21 CFR 862.9 - Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act).

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act). 862.9 Section 862.9 Food and Drugs FOOD AND DRUG... Federal Food, Drug, and Cosmetic Act (the act). The exemption from the requirement of premarket...

Dual drug loaded chitosan nanoparticles-sugar--coated arsenal against pancreatic cancer.

Science.gov (United States)

David, Karolyn Infanta; Jaidev, Leela Raghav; Sethuraman, Swaminathan; Krishnan, Uma Maheswari

2015-11-01

Pancreatic cancer is an aggressive form of cancer with poor survival rates. The increased mortality due to pancreatic cancer arises due to many factors such as development of multidrug resistance, presence of cancer stem cells, development of a stromal barrier and a hypoxic environment due to hypo-perfusion. The present study aims to develop a nanocarrier for a combination of drugs that can address these multiple issues. Quercetin and 5-fluorouracil were loaded in chitosan nanoparticles, individually as well as in combination. The nanoparticles were characterized for morphology, size, zeta potential, percentage encapsulation of drugs as well as their release profiles in different media. The dual drug-loaded carrier exhibited good entrapment efficiency (quercetin 95% and 5-fluorouracil 75%) with chitosan: quercetin: 5-fluorouracil in the ratio 3:1:2. The release profiles suggest that 5-fluorouracil preferentially localized in the periphery while quercetin was located towards the core of chitosan nanoparticles. Both drugs exhibited considerable association with the chitosan matrix. The dual drug-loaded carrier system exhibited significant toxicity towards pancreatic cancer cells both in the 2D as well as in the 3D cultures. We believe that the results from these studies can open up interesting options in the treatment of pancreatic cancer. Copyright © 2015 Elsevier B.V. All rights reserved.

The Prescription Drug Marketing Act of 1987.

Science.gov (United States)

Greenberg, R B

1988-10-01

The Prescription Drug Marketing Act of 1987 is described, and its implications for hospitals and other health-care entities are discussed. The act, which became effective on July 21, 1988, is intended to reduce public health risks from adulterated, misbranded, and counterfeit drug products that enter the marketplace through drug diversion. The law provides that prescription drug products manufactured in the United States and exported can no longer be reimported, except by the product's manufacturer. It also establishes restrictions on sales of prescription drug products and samples. Samples of prescription drug products may be distributed only if a licensed prescriber requests them. Other distribution channels for samples specified in the law are permissible, provided records are maintained. Under the law, wholesale distributors must be licensed by the state and meet uniform standards. Penalties for violations of the law are also identified. According to FDA's advisory guidelines on the statute, the law will permit hospitals to return drug products, provided the return is made to the manufacturer or wholesaler and provided written notice is secured that the goods were received (for manufacturers) or the goods were destroyed or returned to the manufacturer (for wholesalers). The final chapter on drug diversion must await issuance of final FDA regulations.

21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. 1310.11 Section 1310.11 Food and Drugs DRUG ENFORCEMENT... Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. (a) The...

21 CFR 1310.10 - Removal of the exemption of drugs distributed under the Food, Drug and Cosmetic Act.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Removal of the exemption of drugs distributed under the Food, Drug and Cosmetic Act. 1310.10 Section 1310.10 Food and Drugs DRUG ENFORCEMENT... Removal of the exemption of drugs distributed under the Food, Drug and Cosmetic Act. (a) The Administrator...

Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARα+γ Agonists

Directory of Open Access Journals (Sweden)

Martin B. Oleksiewicz

2008-01-01

Full Text Available Despite clinical promise, dual-acting activators of PPARα and γ (here termed PPARα+γ agonists have experienced high attrition rates in preclinical and early clinical development, due to toxicity. In some cases, discontinuation was due to carcinogenic effect in the rat urothelium, the epithelial layer lining the urinary bladder, ureters, and kidney pelvis. Chronic pharmacological activation of PPARα is invariably associated with cancer in rats and mice. Chronic pharmacological activation of PPARγ can in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPARα as well as PPARγ, making it plausible that the urothelial carcinogenicity of PPARα+γ agonists may be caused by receptor-mediated effects (exaggerated pharmacology. Based on previously published mode of action data for the PPARα+γ agonist ragaglitazar, and the available literature about the role of PPARα and γ in rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPARα+γ agonists in the rat urothelium, which combines receptor-mediated and off-target cytotoxic effects. The proposed mode of action hypothesis is being explored in our laboratories, towards understanding the human relevance of the rat cancer findings, and developing rapid in vitro or short-term in vivo screening approaches to faciliate development of new dual-acting PPAR agonist compounds.

