In the present study, the in vitro interactions between three NSAIDs (aspirin, ibuprofen and diclofenac sodium) and commonly used antifungal agents (fluconazole, itraconazole, voriconazole, caspofungin and amphotericin B) against planktonic and biofilm cells of T. asahii were evaluated using the checkerboard microdilution method. The spectrophotometric method and the XTT reduction assay were used to generate data on biofilm cells. The fractional inhibitory concentration index (FICI) and the ΔE model were compared to interpret drug interactions. Using the FICI, the highest percentages of synergistic effects against planktonic cells (86.67%) and biofilm cells (73.33%) were found for amphotericin B/ibuprofen, and caspofungin/ibuprofen showed appreciable percentages (73.33% for planktonic form and 60.00% for biofilm) as well. We did not observe antagonism. The ΔE model gave consistent results with FICI (86.67%). Our findings suggest that amphotericin B/ibuprofen and caspofungin/ibuprofen combinations have potential effects against T. asahii. Further in vivo and animal studies to investigate associated mechanisms need to be conducted. PMID:27275608

  14. Role of ligand-based drug design methodologies toward the discovery of new anti- Alzheimer agents: futures perspectives in Fragment-Based Ligand Design.

    PubMed

    Speck-Planche, A; Luan, F; Cordeiro, M N D S

    2012-01-01

    Alzheimer's disease (AD), a degenerative disease affecting the brain, is the single most common source of dementia in adults. The cause and the progression of AD still remains a mystery among medical experts. As a result, a cure has not yet been discovered, even after decade's worth of research that started since 1906, when the disease was first identified. Despite the efforts of the scientific community, several of the biological receptors associated with AD have not been sufficiently studied to date, limiting in turn the design of new and more potent anti-AD agents. Thus, the search for new drug candidates as inhibitors of different targets associated with AD constitutes an essential part towards the discovery of new and more efficient anti-AD therapies. The present work is focused on the role of the Ligand-Based Drug Design (LBDD) methodologies which have been applied for the elucidation of new molecular entities with high inhibitory activity against targets related with AD. Particular emphasis is given also to the current state of fragment-based ligand approaches as alternatives of the Fragment-Based Drug Discovery (FBDD) methodologies. Finally, several guidelines are offered to show how the use of fragment-based descriptors can be determinant for the design of multi-target inhibitors of proteins associated with AD. PMID:22376033

  15. Consideration for primary angioplasty: impact on the door-to-drug time in AMI patients ultimately treated with thrombolytic agent.

    PubMed

    Brady, W J; Esterowitz, D; Syverud, S A

    2001-01-01

    The objective of this study was to determine if consideration for percutaneous transluminal coronary angioplasty (PTCA) delays administration of thrombolytic therapy in acute myocardial infarction (AMI) patients. Retrospective medical record review of patients ultimately diagnosed with AMI who presented to the ED with chest pain and ST segment elevation on the electrocardiogram; these patients also received acute reperfusion therapy (PTCA or thrombolytic agent). AMI was diagnosed by abnormal elevations in the creatinine phosphokinase MB fraction. The study period covered 2 years (July 1, 1994 to June 30, 1996) in a university hospital ED with an annual volume of 60,000 patient-visits. The use of reperfusion therapies, time intervals, and times of presentation were recorded. Patients were divided into two groups based on cardiac catheterization laboratory (CATH) availability: (group I, CATH currently in operation, Monday to Friday, 7 am to 7 pm and group II, CATH currently not in-operation, all other times). Fifty-two patients with AMI met entry criteria. Patients were treated with thrombolytic therapy in 25 cases; PTCA in 27 cases. Patients received thrombolytic agents within statistically equivalent time intervals regardless of the period of presentation; time to thrombolytic therapy for group I patients was 38 +/- 16 minutes compared with 36 +/- 26 minutes for group II patients (P =. 891). A trend toward significance was noted in the use of PTCA compared with thrombolytic agent; Group I patients were more often treated with PTCA (19) compared with group II patients (11, P =.067). Patients were more rapidly treated with PTCA during CATH operation; the mean time to PTCA for group I patients was 73.5 minutes compared with PTCA for group II patients with 107.8 minutes (P =.033). The consideration for PTCA did not significantly delay the administration of thrombolytic therapy at the study site institution. PTCA was initiated more rapidly in patients presenting with

  16. [Daptomycin: revitalizing a former drug due to the need of new active agents against grampositive multiresistant bacterias].

    PubMed

    Hernández Martí, V; Romá Sánchez, E; Salavert Lletí, M; Bosó Ribelles, V; Poveda Andrés, J L

    2007-09-01

    The development of mechanisms of resistance of many Gram-positive bacterial strains that cause complicated skin and soft tissue infections, as well as sepsis and bacteremia, has necessitated the search for new drugs that will improve treatment strategies. Daptomycin is a cyclic lipopeptide antibacterial that was launched for the treatment of complicated skin and soft tissue infections caused by Gram-positive organisms. The drug's mechanism of action is different from that of any other antibiotic. It binds to bacterial membranes and causes a rapid depolarization of membrane potential. This loss of membrane potential causes inhibition of protein, DNA and RNA synthesis, which results in bacterial cell death. The in vitro spectrum of activity of daptomycin encompasses most clinically relevant aerobic Gram-positive pathogenic bacteria. Compared to other antibiotics with a similar antibacterial spectrum, daptomycin does not cause nephrotoxicity. Taking these and other characteristics into consideration, daptomycin appears to be a good alternative to other drugs used in the treatment of complicated skin and soft tissue infections and in Gram-positive bacteremial infections. PMID:18080024

  17. Pharmacology of antihypertensive drugs.

    PubMed

    Pepper, G A

    1999-01-01

    The wide variety of first-line agents available for managing high blood pressure include diuretics, beta adrenergic receptor blockers, alpha adrenergic receptor blockers, angiotensin converting enzyme inhibitors, and calcium channel blockers. Supplemental agents used for second-line therapy and special indications, such as pregnancy and hypertensive emergencies, include angiotensin receptor blockers, central-acting agents, direct vasodilators, and adrenergic neuron inhibitors. Selection of agents for particular patients requires consideration of research-based evidence for positive long-term outcomes and of the unique patient profile of age, race, co-morbidities, and lifestyle. A thorough understanding of the pharmacology (mechanism, pharmacokinetics, adverse effects and drug interactions, clinical use) of antihypertensive agents is an essential foundation for nursing practice in women's health. PMID:10584919

  18. Molecular characteristics and in vitro susceptibility to antimicrobial agents, including the des-fluoro(6) quinolone DX-619, of Panton-Valentine leucocidin-positive methicillin-resistant Staphylococcus aureus isolates from the community and hospitals.

    PubMed

    Yamamoto, Tatsuo; Dohmae, Soshi; Saito, Kohei; Otsuka, Taketo; Takano, Tomomi; Chiba, Megumi; Fujikawa, Katsuko; Tanaka, Mayumi

    2006-12-01

    Highly virulent, community-acquired methicillin-resistant Staphylococcus aureus (MRSA) strains with Panton-Valentine leucocidin (PVL) genes have been found increasingly worldwide. Among a total of 2,101 MRSA strains isolated from patients in hospitals in Japan, two were positive for PVL genes. One strain was identified as a community-acquired MRSA strain with genotype sequence type 30 (ST30) and spa (staphylococcal protein A gene) type 19 from Japan and was resistant only to beta-lactam antimicrobial agents. The other strain was closely related to PVL+ multidrug-resistant, hospital-acquired MRSA strains (ST30, spa type 43) derived from nosocomial outbreaks in the 1980s to 1990s in Japan but with a divergent sequence type, ST765 (a single-locus variant of ST30). Twenty-two PVL+ MRSA strains, including those from Japan and those from other countries with various sequence types (ST1, ST8, ST30, ST59, and ST80) and genotypes, were examined for susceptibility to 31 antimicrobial agents. Among the agents, DX-619, a des-fluoro(6) quinolone, showed the greatest activity, followed by rifampin and sitafloxacin, a fluoroquinolone. The data suggest that DX-619 exhibits a superior activity against PVL+ MRSA strains with various virulence genetic traits from the community as well as from hospitals. PMID:17043124

  19. Women and Drug Dependence.

    ERIC Educational Resources Information Center

    Valentich, Mary

    1982-01-01

    Presents a feminist perspective which offers a social structural framework for examining women's problematic behavior in traditional gender roles. Examines implications for treatment of women with drug dependence problems including developing the helping agent's awareness of the pervasiveness of sexism and its potentially negative effects.…

  20. Real-time visualization of pH-responsive PLGA hollow particles containing a gas-generating agent targeted for acidic organelles for overcoming multi-drug resistance.

    PubMed

    Ke, Cherng-Jyh; Chiang, Wei-Lun; Liao, Zi-Xian; Chen, Hsin-Lung; Lai, Ping-Shan; Sun, Jui-Sheng; Sung, Hsing-Wen

    2013-01-01

    Chemotherapy research highly prioritizes overcoming the multi-drug resistance (MDR) effect in cancer cells. To overcome the drug efflux mediated by P-glycoprotein (P-gp) transporters, we developed pH-responsive poly(D,L-lactic-co-glycolic acid) hollow particles (PLGA HPs), capable of delivering doxorubicin (DOX) into MDR cells (MCF-7/ADR). The shell wall of PLGA HPs contained DiO (a hydrophobic dye), and their aqueous core carried DOX hydrochloride salt and sodium bicarbonate, a gas-generating agent when present in acidic environments. Both DiO and DOX could serve as fluorescence probes to localize HPs and visualize their intracellular drug release in real-time. Real-time confocal images provided visible evidences of the acid-responsive intracellular release of DOX from PLGA HPs in MDR cells. Via the macropinocytosis pathway, PLGA HPs taken up by cells experienced an increasingly acidic environment as they trafficked through the early endosomes and then matured into more acidic late endosomes/lysosomes. The progressive acidification of the internalized particles in the late endosomes/lysosomes generated CO(2) bubbles, leading to the disruption of HPs, prompt release of DOX, its accumulation in the nuclei, and finally the death of MDR cells. Conversely, taken up via a passive diffusion mechanism, free DOX was found mainly at the perimembrane region and barely reached the cell nuclei; therefore, no apparent cytotoxicity was observed. These results suggest that the developed PLGA HPs were less susceptible to the P-gp-mediated drug efflux in MDR cells and is a highly promising approach in chemotherapy. PMID:23044041

  1. Ion Channel Blockers as Antimicrobial Agents, Efflux Inhibitors, and Enhancers of Macrophage Killing Activity against Drug Resistant Mycobacterium tuberculosis

    PubMed Central

    Perdigão, João; Couto, Isabel; Portugal, Isabel; Martins, Marta; Amaral, Leonard; Anes, Elsa; Viveiros, Miguel

    2016-01-01

    Given the ability of M. tuberculosis to survive as an intracellular pathogen and its propensity to develop resistance to the existing antituberculosis drugs, its treatment requires new approaches. Here the antimycobacterial properties of verapamil, thioridazine, chlorpromazine, flupenthixol and haloperidol were investigated against a panel of drug resistant M. tuberculosis strains, both in vitro and on human-infected macrophages. These compounds are efflux inhibitors that share among them the characteristic of being ion channel blockers. In vitro, all compounds exhibited synergistic inhibitory activities when combined with isoniazid and rifampicin, and were able to inhibit active efflux, demonstrating their role as efflux inhibitors. Gene expression analysis showed that M. tuberculosis efflux genes were overexpressed in response to antibiotic exposure, in vitro and within macrophages, irrespective of their resistance pattern. These compounds displayed a rapid and high killing activity against M. tuberculosis, associated with a decrease in intracellular ATP levels demonstrating that the bactericidal action of the ion channel blockers against M. tuberculosis clinical strains is associated with their interference with energy metabolism. The compounds led to a decrease in the intracellular mycobacterial load by increasing phagosome acidification and activating lysosomal hydrolases. The results presented in this study enable us to propose the following mechanism of action for these compounds: a) in the bacteria, the compounds generate a cascade of events involving the inhibition of the respiratory chain complexes and energy production for efflux activity. Indirectly, this reduce the resistance level to antituberculosis drugs potentiating their activity; b) on the host cell, the treatment with the ion channel blockers increases phagosome acidification and induces the expression of phagosomal hydrolases, leading to bacterial growth restriction irrespective of their

  2. Ion Channel Blockers as Antimicrobial Agents, Efflux Inhibitors, and Enhancers of Macrophage Killing Activity against Drug Resistant Mycobacterium tuberculosis.

    PubMed

    Machado, Diana; Pires, David; Perdigão, João; Couto, Isabel; Portugal, Isabel; Martins, Marta; Amaral, Leonard; Anes, Elsa; Viveiros, Miguel

    2016-01-01

    Given the ability of M. tuberculosis to survive as an intracellular pathogen and its propensity to develop resistance to the existing antituberculosis drugs, its treatment requires new approaches. Here the antimycobacterial properties of verapamil, thioridazine, chlorpromazine, flupenthixol and haloperidol were investigated against a panel of drug resistant M. tuberculosis strains, both in vitro and on human-infected macrophages. These compounds are efflux inhibitors that share among them the characteristic of being ion channel blockers. In vitro, all compounds exhibited synergistic inhibitory activities when combined with isoniazid and rifampicin, and were able to inhibit active efflux, demonstrating their role as efflux inhibitors. Gene expression analysis showed that M. tuberculosis efflux genes were overexpressed in response to antibiotic exposure, in vitro and within macrophages, irrespective of their resistance pattern. These compounds displayed a rapid and high killing activity against M. tuberculosis, associated with a decrease in intracellular ATP levels demonstrating that the bactericidal action of the ion channel blockers against M. tuberculosis clinical strains is associated with their interference with energy metabolism. The compounds led to a decrease in the intracellular mycobacterial load by increasing phagosome acidification and activating lysosomal hydrolases. The results presented in this study enable us to propose the following mechanism of action for these compounds: a) in the bacteria, the compounds generate a cascade of events involving the inhibition of the respiratory chain complexes and energy production for efflux activity. Indirectly, this reduce the resistance level to antituberculosis drugs potentiating their activity; b) on the host cell, the treatment with the ion channel blockers increases phagosome acidification and induces the expression of phagosomal hydrolases, leading to bacterial growth restriction irrespective of their

  3. Nanostructured nanoparticles of self-assembled lipid pro-drugs as a route to improved chemotherapeutic agents

    NASA Astrophysics Data System (ADS)

    Sagnella, Sharon M.; Gong, Xiaojuan; Moghaddam, Minoo J.; Conn, Charlotte E.; Kimpton, Kathleen; Waddington, Lynne J.; Krodkiewska, Irena; Drummond, Calum J.

    2011-03-01

    We demonstrate that oral delivery of self-assembled nanostructured nanoparticles consisting of 5-fluorouracil (5-FU) lipid prodrugs results in a highly effective, target-activated, chemotherapeutic agent, and offers significantly enhanced efficacy over a commercially available alternative that does not self-assemble. The lipid prodrug nanoparticles have been found to significantly slow the growth of a highly aggressive mouse 4T1 breast tumour, and essentially halt the growth of a human MDA-MB-231 breast tumour in mouse xenografts. Systemic toxicity is avoided as prodrug activation requires a three-step, enzymatic conversion to 5-FU, with the third step occurring preferentially at the tumour site. Additionally, differences in the lipid prodrug chemical structure and internal nanostructure of the nanoparticle dictate the enzymatic conversion rate and can be used to control sustained release profiles. Thus, we have developed novel oral nanomedicines that combine sustained release properties with target-selective activation.

  4. Nanostructured nanoparticles of self-assembled lipid pro-drugs as a route to improved chemotherapeutic agents

    SciTech Connect

    Sagnella, Sharon M.; Gong, Xiaojuan; Moghaddam, Minoo J.; Conn, Charlotte E.; Kimpton, Kathleen; Waddington, Lynne J.; Krodkiewska, Irena; Drummond, Calum J.

    2014-09-24

    We demonstrate that oral delivery of self-assembled nanostructured nanoparticles consisting of 5-fluorouracil (5-FU) lipid prodrugs results in a highly effective, target-activated, chemotherapeutic agent, and offers significantly enhanced efficacy over a commercially available alternative that does not self-assemble. The lipid prodrug nanoparticles have been found to significantly slow the growth of a highly aggressive mouse 4T1 breast tumour, and essentially halt the growth of a human MDA-MB-231 breast tumour in mouse xenografts. Systemic toxicity is avoided as prodrug activation requires a three-step, enzymatic conversion to 5-FU, with the third step occurring preferentially at the tumour site. Additionally, differences in the lipid prodrug chemical structure and internal nanostructure of the nanoparticle dictate the enzymatic conversion rate and can be used to control sustained release profiles. Thus, we have developed novel oral nanomedicines that combine sustained release properties with target-selective activation.

  5. Salicylic acid derivatives as potential anti asthmatic agents using disease responsive drug delivery system for prophylactic therapy of allergic asthma.

    PubMed

    Raju, Kalidhindi Rama Satyanarayana; Ambhore, Nilesh S; Mulukutla, Shashank; Gupta, Saurabh; Murthy, Vishakantha; Kumar, M N Kiran; Madhunapantula, Subba Rao V; Kuppuswamy, Gowthamarajan; Elango, Kannan

    2016-02-01

    Asthma is a multi-factorial and complicated lung disorder of the immune system which has expanded to a wider ambit unveiling its etiology to be omnipresent at both ends of the spectrum involving basic pharmacology and in-depth immunology. As asthma occurs through triggered activation of various immune cells due to different stimuli, it poses a great challenge to uncover specific targets for therapeutic interventions. Recent pharmacotherapeutic approaches for asthma have been focused on molecular targeting of transcription factors and their signaling pathways; mainly nucleus factor kappa B (NFκB) and its associated pathways which orchestrate the synthesis of pro-inflammatory cytokines (IL-1β, TNF-α, GM-CSF), chemokines (RANTES, MIP-1a, eotaxin), adhesion molecules (ICAM-1, VCAM-1) and inflammatory enzymes (cyclooxygenase-2 and iNOS). 5-aminosalicylic acid (5-ASA) and sodium salicylate are known to suppress NFκB activation by inhibiting inhibitor of kappa B kinase (IKκB). In order to target the transcription factor, a suitable carrier system for delivering the drug to the intracellular space is essential. 5-ASA and sodium salicylate loaded liposomes incorporated into PEG-4-acrylate and CCRGGC microgels (a polymer formed by crosslinking of trypsin sensitive peptide and PEG-4-acrylate) could probably suit the needs for developing a disease responsive drug delivery system which will serve as a prophylactic therapy for asthmatic patients. PMID:26643666

  6. Diffusion of innovations in social interaction systems. An agent-based model for the introduction of new drugs in markets.

    PubMed

    Pombo-Romero, Julio; Varela, Luis M; Ricoy, Carlos J

    2013-06-01

    The existence of imitative behavior among consumers is a well-known phenomenon in the field of Economics. This behavior is especially common in markets determined by a high degree of innovation, asymmetric information and/or price-inelastic demand, features that exist in the pharmaceutical market. This paper presents evidence of the existence of imitative behavior among primary care physicians in Galicia (Spain) when choosing treatments for their patients. From this and other evidence, we propose a dynamic model for determining the entry of new drugs into the market. To do this, we introduce the structure of the organization of primary health care centers and the presence of groups of doctors who are specially interrelated, as well as the existence of commercial pressure on doctors. For modeling purposes, physicians are treated as spins connected in an exponentially distributed complex network of the Watts-Strogatz type. The proposed model provides an explanation for the differences observed in the patterns of the introduction of technological innovations in different regions. The main cause of these differences is the different structure of relationships among consumers, where the existence of small groups that show a higher degree of coordination over the average is particularly influential. The evidence presented, together with the proposed model, might be useful for the design of optimal strategies for the introduction of new drugs, as well as for planning policies to manage pharmaceutical expenditure. PMID:22487887

  7. Synthesis and biological evaluation of sialyl-oligonucleotide conjugates targeting leukocyte B trans-membranal receptor CD22 as delivery agents for nucleic acid drugs.

    PubMed

    St-Pierre, Gabrielle; Pal, Sudip; Østergaard, Michael E; Zhou, Tianyuan; Yu, Jinghua; Tanowitz, Michael; Seth, Punit P; Hanessian, Stephen

    2016-06-01

    Antisense oligonucleotides (ASOs) modified with ligands which target cell surface receptors have the potential to significantly improve potency in the target tissue. This has recently been demonstrated using triantennary N-acetyl d-galactosamine conjugated ASOs. CD22 is a cell surface receptor expressed exclusively on B cells thus presenting an attractive target for B cell specific delivery of drugs. Herein, we reported the synthesis of monovalent and trivalent ASO conjugates with biphenylcarbonyl (BPC) modified sialic acids and their study as ASO delivery agents into B cells. CD22 positive cells exhibited reduced potency when treated with ligand modified ASOs and mechanistic examination suggested reduced uptake into cells potentially as a result of sequestration of ASO by other cell-surface proteins. PMID:27117693

  8. Sunscreening Agents

    PubMed Central

    Martis, Jacintha; Shobha, V; Sham Shinde, Rutuja; Bangera, Sudhakar; Krishnankutty, Binny; Bellary, Shantala; Varughese, Sunoj; Rao, Prabhakar; Naveen Kumar, B.R.