21 CFR 878.9 - Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act).

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act). 878.9 Section 878.9 Food and Drugs FOOD AND DRUG..., and Cosmetic Act (the act). The exemption from the requirement of premarket notification (section 510...

21 CFR 884.9 - Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act).

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act). 884.9 Section 884.9 Food and Drugs FOOD AND DRUG..., and Cosmetic Act (the act). The exemption from the requirement of premarket notification (section 510...

21 CFR 876.9 - Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act).

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act). 876.9 Section 876.9 Food and Drugs FOOD AND DRUG..., and Cosmetic Act (the act). The exemption from the requirement of premarket notification (section 510...

Reducing Prescriptions of Long-acting Benzodiazepine Drugs in Denmark

DEFF Research Database (Denmark)

Eriksen, Sophie Isabel; Bjerrum, Lars

2015-01-01

Prolonged consumption of benzodiazepine drugs (BZD) and benzodiazepine receptor agonists (zolpidem, zaleplon, zopiclone; altogether Z drugs) is related to potential physiological and psychological dependence along with other adverse effects. This study aimed to analyse the prescribing of long...... to the prescription. The observed reduction in BZD use was correlated to the introduction of new national guidelines on prescription of addictive drugs, but this study was not designed to detect a causal relationship. The prescribing of long-acting BZD decreased considerably more than the prescribing of short......-acting BZD (half-life >10 hr), compared to short-acting BZD in Denmark during a 10-year period. Descriptive analysis of total sales data from the Danish Register of Medicinal Product Statistics, to individuals in the primary healthcare sector, of all BZD and Z-drugs in the period of 2003-2013. Prescription...

21 CFR 874.9 - Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act).

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act). 874.9 Section 874.9 Food and Drugs FOOD AND DRUG... Cosmetic Act (the act). The exemption from the requirement of premarket notification (section 510(k) of the...

21 CFR 870.9 - Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act).

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act). 870.9 Section 870.9 Food and Drugs FOOD AND DRUG... Cosmetic Act (the act). The exemption from the requirement of premarket notification (section 510(k) of the...

21 CFR 868.9 - Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act).

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act). 868.9 Section 868.9 Food and Drugs FOOD AND DRUG... Cosmetic Act (the act). The exemption from the requirement of premarket notification (section 510(k) of the...

Presence of dual diagnosis between users and non-users of licit and illicit drugs in Brazil

Directory of Open Access Journals (Sweden)

Mariana Bandeira Formiga

2015-12-01

Full Text Available ABSTRACT Objective Investigate the occurrence of dual diagnosis in users of legal and illegal drugs. Methods It is an analytical, cross-sectional study with a quantitative approach, non-probabilistic intentional sampling, carried out in two centers for drug addiction treatment, by means of individual interviews. A sociodemographic questionnaire, the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST and the Mini-International Neuropsychiatric Interview (MINI were used. Results One hundred and ten volunteers divided into abstinent users (group 1, alcoholics (group 2 and users of alcohol and illicit drugs (group 3. The substances were alcohol, tobacco, crack and marijuana. A higher presence of dual diagnosis in group 3 (71.8% was observed, which decreased in group 2 (60% and 37.1% of drug abstinent users had psychiatric disorder. Dual diagnosis was associated with the risk of suicide, suicide attempts and the practice of infractions. The crack consumption was associated with the occurrence of major depressive episode and antisocial personality disorder. Conclusion It was concluded that the illicit drug users had a higher presence of dual diagnosis showing the severity of this clinical condition. It is considered essential that this clinical reality is included in intervention strategies in order to decrease the negative effects of consumption of these substances and provide better quality of life for these people.

21 CFR 886.9 - Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act).

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act). 886.9 Section 886.9 Food and Drugs FOOD AND DRUG... Provisions § 886.9 Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act...

21 CFR 872.9 - Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act).

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act). 872.9 Section 872.9 Food and Drugs FOOD AND DRUG... Provisions § 872.9 Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act...

21 CFR 888.9 - Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act).

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act). 888.9 Section 888.9 Food and Drugs FOOD AND DRUG... Provisions § 888.9 Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act...

21 CFR 892.9 - Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act).

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act). 892.9 Section 892.9 Food and Drugs FOOD AND DRUG... Provisions § 892.9 Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act...

21 CFR 882.9 - Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act).

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act). 882.9 Section 882.9 Food and Drugs FOOD AND DRUG... Provisions § 882.9 Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act...

Supramolecular "Trojan Horse" for Nuclear Delivery of Dual Anticancer Drugs.

Science.gov (United States)

Cai, Yanbin; Shen, Haosheng; Zhan, Jie; Lin, Mingliang; Dai, Liuhan; Ren, Chunhua; Shi, Yang; Liu, Jianfeng; Gao, Jie; Yang, Zhimou

2017-03-01

Nuclear delivery and accumulation are very important for many anticancer drugs that interact with DNA or its associated enzymes in the nucleus. However, it is very difficult for neutrally and negatively charged anticancer drugs such as 10-hydroxycamptothecine (HCPT). Here we report a simple strategy to construct supramolecular nanomedicines for nuclear delivery of dual synergistic anticancer drugs. Our strategy utilizes the coassembly of a negatively charged HCPT-peptide amphiphile and the positively charged cisplatin. The resulting nanomaterials behave as the "Trojan Horse" that transported soldiers (anticancer drugs) across the walls of the castle (cell and nucleus membranes). Therefore, they show improved inhibition capacity to cancer cells including the drug resistant cancer cell and promote the synergistic tumor suppression property in vivo. We envision that our strategy of constructing nanomaterials by metal chelation would offer new opportunities to develop nanomedicines for combination chemotherapy.

The impact of the Orphan Drug Act on drug discovery.

Science.gov (United States)

Haffner, Marlene E; Maher, Paul D

2006-11-01

For nearly a quarter of a century the FDA Office of Orphan Products Development has administered the US Orphan Drug Act, which assists in bringing a wide variety of drug and biological (drug) products to treat rare diseases to market. Enthusiasm for rare disease product development has been sustained, seen throughout a wide spectrum of product types and disease conditions, and has resulted in clinically meaningful medical advances. Development of programmes for rare disease treatment worldwide, coupled with the development of drugs for diseases affecting developing countries, attests to the strength of this legislation. The marketing of almost 300 products in the US for rare diseases also testifies to the depth and intensity of scientific endeavour in this area.

Rheological, mechanical and membrane penetration properties of novel dual drug systems for percutaneous delivery.

Science.gov (United States)

Woolfson, A D; Malcolm, R K; Campbell, K; Jones, D S; Russell, J A

2000-07-03

In this study it has been demonstrated that mixtures of two solid drugs, ibuprofen and methyl nicotinate, with different but complementary pharmacological activities and which exist as a single liquid phase over a wide composition range at skin temperature, can be formulated as o/w emulsions without the use of an additional hydrophobic carrier. These novel dual drug systems provided significantly enhanced in vitro penetration rates through a model lipophilic barrier membrane compared to conventional individual formulations of each active. Thus, for ibuprofen, drug penetration flux enhancements of three- and 10-fold were observed when compared to an aqueous ibuprofen suspension and a commercial alcohol-based ibuprofen formulation, respectively. Methyl nicotinate penetration rates were shown to be similar for aqueous gels and emulsified systems. Mechanisms explaining these observations are proposed. Novel dual drug formulations of ibuprofen and methyl nicotinate, formulated within the liquid range at skin temperature, were investigated by oscillatory rheology and texture profile analysis, demonstrating the effects of drug and viscosity enhancer concentrations, and disperse phase type upon the rheological, mechanical and drug penetration properties of these systems.

"Current Good Manufacturing Practices" and the Federal Food, Drug and Cosmetic Act

OpenAIRE

Goldstein, Beth F.