    2013-01-01

    The increasing incidence of skin cancers and photodamaging effects caused by ultraviolet radiation has increased the use of sunscreening agents, which have shown beneficial effects in reducing the symptoms and reoccurrence of these problems. Many sunscreen compounds are in use, but their safety and efficacy are still in question. Efficacy is measured through indices, such as sun protection factor, persistent pigment darkening protection factor, and COLIPA guidelines. The United States Food and Drug Administration and European Union have incorporated changes in their guidelines to help consumers select products based on their sun protection factor and protection against ultraviolet radiation, whereas the Indian regulatory agency has not yet issued any special guidance on sunscreening agents, as they are classified under cosmetics. In this article, the authors discuss the pharmacological actions of sunscreening agents as well as the available formulations, their benefits, possible health hazards, safety, challenges, and proper application technique. New technologies and scope for the development of sunscreening agents are also discussed as well as the role of the physician in patient education about the use of these agents. PMID:23320122

  9. Projecting future drug expenditures--1996.

    PubMed

    Santell, J P

    1996-01-15

    The use of information on inflation, pharmacoeconomics, generic competition, new drug entities, site-specific drug-use patterns, legislation, and the changing health care environment in the projection of drug expenditures is discussed. Drug price inflation has declined from 6.9% in 1991 to 2.1% for part of 1995. Much of the decline is attributable to deep discounts given by manufacturers to managed care institutions. Some marketing specialists are predicting that drug manufacturers will begin to scale back discounts. Pharmaceutical industry analysts project that overall price increase for pharmaceuticals in the next 12-24 months will average 2.8% (range, 0-6%). Pharmacists need to be able to understand and critically evaluate pharmacoeconomic research, particularly studies conducted by the pharmaceutical industry. Savings due to increases in generic product selection may be offset to some degree by extensions of patent expiration dates under the General Agreement on Tariffs and Trade (GATT). Drug budget projections should include a complete review of new drugs and biotechnology agents pending FDA approval, drugs pending approval for new indications, and common unlabeled uses of expensive existing agents. Various methods are available for tracking drug-use patterns in specific practice settings. When resources are limited, pharmacy managers may elect to target only high-cost drugs; a proactive approach, such as projecting costs and developing guidelines for costly agents before their market release and before consideration by the pharmacy and therapeutics committee, is advantageous. Relevant legislative activities in 1995 included reform proposals for Medicare, Medicaid, and FDA; the Federal Acquisition Streamlining Act; and GATT. Disease management and other approaches to pharmacy benefits have increased opportunities for cooperative arrangements between drug companies and health care providers that may have major effects on drug marketing and pricing. Combining

  10. Switching the Loaded Agent from Epirubicin to Cisplatin: Salvage Transcatheter Arterial Chemoembolization with Drug-eluting Microspheres for Unresectable Hepatocellular Carcinoma

    SciTech Connect

    Seki, Akihiko Hori, Shinich

    2012-06-15

    Purpose: There is no consensus on switching anticancer agents loaded onto drug carriers in transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). This study aimed to evaluate the safety and clinical outcomes of TACE with cisplatin-loaded microspheres (CLM-TACE) in HCC patients refractory to TACE with epirubicin-loaded microspheres (ELM-TACE). Methods: Between February 2008 and June 2010, 85 patients with unresectable HCC refractory to ELM-TACE were enrolled to undergo CLM-TACE. The number of ELM-TACE sessions until judgment of resistance ranged from 1 to 4 (median, 2.1). CLM-TACE was performed using 50-100-{mu}m superabsorbent polymer microspheres loaded with 1 mg cisplatin/1 mg microspheres together with hepatic arterial infusion of 25 mg cisplatin and 500 mg 5-fluorouracil per patient. Tumor responses were evaluated by computed tomography according to the European Association for the Study of the Liver criteria. Results: The median number of CLM-TACE treatment sessions was 1.8 (range, 1-5), and the mean total dose of cisplatin per session was 42.8 mg (range, 30.0-59.0). After 6 months, 3 (3.5%) patients achieved complete response, 31 (36.5%) had partial response, 15 (17.6%) had stable disease, and 36 (42.4%) had progressive disease. The median overall survival and time to treatment failure after initial CLM-TACE were 13.3 and 7.2 months, respectively. Overall, 9.4% of patients experienced grade 3/4 adverse events. Conclusions: witching the loaded agent from epirubicin to cisplatin is a safe, well-tolerated, and efficacious treatment strategy for salvage TACE with drug-eluting microspheres in HCC patients refractory to ELM-TACE.

  11. Emerging importance of mismatch repair components including UvrD helicase and their cross-talk with the development of drug resistance in malaria parasite.

    PubMed

    Ahmad, Moaz; Tuteja, Renu

    2014-12-01

    Human malaria is an important parasitic infection responsible for a significant number of deaths worldwide, particularly in tropical and subtropical regions. The recent scenario has worsened mainly because of the emergence of drug-resistant malaria parasites having the potential to spread across the world. Drug-resistant parasites possess a defective mismatch repair (MMR); therefore, it is essential to explore its mechanism in detail to determine the underlying cause. Recently, artemisinin-resistant parasites have been reported to exhibit nonsynonymous single nucleotide polymorphisms in genes involved in MMR pathways such as MutL homolog (MLH) and UvrD. Plasmodium falciparum MLH is an endonuclease required to restore the defective MMR in drug-resistant W2 strain of P. falciparum. Although the role of helicases in eukaryotic MMR has been questioned, the identification and characterization of the UvrD helicase and their cross-talk with MLH in P. falciparum suggests the possible involvement of UvrD in MMR. A comparative genome-wide analysis revealed the presence of the UvrD helicase in Plasmodium species, while it is absent in human host. Therefore, PfUvrD may emerge as a suitable drug target to control malaria. This review study is focused on recent developments in MMR biochemistry, emerging importance of the UvrD helicase, possibility of its involvement in MMR and the emerging cross-talk between MMR components and drug resistance in malaria parasite. PMID:25771870

  12. Preparation of thermo-responsive graft copolymer by using a novel macro-RAFT agent and its application for drug delivery.

    PubMed

    Song, Cunfeng; Yu, Shirong; Liu, Cheng; Deng, Yuanming; Xu, Yiting; Chen, Xiaoling; Dai, Lizong

    2016-05-01

    A methodology to prepare thermo-responsive graft copolymer by using a novel macro-RAFT agent was proposed. The macro-RAFT agent with pendant dithioester (ZC(S)SR) was facilely prepared via the combination of RAFT polymerization and esterification reaction. By means of ZC(S)SR-initiated RAFT polymerization, the thermo-responsive graft copolymer consisting of poly(methyl methacrylate-co-hydroxylethyl methacrylate) (P(MMA-co-HEMA)) backbone and hydrophilic poly(N-isopropylacrylamide) (PNIPAAm) side chains was constructed through the "grafting from" approach. The chemical compositions and molecular weight distributions of the synthesized polymers were respectively characterized by (1)H nuclear magnetic resonance ((1)H NMR) and gel permeation chromatography (GPC). Self-assembly behavior of the amphiphilic graft copolymers (P(MMA-co-HEMA)-g-PNIPAAm) was studied by transmission electron microscopy (TEM), dynamic light scattering (DLS) and spectrofluorimeter. The critical micelle concentration (CMC) value was 0.052mgmL(-1). These micelles have thermo-responsibility and a low critical solution temperature (LCST) of 33.5°C. Further investigation indicated that the guest molecule release property of these micelles, which can be well described by a first-order kinetic model, was significantly affected by temperature. Besides, the micelles exhibited excellent biocompatibility and cellular uptake property. Hence, these micelles are considered to have potential application in controlled drug delivery. PMID:26952396

  13. TiO2 nanotube arrays deposited on Ti substrate by anodic oxidation and their potential as a long-term drug delivery system for antimicrobial agents

    NASA Astrophysics Data System (ADS)

    Moseke, Claus; Hage, Felix; Vorndran, Elke; Gbureck, Uwe

    2012-05-01

    Nanotube arrays on medical titanium surfaces were fabricated by two different anodization methods and their potential for storage and release of antimicrobial substances was evaluated. The treatment of the Ti surfaces in fluoride containing electrolytes on water as well as on polyethylene glycol basis led to the formation of TiO2 nanotubes with up to 6.54 μm length and average diameters of up to 160 nm. Drug release experiments with the model antibiotic vancomycin and with antibacterial silver ions showed that the increased surface area of the anodized samples enabled them to be loaded with up to 450% more active agent than the untreated Ti surfaces. Significant surface-dependent differences in the release kinetics of vancomycin were observed. In comparison to surfaces anodized in an aqueous electrolyte, the release of the antibiotic from surfaces anodized in an electrolyte based on ethylene glycol was significantly retarded, with a release of noticeable amounts over a period of more than 300 days. Loading of nanotube surfaces fabricated in aqueous electrolyte with silver ions revealed increased amounts of adsorbed silver by up to 230%, while the release kinetics showed significant differences in comparison to untreated Ti. It was concluded that nanotube arrays on favored medical implant materials have a high potential for loading with antimicrobial agents and also provide the possibility of tailored release kinetics by variation of anodization parameters.

  14. In vitro susceptibility to antimicrobial agents and ultrastructural characteristics related to swimming motility and drug action in Campylobacter jejuni and C. coli.

    PubMed

    Yabe, Shizuka; Higuchi, Wataru; Takano, Tomomi; Razvina, Olga; Iwao, Yasuhisa; Isobe, Hirokazu; Yamamoto, Tatsuo

    2010-06-01

    Campylobacter jejuni has recently been noted as the most common cause of bacterial food-borne diseases in Japan. In this study, we examined in vitro susceptibility to 36 antimicrobial agents of 109 strains of C. jejuni and C. coli isolated from chickens and patients with enteritis or Guillain-Barré syndrome from 1996 to 2009. Among these agents, carbapenems (imipenem, meropenem, panipenem, and biapenem) showed the greatest activity [minimal inhibitory concentration (MIC)(90), 0.03-0.125 microg/ml]. This was followed by sitafloxacin (MIC(90), 0.25 microg/ml), furazolidone and azithromycin (MIC(90), 0.5 microg/ml), gentamicin and clindamycin (MIC(90), 1 microg/ml), and clavulanic acid (beta-lactamase inhibitor; MIC(90), 2 microg/ml). All or most strains were resistant to aztreonam, sulfamethoxazole, and trimethoprim. Marked resistance was also observed for levofloxacin and tetracyclines. Resistance was not present for macrolides and rare for clindamycin. C. jejuni (and C. coli) exhibited high swimming motility and possessed a unique end-side (cup-like) structure at both ends, in contrast to Helicobacter pylori and Vibrio cholerae O1 and O139. The morphology of C. jejuni (and C. coli) changed drastically after exposure to imipenem (coccoid formation), meropenem (bulking and slight elongation), and sitafloxacin (marked elongation), and exhibited reduced motility. In the HEp-2 cell adherence model, unusually elongated bacteria were also observed for sitafloxacin. The data suggest that although resistance to antimicrobial agents (e.g., levofloxacin) has continuously been noted, carbapenems, sitafloxacin, and others such as beta-lactamase inhibitors alone showed good in vitro activity and that C. jejuni (and C. coli) demonstrated a unique ultrastructural nature related to high swimming motility and drug action. PMID:20225076

  15. Perioperative allergy: uncommon agents.

    PubMed

    Caimmi, S; Caimmi, D; Cardinale, F; Indinnimeo, L; Crisafulli, G; Peroni, D G; Marseglia, G L

    2011-01-01

    Anesthesia may often be considered as a high-risk procedure and anaphylaxis remains a major cause of concern for anesthetists who routinely administer many potentially allergenic agents. Neuromuscular blocking agents, latex and antibiotics are the substances involved in most of the reported reactions. Besides these three agents, a wide variety of substances may cause an anaphylactic reaction during anesthesia. Basically all the administered drugs or substances may be potential causes of anaphylaxis. Among them, those reported the most in literature include hypnotics, opioids, local anesthetics, colloids, dye, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), Iodinated Contrast Media (ICM), antiseptics, aprotinin, ethylene oxyde and formaldehyde, and protamine and heparins. No premedication can effectively prevent an allergic reaction and a systematic preoperative screening is not justified for all patients; nevertheless, an allergy specialist should evaluate those patients with a history of anesthesia-related allergy. Patients must be fully informed of investigation results, and advised to provide a detailed report prior to future anesthesia. PMID:22014927

  16. One-step fabrication of triple-layered microcapsules by a tri-axial flow focusing device for microencapsulation of soluble drugs and imaging agents

    NASA Astrophysics Data System (ADS)

    Yuan, Shuai; Wu, Qiang; Lei, Fan; Li, Guangbin; Si, Ting; Xu, Ronald X.

    2016-04-01

    In this work, the microencapsulation of water-soluble drug (doxorubicin, Dox) and imaging agent (perfluorocarbon, PFC) is performed by a novel liquid driven tri-axial flow focusing (LDTFF) device. The formation of stable triple-layered cone-jet mode can be observed in the simple well-assembled LDTFF device, providing an easy approach to fabricate mono-disperse triple-layered microcapsules with high encapsulation efficiency, high throughput and low cost in just one step. The fluorescence images show that the microcapsules have a satisfactory core-shell structure. The SEM micrographs show spherical and smooth surface views of the triple-layered microcapsules after being stirred 72h to remove the organic solvent totally. The results of thermo-responsive release experiments of the produced triple-layered microcapsules show these multifunctional capsules can be well stimulated when the environment temperature is beyond 55 degree centigrade. In a word, this novel approach has a great potential in applications such as drug delivery and image-guided therapy.

  17. Low density lipoprotein for delivery of a water-insoluble alkylating agent to malignant cells. In vitro and in vivo studies of a drug-lipoprotein complex.

    PubMed Central

    Vitols, S.; Söderberg-Reid, K.; Masquelier, M.; Sjöström, B.; Peterson, C.

    1990-01-01

    Previous studies have shown that human leukaemic cells and certain tumour tissues have a higher receptor-mediated uptake of low density lipoprotein (LDL) than the corresponding normal cells or tissues. LDL has therefore been proposed as a carrier for anti-cancer agents. In the current study, a water-insoluble mitoclomine derivative (WB 4291) was incorporated into LDL. The WB 4291-LDL complex contained about 1,500 drug molecules per LDL particle and showed receptor-mediated toxicity in vitro as judged from the difference in growth inhibitory effect on normal and mutant (LDL-receptor-negative) cultured Chinese hamster ovary cells. However, cellular drug uptake did not exclusively occur by the receptor pathway since mutant cells were also affected to some extent. The LDL part of the complex had the same plasma clearance and organ distribution as native LDL after i.v. injection in mice and rabbits. Therapeutic effects were observed when Balb-C mice with experimental leukaemia were treated with the complex. After i.p. administration to mice with i.p. leukaemia median survival time was prolonged 2.5-fold and 40% became long time survivors. The effect was weaker (42% increase in life span) after i.v. injections of the complex to mice with i.v. leukaemia. Images Figure 3 PMID:2245164

  18. Evaluation of acetylcholine, seizure activity and neuropathology following high-dose nerve agent exposure and delayed neuroprotective treatment drugs in freely moving rats.

    PubMed

    Acon-Chen, Cindy; Koenig, Jeffrey A; Smith, Garrett R; Truitt, Amber R; Thomas, Thaddeus P; Shih, Tsung-Ming

    2016-06-01

    Organophosphorus nerve agents such as soman (GD) inhibit acetylcholinesterase, producing an excess of acetylcholine (ACh), which results in respiratory distress, convulsions and status epilepticus that leads to neuropathology. Several drugs (topiramate, clobazam, pregnanolone, allopregnanolone, UBP 302, cyclopentyladenosine [CPA], ketamine, midazolam and scopolamine) have been identified as potential neuroprotectants that may terminate seizures and reduce brain damage. To systematically evaluate their efficacy, this study employed in vivo striatal microdialysis and liquid chromatography to respectively collect and analyze extracellular ACh in freely moving rats treated with these drugs 20 min after seizure onset induced by a high dose of GD. Along with microdialysis, EEG activity was recorded and neuropathology assessed at 24 h. GD induced a marked increase of ACh, which peaked at 30 min post-exposure to 800% of control levels and then steadily decreased toward baseline levels. Approximately 40 min after treatment, only midazolam (10 mg/kg) and CPA (60 mg/kg) caused a significant reduction of ACh levels, with CPA reducing ACh levels more rapidly than midazolam. Both drugs facilitated a return to baseline levels at least 55 min after treatment. At 24 h, only animals treated with CPA (67%), midazolam (18%) and scopolamine (27%) exhibited seizure termination. While all treatments except for topiramate reduced neuropathology, CPA, midazolam and scopolamine showed the greatest reduction in pathology. Our results suggest that delayed treatment with CPA, midazolam, or scopolamine is effective at reducing GD-induced seizure activity and neuropathology, with CPA and midazolam capable of facilitating a reduction in GD-induced ACh elevation. PMID:27329284

  19. Analytics of nonpeptidic erythropoietin mimetic agents in sports drug testing employing high-resolution/high-accuracy liquid chromatography-mass spectrometry.

    PubMed

    Vogel, Matthias; Dib, Josef; Tretzel, Laura; Piper, Thomas; Thomas, Andreas; Schänzer, Wilhelm; Thevis, Mario

    2016-09-01

    Since its release as anti-anemic drug, recombinant erythropoietin (rEPO) gradually entered the illicit way to sports competitions as endurance-enhancing drug. Novel modifications biopharmaceutically introduced into the rEPO molecule in the form of carbohydrate or polyethylene glycol moieties made robust and sensitive test methods vital to doping controls in order to provide the necessary tools enabling the conviction of dishonest athletes. Modern protein analysis by means of gel electrophoretic separation and western blotting represents the status quo in rEPO anti-doping analysis. However, new therapeutically promising erythropoietin receptor activating compounds have been developed that exhibit cytokine hormone-mimicking properties but lack any protein structure. Progression to evade parenteral application and substitute for rEPO by low molecular mass and orally available compounds is still one of the major objectives in pharmaceutical research. In this approach, four promising in-house synthesized nonpeptidic erythropoietin mimetic agents, namely compound 129, compound 163, A1B10C1, and A5B10C4 were thoroughly evaluated by employing high-resolution/high-accuracy liquid chromatography tandem mass spectrometry experiments. Characteristic product ions were determined supporting the identification of these drugs and putative metabolites as well as related compounds in future doping controls. Test methods employing direct urine injection and receptor affinity purification strategies were assessed, which demonstrated that EPO receptor purification is of limited utility for nonpeptidic EPOR agonists while direct urine injection allowed for comprehensive method characterization. Thereby, achieved limits of detection were 1 ng/mL for compounds 129/163 and 5 ng/mL for A1B10C1/A5B10C4. PMID:27438721

  20. New approaches to drug discovery and development: a mechanism-based approach to pharmaceutical research and its application to BNP7787, a novel chemoprotective agent.

    PubMed

    Hausheer, Frederick H; Kochat, Harry; Parker, Aulma R; Ding, Daoyuan; Yao, Shije; Hamilton, Susan E; Petluru, Pavankumar N; Leverett, Betsy D; Bain, Stacey H; Saxe, Jeffrey D

    2003-07-01

    Any approach applied to drug discovery and development by the medical community and pharmaceutical industry has a direct impact on the future availability of improved, novel, and curative therapies for patients with cancer. By definition, drug discovery is a complex learning process whereby research efforts are directed toward uncovering and assimilating new knowledge to create and develop a drug for the purpose of providing benefit to a defined patient population. Accordingly, a highly desirable technology or approach to drug discovery should facilitate both effective learning and the application of newly discovered observations that can be exploited for therapeutic benefit. However, some believe that drug discovery is largely accomplished by serendipity and therefore appropriately addressed by screening a large number of compounds. Clearly, this approach has not generated an abundance of new drugs for cancer patients and suggests that a tangibly different approach in drug discovery is warranted. We employ an alternative approach to drug discovery, which is based on the elucidation and exploitation of biological, pharmacological, and biochemical mechanisms that have not been previously recognized or fully understood. Mechanism-based drug discovery involves the combined application of physics-based computer simulations and laboratory experimentation. There is increasing evidence that agreement between simulations based on the laws of physics and experimental observations results in a higher probability that such observations are more accurate and better understood as compared with either approach used alone. Physics-based computer simulation applied to drug discovery is now considered by experts in the field to be one of the ultimate methodologies for drug discovery. However, the ability to perform truly comprehensive physics-based molecular simulations remains limited by several factors, including the enormous computer-processing power that is required to perform

  1. Novel extraction and application of okra gum as a film coating agent using theophylline as a model drug.

    PubMed

    Ogaji, Ikoni J; Hoag, Stephen W

    2014-04-01

    The purpose of this study was to investigate the effect of extraction and application of okra gum as an aqueous film coating agent. Powdered okra pods dispersed in demineralized water was heated at 80 ± 2(o)C for 30 minutes in the presence of sodium chloride. The filtrate was successively centrifuged at 4000 rpm for 30, 60, or 120 minutes and freeze dried. The samples were used as film former at different concentrations in aqueous film coating operations. Near infrared (nIR) absorption spectra, photomicrographs, and some physicochemical properties of the coated tablets were evaluated. The okra gum samples had different nIR spectra and possessed good processing and application quality due to relatively low viscosity. A six-fold concentration of this gum from the novel extraction yielded glossy theophylline tablets within a short time. A t (18) = 2.895, P < 0.005, t critical = 1.734 were obtained for the independent analysis of the hardness of core and coated theophylline tablets. A 3.0% concentration of the okra samples at a flow rate of 3 ml/min for 100 minutes showed that F = 3.798, DF = 29, P < 0.035, F critical = 3.354 in tablet hardness among samples and F = 15.632, DF = 29, P < 0.0001, F critical = 2.152 were obtained on film thickness among tablet samples during the coating and drying operation. Novel extraction process enhanced the film coating potential of okra gum by delivering more solids on the substrate at a shorter time with improved operation efficiency. PMID:24959415

  2. Novel extraction and application of okra gum as a film coating agent using theophylline as a model drug

    PubMed Central

    Ogaji, Ikoni J.; Hoag, Stephen W.

    2014-01-01

    The purpose of this study was to investigate the effect of extraction and application of okra gum as an aqueous film coating agent. Powdered okra pods dispersed in demineralized water was heated at 80 ± 2oC for 30 minutes in the presence of sodium chloride. The filtrate was successively centrifuged at 4000 rpm for 30, 60, or 120 minutes and freeze dried. The samples were used as film former at different concentrations in aqueous film coating operations. Near infrared (nIR) absorption spectra, photomicrographs, and some physicochemical properties of the coated tablets were evaluated. The okra gum samples had different nIR spectra and possessed good processing and application quality due to relatively low viscosity. A six-fold concentration of this gum from the novel extraction yielded glossy theophylline tablets within a short time. A t (18) = 2.895, P < 0.005, t critical = 1.734 were obtained for the independent analysis of the hardness of core and coated theophylline tablets. A 3.0% concentration of the okra samples at a flow rate of 3 ml/min for 100 minutes showed that F = 3.798, DF = 29, P < 0.035, F critical = 3.354 in tablet hardness among samples and F = 15.632, DF = 29, P < 0.0001, F critical = 2.152 were obtained on film thickness among tablet samples during the coating and drying operation. Novel extraction process enhanced the film coating potential of okra gum by delivering more solids on the substrate at a shorter time with improved operation efficiency. PMID:24959415

  3. Melatonin, a potent agent in antioxidative defense: Actions as a natural food constituent, gastrointestinal factor, drug and prodrug

    PubMed Central

    Hardeland, Rüdiger; Pandi-Perumal, SR

    2005-01-01

    Melatonin, originally discovered as a hormone of the pineal gland, is also produced in other organs and represents, additionally, a normal food constituent found in yeast and plant material, which can influence the level in the circulation. Compared to the pineal, the gastrointestinal tract contains several hundred times more melatonin, which can be released into the blood in response to food intake and stimuli by nutrients, especially tryptophan. Apart from its use as a commercial food additive, supraphysiological doses have been applied in medical trials and pure preparations are well tolerated by patients. Owing to its amphiphilicity, melatonin can enter any body fluid, cell or cell compartment. Its properties as an antioxidant agent are based on several, highly diverse effects. Apart from direct radical scavenging, it plays a role in upregulation of antioxidant and downregulation of prooxidant enzymes, and damage by free radicals can be reduced by its antiexcitatory actions, and presumably by contributions to appropriate internal circadian phasing, and by its improvement of mitochondrial metabolism, in terms of avoiding electron leakage and enhancing complex I and complex IV activities. Melatonin was shown to potentiate effects of other antioxidants, such as ascorbate and Trolox. Under physiological conditions, direct radical scavenging may only contribute to a minor extent to overall radical detoxification, although melatonin can eliminate several of them in scavenger cascades and potentiates the efficacy of antioxidant vitamins. Melatonin oxidation seems rather important for the production of other biologically active metabolites such as N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), which have been shown to also dispose of protective properties. Thus, melatonin may be regarded as a prodrug, too. AMK interacts with reactive oxygen and nitrogen species, conveys protection to mitochondria, inhibits and downregulates

  4. Synthesis, spectroscopic, structural and thermal characterizations of vanadyl(IV) adenine complex prospective as antidiabetic drug agent

    NASA Astrophysics Data System (ADS)

    El-Megharbel, Samy M.; Hamza, Reham Z.; Refat, Moamen S.