1995-01-01

The Food and Drug Administration (hereinafter, FDA) regulates food, drugs, and cosmetics in order to ensure that these products are safe and truthfully labelled. As part of its responsibilities under the Federal Food, Drug, and Cosmetic Act (hereinafter, Act), the FDA monitors the manufacturing practices of companies involved in the production of food, drugs, and medical devices. The manufacturing practices used by these companies must comply with certain standards, identified in the Act as "...

Novel approach for a PTX/VEGF dual drug delivery system in cardiovascular applications-an innovative bulk and surface drug immobilization.

Science.gov (United States)

Wulf, Katharina; Teske, Michael; Matschegewski, Claudia; Arbeiter, Daniela; Bajer, Dalibor; Eickner, Thomas; Schmitz, Klaus-Peter; Grabow, Niels

2018-06-01

The successive incorporation of several drugs into the polymeric bulk of implants mostly results in loss of considerable quantity of one drug, and/or the loss in quality of the coating and also in changes of drug release time points. A dual drug delivery system (DDDS) based on poly-L-lactide (PLLA) copolymers combining the effective inhibition of smooth muscle cell proliferation while simultaneously promoting re-endothelialization was successfully developed. To overcome possible antagonistic drug interactions and the limitation of the polymeric bulk material as release system for dual drugs, a novel concept which combines the bulk and surface drug immobilization for a DDDS was investigated. The advantage of this DDDS is that the bulk incorporation of fluorescein diacetate (FDAc) (model drug for paclitaxel (PTX)) via spray coating enhanced the subsequent cleavable surface coupling of vascular endothelial growth factor (VEGF) via the crosslinker bissulfosuccinimidyl suberate (BS 3 ). In the presence of the embedded FDAc, the VEGF loading and release are about twice times higher than in absence. Furthermore, the DDDS combines the diffusion drug delivery (FDAc or PTX) and the chemical controlled drug release, VEGF via hydrolysable ester bonds, without loss in quantity and quality of the drug release curves. Additionally, the performed in vitro biocompatibility study showed the bimodal influences of PTX and VEGF on human endothelial EA.hy926 cells. In conclusion, it was possible to show the feasibility to develop a novel DDDS which has a high potential for the medical application due to the possible easy and short modification of a polymer-based PTX delivery system.

Sign my e-petition to make changes to misuse of drugs act.

Science.gov (United States)

Griffiths, Matt

2012-02-29

My medicines management article (reflections February 8) highlighted legal muddles over the prescription of controlled drugs. The Medicines Act was amended four years ago to allow independent nurse prescribers to prescribe almost all controlled drugs. But the Misuse of Drugs Act needs to amended to make this legally possible.

Development of sustained and dual drug release co-extrusion formulations for individual dosing.

Science.gov (United States)

Laukamp, Eva Julia; Vynckier, An-Katrien; Voorspoels, Jody; Thommes, Markus; Breitkreutz, Joerg

2015-01-01

In personalized medicine and patient-centered medical treatment individual dosing of medicines is crucial. The Solid Dosage Pen (SDP) allows for an individual dosing of solid drug carriers by cutting them into tablet-like slices. The aim of the present study was the development of sustained release and dual release formulations with carbamazepine (CBZ) via hot-melt co-extrusion for the use in the SDP. The selection of appropriate coat- and core-formulations was performed by adapting the mechanical properties (like tensile strength and E-modulus) for example. By using different excipients (polyethyleneglycols, poloxamers, white wax, stearic acid, and carnauba wax) and drug loadings (30-50%) tailored dissolution kinetics was achieved showing cube root or zero order release mechanisms. Besides a biphasic drug release, the dose-dependent dissolution characteristics of sustained release formulations were minimized by a co-extruded wax-coated formulation. The dissolution profiles of the co-extrudates were confirmed during short term stability study (six months at 21.0 ± 0.2 °C, 45%r.h.). Due to a good layer adhesion of core and coat and adequate mechanical properties (maximum cutting force of 35.8 ± 2.0 N and 26.4 ± 2.8 N and E-modulus of 118.1 ± 8.4 and 33.9 ± 4.5 MPa for the dual drug release and the wax-coated co-extrudates, respectively) cutting off doses via the SDP was precise. While differences of the process parameters (like the barrel temperature) between the core- and the coat-layer resulted in unsatisfying content uniformities for the wax-coated co-extrudates, the content uniformity of the dual drug release co-extrudates was found to be in compliance with pharmacopoeial specification. Copyright © 2015 Elsevier B.V. All rights reserved.