    2015-01-01

    The vanadyl(IV) adenine complex; [VO(Adn)2]ṡSO4; was synthesized and characterized. The molar conductivity of this complex was measured in DMSO solution that showed an electrolyte nature. Spectroscopic investigation of the green solid complex studied here indicate that the adenine acts as a bidentate ligand, coordinated to vanadyl(IV) ions through the nitrogen atoms N7 and nitrogen atom of amino group. Thus, from the results presented the vanadyl(IV) complex has square pyramid geometry. Further characterizations using thermal analyses and scanning electron techniques was useful. The aim of this paper was to introduce a new drug model for the diabetic complications by synthesized a novel mononuclear vanadyl(IV) adenine complex to mimic insulin action and reducing blood sugar level. The antidiabetic ability of this complex was investigated in STZ-induced diabetic mice. The results suggested that VO(IV)/adenine complex has antidiabetic activity, it improved the lipid profile, it improved liver and kidney functions, also it ameliorated insulin hormone and blood glucose levels. The vanadyl(IV) complex possesses an antioxidant activity and this was clear through studying SOD, CAT, MDA, GSH and methionine synthase. The current results support the therapeutic potentiality of vanadyl(IV)/adenine complex for the management and treatment of diabetes.

  5. Caspase-responsive smart gadolinium-based contrast agent for magnetic resonance imaging of drug-induced apoptosis†

    PubMed Central

    Ye, Deju; Shuhendler, Adam J.; Pandit, Prachi; Brewer, Kimberly D.; Tee, Sui Seng; Cui, Lina; Tikhomirov, Grigory

    2014-01-01

    Non-invasive detection of caspase-3/7 activity in vivo has provided invaluable predictive information regarding tumor therapeutic efficacy and anti-tumor drug selection. Although a number of caspase-3/7 targeted fluorescence and positron emission tomography (PET) imaging probes have been developed, there is still a lack of gadolinium (Gd)-based magnetic resonance imaging (MRI) probes that enable high spatial resolution detection of caspase-3/7 activity in vivo. Here we employ a self-assembly approach and develop a caspase-3/7 activatable Gd-based MRI probe for monitoring tumor apoptosis in mice. Upon reduction and caspase-3/7 activation, the caspase-sensitive nano-aggregation MR probe (C-SNAM: 1) undergoes biocompatible intramolecular cyclization and subsequent self-assembly into Gd-nanoparticles (GdNPs). This results in enhanced r1 relaxivity—19.0 (post-activation) vs. 10.2 mM−1 s−1 (pre-activation) at 1 T in solution—and prolonged accumulation in chemotherapy-induced apoptotic cells and tumors that express active caspase-3/7. We demonstrate that C-SNAM reports caspase-3/7 activity by generating a significantly brighter T1-weighted MR signal compared to non-treated tumors following intravenous administration of C-SNAM, providing great potential for high-resolution imaging of tumor apoptosis in vivo. PMID:25429349

  6. Antibiotic Conjugated Fluorescent Carbon Dots as a Theranostic Agent for Controlled Drug Release, Bioimaging, and Enhanced Antimicrobial Activity

    PubMed Central

    Patil, Vaibhav; Khade, Monika; Goshi, Ekta; Sharon, Madhuri

    2014-01-01

    A novel report on microwave assisted synthesis of bright carbon dots (C-dots) using gum arabic (GA) and its use as molecular vehicle to ferry ciprofloxacin hydrochloride, a broad spectrum antibiotic, is reported in the present work. Density gradient centrifugation (DGC) was used to separate different types of C-dots. After careful analysis of the fractions obtained after centrifugation, ciprofloxacin was attached to synthesize ciprofloxacin conjugated with C-dots (Cipro@C-dots conjugate). Release of ciprofloxacin was found to be extremely regulated under physiological conditions. Cipro@C-dots were found to be biocompatible on Vero cells as compared to free ciprofloxacin (1.2 mM) even at very high concentrations. Bare C-dots (∼13 mg mL−1) were used for microbial imaging of the simplest eukaryotic model—Saccharomyces cerevisiae (yeast). Bright green fluorescent was obtained when live imaging was performed to view yeast cells under fluorescent microscope suggesting C-dots incorporation inside the cells. Cipro@C-dots conjugate also showed enhanced antimicrobial activity against both model gram positive and gram negative microorganisms. Thus, the Cipro@C-dots conjugate paves not only a way for bioimaging but also an efficient new nanocarrier for controlled drug release with high antimicrobial activity, thereby serving potential tool for theranostics. PMID:24744921

  7. Synthesis, spectroscopic, structural and thermal characterizations of vanadyl(IV) adenine complex prospective as antidiabetic drug agent.

    PubMed

    El-Megharbel, Samy M; Hamza, Reham Z; Refat, Moamen S

    2015-01-25

    The vanadyl(IV) adenine complex; [VO(Adn)2]⋅SO4; was synthesized and characterized. The molar conductivity of this complex was measured in DMSO solution that showed an electrolyte nature. Spectroscopic investigation of the green solid complex studied here indicate that the adenine acts as a bidentate ligand, coordinated to vanadyl(IV) ions through the nitrogen atoms N7 and nitrogen atom of amino group. Thus, from the results presented the vanadyl(IV) complex has square pyramid geometry. Further characterizations using thermal analyses and scanning electron techniques was useful. The aim of this paper was to introduce a new drug model for the diabetic complications by synthesized a novel mononuclear vanadyl(IV) adenine complex to mimic insulin action and reducing blood sugar level. The antidiabetic ability of this complex was investigated in STZ-induced diabetic mice. The results suggested that VO(IV)/adenine complex has antidiabetic activity, it improved the lipid profile, it improved liver and kidney functions, also it ameliorated insulin hormone and blood glucose levels. The vanadyl(IV) complex possesses an antioxidant activity and this was clear through studying SOD, CAT, MDA, GSH and methionine synthase. The current results support the therapeutic potentiality of vanadyl(IV)/adenine complex for the management and treatment of diabetes. PMID:25150436

  8. New metal based drug as a therapeutic agent: Spectral, electrochemical, DNA-binding, surface morphology and photoluminescence properties

    NASA Astrophysics Data System (ADS)

    Muslu, Harun; Gölcü, Ayşegül

    2015-07-01

    Cu(II) complexes of non-steroidal anti-inflammatory drug (NSAID) Meloxicam (H2MLX) was synthesized and characterized via spectroscopic and analytical techniques. The thermal behavior of the complex was also analyzed. The photoluminescence properties of the compounds were analyzed under different conditions. The electrochemical properties of both ligand and complex have been analyzed by Cyclic Voltammetry (CV) using glassy carbon electrode. The biological activities of the compounds were evaluated through examining their capacity to bind to fish sperm double strand DNA (FSdsDNA) with absorption spectroscopy and differential pulse voltammetry (DPV). Absorption studies of the interaction of the H2MLX and its Cu(II) complex with FSdsDNA have indicated that these compounds could bind to FSdsDNA, and the binding constants were calculated. The morphology of the FSdsDNA, H2MLX, and Cu(II) complex were analyzed thanks to using scanning electron microscopy (SEM). In the DPV technique, pencil graphite electrode was used as a working electrode. The decrease in the intensity of the guanine oxidation signals was used as an indicator for the interaction mechanism.

  9. Trends in the susceptibility of commonly encountered clinically significant anaerobes and susceptibilities of blood isolates of anaerobes to 16 antimicrobial agents, including fidaxomicin and rifaximin, 2008-2012, northern Taiwan.

    PubMed

    Wang, F D; Liao, C H; Lin, Y T; Sheng, W H; Hsueh, P R

    2014-11-01

    We investigated the antimicrobial resistance trends and profiles of clinical anaerobic isolates in northern Taiwan. Trends in the susceptibility of five commonly encountered clinical anaerobic isolates to seven agents from 2008 to 2012 were measured using the Cochran-Armitage trend test. The minimum inhibitory concentrations (MICs) of 16 antimicrobial agents, including fidaxomicin and rifaximin, against anaerobic blood isolates from two medical centers were determined using the agar dilution method. During the study period, susceptibility data on 11,105 isolates were evaluated. Metronidazole and chloramphenicol retained excellent activities. Around 20-30 % of isolates of Bacteroides and Prevotella species were resistant to ampicillin-sulbactam, cefmetazole, flomoxef, and clindamycin. Of the 507 tested blood isolates, the rates of resistance to commonly used agents were much higher, namely, 16.2 % for amoxicillin-clavulanate, 15.6 % for ampicillin-sulbactam, 24.7 % for cefmetazole, and 36.1 % for clindamycin. Notably, 13.5 % of B. fragilis isolates were resistant to ertapenem. Also, 15.2 % of B. uniformis, 17.2 % of other Bacteroides species, 14.3 % of Prevotella species, and 14 % of Clostridium other than C. perfringens isolates were resistant to moxifloxacin. Cefoperazone-sulbactam was active against most isolates, except for Clostridium species other than perfringens (resistance rate, 18.6 %). Fidaxomicin exerted poor activities against most anaerobes tested (MIC90 of >128 μg/ml for B. fragilis and all isolates), except for C. perfringens (MIC90 of 0.03 μg/ml) and Peptostreptococcus micros (MIC90 of 2 μg/ml). However, rifaximin showed a wide range of susceptibilities against the tested anaerobes (MIC90 of 0.5 μg/ml for B. fragilis). The emergence of resistance to ertapenem and moxifloxacin among bacteremic anaerobes highlights the need for continuous monitoring. PMID:24930042

  10. The level of intracellular glutathione is a key regulator for the induction of stress-activated signal transduction pathways including Jun N-terminal protein kinases and p38 kinase by alkylating agents.

    PubMed Central

    Wilhelm, D; Bender, K; Knebel, A; Angel, P

    1997-01-01

    Monofunctional alkylating agents like methyl methanesulfonate (MMS) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) are potent inducers of cellular stress leading to chromosomal aberrations, point mutations, and cell killing. We show that these agents induce a specific cellular stress response program which includes the activation of Jun N-terminal kinases/stress-activated protein kinases (JNK/SAPKs), p38 mitogen-activated protein kinase, and the upstream kinase SEK1/MKK4 and which depends on the reaction mechanism of the alkylating agent in question. Similar to another inducer of cellular stress, UV irradiation, damage of nuclear DNA by alkylation is not involved in the MMS-induced response. However, in contrast to UV and other inducers of the JNK/SAPKs and p38 pathways, activation of growth factor and G-protein-coupled receptors does not play a role in the MMS response. We identified the intracellular glutathione (GSH) level as critical for JNK/SAPK activation by MMS: enhancing the GSH level by pretreatment of the cells with GSH or N-acetylcysteine inhibits, whereas depletion of the cellular GSH pool causes hyperinduction of JNK/SAPK activity by MMS. In light of the JNK/SAPK-dependent induction of c-jun and c-fos transcription, and the Jun/Fos-induced transcription of xenobiotic-metabolizing enzymes, these data provide a potential critical role of JNK/SAPK and p38 in the induction of a cellular defense program against cytotoxic xenobiotics such as MMS. PMID:9234735

  11. T4-like phage Bp7, a potential antimicrobial agent for controlling drug-resistant Escherichia coli in chickens.

    PubMed

    Zhang, Can; Li, Wenli; Liu, Wenhua; Zou, Ling; Yan, Chen; Lu, Kai; Ren, Huiying

    2013-09-01

    Chicken-pathogenic Escherichia coli is severely endangering the poultry industry in China and worldwide, and antibiotic therapy is facing an increasing problem of antibiotic resistance. Bacteriophages can kill bacteria with no known activity in human or animal cells, making them an attractive alternative to antibiotics. In this study, we present the characteristics of a novel virulent bacteriophage, Bp7, specifically infecting pathogenic multidrug-resistant E. coli. Phage Bp7 was isolated from chicken feces. Bp7 belongs to the family Myoviridae, possessing an elongated icosahedral head and contractile sheathed tail. It has a 168-kb double-stranded DNA genome. For larger yields, its optimal multiplicity of infection (MOI) to infect E. coli was about 0.001. The latent period was 10 to 15 min, and the burst size was 90 PFU/infected cell. It was stable both at pH 5.0 to 10.0 and at 40°C or 50°C for at least 1 h. Bp7 could infect 46% of pathogenic clinical E. coli strains. Bp7 harbored 791 open reading frames (ORFs) and 263 possible genes. Among the 263 genes, 199 possessed amino acid sequence identities with ORFs of phage T4, 62 had identities with other T4-like phages, and only one lacked any database match. The genome of Bp7 manifested obvious division and rearrangement compared to phages T4, JS98, and IME08. Bp7 is a new member of the "T4-like" genus, family Myoviridae. Its wide host range, strong cell-killing activity, and high stability to pH make it an alternative to antimicrobials for controlling drug-resistant E. coli in chickens. PMID:23835183

  12. Prior antipsychotic drug treatment prevents response to novel antipsychotic agent in the methylazoxymethanol acetate model of schizophrenia.

    PubMed

    Gill, Kathryn M; Cook, James M; Poe, Michael M; Grace, Anthony A

    2014-03-01

    Trials of novel compounds for the treatment of schizophrenia are typically tested in patients following brief withdrawal of ongoing medication despite known long-term changes in the dopamine (DA) system following chronic antipsychotic drug therapy. The present study explored the impact of withdrawal from repeated haloperidol (HAL) treatment, as well as the response to a novel α5 gamma-aminobutyric acid (GABA(A)) receptor positive allosteric modulator (α5PAM), on the activity of the DA system in the methylazoxymethanol acetate (MAM) neurodevelopmental model of schizophrenia. Electrophysiological recordings were conducted from DA neurons in the ventral tegmental area of MAM and saline (SAL) rats following 7-day withdrawal from repeated HAL (21 d, 0.6 mg/kg, orally). In separate animals, amphetamine-induced locomotion was measured to assess changes in DA behavioral sensitivity. SAL rats withdrawn from HAL demonstrated reduced spontaneous DA neuron activity along with an enhanced locomotor response to amphetamine, indicative of the development of DA supersensitivity. Both α5PAM treatment and ventral hippocampal (vHPC) inactivation reversed the DA neuron depolarization block following HAL withdrawal in SAL rats. In contrast, MAM rats withdrawn from HAL exhibited reduced spontaneous DA activity and enhanced locomotor response to amphetamine compared with untreated SAL rats; however, this condition was unresponsive to α5PAM treatment or vHPC inactivation. Withdrawal from prior HAL treatment interferes with the therapeutic actions of this novel treatment in the MAM model of schizophrenia. Consequently, testing novel compounds on chronically treated schizophrenia patients may be ineffective. PMID:24464874

  13. Emerging Drugs for Uveitis

    PubMed Central

    Larson, Theresa; Nussenblatt, Robert B.; Sen, H. Nida

    2010-01-01

    Importance of the Field Uveitis is a challenging disease covering both infectious and noninfectious conditions. The current treatment strategies are hampered by the paucity of randomized controlled trials (RCTs) and few trials comparing efficacy of different agents. Areas Covered in this Review This review describes the current and future treatments of uveitis. A literature search was performed in PUBMED from 1965 to 2010 on drugs treating ocular inflammation with emphasis placed on more recent, larger studies. What the Reader Will Gain Readers should gain a basic understanding of current treatment strategies beginning with corticosteroids and transitioning to steroid sparing agents. Steroid sparing agents include the antimetabolites which include methotrexate, azathioprine, and mycophenolate mofetil; the calcineurin inhibitors which include cyclosporine, tacrolimus; alkylating agents which include cyclophosphamide and chlorambucil; and biologics which include the TNF-α inhibitors infliximab, adalimumab, and etanercept; daclizumab, interferon α2a, and rituximab. Take Home Message Newer agents are typically formulated from existing drugs or developed based on new advances in immunology. Future treatment will require a better understanding of the mechanisms involved in autoimmune diseases and better delivery systems in order to provide targeted treatment with minimal side effects. PMID:21210752

  14. Projecting future drug expenditures--1994.

    PubMed

    Santell, J P

    1994-01-15

    The use of information on inflation, generic competition, market introduction of new drug entities, institution-specific drug-use patterns, and federal legislation to project drug expenditures is discussed. Inflation of pharmaceutical prices has been decreasing over the past few years. Increases in the producer price index for drugs and pharmaceuticals diminished from 6.9% in 1991 to 4.3% in the first half of 1993; the specter of government regulation may be one reason. Pharmacy group purchasing organizations (GPOs) predicted that in 1994 expenditures would increase an average of 2.1% for contracted drug items and 8.3% for noncontracted items. Expenditures for biotechnology drugs in January through July 1993 increased 16% over the same period in 1992; such agents are now hospital pharmacies' third most costly drug category, at 10% of total expenditures. Future price competition by generic drug products can be predicted from information on patent or market-exclusivity expiration. To predict the market release of new drug products, new-drug applications filed with FDA can be monitored. The most important component in projecting drug expenditures is a specific institution's pattern of use of high-cost drugs. Mechanisms that can be used to monitor changes in therapeutic strategies and drug-use protocols include drug cost indexes, assessment of drug-use patterns by outside companies, and computerized models for specific high-cost drugs. Drug expenditures can be affected by legislative changes such as the Medicaid rebate provisions of the Omnibus Budget Reconciliation Act of 1990 and the Medicare outpatient drug benefit in the proposed American Health Security Act. The accuracy of projections of drug expenditures can be improved by examining inflation, generic competition, the introduction of new drug entities, institution-specific drug-use patterns, and legislative issues. Pharmacy managers need better methods for estimating institution-specific use of high-cost drugs

  15. LC-MS/MS structural characterization of stress degradation products including the development of a stability indicating assay of Darunavir: An anti-HIV drug.

    PubMed

    Rao, R Nageswara; Ramachandra, B; Sravan, B; Khalid, Sara

    2014-02-01

    Darunavir, an anti-HIV drug was subjected to forced degradation under acid, base, thermal and neutral hydrolysis, oxidation and photolysis as prescribed by ICH guidelines. Four major degradation products were formed under acid and base hydrolysis, while stable under neutral and thermal hydrolysis, oxidative and photolysis. The drug and its degradation products were separated on Hiber, LiChrospher® 60, RP-select B, C8 column (250mm×4.6mm i.d., 5μm) using 10mM ammonium acetate: acetonitrile (52:48, v/v) as mobile phase in an isocratic elution mode by LC. The degradation products were characterized by LC-MS/MS and fragmentation pathways were proposed. The proposed structures of degradation products were confirmed by HRMS and the LC method was validated with respect to specificity, linearity, accuracy, recovery, LOD and LOQ. PMID:24252722

  16. What do you do with the antiplatelet agents in patients with drug eluting stents who then receive a mechanical valve?

    PubMed Central

    Rossi, Michele; Serraino, Giuseppe Filiberto; Spadafora, Andrea; Renzulli, Attilio

    2012-01-01

    Dual antiplatelet therapy (DAT) with aspirin and clopidogrel is a cornerstone of treatment during and after percutaneous coronary interventions with drug-eluting stent (DES) implantation. Oral anticoagulation (OAC) is the recommended treatment for patients with mechanical heart valves. When patients with DES need a mechanical heart valve or vice versa, we face the difficult choice of their antithrombotic therapy. Different institutions empirically follow a combination of OAC and single or DAT, the so-called triple antithrombotic therapy (TT) aiming to find the best balance between the thrombotic and bleeding risk for this subset of patients. A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether there is an optimal antithrombotic management for patients with DES undergoing mechanical heart valve or vice versa. Altogether, more than 148 papers were found using the reported search, of which 16 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude that DES implantation in patients who could potentially need valve surgery in the future should be discouraged and bare-metal stent or an aortic bioprosthesis preferred. However, in high-risk patients with DES, the recommendation is to postpone elective surgery for 1 year and, if surgery cannot be deferred, continue aspirin during the perioperative period. Moreover, when OAC is given in combination with clopidogrel and/or low-dose aspirin, the target INR should be 2.0–2.5 (Class IIb, level of evidence C). As per the long-term management, antithrombotic management with DAT alone in mechanical aortic valve replacement might be possible, but there is not enough evidence to support it. The available evidence suggests that triple anticoagulation (OAC + DAT) is associated with the best

  17. A novel hybrid drug between two potent anti-tubulin agents as a potential prolonged anticancer approach.

    PubMed

    Marchetti, Paolo; Pavan, Barbara; Simoni, Daniele; Baruchello, Riccardo; Rondanin, Riccardo; Mischiati, Carlo; Feriotto, Giordana; Ferraro, Luca; Hsu, Lih-Ching; Lee, Ray M; Dalpiaz, Alessandro

    2016-08-25

    We report the design, synthesis and biological characterisation of a novel hybrid drug by conjugation of two tubulin inhibitors, a hemiasterlin derivative A (H-Mpa-Tle-Aha-OH), obtained by condensation of three non-natural amino acids, and cis-3,4',5-trimethoxy-3'aminostilbene (B). As we have previously demonstrated synergy between A and B, we used a monocarbonyl derivative of triethylene glycol as linker (L) to synthesise compounds A-L and A-L-B; via HPLC we analysed the release of its potential hydrolysis products A, A-L, B and B-L in physiological fluids: the hybrid A-L-B undergo hydrolysis in rat whole blood of the ester bond between A and L (half-life=118.2±9.5min) but not the carbamate bond between B and L; the hydrolysis product B-L was further hydrolyzed, but with a slower rate (half-life=288±12min). The compound A-L was the faster hydrolyzed conjugate (half-life=25.4±1.1min). The inhibitory activity of the compounds against SKOV3 ovarian cancer cell growth was analysed. The IC50 values were 7.48±1.27nM for A, 40.3±6.28nM for B, 738±38.5nM for A-L and 37.9±2.11nM for A-L-B. The anticancer effect of A-L-B was evidenced to be obtained via microtubule dynamics suppression. Finally, we stated the expression of the active efflux transporters P-gp (ABCB1) and MRP1 (ABCC1) in the human normal colon epithelial NCM460 cell line by reverse-transcription PCR. Via permeation studies across NCM460 monolayers we demonstrate the poor aptitude of A to interact with active efflux transporters (AET): indeed, the ratio between its permeability coefficients for the basolateral (B)→apical (A) and B→A transport was 1.5±0.1, near to the ratio of taltobulin (1.12±0.06), an hemiasterlin derivative able to elude AETs, and significantly different form the ratio of celiprolol (3.4±0.2), an AET substrate. PMID:27262542

  18. Regorafenib as a potential adjuvant chemotherapy agent in disseminated small colon cancer: Drug selection outcome of a novel screening system using nanoimprinting 3-dimensional culture with HCT116-RFP cells.

    PubMed

    Yoshii, Yukie; Furukawa, Takako; Aoyama, Hironori; Adachi, Naoya; Zhang, Ming-Rong; Wakizaka, Hidekatsu; Fujibayashi, Yasuhisa; Saga, Tsuneo

    2016-04-01

    Colon cancer is one of the leading causes of cancer death worldwide. Adjuvant chemotherapy following primary surgical treatment is suggested to be beneficial in eradicating invisible disseminated small tumors in colon cancer; however, an effective drug remains to be developed. Recently, we reported a novel drug screening system using a nanoimprinting 3-dimensional (3D) culture that creates multicellular spheroids, which simulate in vivo conditions and, thereby, predict effective drugs in vivo. This study aimed to perform drug selection using our recently developed 3D culture system in a human colon cancer HCT116 cell line stably expressing red fluorescent protein (HCT116-RFP), to determine the most effective agent in a selection of clinically used antitumor agents for colon cancer. In addition, we confirmed the efficacy of the selected drug regorafenib, in vivo using a mouse model of disseminated small tumors. HCT116-RFP cells were cultured using a nanoimprinting 3D culture and in vitro drug selection was performed with 8 clinically used drugs [bevacizumab, capecitabine, cetuximab, 5-fluorouracil (5-FU), irinotecan, oxaliplatin, panitumumab and regorafenib]. An in vivo study was performed in mice bearing HCT116-RFP intraperitoneally disseminated small tumors using 3'-[18F]-fluoro-3'-deoxythymidine-positron emission tomography and fluorescence microscopy imaging to evaluate the therapeutic effects. Regorafenib was determined to be the most effective drug in the 3D culture, and significantly inhibited tumor growth in vivo, compared to the untreated control and 5-FU-treated group. The drug 5-FU is commonly used in colon cancer treatment and was used as a reference. Our results demonstrate that regorafenib is a potentially efficacious adjuvant chemotherapeutic agent for the treatment of disseminated small colon cancer and, therefore, warrants further preclinical and clinical studies. PMID:26820693

  19. Antiparasitic agents.

    PubMed

    Rosenblatt, J E

    1999-11-01

    Several important developments have occurred in recent years in the chemotherapy for and prophylaxis of parasitic infections. Although mefloquine is clearly the most effective agent for prevention of chloroquine-resistant falciparum malaria, its use has been compromised by side effects, both real and imagined. Well-designed studies have shown that side effects occur no more frequently with low-dose mefloquine than with chloroquine. Use of mefloquine in pregnant women has not been associated with birth defects, but the incidence of stillbirths may be increased. Malarone is a new agent that combines atovaquone and proguanil, and it may be as effective as mefloquine; however, it is not yet available in the United States. Several newer agents have appeared in response to the development of multidrug resistant Plasmodium falciparum, especially in Southeast Asia. Halofantrine is available for the treatment of mild to moderate malaria due to P. falciparum and for P. vivax infections. Because of severe toxic effects, use of halofantrine should be restricted to only those unusual and rare situations in which other agents cannot be used. Artemisinin (an extract of the Chinese herbal remedy qinghaosu) and two derivatives, artesunate and artemether, are active against multidrug resistant P. falciparum and are widely used in Asia in oral, parenteral, and rectal forms. The antibacterial azithromycin in combination with atovaquone or quinine has now been reported to treat babesiosis effectively in experimental animals and in a few patients. Azithromycin in combination with paromomycin has also shown promise in the treatment of cryptosporidiosis (and toxoplasmosis when combined with pyrimethamine) in patients with the acquired immunodeficiency syndrome (AIDS). Albendazole is currently the only systemic agent available for treatment of microsporidiosis, an infection primarily of patients with AIDS. In addition, albendazole and ivermectin have emerged as effective broad

  20. Radiation recall with anticancer agents.

    PubMed

    Burris, Howard A; Hurtig, Jane

    2010-01-01

    Radiation recall is an acute inflammatory reaction confined to previously irradiated areas that can be triggered when chemotherapy agents are administered after radiotherapy. It remains a poorly understood phenomenon, but increased awareness may aid early diagnosis and appropriate management. A diverse range of drugs used in the treatment of cancer has been associated with radiation recall. As most data come from case reports, it is not possible to determine the true incidence, but to date the antineoplastic drugs for which radiation recall reactions have been most commonly reported include the anthracycline doxorubicin, the taxanes docetaxel and paclitaxel, and the antimetabolites gemcitabine and capecitabine. Radiation recall is drug-specific for any individual patient; it is not possible to predict which patients will react to which drugs, and rechallenge does not uniformly induce a reaction. There are no identifiable characteristics of drugs that cause radiation recall, and thus, it is a possibility that must be kept in mind with use of any drug after radiotherapy, including those from new drug classes. Although it is not yet possible to design treatment regimens to eliminate the risk of radiation recall, it seems likely that risks can be minimized by prolonging the interval between completion of radiotherapy and initiation of chemotherapy. PMID:21045191

  1. An overview of the causes of current practices in Pratinidhi Dravyas (substitution of drugs) in Ayurveda including newer techniques for their evaluation

    PubMed Central

    Joshi, Pravin R.; Patel, Bhupesh R.; Shukla, Vinay J.

    2012-01-01

    Many Pratinidhi Dravyas in Ayurvedic classics are mentioned and certainly are based on a methodical approach, which involves many aspects. These principles on which Pratinidhis were decided are quoted nowhere; so both to understand the established Pratinidhis and to find new ones a rational approach is the need of the hour. This article is an effort in the direction to study this concept meticulously in light of modern techniques for its better understanding and application. As there are very few established parameters, which help for selection and evaluation of Pratinidhi Dravyas. A rational technique like Fourier transform infrared spectroscopy may be incorporated to set a new dimension. As most of the routine analytical techniques are separation based, overall component load cannot be predicted. Thus, it is prime necessity to compare the drugs with a whole aspect, which goes in hand by hand with a holistic approach of Ayurveda “Treat the man as Whole – Take the drug as whole.” PMID:23723663

  2. Direct anti-HCV agents.

    PubMed

    Zhang, Xingquan

    2016-01-01

    Unlike human immunodeficiency virus (HIV) and hepatitis B virus (HBV), hepatitis C virus (HCV) infection is a curable disease. Current direct antiviral agent (DAA) targets are focused on HCV NS3/4A protein (protease), NS5B protein (polymerase) and NS5A protein. The first generation of DAAs includes boceprevir and telaprevir, which are protease inhibitors and were approved for clinical use in 2011. The cure rate for genotype 1 patients increased from 45% to 70% when boceprevir or telaprevir was added to standard PEG-IFN/ribavirin. More effective and less toxic second generation DAAs supplanted these drugs by 2013. The second generation of DAAs includes sofosbuvir (Sovaldi), simeprevir (Olysio), and fixed combination medicines Harvoni and Viekira Pak. These drugs increase cure rates to over 90% without the need for interferon and effectively treat all HCV genotypes. With these drugs the "cure HCV" goal has become a reality. Concerns remain about drug resistance mutations and the high cost of these drugs. The investigation of new HCV drugs is progressing rapidly; fixed dose combination medicines in phase III clinical trials include Viekirax, asunaprevir+daclatasvir+beclabuvir, grazoprevir+elbasvir and others. PMID:26904396

  3. Direct anti-HCV agents

    PubMed Central

    Zhang, Xingquan

    2015-01-01

    Unlike human immunodeficiency virus (HIV) and hepatitis B virus (HBV), hepatitis C virus (HCV) infection is a curable disease. Current direct antiviral agent (DAA) targets are focused on HCV NS3/4A protein (protease), NS5B protein (polymerase) and NS5A protein. The first generation of DAAs includes boceprevir and telaprevir, which are protease inhibitors and were approved for clinical use in 2011. The cure rate for genotype 1 patients increased from 45% to 70% when boceprevir or telaprevir was added to standard PEG-IFN/ribavirin. More effective and less toxic second generation DAAs supplanted these drugs by 2013. The second generation of DAAs includes sofosbuvir (Sovaldi), simeprevir (Olysio), and fixed combination medicines Harvoni and Viekira Pak. These drugs increase cure rates to over 90% without the need for interferon and effectively treat all HCV genotypes. With these drugs the “cure HCV” goal has become a reality. Concerns remain about drug resistance mutations and the high cost of these drugs. The investigation of new HCV drugs is progressing rapidly; fixed dose combination medicines in phase III clinical trials include Viekirax, asunaprevir+daclatasvir+beclabuvir, grazoprevir+elbasvir and others. PMID:26904396

  4. Antidiabetic Agents.

    ERIC Educational Resources Information Center

    Plummer, Nancy; Michael, Nancy, Ed.

    This module on antidiabetic agents is intended for use in inservice or continuing education programs for persons who administer medications in long-term care facilities. Instructor information, including teaching suggestions, and a listing of recommended audiovisual materials and their sources appear first. The module goal and objectives are then…

  5. Drug-induced hyperkalemia.

    PubMed

    Ben Salem, Chaker; Badreddine, Atef; Fathallah, Neila; Slim, Raoudha; Hmouda, Houssem

    2014-09-01

    Hyperkalemia is a common clinical condition that can be defined as a serum potassium concentration exceeding 5.0 mmol/L. Drug-induced hyperkalemia is the most important cause of increased potassium levels in everyday clinical practice. Drug-induced hyperkalemia may be asymptomatic. However, it may be dramatic and life threatening, posing diagnostic and management problems. A wide range of drugs can cause hyperkalemia by a variety of mechanisms. Drugs can interfere with potassium homoeostasis either by promoting transcellular potassium shift or by impairing renal potassium excretion. Drugs may also increase potassium supply. The reduction in renal potassium excretion due to inhibition of the renin-angiotensin-aldosterone system represents the most important mechanism by which drugs are known to cause hyperkalemia. Medications that alter transmembrane potassium movement include amino acids, beta-blockers, calcium channel blockers, suxamethonium, and mannitol. Drugs that impair renal potassium excretion are mainly represented by angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, direct renin inhibitors, nonsteroidal anti-inflammatory drugs, calcineurin inhibitors, heparin and derivatives, aldosterone antagonists, potassium-sparing diuretics, trimethoprim, and pentamidine. Potassium-containing agents represent another group of medications causing hyperkalemia. Increased awareness of drugs that can induce hyperkalemia, and monitoring and prevention are key elements for reducing the number of hospital admissions, morbidity, and mortality related to drug-induced hyperkalemia. PMID:25047526

  6. Enantioselective inhibition of Cytochrome P450-mediated drug metabolism by a novel antithrombotic agent, S002-333: Major effect on CYP2B6.

    PubMed

    Bhateria, Manisha; Ramakrishna, Rachumallu; Puttrevu, Santosh Kumar; Saxena, Anil K; Bhatta, Rabi Sankar

    2016-08-25

    A significant number of new chemical entities (NCEs) fail in drug discovery due to inhibition of Cytochrome P450 (CYP) enzymes. Therefore, to avert costly drug failure at the clinical phase it becomes indispensable to evaluate the CYP inhibition profile of NCEs early in drug discovery. In light of these concerns, we envisioned to investigate the inhibitory effects of S002-333 [2-(4-methoxy-benzenesulfonyl)-2,3,4,9-tetrahydro-1H-b-carboxylic acid amide], a novel and potent antithrombotic agent, on nine major CYP enzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4) of human liver microsomes (HLM). S002-333 exists as racemic mixture of S004-1032 (R-isomer) and S007-1558 (S-isomer), consequently, we further examined the enantioselective differences of S002-333 in the inhibition of human CYP enzymes. Of the CYP enzymes tested, CYP2B6-catalyzed bupropion 6-hydroxylation was inhibited by S002-333 (IC50 ∼ 9.25 ± 2.46 μM) in a stereoselective manner with (S)-isomer showing potent inhibition (IC50 ∼ 5.28 ± 1.25 μM) in contrast to (R)-isomer which showed negligible inhibition on CYP2B6 activity (IC50 > 50 μM). S002-333 and its (S)-isomer inhibited CYP2B6 activity in a non-competitive fashion with estimated Ki values of 10.1 ± 3.4 μM and 5.09 ± 1.05 μM, respectively. No shift in the IC50 value was observed for S002-333 and its isomers when preincubated for 30 min in the presence of NADPH suggesting that neither S002-333 nor its enantiomers are time-dependent inhibitors. Thus, the present findings signified that S002-333 is a potent stereoselective inhibitor of CYP2B6, whereas, inhibition for other CYPs was substantially negligible. These in vitro findings would be useful in deciding the development of S002-333 as a single-enantiomer or as a racemic mixture. PMID:27387538

  7. Adverse Drug Reactions of the Lower Extremities.

    PubMed

    Adigun, Chris G

    2016-07-01

    Adverse drug reactions (ADRs) are a common cause of dermatologic consultation, involving 2 to 3 per 100 medical inpatients in the United States. Female patients are 1.3 to 1.5 times more likely to develop ADRs, except in children less than 3 years of age, among whom boys are more often affected. Certain drugs are more frequent causes, including aminopenicillins, trimethoprim-sulfamethoxazole, and nonsteroidal antiinflammatory drugs. Chemotherapeutic agents commonly cause adverse reactions to the skin and nails, with certain agents causing particular patterns of reactions. ADRs can involve any area of the skin; the appendages, including hair and nails; as well as mucosa. PMID:27215159

  8. Fluorescence Spectrometric Determination of Drugs Containing α-Methylene Sulfone/Sulfonamide Functional Groups Using N1-Methylnicotinamide Chloride as a Fluorogenic Agent

    PubMed Central

    Elokely, Khaled M.; Eldawy, Mohamed A.; Elkersh, Mohamed A.; El-Moselhy, Tarek F.

    2011-01-01

    A simple spectrofluorometric method has been developed, adapted, and validated for the quantitative estimation of drugs containing α-methylene sulfone/sulfonamide functional groups using N1-methylnicotinamide chloride (NMNCl) as fluorogenic agent. The proposed method has been applied successfully to the determination of methyl sulfonyl methane (MSM) (1), tinidazole (2), rofecoxib (3), and nimesulide (4) in pure forms, laboratory-prepared mixtures, pharmaceutical dosage forms, spiked human plasma samples, and in volunteer's blood. The method showed linearity over concentration ranging from 1 to 150 μg/mL, 10 to 1000 ng/mL, 1 to 1800 ng/mL, and 30 to 2100 ng/mL for standard solutions of 1, 2, 3, and 4, respectively, and over concentration ranging from 5 to 150 μg/mL, 10 to 1000 ng/mL, 10 to 1700 ng/mL, and 30 to 2350 ng/mL in spiked human plasma samples of 1, 2, 3, and 4, respectively. The method showed good accuracy, specificity, and precision in both laboratory-prepared mixtures and in spiked human plasma samples. The proposed method is simple, does not need sophisticated instruments, and is suitable for quality control application, bioavailability, and bioequivalency studies. Besides, its detection limits are comparable to other sophisticated chromatographic methods. PMID:21647288

  9. Druggable targets in pediatric neurocutaneous melanocytosis: Molecular and drug sensitivity studies in xenograft and ex vivo tumor cell culture to identify agents for therapy

    PubMed Central

    Ruan, Yibing; Kovalchuk, Anna; Jayanthan, Aarthi; Lun, Xueqing; Nagashima, Yoji; Kovalchuk, Olga; Wright, James R.; Pinto, Alfredo; Kirton, Adam; Anderson, Ronald; Narendran, Aru

    2015-01-01

    Background Neurocutaneous melanocytosis (NCM) is a rare congenital disorder that presents with pigmented cell lesions of the brain or leptomeninges in children with large or multiple congenital melanocytic nevi. Although the exact pathological processes involved are currently unclear, NCM appears to arise from an abnormal development of melanoblasts or melanocyte precursors. Currently, it has an extremely poor prognosis due to rapid disease progression and lack of effective treatment modalities. Methods In this study, we report on an experimental approach to examining NCM cells by establishing subcutaneous tumors in nude mice, which can be further expanded for conducting molecular and drug sensitivity experiments. Results Analysis of the NRAS gene-coding sequences of an established NCM cell line (YP-MEL) and NCM patient cells revealed heterogeneity in NRAS Q61K that activated mutation and possibly consequential differential sensitivity to MEK inhibition. Gene expression studies were performed to compare the molecular profiles of NCM cells with normal skin fibroblasts. In vitro cytotoxicity screens of libraries of targeted small-molecule inhibitors revealed prospective agents for further evaluation. Conclusions Our studies provide an experimental platform for the generation of NCM cells for preclinical studies and the production of molecular and in vitro data with which to identify druggable targets for the treatment. PMID:25395461

  10. Aprepitant: drug-drug interactions in perspective.

    PubMed

    Aapro, M S; Walko, C M

    2010-12-01

    The implications of chemotherapeutic drug-drug interactions can be serious and thus need to be addressed. This review concerns the potential interactions of the antiemetic aprepitant, a neurokinin-1 receptor antagonist indicated for use (in Europe) in highly emetogenic chemotherapy and moderately emetogenic chemotherapy (MEC) in combination with a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist and corticosteroids and (in the United States) in combination with other antiemetic agents, for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy including high-dose cisplatin. When considering use of aprepitant for prevention of chemotherapy-induced nausea and vomiting, its potential drug-drug interaction profile as a moderate inhibitor of cytochrome P-450 isoenzyme 3A4 (CYP3A4) has been a source of concern for some physicians and other health care professionals. We explore in this paper how real those concerns are. Our conclusion is that either no interaction or no clinically relevant interaction exists with chemotherapeutic agents (intravenous cyclophosphamide, docetaxel, intravenous vinorelbine) or 5-HT3 antagonists (granisetron, ondansetron, palonosetron). For relevant interactions, appropriate measures, such as corticosteroid dose modifications and extended International Normalized Ratio monitoring of patients on warfarin therapy, can be taken to effectively manage them. Therefore, the concern of negative interactions remains largely theoretical but needs to be verified with new agents extensively metabolized through the 3A4 pathway. PMID:20488873

  11. Role of Biotransformation in Drug-Induced Toxicity: Influence of Intra- and Inter-Species Differences in Drug Metabolism

    PubMed Central

    Baillie, Thomas A.; Rettie, Allan E.

    2015-01-01

    It is now widely appreciated that drug metabolites, in addition to the parent drugs themselves, can mediate the serious adverse effects of new therapeutic agents, as a result of which there has been heightened interest in the field of drug metabolism from researchers in academia, the pharmaceutical industry, and regulatory agencies. Much progress has been made in recent years in understanding mechanisms of toxicities caused by drug metabolites, and the numerous factors that influence individual exposure to products of drug biotransformation. This review addresses some of these factors, including the role of drug-drug interactions, reactive metabolite formation, individual susceptibility, and species differences in drug disposition caused by genetic polymorphisms in drug metabolizing enzymes. Examples are provided of adverse reactions that are linked to drug metabolism, and the mechanisms underlying variability in toxic response are discussed. Finally, some future directions for research in this field are highlighted in the context of the discovery and development of new therapeutic agents. PMID:20978360

  12. White Paper: Recommendations on the Conduct of Superiority and Organism-Specific Clinical Trials of Antibacterial Agents for the Treatment of Infections Caused by Drug-Resistant Bacterial Pathogens

    PubMed Central

    2012-01-01

    There is a critical need for new pathways to develop antibacterial agents to treat life-threatening infections caused by highly resistant bacteria. Traditionally, antibacterial agents have been studied in noninferiority clinical trials that focus on one site of infection (eg, pneumonia, intra-abdominal infection). Conduct of superiority trials for infections caused by highly antibiotic-resistant bacteria represents a new, and as yet, untested paradigm for antibacterial drug development. We sought to define feasible trial designs of antibacterial agents that could enable conduct of superiority and organism-specific clinical trials. These recommendations are the results of several years of active dialogue among the white paper's drafters as well as external collaborators and regulatory officials. Our goal is to facilitate conduct of new types of antibacterial clinical trials to enable development and ultimately approval of critically needed new antibacterial agents. PMID:22891041

  13. New antifungal agents.

    PubMed

    Gupta, Aditya K; Tomas, Elizabeth

    2003-07-01

    Currently, use of standard antifungal therapies can be limited because of toxicity, low efficacy rates, and drug resistance. New formulations are being prepared to improve absorption and efficacy of some of these standard therapies. Various new antifungals have demonstrated therapeutic potential. These new agents may provide additional options for the treatment of superficial fungal infections and they may help to overcome the limitations of current treatments. Liposomal formulations of AmB have a broad spectrum of activity against invasive fungi, such as Candida spp., C. neoformans, and Aspergillus spp., but not dermatophyte fungi. The liposomal AmB is associated with significantly less toxicity and good rates of efficacy, which compare or exceed that of standard AmB. These factors may provide enough of an advantage to patients to overcome the increased costs of these formulations. Three new azole drugs have been developed, and may be of use in both systemic and superficial fungal infections. Voriconazole, ravuconazole, and posaconazole are triazoles, with broad-spectrum activity. Voriconazole has a high bioavailability, and has been used with success in immunocompromised patients with invasive fungal infections. Ravuconazole has shown efficacy in candidiasis in immunocompromised patients, and onychomycosis in healthy patients. Preliminary in vivo studies with posaconazole indicated potential use in a variety of invasive fungal infections including oropharyngeal candidiasis. Echinocandins and pneumocandins are a new class of antifungals, which act as fungal cell wall beta-(1,3)-D-glucan synthase enzyme complex inhibitors. Caspofungin (MK-0991) is the first of the echinocandins to receive Food and Drug Administration approval for patients with invasive aspergillosis not responding or intolerant to other antifungal therapies, and has been effective in patients with oropharyngeal and esophageal candidiasis. Standardization of MIC value determination has improved the

  14. Fluoroquinolone antimicrobial agents.

    PubMed Central

    Wolfson, J S; Hooper, D C

    1989-01-01

    The fluoroquinolones, a new class of potent orally absorbed antimicrobial agents, are reviewed, considering structure, mechanisms of action and resistance, spectrum, variables affecting activity in vitro, pharmacokinetic properties, clinical efficacy, emergence of resistance, and tolerability. The primary bacterial target is the enzyme deoxyribonucleic acid gyrase. Bacterial resistance occurs by chromosomal mutations altering deoxyribonucleic acid gyrase and decreasing drug permeation. The drugs are bactericidal and potent in vitro against members of the family Enterobacteriaceae, Haemophilus spp., and Neisseria spp., have good activity against Pseudomonas aeruginosa and staphylococci, and (with several exceptions) are less potent against streptococci and have fair to poor activity against anaerobic species. Potency in vitro decreases in the presence of low pH, magnesium ions, or urine but is little affected by different media, increased inoculum, or serum. The effects of the drugs in combination with a beta-lactam or aminoglycoside are often additive, occasionally synergistic, and rarely antagonistic. The agents are orally absorbed, require at most twice-daily dosing, and achieve high concentrations in urine, feces, and kidney and good concentrations in lung, bone, prostate, and other tissues. The drugs are efficacious in treatment of a variety of bacterial infections, including uncomplicated and complicated urinary tract infections, bacterial gastroenteritis, and gonorrhea, and show promise for therapy of prostatitis, respiratory tract infections, osteomyelitis, and cutaneous infections, particularly when caused by aerobic gram-negative bacilli. Fluoroquinolones have also proved to be efficacious for prophylaxis against travelers' diarrhea and infection with gram-negative bacilli in neutropenic patients. The drugs are effective in eliminating carriage of Neisseria meningitidis. Patient tolerability appears acceptable, with gastrointestinal or central nervous

  15. New drugs of abuse.

    PubMed

    Rech, Megan A; Donahey, Elisabeth; Cappiello Dziedzic, Jacqueline M; Oh, Laura; Greenhalgh, Elizabeth

    2015-02-01

    Drug abuse is a common problem and growing concern in the United States, and over the past decade, novel or atypical drugs have emerged and have become increasingly popular. Recognition and treatment of new drugs of abuse pose many challenges for health care providers due to lack of quantitative reporting and routine surveillance, and the difficulty of detection in routine blood and urine analyses. Furthermore, street manufacturers are able to rapidly adapt and develop new synthetic isolates of older drugs as soon as law enforcement agencies render them illegal. In this article, we describe the clinical and adverse effects and purported pharmacology of several new classes of drugs of abuse including synthetic cannabinoids, synthetic cathinones, salvia, desomorphine, and kratom. Because many of these substances can have severe or life-threatening adverse effects, knowledge of general toxicology is key in recognizing acute intoxication and overdose; however, typical toxidromes (e.g., cholinergic, sympathomimetic, opioid, etc.) are not precipitated by many of these agents. Medical management of patients who abuse or overdose on these drugs largely consists of supportive care, although naloxone may be used as an antidote for desomorphine overdose. Symptoms of aggression and psychosis may be treated with sedation (benzodiazepines, propofol) and antipsychotics (haloperidol or atypical agents such as quetiapine or ziprasidone). Other facets of management to consider include treatment for withdrawal or addiction, nutrition support, and potential for transmission of infectious diseases. PMID:25471045

  16. Steering Organoids Toward Discovery: Self-Driving Stem Cells Are Opening a World of Possibilities, Including Drug Testing and Tissue Sourcing.