76 FR 79195 - Animal Drug User Fee Act; Reopening of the Comment Period

Science.gov (United States)

2011-12-21

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-N-0656] Animal Drug User Fee Act; Reopening of the Comment Period AGENCY: Food and Drug Administration, HHS... notice, FDA requested comments on the Animal Drug User Fee Act (ADUFA) program to date and solicited...

Bone scintigraphy during therapy with cytostatically acting drugs

International Nuclear Information System (INIS)

Schmidt, U.; Pries, H.H.; Joseph, K.; Mahlstedt, J.; Marburg Univ.

1976-01-01

Case reports show up, that bone scintigraphy during therapy of metastasing cancer of mamma or prostata with cytostatically acting drugs may reveal 'pseudonormal' results. False negative diagnosis can be excluded only by carefully regarding drug history. Gamma-camera with wholebody scan device for scintigraphy in two projections simplifies safe evaluation significantly. (orig.) [de

Biocompatible magnetic and molecular dual-targeting polyelectrolyte hybrid hollow microspheres for controlled drug release.

Science.gov (United States)

Du, Pengcheng; Zeng, Jin; Mu, Bin; Liu, Peng

2013-05-06

Well-defined biocompatible magnetic and molecular dual-targeting polyelectrolyte hybrid hollow microspheres have been accomplished via the layer-by-layer (LbL) self-assembly technique. The hybrid shell was fabricated by the electrostatic interaction between the polyelectrolyte cation, chitosan (CS), and the hybrid anion, citrate modified ferroferric oxide nanoparticles (Fe3O4-CA), onto the uniform polystyrene sulfonate microsphere templates. Then the magnetic hybrid core/shell composite particles were modified with a linear, functional poly(ethylene glycol) (PEG) monoterminated with a biotargeting molecule (folic acid (FA)). Afterward the dual targeting hybrid hollow microspheres were obtained after etching the templates by dialysis. The dual targeting hybrid hollow microspheres exhibit exciting pH response and stability in high salt-concentration media. Their pH-dependent controlled release of the drug molecule (anticancer drug, doxorubicin (DOX)) was also investigated in different human body fluids. As expected, the cell viability of the HepG2 cells which decreased more rapidly was treated by the FA modified hybrid hollow microspheres rather than the unmodified one in the in vitro study. The dual-targeting hybrid hollow microspheres demonstrate selective killing of the tumor cells. The precise magnetic and molecular targeting properties and pH-dependent controlled release offers promise for cancer treatment.

21 CFR 864.9 - Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act).

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act). 864.9 Section 864.9 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY...

Adolescents at Risk for Drug Abuse: A 3-Year Dual Process Analysis

Science.gov (United States)

Ames, S.L.; Xie, B.; Shono, Y.; Stacy, A.W.

2016-01-01

Aims To test longitudinal additive and synergistic dual process models in youth at documented risk for drug use. The specific dual process approach examined suggests that engaging in drug use behaviors results from a dynamic interplay between automatically-activated associative memory processes and executive reflective/control processes. Design This 3-year, three-wave population-based prospective study used mobile computer-based assessments. Setting Self-directed computer assessments were completed in school settings in the Los Angeles metropolitan area, California, USA. Participants 725 at-risk adolescents (44% female) in continuation high schools were recruited during 9th grade (age at recruitment, 14 to 16). Measurements Key outcome measures included past year alcohol, marijuana and cigarette use at each assessment. Predictors included working memory capacity (WMC), associative memory, the interaction term WMC by associative memory, sex, age, ethnicity, and acculturation. Findings A significant cross-sectional interaction revealed tobacco-relevant associations were weaker predictors of cigarette use among males with higher WMC than among those with lower WMC (p<0.004). Alternatively, drug-relevant associations were stronger predictors of past year alcohol (p<0.001) and marijuana use (p=0.02) among females with higher WMC than among those with lower WMC. Longitudinal analyses revealed no significant interactions after adjusting for predictive effects of previous drug use. With respect to WMC, females with higher WMC were less likely to use marijuana at two-year follow-up (p=0.03). First-order effects of drug-related associations prospectively predicted greater alcohol and marijuana use in males at one and two-year follow up (p≤0.03), and greater past year alcohol and marijuana use in females at one-year follow up (p≤0.03). Conclusions Drug-relevant memory associations play a key role in drug use behavior in at-risk youth. PMID:28010052

Adolescents at risk for drug abuse: a 3-year dual-process analysis.