    PubMed

    Solis, Michele

    2016-01-01

    Since the 1980s, stem cells' shape-shifting abilities have wowed scientists. With proper handling, a few growth factors, and some time, stem cells can be cooked up into specific cell types, including neurons, muscle, and skin. PMID:27414630

  17. Chemically modified tetracyclines: The novel host modulating agents

    PubMed Central

    Swamy, Devulapalli Narasimha; Sanivarapu, Sahitya; Moogla, Srinivas; Kapalavai, Vasavi

    2015-01-01

    Periodontal pathogens and destructive host responses are involved in the initiation and progression of periodontitis. The emergence of host response modulation as a treatment concept has resulted from our improved understanding of the pathogenesis of periodontal disease. A variety of drugs have been evaluated as host modulation agents (HMA), including Non Steroidal Anti Inflammatory Drugs (NSAIDS), bisphosphonates, tetracyclines, enamel matrix proteins and bone morphogenetic proteins. Chemically modified tetracyclines (CMTs) are one such group of drugs which have been viewed as potential host modulating agents by their anticollagenolytic property. The CMTs are designed to be more potent inhibitors of pro inflammatory mediators and can increase the levels of anti inflammatory mediators. PMID:26392682

  18. Chemically modified tetracyclines: The novel host modulating agents.

    PubMed

    Swamy, Devulapalli Narasimha; Sanivarapu, Sahitya; Moogla, Srinivas; Kapalavai, Vasavi

    2015-01-01

    Periodontal pathogens and destructive host responses are involved in the initiation and progression of periodontitis. The emergence of host response modulation as a treatment concept has resulted from our improved understanding of the pathogenesis of periodontal disease. A variety of drugs have been evaluated as host modulation agents (HMA), including Non Steroidal Anti Inflammatory Drugs (NSAIDS), bisphosphonates, tetracyclines, enamel matrix proteins and bone morphogenetic proteins. Chemically modified tetracyclines (CMTs) are one such group of drugs which have been viewed as potential host modulating agents by their anticollagenolytic property. The CMTs are designed to be more potent inhibitors of pro inflammatory mediators and can increase the levels of anti inflammatory mediators. PMID:26392682

  19. Incidence of potential drug-drug interactions with antidiabetic drugs.

    PubMed

    Samardzic, I; Bacic-Vrca, V

    2015-06-01

    In an effort to achieve normoglycemia more than one antidiabetic agent is usually needed. Diabetes is associated with several comorbidities and patients with diabetes are often treated with multiple medications. Therefore, patients with diabetes are especially exposed to drug-drug interactions (DDIs). The aim of this study was to analyse the incidence and type of potential DDIs of antidiabetic drugs in patients with diabetes. This retrospective study analyzed pharmacy record data of 225 patients with diabetes mellitus. Both type 1 and type 2 diabetic patients who were taking at least one antidiabetic agent during the period of six months were included. We investigated associated therapy in that period in order to identify potential DDIs with antidiabetic therapy. Potential interactions were identified by Lexicomp Lexi-Interat Online (Lexi-Comp, Inc., Hudson, USA) software which categorizes potential DDIs according to clinical significance in five types (A, B, C, D and X). Categories C, D and X are of clinical concern and always require medical attention (therapy monitoring, therapy modification or avoiding combination). We found that 80.9% of patients had at least one potential category C interaction while there were no D and X interactions. Most frequently encountered potential DDI (n = 176) included antidiabetic drugs and thiazide or thiazide like diuretics. Patients with diabetes are exposed to a large number of potential clinically significant DDIs that may require appropriate monitoring. Using databases of DDIs could be helpful in reducing the risk of potential clinically significant DDIs. PMID:26189304

  20. Pretreatment drugs against organophosphorus agents based on azabicyclic n-alkyl oximino o-carbamates. Annual report, 24 September 1991-23 September 1992

    SciTech Connect

    Moriarty, R.M.

    1992-11-11

    During the past year, 27 compounds of azabicyclic and carbocyclic oximino carbamate structural types have been prepared and submitted for biological testing as pretreatment agents against organophosphorus nerve agent poisoning. Biological data has been tabulated and has shown that the carbocyclic norbornanone derived oximino carbamates offer potential as pretreatment agents.

  1. Development and Validation of an Immuno-PET Tracer as a Companion Diagnostic Agent for Antibody-Drug Conjugate Therapy to Target the CA6 Epitope

    PubMed Central

    Ilovich, Ohad; Natarajan, Arutselvan; Hori, Sharon; Sathirachinda, Ataya; Kimura, Richard; Srinivasan, Ananth; Gebauer, Mathias; Kruip, Jochen; Focken, Ingo; Lange, Christian; Carrez, Chantal; Sassoon, Ingrid; Blanc, Veronique; Sarkar, Susanta K.

    2015-01-01

    Purpose To develop and compare three copper 64 (64Cu)–labeled antibody fragments derived from a CA6-targeting antibody (huDS6) as immuno-positron emission tomography (immuno-PET)–based companion diagnostic agents for an antibody-drug conjugate by using huDS6. Materials and Methods Three antibody fragments derived from huDS6 were produced, purified, conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and evaluated in the following ways: (a) the affinity of the fragments and the DOTA conjugates was measured via flow cytometry, (b) the stability of the labeled fragments was determined ex vivo in human serum over 24 hours, and (c) comparison of the in vivo imaging potential of the fragments was evaluated in mice bearing subcutaneous CA6-positive and CA6-negative xenografts by using serial PET imaging and biodistribution. Isotype controls with antilysozyme and anti-DM4 B-Fabs and blocking experiments with an excess of either B-Fab or huDS6 were used to determine the extent of the antibody fragment 64Cu-DOTA-B-Fab binding specificity. Immunoreactivity and tracer kinetics were evaluated by using cellular uptake and 48-hour imaging experiments, respectively. Statistical analyses were performed by using t tests, one-way analysis of variance, and Wilcoxon and Mann-Whitney tests. Results The antibody fragment 64Cu-DOTA-B-Fab was more than 95% stable after 24 hours in human serum, had an immunoreactivity of more than 70%, and allowed differentiation between CA6-positive and CA6-negative tumors in vivo as early as 6 hours after injection, with a 1.7-fold uptake ratio between tumors. Isotype and blocking studies experiments showed tracer-specific uptake in antigen-positive tumors, despite some nonspecific uptake in both tumor models. Conclusion Three antibody fragments were produced and examined as potential companion diagnostic agents. 64Cu-DOTA-B-Fab is a stable and effective immuno-PET tracer for CA6 imaging in vivo. © RSNA, 2015 Online

  2. The development and assessment of high-throughput mass spectrometry-based methods for the quantification of a nanoparticle drug delivery agent in cellular lysate.

    PubMed

    Buse, Joshua; Purves, Randy W; Verrall, Ronald E; Badea, Ildiko; Zhang, Haixia; Mulligan, Christopher C; Peru, Kerry M; Bailey, Jonathan; Headley, John V; El-Aneed, Anas

    2014-11-01

    The safe use of lipid-based drug delivery agents requires fast and sensitive qualitative and quantitative assessment of their cellular interactions. Many mass spectrometry (MS) based analytical platforms can achieve such task with varying capabilities. Therefore, four novel high-throughput MS-based quantitative methods were evaluated for the analysis of a small organic gene delivery agent: N,N-bis(dimethylhexadecyl)-1,3-propane-diammonium dibromide (G16-3). Analysis utilized MS instruments that detect analytes using low-resolution tandem MS (MS/MS) analysis (i.e. QTRAP or linear ion trap in this work) or high-resolution MS analysis (i.e. time of flight (ToF) or Orbitrap). Our results indicate that the validated fast chromatography (FC)-QTRAP-MS/MS, FC- LTQ-Orbitrap-MS, desorption electrospray ionization-collision-induced dissociation (CID)-MS/MS and matrix assisted laser desorption ionization-ToF/ToF-MS MS methods were superior in the area of method development and sample analysis time to a previously developed liquid chromatography (LC)-CID-MS/MS. To our knowledge, this is the first evaluation of the abilities of five MS-based quantitative methods that target a single pharmaceutical analyte. Our findings indicate that, in comparison to conventional LC-CID-MS/MS, the new MS-based methods resulted in a (1) substantial reduction in the analysis time, (2) reduction in the time required for method development and (3) production of either superior or comparable quantitative data. The four new high-throughput MS methods, therefore, were faster, more efficient and less expensive than a conventional LC-CID-MS/MS for the quantification of the G16-3 analyte within tissue culture. When applied to cellular lysate, no significant change in the concentration of G16-3 gemini surfactant within PAM212 cells was observed between 5 and 53 h, suggesting the absence of any metabolism/excretion from PAM212 cells. PMID:25395133

  3. Simplifying sample pretreatment: application of dried blood spot (DBS) method to blood samples, including postmortem, for UHPLC-MS/MS analysis of drugs of abuse.

    PubMed

    Odoardi, Sara; Anzillotti, Luca; Strano-Rossi, Sabina

    2014-10-01

    The complexity of biological matrices, such as blood, requires the development of suitably selective and reliable sample pretreatment procedures prior to their instrumental analysis. A method has been developed for the analysis of drugs of abuse and their metabolites from different chemical classes (opiates, methadone, fentanyl and analogues, cocaine, amphetamines and amphetamine-like substances, ketamine, LSD) in human blood using dried blood spot (DBS) and subsequent UHPLC-MS/MS analysis. DBS extraction required only 100μL of sample, added with the internal standards and then three droplets (30μL each) of this solution were spotted on the card, let dry for 1h, punched and extracted with methanol with 0.1% of formic acid. The supernatant was evaporated and the residue was then reconstituted in 100μL of water with 0.1% of formic acid and injected in the UHPLC-MS/MS system. The method was validated considering the following parameters: LOD and LOQ, linearity, precision, accuracy, matrix effect and dilution integrity. LODs were 0.05-1ng/mL and LOQs were 0.2-2ng/mL. The method showed satisfactory linearity for all substances, with determination coefficients always higher than 0.99. Intra and inter day precision, accuracy, matrix effect and dilution integrity were acceptable for all the studied substances. The addition of internal standards before DBS extraction and the deposition of a fixed volume of blood on the filter cards ensured the accurate quantification of the analytes. The validated method was then applied to authentic postmortem blood samples. PMID:24814508

  4. Prescription of and Adherence to Non-Steroidal Anti-Inflammatory Drugs and Gastroprotective Agents in At-Risk Gastrointestinal Patients

    PubMed Central

    Lanas, Angel; Polo-Tomás, Mónica; Roncales, Pilar; Gonzalez, Miguel A; Zapardiel, Javier

    2012-01-01

    OBJECTIVES: Patients with gastrointestinal (GI) risk factors who take non-steroidal anti-inflammatory drugs (NSAIDs) should also take gastroprotective agents (GPAs). No studies have evaluated adherence and reasons for non-adherence to GPA and NSAID therapies. METHODS: This was a prospective, multicenter, observational, longitudinal study. Patients attending rheumatology/orthopedic clinics who were co-prescribed NSAID plus GPA for at least 15 days and had risk factors for GI complications were followed up by telephone call. Optimal adherence was defined as taking the drug for ≥80% of prescribed days. Multivariate logistic regression analysis was used to determine factors associated with non-adherence. RESULTS: Of 1,232 patients interviewed, 192 were excluded because of inaccurate data. Of the remaining 1,040 patients, 74% were prescribed low-dose NSAIDs and 99.8% were prescribed a standard or high-dose GPA. In all, 70% of NSAIDs and 63.1% of GPA prescriptions were short term (<30 days). The majority of patients who were prescribed either an NSAID (92.5%) or GPA (85.9%) started therapy. Optimal adherence to GPA or NSAIDs was reported by 79.7% (95% confidence interval (CI): 76.9−82.2%) and 84.1% (95% CI: 81.7−86.3%) of patients, respectively. More adverse events occurred among patients who reported non-optimal adherence than among patients with optimal adherence to GPA (22.1 vs. 1.9%, P<0.0001). As reasons for non-adherence, patients most frequently cited infrequent/low-intensity rheumatic pain (NSAIDs) or forgetfulness (GPAs). Adverse events and short-term treatment were independent factors associated with poor adherence for both NSAIDs and GPAs. History of uncomplicated peptic ulcer and frequent dosing were additional factors associated with non-adherence to NSAIDs. CONCLUSIONS: Most frequent reasons for non-adherence are infrequent/low-intensity rheumatic pain (NSAIDs) or forgetfulness (GPAs). Short-term treatment and adverse events were associated with poor

  5. [Drug-related psoriasis].

    PubMed

    Piérard-Franchimont, C; Piérard, G E

    2012-03-01

    Psoriasis is a common genetic disorder that may be initiated (drug-induced psoriasis) or exacerbated (drug-triggered psoriasis) by some drug intakes. Beta-blockers, lithium, some antimelarial drugs, non steroidal anti-inflammatory agents and tetracyclines are recognized to influence the clinical course of psoriasis. Other drugs are likely or possibly involved in this process. PMID:22611830

  6. Thyroid dysfunction from antineoplastic agents.

    PubMed

    Hamnvik, Ole-Petter Riksfjord; Larsen, P Reed; Marqusee, Ellen

    2011-11-01

    Unlike cytotoxic agents that indiscriminately affect rapidly dividing cells, newer antineoplastic agents such as targeted therapies and immunotherapies are associated with thyroid dysfunction. These include tyrosine kinase inhibitors, bexarotene, radioiodine-based cancer therapies, denileukin diftitox, alemtuzumab, interferon-α, interleukin-2, ipilimumab, tremelimumab, thalidomide, and lenalidomide. Primary hypothyroidism is the most common side effect, although thyrotoxicosis and effects on thyroid-stimulating hormone secretion and thyroid hormone metabolism have also been described. Most agents cause thyroid dysfunction in 20%-50% of patients, although some have even higher rates. Despite this, physicians may overlook drug-induced thyroid dysfunction because of the complexity of the clinical picture in the cancer patient. Symptoms of hypothyroidism, such as fatigue, weakness, depression, memory loss, cold intolerance, and cardiovascular effects, may be incorrectly attributed to the primary disease or to the antineoplastic agent. Underdiagnosis of thyroid dysfunction can have important consequences for cancer patient management. At a minimum, the symptoms will adversely affect the patient's quality of life. Alternatively, such symptoms can lead to dose reductions of potentially life-saving therapies. Hypothyroidism can also alter the kinetics and clearance of medications, which may lead to undesirable side effects. Thyrotoxicosis can be mistaken for sepsis or a nonendocrinologic drug side effect. In some patients, thyroid disease may indicate a higher likelihood of tumor response to the agent. Both hypothyroidism and thyrotoxicosis are easily diagnosed with inexpensive and specific tests. In many patients, particularly those with hypothyroidism, the treatment is straightforward. We therefore recommend routine testing for thyroid abnormalities in patients receiving these antineoplastic agents. PMID:22010182

  7. [Evaluation of the association between the use of oral anti-hyperglycemic agents and hypoglycemia in Japan by data mining of the Japanese Adverse Drug Event Report (JADER) database].

    PubMed

    Umetsu, Ryogo; Nishibata, Yuri; Abe, Junko; Suzuki, Yukiya; Hara, Hideaki; Nagasawa, Hideko; Kinosada, Yasutomi; Nakamura, Mitsuhiro

    2014-01-01

    Hypoglycemia due to treatment with oral anti-hyperglycemic agents (OHAs) is a major clinical problem in patients with type 2 diabetes mellitus. The aim of the present study was to evaluate the risk of hypoglycemia due to OHA use by using the Japanese Adverse Drug Event Report (JADER) database. To this end, reports of hypoglycemia events included in the JADER database between 2004 and 2012 were analyzed by calculating the reporting odds ratio (OR). The Medical Dictionary for Regulatory Activities Preferred Terms was used to identify hypoglycemia; 254392 reports were found in the JADER database, of which 13269 were excluded because the age and sex of the patient were not reported. Finally, 241123 reports were analyzed. Among OHAs, sulfonylureas showed the highest adjusted OR (adjusted OR, 10.13; 95% confidence interval, 9.08-11.26). The adjusted ORs for meglitinides, biguanide, thiazolidinedione, alpha-glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors were significantly lower than that of sulfonylureas. The adjusted OR of meglitinides (3.17; 95% confidence interval, 2.23-4.36) was significantly higher than that of alpha-glucosidase inhibitors or thiazolidinedione. We observed no difference between the adjusted ORs for biguanide, thiazolidinedione, alpha-glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors. Data mining of the JADER database was useful for analyzing OHA-associated hypoglycemia events. The results of our study suggested a low risk of hypoglycemia associated with biguanide, thiazolidinedione, alpha-glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors in clinical practice. PMID:24492232

  8. Projecting future drug expenditures--1995.

    PubMed

    Santell, J P

    1995-01-15

    Use of information on inflation, pharmacoeconomics, market introduction of new drug entities, practice-site-specific drug-use patterns, federal legislation, and the changing structure of health care delivery to project drug expenditures is discussed. Drug price inflation has been declining over the past several years, from 6.9% in 1991 to 2.2% for part of 1994. This can be attributed to both the growth of managed care and the industry's fear of government price controls. Pharmaceutical industry analysts project the overall price increase for pharmaceuticals in the next 12-24 months to be 2-5%. Pharmacoeconomic research is likely to become increasingly important; pharmacists will need to understand and critically evaluate this research. Drug budget projections should include a complete review of new drugs and biotechnology agents pending FDA approval, drugs pending approval for new indications, and common unlabeled uses of expensive existing agents. Various methods are available for tracking practice-site-specific drug-use patterns; those that categorize expenditures by diagnosis-related group may underestimate total expenditures associated with treating a given condition. State and federal legislation may affect drug rebates, prices, and ultimately drug expenditures. Although health care reform legislation did not pass in 1994, changes are occurring in both the pharmaceutical industry and in health care delivery, shifting the control of drug selection, utilization, and expenditures from individual prescribers to large purchasers. The accuracy of projections of drug expenditures can be improved by examining inflation, pharmacoeconomic research, the introduction of new drug entities, practice-site-specific drug-use patterns, federal legislation, and the changing structure of health care delivery. PMID:12879542

  9. Hypersensitivity to antineoplastic agents.

    PubMed

    Castells, M C

    2008-01-01

    The need to offer first line therapy for primary and recurrent cancers has spurred the clinical development of rapid desensitizations for chemotherapy and monoclonal antibodies. Rapid desensitizations allow patients to be treated with medications to which they have presented with hypersensitivity reactions (HSRs), including anaphylaxis. Rapid desensitization achieves temporary tolerization to full therapeutic doses by slow administration of incremental doses of the drug inducing the HSR. Protocols are available for most chemotherapy agents, including taxanes, platins, doxorubicin, monoclonal antibodies, and others. Candidate patients include those who present with type I HSRs, mast cell/IgE dependent, including anaphylaxis, and non-IgE mediated HSRs, during the chemotherapy infusion or shortly after. Idiosyncratic reactions, erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis are not amenable to rapid desensitization. The recommendation for rapid desensitization can only be made by allergy and immunology specialists and can only be performed in settings with one-to-one nurse-patient care and where resuscitation personnel and resources are readily available. Repeated desensitizations can be safely performed in outpatient settings with similar conditions, which allow cancer patients to remain in clinical studies. We have generated a universal 12-step protocol that was applied to 413 cases of intravenous and intraperitoneal rapid desensitizations using taxanes, platins, liposomal doxorubicin, doxorubicin, rituximab, and other chemotherapy drugs. Under this protocol all patients were able to complete their target dose, and 94% of the patients had limited or no reactions. No deaths or codes were reported, indicating that the procedure was safe and effective in delivering first line chemotherapy drugs. PMID:18991707

  10. Adverse drug reactions in dermatology.

    PubMed

    Ferner, R E

    2015-03-01

    Adverse drug reactions (ADRs) - that is, unintended and harmful responses to medicines - are important to dermatologists because many present with cutaneous signs and because dermatological treatments can cause serious ADRs. The detection of ADRs to new drugs is often delayed because they have a long latency or are rare or unexpected. This means that ADRs to newer agents emerge only slowly after marketing. ADRs are part of the differential diagnosis of unusual rashes. A good drug history that includes details of drug dose, time-course of the reaction and factors that may make the patient more susceptible, will help. For example, Stevens-Johnson syndrome with abacavir is much commoner in patients with HLA-B*5701, and has a characteristic time course. Newer agents have brought newer reactions; for example, acneiform rashes associated with epidermal growth factor receptor inhibitors such as erlotinib. Older systemic agents used to treat skin disease, including corticosteroids and methotrexate, cause important ADRs. The adverse effects of newer biological agents used in dermatology are becoming clearer; for example, hypersensitivity reactions or loss of efficacy from antibody formation and progressive multifocal leucoencephalopathy due to reactivation of latent JC (John Cunningham) virus infections during efalizumab treatment. Unusual or serious harm from medicines, including ADRs, medication errors and overdose, should be reported. The UK Yellow Card scheme is online, and patients can report their own ADRs. PMID:25622648

  11. Drug discovery in ovarian cancer.

    PubMed

    Chase, Dana M; Mathur, Nidhee; Tewari, Krishnansu S

    2010-11-01

    Drug discovery in the ovarian cancer arena has led to the activation of several important clinical trials. Many biologic agents have come down the pipeline and are being studied in phase II trials for recurrent disease. These agents include antivascular compounds that disrupt angiogenesis through a variety of mechanisms (e.g., prevention of ligand-binding to the vascular endothelial growth factor receptor-2 (VEGF-R2), high-affinity VEGF blockade, oral inhibitors of tyrosine kinases stimulated by VEGF, inhibition of alpha5beta1 integrin, neutralization of angioproteins, etc.). Other novel drugs include oral platinum compounds as well as those that antagonize the tumor proliferation genes in the Hedgehog pathway, and that target folic acid receptors which are expressed by ovarian cancer cells. In addition, studies are underway with oral agents that inhibit the tyrosine kinase activity associated with two oncogenes (epidermal growth factor receptor (EGFR) and HER-2/neu). Finally, emerging technologies in clinical trials include nanotechnology to enhance delivery of chemotherapy to ovarian tumors, drug resistance/sensitivity assays to guide therapy, and agents that mobilize and induce proliferation of hematopoetic progenitor cells to aid in red blood cell, white blood cell, and platelet recovery following chemotherapy. The relevant patents in drug discovery of ovarian cancer are discussed. PMID:20524931

  12. Controlled drugs.

    PubMed

    2016-05-18

    Essential facts Controlled drugs are defined and governed by the Misuse of Drugs Act 1971 and associated regulations. Examples of controlled drugs include morphine, pethidine and methadone. Since 2012, appropriately qualified nurses and midwives can prescribe controlled drugs for medical conditions within their competence. There are some exceptions when treating addiction. PMID:27191427

  13. The application of poly(N-isopropylacrylamide)-co-polystyrene nanofibers as an additive agent to facilitate the cellular uptake of an anticancer drug

    NASA Astrophysics Data System (ADS)

    Song, Min; Guo, Dadong; Pan, Chao; Jiang, Hui; Chen, Chen; Zhang, Renyun; Gu, Zhongze; Wang, Xuemei

    2008-04-01

    In this paper, we have fabricated poly(N-isopropylacrylamide)-co-polystyrene (PNIPAM-co-PS) nanofibers by electrospinning and explored the possibility to utilize the PNIPAM-co-PS nanofibers to enhance the permeation and uptake of the anticancer drug daunorubicin in drug-sensitive and drug-resistant leukemia K562 cells. Our MTT assay and electrochemical studies demonstrate that PNIPAM-co-PS nanofibers could play an important role in facilitating the cell track and drug delivery to the cancer cells. Meanwhile, the observations of atomic force microscopy (AFM) and confocal fluorescence microscopy indicate that the relevant interaction of the PNIPAM-co-PS nanofibers with bioactive molecules on the membrane of leukemia cell lines could affect the intracellular drug uptake positively and lead to the efficient accumulation of daunorubicin in drug-sensitive and drug-resistant cancer cells.

  14. Hydroxypyridonate chelating agents

    DOEpatents

    Raymond, Kenneth N.; Scarrow, Robert C.; White, David L.

    1987-01-01

    Chelating agents having 1-hydroxy-2-pyridinone (HOPO) and related moieties incorporated within their structures, including polydentate HOPO-substituted polyamines such as spermidine and spermine, and HOPO-substituted desferrioxamine. The chelating agents are useful in selectively removing certain cations from solution, and are particularly useful as ferric ion and actinide chelators. Novel syntheses of the chelating agents are provided.

  15. Pretreatment drugs against organophosphorus agents based on azabicyclic n-alkyl oximino o-carbamates. Annual report, 24 September 1990-23 September 1991

    SciTech Connect

    Moriarty, R.M.

    1991-11-12

    During the past year, a number of purely carbocyclic norbonanone derived oximino carbamates and their methiodide salts have been synthesized and submitted for biological evaluation as pretreatment agents against organophosphorus agents. Additionally, a synthetic route has been devised and employed for the preparation of 2-tropinone, a key precursor for the synthesis of structurally important oximino carbamate derivatives.

  16. New Antithrombotic Drugs

    PubMed Central

    Eikelboom, John W.; Samama, Meyer Michel

    2012-01-01

    This article focuses on new antithrombotic drugs that are in or are entering phase 3 clinical testing. Development of these new agents was prompted by the limitations of existing antiplatelet, anticoagulant, or fibrinolytic drugs. Addressing these unmet needs, this article (1) outlines the rationale for development of new antithrombotic agents; (2) describes the new antiplatelet, anticoagulant, and fibrinolytic drugs; and (3) provides clinical perspectives on the opportunities and challenges faced by these novel agents. PMID:22315258

  17. Systematic structure modifications of multitarget prostate cancer drug candidate galeterone to produce novel androgen receptor down-regulating agents as an approach to treatment of advanced prostate cancer.

    PubMed

    Purushottamachar, Puranik; Godbole, Abhijit M; Gediya, Lalji K; Martin, Marlena S; Vasaitis, Tadas S; Kwegyir-Afful, Andrew K; Ramalingam, Senthilmurugan; Ates-Alagoz, Zeynep; Njar, Vincent C O

    2013-06-27

    As part of our program to explore the influence of small structural modifications of our drug candidate 3β-(hydroxy)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (galeterone, 5) on the modulation of the androgen receptor (AR), we have prepared and evaluated a series of novel C-3, C-16, and C-17 analogues. Using structure activity analysis, we established that the benzimidazole moiety at C-17 is essential and optimal and also that hydrophilic and heteroaromatic groups at C-3 enhance both antiproliferative (AP) and AR degrading (ARD) activities. The most potent antiproliferative compounds were 3β-(1H-imidazole-1-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (47), 3-((EZ)-hydroximino)-17-(1H-benzimidazol-1-yl)androsta-4,16-diene (36), and 3β-(pyridine-4-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (43), with GI50 values of 0.87, 1.91, and 2.57 μM, respectively. Compared to 5, compound 47 was 4- and 8-fold more potent with respect to AP and ARD activities, respectively. Importantly, we also discovered that our compounds, including 5, 36, 43, and 47, could degrade both full-length and truncated ARs in CWR22rv1 human prostate cancer cells. With these activities, they have potential for development as new drugs for the treatment of all forms of prostate cancer. PMID:23713567

  18. Agent Orange

    MedlinePlus

    ... Index Agent Orange Agent Orange Home Facts about Herbicides Veterans' Diseases Birth Defects Benefits Exposure Locations Provider ... millions of gallons of Agent Orange and other herbicides on trees and vegetation during the Vietnam War. ...

  19. Novel agents in the management of Mycobacterium tuberculosis disease.

    PubMed

    Barry, P J; O'Connor, T M

    2007-01-01

    The goals of tuberculosis control are to cure active disease, prevent relapse, reduce transmission and avert the emergence of drug resistance. However, since the 1960s, there have been few developments in available therapies. Currently available agents are complicated by numerous side-effects, drug interactions and the need for a long duration of therapy. Rifampicin-containing regimes lead to hepatic enzyme induction which can complicate or preclude the use of protease inhibitors and non-nucleoside reverse transcriptase inhibitors in patients infected with the human immunodeficiency virus. Furthermore, emerging drug resistance has complicated management for many patients and clinicians. Therefore, new chemotherapeutic agents are urgently needed. Existing antimicrobials are emerging as potent antituberculous agents. Recent studies have demonstrated the antituberculous activity of newer fluoroquinolones including levofloxacin, moxifloxacin, and gatifloxacin. Their use as first line antituberculous agents is currently under investigation. Furthermore, the oxazolidinones linezolid and PNU-100480 have been shown to have antituberculous activity in addition to their antibacterial effects. Several other agents are currently being developed for the treatment of tuberculosis. These agents include diarylquinolones (R207910), nitroimidazopyrans (PA-824, OPC-67683), ethambutol analogues (SQ109), cerulenin, trans-cinnamic acid, macrolides, pyrroles (LL3858), long-acting rifamycins and inhaled interferon-gamma. Furthermore, vaccines are being explored for pre-exposure and post-exposure use. This review will describe therapeutic developments in the management of tuberculosis, highlighting mechanisms of action of new pharmacological agents and their potential for clinical use. PMID:17691942

  20. Drug-induced nightmares.

    PubMed

    2000-12-01

    (1) A wide variety of drugs have been implicated in nightmares, often on inadequate evidence. (2) Recurrent nightmares can be induced by many drugs, and not only agents with psychotropic or neurological effects. PMID:11475499

  1. Rational drug design and the discovery of the delta2-1,2,3-triazolines, a unique class of anticonvulsant and antiischemic agents.

    PubMed

    Kadaba, Pankaja K

    2003-10-01

    in vivo oxidation of V or oxidative biotransformation of TR or aziridine by hydroxylation at the methylene group occurred. While triazoline significantly decreased Ca(2+) -dependent, k(+)-evoked L-Glu release (83% at 100 micro M drug concentration ), some triazolines showed an augmentation of 50-63%, in the Cl(-) channel activity, a useful membrane action that reduces the excessive L-Glu release that occurs during epileptic seizures. The high anticonvulsant activity of TRs in a variety of seizure models including their effectiveness in the kindling model of complex partial seizures may be due to their unique dual-action mechanism whereby the TR and V together effectively impair both pre- and postsynaptic aspects of EAA neurotransmission; thus the TRs have clinical potential in the treatment of complex partial epilepsy which is refractory to currently available drugs. Since there is strong evidence that L-Glu plays an important role in human epilepsy as well as in brain ischemia/stroke, and since the TRs act by inhibiting EAA neurotransmission, it was logical to expect that the anticonvulsant TRs may evince beneficial therapeutic potential in cerebral ischemia resulting from stroke as well. And indeed, several TRs, when tested in the standard gerbil model of global ischemia did evince remarkable ability to prevent neuronal death. PMID:12871087

  2. Allergic rhinitis: meaningful and less meaningful combination treatments including reminiscences.

    PubMed

    Szelenyi, I

    2014-06-01

    Allergic rhinitis (AR) results from a complex allergen-driven mucosal inflammation in the nasal cavity. Current guideline-based therapy for allergic rhinitis include oral and nasal antihistamines, topical and systemic glucocorticoids, decongestants, antimuscarinic agents, mast cell stabilizing drugs, leukotriene-receptor antagonists, and others. In spite of guideline recommendations, most patients are using multiple therapies in an attempt to achieve symptom control. Therefore, more effective therapies for the management of AR are clearly required. Recently, a novel fixed dose combination containing azelastine and fluticasone propionate has successfully been introduced. At present, it represents the only meaningful topical drug combination. Perhaps, it will be followed by others. PMID:24974572

  3. [New agents for hypercholesterolemia].

    PubMed

    Pintó, Xavier; García Gómez, María Carmen

    2016-02-19

    An elevated proportion of high cardiovascular risk patients do not achieve the therapeutic c-LDL goals. This owes to physicians' inappropriate or insufficient use of cholesterol lowering medications or to patients' bad tolerance or therapeutic compliance. Another cause is an insufficient efficacy of current cholesterol lowering drugs including statins and ezetimibe. In addition, proprotein convertase subtilisin kexin type 9 inhibitors are a new cholesterol lowering medications showing safety and high efficacy to reduce c-LDL in numerous already performed or underway clinical trials, potentially allowing an optimal control of hypercholesterolemia in most patients. Agents inhibiting apolipoprotein B synthesis and microsomal transfer protein are also providing a new potential to decrease cholesterol in patients with severe hypercholesterolemia and in particular in homozygote familial hypercholesterolemia. Last, cholesteryl ester transfer protein inhibitors have shown powerful effects on c-HDL and c-LDL, although their efficacy in cardiovascular prevention and safety has not been demonstrated yet. We provide in this article an overview of the main characteristics of therapeutic agents for hypercholesterolemia, which have been recently approved or in an advanced research stage. PMID:25817449

  4. Large Scale Solid Phase Synthesis of Peptide Drugs: Use of Commercial Anion Exchange Resin as Quenching Agent for Removal of Iodine during Disulphide Bond Formation

    PubMed Central

    Reddy, K. M. Bhaskara; Kumari, Y. Bharathi; Mallikharjunasarma, Dokka; Bulliraju, Kamana; Sreelatha, Vanjivaka; Ananda, Kuppanna

    2012-01-01

    The S-acetamidomethyl (Acm) or trityl (Trt) protecting groups are widely used in the chemical synthesis of peptides that contain one or more disulfide bonds. Treatment of peptides containing S-Acm protecting group with iodine results in simultaneous removal of the sulfhydryl protecting group and disulfide formation. However, the excess iodine needs to be quenched or adsorbed as quickly as possible after completion of the disulfide bond formation in order to minimize side reactions that are often associated with the iodination step. We report here a simple method for simultaneous quenching and removal of iodine and isolation of disulphide bridge peptides. The use of excess inexpensive anion exchange resin to the oxidized peptide from the aqueous acetic acid/methanol solution affords quantitative removal of iodine and other color impurities. This improves the resin life time of expensive chromatography media that is used in preparative HPLC column during the purification of peptide using preparative HPLC. Further, it is very useful for the conversion of TFA salt to acetate in situ. It was successfully applied commercially, to the large scale synthesis of various peptides including Desmopressin, Oxytocin, and Octreotide. This new approach offers significant advantages such as more simple utility, minimal side reactions, large scale synthesis of peptide drugs, and greater cost effectiveness. PMID:23118772

  5. 21 CFR 178.3125 - Anticorrosive agents.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... agents in food-contact materials subject to the provisions of this section: Substances Limitations Zinc... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Anticorrosive agents. 178.3125 Section 178.3125 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES...

  6. Antineoplastic Drugs

    NASA Astrophysics Data System (ADS)

    Sadée, Wolfgang; El Sayed, Yousry Mahmoud

    The limited scope of therapeutic drug-level monitoring in cancer chemotherapy results from the often complex biochemical mechanisms that contribute to antineoplastic activity and obscure the relationships among drug serum levels and therapeutic benefits. Moreover, new agents for cancer chemotherapy are being introduced at a more rapid rate than for the treatment of other diseases, although the successful application of therapeutic drug-level monitoring may require several years of intensive study of the significance of serum drug levels. However, drug level monitoring can be of considerable value during phase I clinical trials of new antineoplastic agents in order to assess drug metabolism, bioavailability, and intersubject variability; these are important parameters in the interpretation of clinical studies, but have no immediate benefit to the patient. High performance liquid chromatography (HPLC) probably represents the most versatile and easily adaptable analytical technique for drug metabolite screening (1). HPLC may therefore now be the method of choice during phase I clinical trials of antineoplastic drugs. For example, within a single week we developed an HPLC assay—using a C18 reverse-phase column, UV detection, and direct serum injection after protein precipitation—for the new radiosensitizer, misonidazole (2).

  7. [Drug dependence and psychotropic drugs].

    PubMed

    Giraud, M J; Lemonnier, E; Bigot, T

    1994-11-01

    Although the utility of psychotropic drugs has been well demonstrated, caution must still be exercised in their use. Among their potential risks, drug dependency must be kept in mind. This risk is well accepted with regard to benzodiazepines, and it appeared useful to study the potential risk for antidepressants, neuroleptics and thymoregulatory agents. Whatever the drug, the predominant factor appears to be psychological dependency. Prevention of drug dependency is most often achieved by informing the patient, limiting the length of use of the drug, making regular reevaluation of symptoms and of drug indication, and frequently be establishing a "treatment contract". The importance of the patient-physician relationship in the prescription of such treatment must be underlined. PMID:7984941

  8. pH-dependent drug-drug interactions for weak base drugs: potential implications for new drug development.

    PubMed

    Zhang, L; Wu, F; Lee, S C; Zhao, H; Zhang, L

    2014-08-01

    Absorption of an orally administered drug with pH-dependent solubility may be altered when it is coadministered with a gastric acid-reducing agent (ARA). Assessing a drug's potential for pH-dependent drug-drug interactions (DDIs), considering study design elements for such DDI studies, and interpreting and communicating study results in the drug labeling to guide drug dosing are important for drug development. We collected pertinent information related to new molecular entities approved from January 2003 to May 2013 by the US Food and Drug Administration for which clinical DDI studies with ARAs were performed. On the basis of assessments of data on pH solubility and in vivo DDIs with ARAs, we proposed a conceptual framework for assessing the need for clinical pH-dependent DDI studies for weak base drugs (WBDs). Important study design considerations include selection of ARAs and timing of dosing of an ARA relative to the WBD in a DDI study. Labeling implications for drugs having DDIs with ARAs are also illustrated. PMID:24733008

  9. Alcohol and Other Drug Use Among Undergraduates at Indiana University, Bloomington, Including a Comparison Between I.U. Students and the State's High School Population. Indiana Studies in Higher Education, No. 49.

    ERIC Educational Resources Information Center

    Wakefield, Linda Morton

    The use of alcohol and six classes of illicit drugs among 485 undergraduates at Indiana University, Bloomington, was studied in 1981-1982 and compared to a state study of alcohol/drug use by high school students. Attention was focused on the following questions: When does drug experimentation begin, and which drugs are currently most popular? How…

  10. [Biosimilar drugs in oncology].

    PubMed

    Levêque, Dominique

    2016-03-01

    Biosimilar drugs are biologic drugs clinically similar to the reference products. They correspond to a generic approach applied to biologic agents. Biosimilars are aimed to provide cheaper drugs by enhancing the concurrency. The approval of biosimilars is abbreviated when compared to that of the reference biologics but includes clinical trials (distinguishing them from the generics). Current available biosimilars in oncology are filgrastim and epoietin alpha. In the next future, will be launched rituximab and trastuzumab. In France, the development of biosimilars is faced with many hurdles that necessitates a better information of physicians and a greater price discount in the out-patient setting. More globally, harmonisation of recommendations particularly concerning extrapolation of indications and nomenclature are needed for a better acceptance. PMID:26832422

  11. Tuberculosis Drug Development

    PubMed Central

    Getahun, Haileyesus; Chamie, Gabriel; Lienhardt, Christian; Havlir, Diane V.

    2011-01-01

    An unprecedented number of new tuberculosis (TB) medications are currently in development, and there will be great pressure to deploy these new drugs among all populations after their efficacy is demonstrated. People living with HIV experience a large burden of TB and have a particularly pressing need for TB treatments that are shorter and less toxic. In addition, all people living with HIV now require antiretroviral therapy during TB treatment. A roadmap of the research, programmatic, and regulatory considerations includes the following: (1) inclusion of people living with HIV early in clinical trials for treatment and prevention using new TB medications, (2) prioritization of key studies of HIV–TB drug interactions and interactions between new TB agents, and (3) optimization of clinical trial infrastructure, laboratory capacity, and drug susceptibility testing. PMID:21868507

  12. Integrating subpathway analysis to identify candidate agents for hepatocellular carcinoma

    PubMed Central

    Wang, Jiye; Li, Mi; Wang, Yun; Liu, Xiaoping

    2016-01-01

    Hepatocellular carcinoma (HCC) is the second most common cause of cancer-associated death worldwide, characterized by a high invasiveness and resistance to normal anticancer treatments. The need to develop new therapeutic agents for HCC is urgent. Here, we developed a bioinformatics method to identify potential novel drugs for HCC by integrating HCC-related and drug-affected subpathways. By using the RNA-seq data from the TCGA (The Cancer Genome Atlas) database, we first identified 1,763 differentially expressed genes between HCC and normal samples. Next, we identified 104 significant HCC-related subpathways. We also identified the subpathways associated with small molecular drugs in the CMap database. Finally, by integrating HCC-related and drug-affected subpathways, we identified 40 novel small molecular drugs capable of targeting these HCC-involved subpathways. In addition to previously reported agents (ie, calmidazolium), our method also identified potentially novel agents for targeting HCC. We experimentally verified that one of these novel agents, prenylamine, induced HCC cell apoptosis using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, an acridine orange/ethidium bromide stain, and electron microscopy. In addition, we found that prenylamine not only affected several classic apoptosis-related proteins, including Bax, Bcl-2, and cytochrome c, but also increased caspase-3 activity. These candidate small molecular drugs identified by us may provide insights into novel therapeutic approaches for HCC. PMID:27022281

  13. Integrating subpathway analysis to identify candidate agents for hepatocellular carcinoma.

    PubMed

    Wang, Jiye; Li, Mi; Wang, Yun; Liu, Xiaoping

    2016-01-01

    Hepatocellular carcinoma (HCC) is the second most common cause of cancer-associated death worldwide, characterized by a high invasiveness and resistance to normal anticancer treatments. The need to develop new therapeutic agents for HCC is urgent. Here, we developed a bioinformatics method to identify potential novel drugs for HCC by integrating HCC-related and drug-affected subpathways. By using the RNA-seq data from the TCGA (The Cancer Genome Atlas) database, we first identified 1,763 differentially expressed genes between HCC and normal samples. Next, we identified 104 significant HCC-related subpathways. We also identified the subpathways associated with small molecular drugs in the CMap database. Finally, by integrating HCC-related and drug-affected subpathways, we identified 40 novel small molecular drugs capable of targeting these HCC-involved subpathways. In addition to previously reported agents (ie, calmidazolium), our method also identified potentially novel agents for targeting HCC. We experimentally verified that one of these novel agents, prenylamine, induced HCC cell apoptosis using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, an acridine orange/ethidium bromide stain, and electron microscopy. In addition, we found that prenylamine not only affected several classic apoptosis-related proteins, including Bax, Bcl-2, and cytochrome c, but also increased caspase-3 activity. These candidate small molecular drugs identified by us may provide insights into novel therapeutic approaches for HCC. PMID:27022281

  14. 21 CFR 349.16 - Ophthalmic hypertonicity agent.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Ophthalmic hypertonicity agent. 349.16 Section 349.16 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE OPHTHALMIC DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE Active Ingredients § 349.16 Ophthalmic hypertonicity agent. The...

  15. [From alcohol to liquid ecstasy (GHB)--a survey of old and modern knockout agents. Part 2: benzodiazepines and other sedatives/hypnotic drugs].

    PubMed

    Schütz, Harald; Jansen, Malin; Verhoff, Marcel A

    2011-01-01

    Owing to the rapid progress in the development of synthetic pharmaceuticals, the classical knockout drugs such as chloroform and diethyl ether have been superseded by highly effective sedative and hypnotic drugs (e. g. methyprylone, clozapine and especially benzodiazepines). These are frequently given to the victim unnoticed by adding them to an alcoholic drink. In this way, alcohol still plays an important role as an interaction partner. The article presents relevant case examples together with their criminalistic background. PMID:22276365

  16. Clinical drugs that interact with St. John's wort and implication in drug development.

    PubMed

    Di, Yuan Ming; Li, Chun Guang; Xue, Charlie Changli; Zhou, Shu-Feng

    2008-01-01

    St. John's wort (Hypericum perforatum, SJW) is one of the most commonly used herbal antidepressants for the treatment of minor to moderate depression. A major safety concern about SJW is its ability to alter the pharmacokinetics and/or clinical response of a variety of clinically important drugs that have distinctive chemical structure, mechanism of action and metabolic pathways. This review highlights and updates the knowledge on clinical interactions of prescribed drugs with SJW and the implication in drug development. A number of clinically significant interactions of SJW have been identified with conventional drugs, including anticancer agents (imatinib and irinotecan), anti-HIV agents (e.g. indinavir, lamivudine and nevirapine), anti-inflammatory agents (e.g. ibuprofen and fexofenadine), antimicrobial agents (e.g. erythromycin and voriconazole), cardiovascular drugs (e.g. digoxin, ivabradine, warfarin, verapamil, nifedipine and talinolol), central nervous system agents (e.g. amitriptyline, buspirone, phenytoin, methadone, midazolam, alprazolam, and sertraline), hypoglycaemic agents (e.g. tolbutamide and gliclazide), immuno-modulating agents (e.g. cyclosporine and tacrolimus), oral contraceptives, proton pump inhibitor (e.g. omeprazole), respiratory system agent (e.g. theophylline), statins (e.g. atorvastatin and pravastatin). Both pharmacokinetic and pharmacodynamic components may play a role in the interactions of drugs with SJW. For pharmacokinetic changes of drugs by SJW, induction of cytochrome P450s (e.g. CYP2C9 and 3A4) and P-glycoprotein (P-gp) are considered the major mechanism. Thus, it is not a surprise that many drugs that interact with SJW are substrates of CYP3A4, CYP2C9 and P-gp. A comprehensive understanding of clinical drugs that interact with SJW has important implications in drug development. New drugs may be designed to minimize interactions with SJW; and new SJW formulations may be designed to avoid drug interactions. Further clinical and

  17. Drugs Approved for Leukemia

    Cancer.gov

    This page lists cancer drugs approved by the FDA for use in leukemia. The drug names link to NCI's Cancer Drug Information summaries. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters.

  18. Drugs Approved for Retinoblastoma

    Cancer.gov

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for retinoblastoma. The list includes generic names and brand names. The drug names link to NCI’s Cancer Drug Information summaries.

  19. Drugs Approved for Neuroblastoma

    Cancer.gov

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for neuroblastoma. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  20. Drug abuse first aid

    MedlinePlus

    Drug abuse is the misuse or overuse of any medication or drug, including alcohol. This article discusses first ... use of these drugs is a form of drug abuse. Legitimate medications can be abused by people who ...

  1. [Novel insomnia drugs, including drugs currently under development].

    PubMed

    Inada, Ken

    2009-08-01

    Insomnia has mainly been treated with the hypnotic benzodiazepine (BZ). Recent studies have revealed the role and mechanisms of BZ receptors and have led to the development of non-BZ hypnotics. The chemical structures of non-BZ hypnotics differ from that of BZ; these hypnotics selectively bind to the omega 1 receptor of the gamma-aminobutyric acid (GABA)-BZ receptor complex. Because the omega 2 BZ receptors have adverse effects such as muscle relaxant actions, non-BZ hypnotics have lesser adverse effects than BZ. Antipsychotics, antidepressants, and antihistamines are also used for the treatment of insomnia in patients with other medical problems such as schizophrenia and depression. Currently, novel hypnotics are being developed with the manipulation of neurotransmitters and non-GABAergic receptors such as the melatonin and serotonin receptors. PMID:19768946

  2. Demethylating Agents in the Treatment of Cancer

    PubMed Central

    Howell, Paul M.; Liu, Zixing; Khong, Hung T.

    2010-01-01

    Gene silencing resulting from aberrant DNA methylation can lead to tumorigenesis. Therefore, drugs that inhibit or interfere with DNA methylation have been used to reactivate and induce silenced gene re-expression in malignancies. Two demethylating agents, azacitidine and decitabine, are approved for the treatment of myelodysplastic syndromes (MDS) by the U.S. Food and Drug Administration (FDA), and are now considered the standard of care in MDS. In this review, we discuss clinical data, including clinical benefits and toxicities, which led to the approval of azacitidine and decitabine. We also summarize findings from clinical trials that used these two demethylating agents in the treatment of solid tumors. Lastly, we discuss some limitations in the use of azacitidine and decitabine in cancer therapy.

  3. Development of anticancer agents: wizardry with osmium.

    PubMed

    Hanif, Muhammad; Babak, Maria V; Hartinger, Christian G

    2014-10-01

    Platinum compounds are one of the pillars of modern cancer chemotherapy. The apparent disadvantages of existing chemotherapeutics have led to the development of novel anticancer agents with alternative modes of action. Many complexes of the heavy metal osmium (Os) are potent growth inhibitors of human cancer cells and are active in vivo, often superior or comparable to cisplatin, as the benchmark metal-based anticancer agent, or clinically tested ruthenium (Ru) drug candidates. Depending on the choice of ligand system, osmium compounds exhibit diverse modes of action, including redox activation, DNA targeting or inhibition of protein kinases. In this review, we highlight recent advances in the development of osmium anticancer drug candidates and discuss their cellular mechanisms of action. PMID:24955838

  4. Pharmacologic Agents for Chronic Diarrhea

    PubMed Central

    2015-01-01

    Chronic diarrhea is usually associated with a number of non-infectious causes. When definitive treatment is unavailable, symptomatic drug therapy is indicated. Pharmacologic agents for chronic diarrhea include loperamide, 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, diosmectite, cholestyramine, probiotics, antispasmodics, rifaximin, and anti-inflammatory agents. Loperamide, a synthetic opiate agonist, decreases peristaltic activity and inhibits secretion, resulting in the reduction of fluid and electrolyte loss and an increase in stool consistency. Cholestyramine is a bile acid sequestrant that is generally considered as the first-line treatment for bile acid diarrhea. 5-HT3 receptor antagonists have significant benefits in patients with irritable bowel syndrome (IBS) with diarrhea. Ramosetron improves stool consistency as well as global IBS symptoms. Probiotics may have a role in the prevention of antibiotic-associated diarrhea. However, data on the role of probiotics in the treatment of chronic diarrhea are lacking. Diosmectite, an absorbent, can be used for the treatment of chronic functional diarrhea, radiation-induced diarrhea, and chemotherapy-induced diarrhea. Antispasmodics including alverine citrate, mebeverine, otilonium bromide, and pinaverium bromide are used for relieving diarrheal symptoms and abdominal pain. Rifaximin can be effective for chronic diarrhea associated with IBS and small intestinal bacterial overgrowth. Budesonide is effective in both lymphocytic colitis and collagenous colitis. The efficacy of mesalazine in microscopic colitis is weak or remains uncertain. Considering their mechanisms of action, these agents should be prescribed properly. PMID:26576135

  5. Pharmacologic Agents for Chronic Diarrhea.

    PubMed

    Lee, Kwang Jae

    2015-10-01

    Chronic diarrhea is usually associated with a number of non-infectious causes. When definitive treatment is unavailable, symptomatic drug therapy is indicated. Pharmacologic agents for chronic diarrhea include loperamide, 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, diosmectite, cholestyramine, probiotics, antispasmodics, rifaximin, and anti-inflammatory agents. Loperamide, a synthetic opiate agonist, decreases peristaltic activity and inhibits secretion, resulting in the reduction of fluid and electrolyte loss and an increase in stool consistency. Cholestyramine is a bile acid sequestrant that is generally considered as the first-line treatment for bile acid diarrhea. 5-HT3 receptor antagonists have significant benefits in patients with irritable bowel syndrome (IBS) with diarrhea. Ramosetron improves stool consistency as well as global IBS symptoms. Probiotics may have a role in the prevention of antibiotic-associated diarrhea. However, data on the role of probiotics in the treatment of chronic diarrhea are lacking. Diosmectite, an absorbent, can be used for the treatment of chronic functional diarrhea, radiation-induced diarrhea, and chemotherapy-induced diarrhea. Antispasmodics including alverine citrate, mebeverine, otilonium bromide, and pinaverium bromide are used for relieving diarrheal symptoms and abdominal pain. Rifaximin can be effective for chronic diarrhea associated with IBS and small intestinal bacterial overgrowth. Budesonide is effective in both lymphocytic colitis and collagenous colitis. The efficacy of mesalazine in microscopic colitis is weak or remains uncertain. Considering their mechanisms of action, these agents should be prescribed properly. PMID:26576135

  6. Reversal agents in anaesthesia and critical care

    PubMed Central

    Pani, Nibedita; Dongare, Pradeep A; Mishra, Rajeeb Kumar

    2015-01-01

    Despite the advent of short and ultra-short acting drugs, an in-depth knowledge of the reversal agents used is a necessity for any anaesthesiologist. Reversal agents are defined as any drug used to reverse the effects of anaesthetics, narcotics or potentially toxic agents. The controversy on the routine reversal of neuromuscular blockade still exists. The advent of newer reversal agents like sugammadex have made the use of steroidal neuromuscular blockers like rocuronium feasible in rapid sequence induction situations. We made a review of the older reversal agents and those still under investigation for drugs that are regularly used in our anaesthesia practice. PMID:26644615

  7. A Food and Drug Administration-approved Asthma Therapeutic Agent Impacts Amyloid β in the Brain in a Transgenic Model of Alzheimer Disease*

    PubMed Central

    Hori, Yukiko; Takeda, Shuko; Cho, Hansang; Wegmann, Susanne; Shoup, Timothy M.; Takahashi, Kazue; Irimia, Daniel; Elmaleh, David R.; Hyman, Bradley T.; Hudry, Eloise

    2015-01-01

    Interfering with the assembly of Amyloid β (Aβ) peptides from monomer to oligomeric species and fibrils or promoting their clearance from the brain are targets of anti-Aβ-directed therapies in Alzheimer disease. Here we demonstrate that cromolyn sodium (disodium cromoglycate), a Food and Drug Administration-approved drug already in use for the treatment of asthma, efficiently inhibits the aggregation of Aβ monomers into higher-order oligomers and fibrils in vitro without affecting Aβ production. In vivo, the levels of soluble Aβ are decreased by over 50% after only 1 week of daily intraperitoneally administered cromolyn sodium. Additional in vivo microdialysis studies also show that this compound decreases the half-life of soluble Aβ in the brain. These data suggest a clear effect of a peripherally administered, Food and Drug Administration-approved medication on Aβ economy, supporting further investigation of the potential long-term efficacy of cromolyn sodium in Alzheimer disease. PMID:25468905

  8. 4H-Chromene-based anticancer agents towards multi-drug resistant HL60/MX2 human leukemia: SAR at the 4th and 6th positions.

    PubMed

    Puppala, Manohar; Zhao, Xinghua; Casemore, Denise; Zhou, Bo; Aridoss, Gopalakrishnan; Narayanapillai, Sreekanth; Xing, Chengguo

    2016-03-15

    4H-Chromene-based compounds, for example, CXL017, CXL035, and CXL055, have a unique anticancer potential that they selectively kill multi-drug resistant cancer cells. Reported herein is the extended structure-activity relationship (SAR) study, focusing on the ester functional group at the 4th position and the conformation at the 6th position. Sharp SARs were observed at both positions with respect to cellular cytotoxic potency and selectivity between the parental HL60 and the multi-drug resistant HL60/MX2 cells. These results provide critical guidance for future medicinal optimization. PMID:26867486

  9. Radioprotective agents for radiation therapy: future trends.

    PubMed

    Johnke, Roberta M; Sattler, Jennifer A; Allison, Ron R

    2014-12-01

    Only two radioprotective compounds, amifostine and palifermin, currently have the US FDA approval for use in radiation therapy. However, several agents have been reported that show therapeutic promise. Many of these agents are free radical scavengers/antioxidants. Superoxide dismutase and superoxide dismutase mimetics, nitroxides and dietary antioxidants are all being investigated. Recently, alternative strategies of drug development have been evolving, which focus on targeting the series of cellular insult recognition/repair responses initiated following radiation. These agents, which include cytokines/growth factors, angiotensin-converting enzyme inhibitors and apoptotic modulators, show promise of having significant impact on the mitigation of radiation injury. Herein, we review current literature on the development of radioprotectors with emphasis on compounds with proven or potential usefulness in radiation therapy. PMID:25525844

  10. Application of a novel 3-fluid nozzle spray drying process for the microencapsulation of therapeutic agents using incompatible drug-polymer solutions.

    PubMed

    Sunderland, Tara; Kelly, John G; Ramtoola, Zebunnissa

    2015-04-01

    The aim of this study was to evaluate a novel 3-fluid concentric nozzle (3-N) spray drying process for the microencapsulation of omeprazole sodium (OME) using Eudragit L100 (EL100). Feed solutions containing OME and/or EL100 in ethanol were assessed visually for OME stability. Addition of OME solution to EL100 solution resulted in precipitation of OME followed by degradation of OME reflected by a colour change from colourless to purple and brown. This was related to the low pH of 2.8 of the EL100 solution at which OME is unstable. Precipitation and progressive discoloration of the 2-fluid nozzle (2-N) feed solution was observed over the spray drying time course. In contrast, 3-N solutions of EL100 or OME in ethanol were stable over the spray drying period. Microparticles prepared using either nozzle showed similar characteristics and outer morphology however the internal morphology was different. DSC showed a homogenous matrix of drug and polymer for 2-N microparticles while 3-N microparticles had defined drug and polymer regions distributed as core and coat. The results of this study demonstrate that the novel 3-N spray drying process can allow the microencapsulation of a drug using an incompatible polymer and maintain the drug and polymer in separate regions of the microparticles. PMID:24170510

  11. Synthesis of mesoporous-silica-coated Gd2O3:Eu@silica particles as cell imaging and drug delivery agents.

    PubMed

    Song, Weiye; Di, Weihua; Qin, Weiping

    2016-04-25

    Mesoporous-silica-coated Gd2O3:Eu/silica nanoparticles were synthesized by a multistep chemical process and characterized by XRD, TEM and N2 adsorption/desorption isotherms in terms of size, morphology and porosity. The core Gd2O3:Eu obtained by this method was highly luminescent upon excitation, giving the function of cell imaging upon incubation with the human cervical carcinoma (HeLa) cells. The outer porous silica shell is able to load the anticancer drug with a relatively high loading efficiency and release the loaded drugs at a sustained rate. The HeLa cells can be killed effectively on incubation with the core-shell porous particles loaded with the anticancer drug DOX. Meanwhile, the accumulation of mesoporous nanoparticles loaded with drugs in the target location could be monitored via fluorescence imaging. Therefore, the core-shell hybrid nanoparticles presented in this work are potential multifunctional biomaterials for smart detection or diagnosis and therapy in future biomedical engineering. PMID:27040176

  12. Comprehensive drug screening in blood for detecting abused drugs or drugs potentially hazardous for traffic safety.

    PubMed

    Lillsunde, P; Michelson, L; Forsstrom, T; Korte, T; Schultz, E; Ariniemi, K; Portman, M; Sihvonen, M L; Seppala, T

    1996-02-01

    A comprehensive drug screening procedure for detecting drugs in the blood samples of car drivers suspected of driving under the influence of drugs, is presented. Amphetamines, cannabinoids, opioids, cocaine and benzodiazepines were screened by an immunological EMIT ETS system after acetone precipitation. Gas chromatographic methods were used to screen and quantitate basic, neutral and acidic drugs. The free amino groups of basic drugs were derivatized with heptafluorobutyric anhydride. Analysis was performed by a dual channel gas chromatograph combined with a nitrogen phosphorus and an electron capture detector. Phenyltrimethylammonium hydroxide was used as a methylathing agent for acidic substances before analysis with a gas chromatograph connected to a nitrogen phosphorus detector. A gas chromatograph/mass spectrometry was used as a common confirmation method. Tetrahydrocannabinol was quantitated after bis(trimethylsilyl)trifluoroacetamide derivatization, opiates after pentafluoropropionic anhydride derivatization and benzoylecgonine after pentafluoropropionic anhydride and pentafluoropropanol derivatization. Excluding benzodiazepines, which were confirmed with a gas chromatograph connected to a nitrogen phosphorus and an electron capture detector, the other basic drugs as well as the acidic drugs were confirmed after the same derivatization procedures as in the screening methods. Alcohols were quantitated in triplicate by gas chromatography using three different kinds of columns. Although urine is the most important specimen for screening abused drugs, it has only limited use in forensic toxicology. The described system is most useful for analyzing a wide range of substances, including illicit drugs, benzodiazepines, barbiturates, antidepressants and phenothiazenes in forensic samples when urine is not available. PMID:8819994

  13. 21 CFR 878.4490 - Absorbable hemostatic agent and dressing.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Absorbable hemostatic agent and dressing. 878.4490 Section 878.4490 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... hemostatic agent and dressing. (a) Identification. An absorbable hemostatic agent or dressing is a...

  14. Performance-enhancing drugs: understanding the risks.

    PubMed

    Hatton, Caroline K; Green, Gary A; Ambrose, Peter J

    2014-11-01

    To help clinicians understand the risks associated with performance-enhancing drugs, this overview covers prohibited lists of substances and methods, therapeutic use exemptions, the legitimate indications and adverse effects, including for megadose and polypharmacy doping of stimulants, anabolic steroids, erythropoiesis-stimulating agents, and growth hormone and ways in which physicians or patients risk committing anti-doping rule violations inadvertently. PMID:25442165

  15. Lipoidal Soft Hybrid Biocarriers of Supramolecular Construction for Drug Delivery

    PubMed Central

    Kumar, Dinesh; Sharma, Deepak; Singh, Gurmeet; Singh, Mankaran; Rathore, Mahendra Singh

    2012-01-01

    Lipid-based innovations have achieved new heights during the last few years as an essential component of drug development. The current challenge of drug delivery is liberation of drug agents at the right time in a safe and reproducible manner to a specific target site. A number of novel drug delivery systems has emerged encompassing various routes of administration, to achieve controlled and targeted drug delivery. Microparticulate lipoidal vesicular system represents a unique technology platform suitable for the oral and systemic administration of a wide variety of molecules with important therapeutic biological activities, including drugs, genes, and vaccine antigens. The success of liposomes as drug carriers has been reflected in a number of liposome-based formulations, which are commercially available or are currently undergoing clinical trials. Also, novel lipid carrier-mediated vesicular systems are originated. This paper has focused on the lipid-based supramolecular vesicular carriers that are used in various drug delivery and drug targeting systems. PMID:22888455

  16. State-of-the-Art Materials for Ultrasound-Triggered Drug Delivery

    PubMed Central

    Sirsi, Shashank; Borden, Mark

    2014-01-01

    Ultrasound is a unique and exciting theranostic modality that can be used to track drug carriers, trigger drug release and improve drug deposition with high spatial precision. In this review, we briefly describe the mechanisms of interaction between drug carriers and ultrasound waves, including cavitation, streaming and hyperthermia, and how those interactions can promote drug release and tissue uptake. We then discuss the rational design of some state-of-the-art materials for ultrasound-triggered drug delivery and review recent progress for each drug carrier, focusing on the delivery of chemotherapeutic agents such as doxorubicin. These materials include nanocarrier formulations, such as liposomes and micelles, designed specifically for ultrasound-triggered drug release, as well as microbubbles, microbubble-nanocarrier hybrids, microbubble-seeded hydrogels and phase-change agents. PMID:24389162

  17. [Anti-HIV drugs and drug delivery system].

    PubMed

    Obaru, K; Mitsuya, H

    1998-03-01

    A number of candidate drugs for therapy of HIV-1 infection which show significant activity against the virus in vitro were reported; however, many of them have been dropped from drug development due to (i) insufficient intracellular activation in certain human target cells (particularly in case of nucleoside reverse transcriptase inhibitors), (ii) poor pharmacokinetic profiles, or (iii) intolerable in vitro and/or in vivo toxicities. To circumvent some of these problems, certain drug delivery systems have been applied and several candidate drugs including two novel nucleoside reverse transcriptase inhibitors, abacavir and adefovir, have acquired favorable properties in the clinical setting. This paper reviews several avenues for developing prodrugs of anti-HIV-1 agents to overcome their inherent limitations. PMID:9549371

  18. Chemical crowd control agents.

    PubMed

    Menezes, Ritesh G; Hussain, Syed Ather; Rameez, Mansoor Ali Merchant; Kharoshah, Magdy A; Madadin, Mohammed; Anwar, Naureen; Senthilkumaran, Subramanian

    2016-03-01

    Chemical crowd control agents are also referred to as riot control agents and are mainly used by civil authorities and government agencies to curtail civil disobedience gatherings or processions by large crowds. Common riot control agents used to disperse large numbers of individuals into smaller, less destructive, and more easily controllable numbers include chloroacetophenone, chlorobenzylidenemalononitrile, dibenzoxazepine, diphenylaminearsine, and oleoresin capsicum. In this paper, we discuss the emergency medical care needed by sufferers of acute chemical agent contamination and raise important issues concerning toxicology, safety and health. PMID:26658556

  19. Drug-induced lupus erythematosus.

    PubMed

    Vedove, Camilla Dalle; Del Giglio, Micol; Schena, Donatella; Girolomoni, Giampiero

    2009-01-01

    Drug-induced lupus erythematosus (DILE) is defined as a lupus-like syndrome temporally related to continuous drug exposure which resolves after discontinuation of the offending drug. There are currently no standard diagnostic criteria for DILE and the pathomechanisms are still unclear. Similarly to idiopathic lupus, DILE can be diveded into systemic (SLE), subacute cutaneous (SCLE) and chronic cutaneous lupus (CCLE). Systemic DILE is characterized by typical lupus-like symptoms including skin signs, usually mild systemic involvement and a typical laboratory profile with positive antinuclear and anti-histone antibodies, while anti-double strand (ds) DNA and anti-extractable nuclear antigens antibodies are rare. High risk drugs include hydralazine, procainamide and isoniazid. Drug-induced SCLE is very similar to idiopathic SCLE in terms of clinical and serologic characteristic, and it is more common than the systemic form of DILE. Drugs associated with SCLE include calcium channel blockers, angiotensin-converting enzyme inhibitors, interferons, thiazide diuretics and terbinafine. Drug-induced CCLE is very rarely reported in the literature and usually refers to fluorouracile agents or non steroidal anti-inflammatory drugs. Recently, cases of DILE have been reported with anti-TNFalpha agents. These cases present with disparate clinical features including arthritis/arthralgia, skin rash, serositis, cytopenia and variable laboratory abnormalities. DILE to anti-TNFalpha agents differs in several ways to classic DILE. The incidence of rashes is higher compared to classical systemic DILE. In most cases of classic DILE visceral involvement is rare, whereas several cases of anti-TNFalpha DILE with evidence of renal disease have been reported. Low serum complement levels as well as anti-extractable nuclear antigen antibodies and anti-dsDNA antibodies are rarely present in classic DILE, whereas they are reported in half the cases of anti-TNFalpha DILE; in contrast, anti

  20. Discovery of Novel Tricyclic Thiazepine Derivatives as Anti-Drug-Resistant Cancer Agents by Combining Diversity-Oriented Synthesis and Converging Screening Approach.

    PubMed

    Xiang, Jinbao; Zhang, Zhuoqi; Mu, Yan; Xu, Xianxiu; Guo, Sigen; Liu, Yongjin; Russo, Daniel P; Zhu, Hao; Yan, Bing; Bai, Xu

    2016-05-01

    An efficient discovery strategy by combining diversity-oriented synthesis and converging cellular screening is described. By a three-round screening process, we identified novel tricyclic pyrido[2,3-b][1,4]benzothiazepines showing potent inhibitory activity against paclitaxel-resistant cell line H460TaxR (EC50 < 1.0 μM), which exhibits much less toxicity toward normal cells (EC50 > 100 μM against normal human fibroblasts). The most active hits also exhibited drug-like properties suitable for further preclinical research. This redeployment of antidepressing compounds for anticancer applications provides promising future prospects for treating drug-resistant tumors with fewer side effects. PMID:27082930

  1. Fabrication of hollow and porous structured GdVO4:Dy3+ nanospheres as anticancer drug carrier and MRI contrast agent.

    PubMed

    Kang, Xiaojiao; Yang, Dongmei; Ma, Ping'an; Dai, Yunlu; Shang, Mengmeng; Geng, Dongling; Cheng, Ziyong; Lin, Jun

    2013-01-29

    Hollow and porous structured GdVO(4):Dy(3+) spheres were fabricated via a facile self-sacrificing templated method. The large cavity allows them to be used as potential hosts for therapeutic drugs, and the porous feature of the shell allows guest molecules to easily pass through the void space and surrounding environment. The samples show strong yellow-green emission of Dy(3+) (485 nm, (4)F(9/2) → (6)H(15/2); 575 nm, (4)F(9/2) → (6)H(13/2)) under UV excitation. The emission intensity of GdVO(4):Dy(3+) was weakened after encapsulation of anticancer drug (doxorubicin hydrochloride, DOX) and gradually restored with the cumulative released time of DOX. These hollow spheres were nontoxic to HeLa cells, while DOX-loaded samples led to apparent cytotoxicity as a result of the sustained release of DOX. ICP measurement indicates that free toxic Gd ions can hardly dissolate from the matrix. The endocytosis process of DOX-loaded hollow spheres is observed using confocal laser scanning microscopy (CLSM). Furthermore, GdVO(4):Dy(3+) hollow spheres can be used for T(1)-weighted magnetic resonance (MR) imaging. These results implicate that the luminescent GdVO(4):Dy(3+) spheres with hollow and porous structure are promising platforms for drug storage/release and MR imaging. PMID:23281806

  2. Molecular determinants for drug-receptor interactions. Part 2. An ab initio molecular orbital and dipole moment study of the novel nootropic agent piracetam (2-oxopyrrolidin-1-ylacetamide)

    NASA Astrophysics Data System (ADS)

    Lumbroso, H.; Liégeois, C.; Pappalardo, G. C.; Grassi, A.

    From the ab initio molecular energies of the possible conformers and from a classical dipole moment analysis of 2-oxopyrrolidin-l-ylacetamide (μ = 4.02 D in dioxan at 30.0°C), the preferred conformation in solution of this novel nootropic agent has been determined. The exocyclic N-CH 2 bond is rotated in one sense by 90° and the exocyclic CH 2-C bond rotated in the same sense by 120° from the "planar" ( OO)- cis conformation. The structures of the two enantiomers in solution differ from that of the crystalline molecule.

  3. Drug therapies in dermatology.

    PubMed

    Aslam, Arif; Griffiths, Christopher E M

    2014-02-01

    This article explores the current and emerging therapies for skin disease, with a particular focus on chronic plaque psoriasis and metastatic malignant melanoma. We discuss the current biological therapies used for psoriasis and those on the horizon, including small molecules and biosimilars. We also summarise the recent advances in the use of novel therapeutic agents in other dermatological diseases and outline the promise of translational research and stratified medicine approaches in dermatology. Better matching of patients with therapies is anticipated to have a major effect on both clinical practice and the development of new drugs and diagnostics. PMID:24532745

  4. Chapter 30: Drug allergy.

    PubMed

    Greenberger, Paul A

    2012-01-01

    Drug allergy describes clinical adverse reactions that are proved or presumed to be immunologically based. Allergic drug reactions do not resemble pharmacologic actions of the incriminated drug and may occur at fractions of what would be the therapeutic dosage. Allergic drug reactions are unpredictable; nevertheless, there is increased risk of drug hypersensitivity in (1) patients with cystic fibrosis who receive antibiotics; (2) patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) who receive trimethoprim/sulfamethoxazole of if HLA-B*5701(+) and receive the antiretroviral agent, abacavir; (3) other genetically susceptible populations such as Han-Chinese who are HLA-B*1502(+) who develop Stevens-Johnson syndrome and toxic epidermal necrolysis from carbamazepine or if HLA-B*5801(+) are at increased risk for such reactions from allopurinol; and (4) patients with a history of previous compatible allergic reaction to the same medication, similar class, or potentially unrelated medication. Specific patient groups at higher risk for drug allergy include those with Ebstein-Barr virus infection, chronic lymphatic leukemia, HIV/AIDS, cystic fibrosis, patients with seizures being treated with antiepileptic medications, and patients with asthma (especially severe asthma) who are at increased risk of anaphylaxis from any cause including drugs compared with patients without asthma. In patients with a history of penicillin allergy, skin testing helps clarify the current level of risk for anaphylaxis by using the major (penicilloyl-polylysine) and minor penicillin determinants where sensitivity is 99%. If penicilloyl-polylysine and penicillin G are used for skin testing, the sensitivity is ∼85%. When skin tests are negative, graded challenges are performed to administer optimal or truly essential antibiotics. PMID:22794703

  5. Antiretroviral drugs.

    PubMed

    De Clercq, Erik

    2010-10-01

    In October 2010, it will be exactly 25 years ago that the first antiretroviral drug, AZT (zidovudine, 3'-azido-2',3'-dideoxythymidine), was described. It was the first of 25 antiretroviral drugs that in the past 25 years have been formally licensed for clinical use. These antiretroviral drugs fall into seven categories [nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors (FIs), co-receptor inhibitors (CRIs) and integrase inhibitors (INIs). The INIs (i.e. raltegravir) represent the most recent advance in the search for effective and selective anti-HIV agents. Combination of several anti-HIV drugs [often referred to as highly active antiretroviral therapy (HAART)] has drastically altered AIDS from an almost uniformly fatal disease to a chronic manageable one. PMID:20471318

  6. Per-residue energy decomposition pharmacophore model to enhance virtual screening in drug discovery: a study for identification of reverse transcriptase inhibitors as potential anti-HIV agents

    PubMed Central

    Cele, Favourite N; Ramesh, Muthusamy; Soliman, Mahmoud ES

    2016-01-01

    A novel virtual screening approach is implemented herein, which is a further improvement of our previously published “target-bound pharmacophore modeling approach”. The generated pharmacophore library is based only on highly contributing amino acid residues, instead of arbitrary pharmacophores, which are most commonly used in the conventional approaches in literature. Highly contributing amino acid residues were distinguished based on free binding energy contributions obtained from calculation from molecular dynamic (MD) simulations. To the best of our knowledge; this is the first attempt in the literature using such an approach; previous approaches have relied on the docking score to generate energy-based pharmacophore models. However, docking scores are reportedly unreliable. Thus, we present a model for a per-residue energy decomposition, constructed from MD simulation ensembles generating a more trustworthy pharmacophore model, which can be applied in drug discovery workflow. This work is aimed at introducing a more rational approach to the field of drug design, rather than comparing the validity of this approach against those previously reported. We recommend additional computational and experimental work to further validate this approach. This approach was used to screen for potential reverse transcriptase inhibitors using the pharmacophoric features of compound GSK952. The complex was subjected to docking, thereafter, MD simulation confirmed the stability of the system. Experimentally determined inhibitors with known HIV-reverse transcriptase inhibitory activity were used to validate the protocol. Two potential hits (ZINC46849657 and ZINC54359621) showed a significant potential with regard to free binding energy. Reported results obtained from this work confirm that this new approach is favorable in the future of the drug design industry. PMID:27114700

  7. Per-residue energy decomposition pharmacophore model to enhance virtual screening in drug discovery: a study for identification of reverse transcriptase inhibitors as potential anti-HIV agents.

    PubMed

    Cele, Favourite N; Ramesh, Muthusamy; Soliman, Mahmoud Es

    2016-01-01

    A novel virtual screening approach is implemented herein, which is a further improvement of our previously published "target-bound pharmacophore modeling approach". The generated pharmacophore library is based only on highly contributing amino acid residues, instead of arbitrary pharmacophores, which are most commonly used in the conventional approaches in literature. Highly contributing amino acid residues were distinguished based on free binding energy contributions obtained from calculation from molecular dynamic (MD) simulations. To the best of our knowledge; this is the first attempt in the literature using such an approach; previous approaches have relied on the docking score to generate energy-based pharmacophore models. However, docking scores are reportedly unreliable. Thus, we present a model for a per-residue energy decomposition, constructed from MD simulation ensembles generating a more trustworthy pharmacophore model, which can be applied in drug discovery workflow. This work is aimed at introducing a more rational approach to the field of drug design, rather than comparing the validity of this approach against those previously reported. We recommend additional computational and experimental work to further validate this approach. This approach was used to screen for potential reverse transcriptase inhibitors using the pharmacophoric features of compound GSK952. The complex was subjected to docking, thereafter, MD simulation confirmed the stability of the system. Experimentally determined inhibitors with known HIV-reverse transcriptase inhibitory activity were used to validate the protocol. Two potential hits (ZINC46849657 and ZINC54359621) showed a significant potential with regard to free binding energy. Reported results obtained from this work confirm that this new approach is favorable in the future of the drug design industry. PMID:27114700

  8. The generation of induced pluripotent stem cells for macular degeneration as a drug screening platform: identification of curcumin as a protective agent for retinal pigment epithelial cells against oxidative stress

    PubMed Central

    Chang, Yun-Ching; Chang, Wei-Chao; Hung, Kuo-Hsuan; Yang, Der-Ming; Cheng, Yung-Hsin; Liao, Yi-Wen; Woung, Lin-Chung; Tsai, Ching-Yao; Hsu, Chih-Chien; Lin, Tai-Chi; Liu, Jorn-Hon; Chiou, Shih-Hwa; Peng, Chi-Hsien; Chen, Shih-Jen

    2014-01-01

    Age-related macular degeneration (AMD) is one retinal aging process that may lead to irreversible vision loss in the elderly. Its pathogenesis remains unclear, but oxidative stress inducing retinal pigment epithelial (RPE) cells damage is perhaps responsible for the aging sequence of retina and may play an important role in macular degeneration. In this study, we have reprogrammed T cells from patients with dry type AMD into induced pluripotent stem cells (iPSCs) via integration-free episomal vectors and differentiated them into RPE cells that were used as an expandable platform for investigating pathogenesis of the AMD and in-vitro drug screening. These patient-derived RPEs with the AMD-associated background (AMD-RPEs) exhibited reduced antioxidant ability, compared with normal RPE cells. Among several screened candidate drugs, curcumin caused most significant reduction of ROS in AMD-RPEs. Pre-treatment of curcumin protected these AMD-RPEs from H2O2-induced cell death and also increased the cytoprotective effect against the oxidative stress of H2O2 through the reduction of ROS levels. In addition, curcumin with its versatile activities modulated the expression of many oxidative stress-regulating genes such as PDGF, VEGF, IGFBP-2, HO1, SOD2, and GPX1. Our findings indicated that the RPE cells derived from AMD patients have decreased antioxidative defense, making RPE cells more susceptible to oxidative damage and thereby leading to AMD formation. Curcumin represented an ideal drug that can effectively restore the neuronal functions in AMD patient-derived RPE cells, rendering this drug an effective option for macular degeneration therapy and an agent against aging-associated oxidative stress. PMID:25136316

  9. Gold-based drug encapsulation within a ferritin nanocage: X-ray structure and biological evaluation as a potential anticancer agent of the Auoxo3-loaded protein.

    PubMed

    Ferraro, Giarita; Monti, Daria Maria; Amoresano, Angela; Pontillo, Nicola; Petruk, Ganna; Pane, Francesca; Cinellu, Maria Agostina; Merlino, Antonello

    2016-07-21

    Auoxo3, a cytotoxic gold(iii) compound, was encapsulated within a ferritin nanocage. Inductively coupled plasma mass spectrometry, circular dichroism, UV-Vis absorption spectroscopy and X-ray crystallography confirm the potential-drug encapsulation. The structure shows that naked Au(i) ions bind to the side chains of Cys48, His49, His114, His114 and Cys126, Cys126, His132, His147. The gold-encapsulated nanocarrier has a cytotoxic effect on different aggressive human cancer cells, whereas it is significantly less cytotoxic for non-tumorigenic cells. PMID:27326513

  10. The National Cancer Institute's PREVENT Cancer Preclinical Drug Development Program: overview, current projects, animal models, agent development strategies, and molecular targets.

    PubMed

    Shoemaker, Robert H; Suen, Chen S; Holmes, Cathy A; Fay, Judith R; Steele, Vernon E

    2016-02-01

    The PREVENT Cancer Preclinical Drug Development Program (PREVENT) is a National Cancer Institute, Division of Cancer Prevention (NCI, DCP)-supported program whose primary goal is to bring new cancer preventive interventions (small molecules and vaccines) and biomarkers through preclinical development towards clinical trials by creating partnerships between the public sector (eg, academia, industry) and DCP. PREVENT has a formalized structure for moving interventions forward in the prevention pipeline using a stage-gate process with go/no go decision points along the critical path for development. This review describes the structure of the program, its focus areas, and provides examples of projects currently in the pipeline. PMID:26970137

  11. Natural Product Leads for Drug Discovery: Isolation, Synthesis and Biological Evaluation of 6-Cyano-5-methoxyindolo[2,3-a]carbazole Based Ligands as Antibacterial Agents

    PubMed Central

    Guo, Songpo; Tipparaju, Suresh K.; Pegan, Scott D.; Wan, Baojie; Mo, Shunyan; Orjala, Jimmy; Mesecar, Andrew D.; Franzblau, Scott G.; Kozikowski, Alan P.

    2010-01-01

    Indolo[2,3-a]carbazole based inhibitors were synthesized from readily available indigo via a seven-step linear synthetic sequence with a moderate overall yield. The inhibitors were selectively and readily functionalized at the nitrogen on the indole portion of the carbazole unit. The synthesized analogs displayed moderate inhibitory activities toward B. anthracis and M. tuberculosis, indicating that indolo[2,3-a]carbazoles could serve as promising leads in the development of new drugs to combat anthrax and tuberculosis infections. PMID:19783449

  12. Emerging Drugs and Vaccines for Candidemia

    PubMed Central

    Moriyama, Brad; Gordon, Lori A.; McCarthy, Matthew; Henning, Stacey A.; Walsh, Thomas J.; Penzak, Scott R.

    2014-01-01

    Summary Candidemia and other forms of invasive candidiasis are important causes of morbidity and mortality. The evolving challenge of antimicrobial resistance among fungal pathogens continues to highlight the need for potent, new antifungal agents. MEDLINE, EMBASE, Scopus, and Web of Science searches (up to January 2014) of the English-language literature were performed with the keywords “Candida” or “Candidemia” or “Candidiasis” and terms describing investigational drugs with activity against Candida spp. Conference abstracts and the bibliographies of pertinent articles were also reviewed for relevant reports. ClinicalTrials.gov was searched for relevant clinical trials. Currently available antifungal agents for the treatment of candidemia are summarized. Investigational antifungal agents with potential activity against Candida bloodstream infections and other forms of invasive candidiasis and vaccines for prevention of Candida infections are also reviewed as are selected antifungal agents no longer in development. Antifungal agents currently in clinical trials include isavuconazole, albaconazole, SCY-078, VT-1161, and T-2307. Further data are needed to determine the role of these compounds in the treatment of candidemia and other forms of invasive candidiasis. The progressive reduction in antimicrobial drug development may result in a decline in antifungal drug discovery. Still there remains a critical need for new antifungal agents to treat and prevent invasive candidiasis and other life-threatening mycoses. PMID:25294098

  13. Drug watch.

    PubMed

    Whitson, S

    1999-01-01

    Recent developments on new anti-HIV agents and drugs for opportunistic infections are highlighted. Information is provided on the infusion inhibitor T-20; DuPont's second generation non-nukes, DPC 961 and DPC 963; Papirine (PEN203) for the human papilloma virus; Sporanox for treating fungal infections; and the antiretroviral protein, lysozyme. In addition, information is given on a plant found in the Bolivian rainforest that may contain compounds to prevent HIV infection by blocking the enzyme, integrase. Other promising new drugs addressed at the 6th Conference on Retroviruses and Opportunistic Infections are listed in a table. Contact information for US clinical trials is provided. PMID:11366758

  14. 22 CFR 51.22 - Passport agents and passport acceptance agents.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... embezzlement, identity theft, misappropriation, document fraud, drug offenses, or dishonesty in carrying out a... following: (1) Certifying the identity of each applicant. Passport acceptance agents must certify that...

  15. 22 CFR 51.22 - Passport agents and passport acceptance agents.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... embezzlement, identity theft, misappropriation, document fraud, drug offenses, or dishonesty in carrying out a... following: (1) Certifying the identity of each applicant. Passport acceptance agents must certify that...

  16. 22 CFR 51.22 - Passport agents and passport acceptance agents.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... embezzlement, identity theft, misappropriation, document fraud, drug offenses, or dishonesty in carrying out a... following: (1) Certifying the identity of each applicant. Passport acceptance agents must certify that...

  17. 22 CFR 51.22 - Passport agents and passport acceptance agents.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... embezzlement, identity theft, misappropriation, document fraud, drug offenses, or dishonesty in carrying out a... following: (1) Certifying the identity of each applicant. Passport acceptance agents must certify that...

  18. Dual delivery of active antibactericidal agents and bone morphogenetic protein at sustainable high concentrations using biodegradable sheath-core-structured drug-eluting nanofibers

    PubMed Central

    Hsu, Yung-Hen; Lin, Chang-Tun; Yu, Yi-Hsun; Chou, Ying-Chao; Liu, Shih-Jung; Chan, Err-Cheng

    2016-01-01

    In this study, we developed biodegradable sheath-core-structured drug-eluting nanofibers for sustainable delivery of antibiotics (vancomycin and ceftazidime) and recombinant human bone morphogenetic protein (rhBMP-2) via electrospinning. To prepare the biodegradable sheath-core nanofibers, we first prepared solutions of poly(d,l)-lactide-co-glycolide, vancomycin, and ceftazidime in 1,1,1,3,3,3-hexafluoro-2-propanol and rhBMP-2 in phosphate-buffered solution. The poly(d,l)-lactide-co-glycolide/antibiotics and rhBMP-2 solutions were then fed into two different capillary tubes controlled by two independent pumps for coaxial electrospinning. The electrospun nanofiber morphology was observed under a scanning electron microscope. We further characterized the in vitro antibiotic release from the nanofibers via high-performance liquid chromatography and that of rhBMP-2 via enzyme-linked immunosorbent assay and alkaline phosphatase activity. We showed that the biodegradable coaxially electrospun nanofibers could release high vancomycin/ceftazidime concentrations (well above the minimum inhibition concentration [MIC]90) and rhBMP-2 for >4 weeks. These experimental results demonstrate that novel biodegradable nanofibers can be constructed with various pharmaceuticals and proteins for long-term drug deliveries. PMID:27574423

  19. Dual delivery of active antibactericidal agents and bone morphogenetic protein at sustainable high concentrations using biodegradable sheath-core-structured drug-eluting nanofibers.

    PubMed

    Hsu, Yung-Hen; Lin, Chang-Tun; Yu, Yi-Hsun; Chou, Ying-Chao; Liu, Shih-Jung; Chan, Err-Cheng

    2016-01-01

    In this study, we developed biodegradable sheath-core-structured drug-eluting nanofibers for sustainable delivery of antibiotics (vancomycin and ceftazidime) and recombinant human bone morphogenetic protein (rhBMP-2) via electrospinning. To prepare the biodegradable sheath-core nanofibers, we first prepared solutions of poly(d,l)-lactide-co-glycolide, vancomycin, and ceftazidime in 1,1,1,3,3,3-hexafluoro-2-propanol and rhBMP-2 in phosphate-buffered solution. The poly(d,l)-lactide-co-glycolide/antibiotics and rhBMP-2 solutions were then fed into two different capillary tubes controlled by two independent pumps for coaxial electrospinning. The electrospun nanofiber morphology was observed under a scanning electron microscope. We further characterized the in vitro antibiotic release from the nanofibers via high-performance liquid chromatography and that of rhBMP-2 via enzyme-linked immunosorbent assay and alkaline phosphatase activity. We showed that the biodegradable coaxially electrospun nanofibers could release high vancomycin/ceftazidime concentrations (well above the minimum inhibition concentration [MIC]90) and rhBMP-2 for >4 weeks. These experimental results demonstrate that novel biodegradable nanofibers can be constructed with various pharmaceuticals and proteins for long-term drug deliveries. PMID:27574423

  20. Anaesthetic, cardiovascular and respiratory effects of a new steroidal agent CT 1341: a comparison with other intravenous anaesthetic drugs in the unrestrained cat.

    PubMed

    Child, K J; Davis, B; Dodds, M G; Twissell, D J

    1972-10-01

    1. The anaesthetic, cardiovascular, respiratory and adverse effects produced by the intravenous injection of CT 1341, thiopentone, methohexitone, pentobarbitone, propanidid and ketamine have been compared in unrestrained cats prepared with chronically implanted venous and arterial cannulae. Aortic blood pressure and heart rates were monitored before, during and after loss of consciousness.2. CT 1341 produced rapid induction of anaesthesia followed by moderately rapid recovery, was active over a wide range of doses and caused minimal respiratory depression and few adverse effects. It caused an initial short-lasting tachycardia and fall in aortic blood pressure succeeded by a secondary depressor response.3. The safety margin was narrower with the barbiturate drugs than with CT 1341, and large doses induced apnoea and respiratory depression. Small doses of methohexitone elicited excitatory effects and large doses caused severe respiratory and circulatory depression, and recovery from anaesthesia was protracted.4. Propanidid induced short-lasting light anaesthesia. The safety margin was narrowest with this drug and induction was associated with adverse circulatory, respiratory and other effects.5. Ketamine was active over a wide range of doses but exhibited qualitatively different properties from the other anaesthetics. Induction was slower after small doses and these produced circulatory stimulation, catatonia and bizarre behavioural effects. Large doses caused respiratory and circulatory depression and recovery was protracted.6. It is concluded that CT 1341 has a wider therapeutic latitude, produces less respiratory depression and has other advantages over the currently used intravenous anaesthetics. PMID:4651769