Science.gov (United States)

Ames, Susan L; Xie, Bin; Shono, Yusuke; Stacy, Alan W

2017-05-01

To test longitudinal additive and synergistic dual-process models in youth at documented risk for drug use. The specific dual-process approach examined suggests that engaging in drug use behaviors results from a dynamic interplay between automatically activated associative memory processes and executive reflective/control processes. This 3-year, three-wave population-based prospective study used mobile computer-based assessments. Self-directed computer assessments were completed in school settings in the Los Angeles metropolitan area, California, USA. Seven hundred and twenty-five at-risk adolescents (44% female) in continuation high schools were recruited during 9th grade (age at recruitment, 14-16). Key outcome measures included past year alcohol, marijuana and cigarette use at each assessment. Predictors included working memory capacity (WMC), associative memory, the interaction term WMC by associative memory, sex, age, ethnicity and acculturation. A significant cross-sectional interaction revealed tobacco-relevant associations were weaker predictors of cigarette use among males with higher WMC than among those with lower WMC (P < 0.004). Alternatively, drug-relevant associations were stronger predictors of past year alcohol (P < 0.001) and marijuana use (P = 0.02) among females with higher WMC than among those with lower WMC. Longitudinal analyses revealed no significant interactions after adjusting for predictive effects of previous drug use. With respect to WMC, females with higher WMC were less likely to use marijuana at 2-year follow-up (P = 0.03). First-order effects of drug-related associations predicted greater alcohol and marijuana use prospectively in males at 1- and 2-year follow up (P ≤ 0.03), and greater past year alcohol and marijuana use in females at 1-year follow up (P ≤ 0.03). Drug-relevant memory associations play a key role in drug use behavior in at-risk youth. © 2016 Society for the Study of Addiction.

Prevalence of Malaria Parasitemia and Purchase of Artemisinin-Based Combination Therapies (ACTs) among Drug Shop Clients in Two Regions in Tanzania with ACT Subsidies

Science.gov (United States)

Briggs, Melissa A.; Kalolella, Admirabilis; Bruxvoort, Katia; Wiegand, Ryan; Lopez, Gerard; Festo, Charles; Lyaruu, Pierre; Kenani, Mitya; Abdulla, Salim; Goodman, Catherine; Kachur, S. Patrick

2014-01-01

Background Throughout Africa, many people seek care for malaria in private-sector drug shops where diagnostic testing is often unavailable. Recently, subsidized artemisinin-based combination therapies (ACTs), a first-line medication for uncomplicated malaria, were made available in these drug shops in Tanzania. This study assessed the prevalence of malaria among and purchase of ACTs by drug shop clients in the setting of a national ACT subsidy program and sub-national drug shop accreditation program. Method and Findings A cross-sectional survey of drug shop clients was performed in two regions in Tanzania, one with a government drug shop accreditation program and one without, from March-May, 2012. Drug shops were randomly sampled from non-urban districts. Shop attendants were interviewed about their education, training, and accreditation status. Clients were interviewed about their symptoms and medication purchases, then underwent a limited physical examination and laboratory testing for malaria. Malaria prevalence and predictors of ACT purchase were assessed using univariate analysis and multiple logistic regression. Amongst 777 clients from 73 drug shops, the prevalence of laboratory-confirmed malaria was 12% (95% CI: 6–18%). Less than a third of clients with malaria had purchased ACTs, and less than a quarter of clients who purchased ACTs tested positive for malaria. Clients were more likely to have purchased ACTs if the participant was 5 years, experience (aOR: 2.8; 95% CI: 1.2–6.3). Having malaria was only a predictor of ACT purchase in the region with a drug shop accreditation program (aOR: 3.4; 95% CI: 1.5–7.4). Conclusion Malaria is common amongst persons presenting to drug shops with a complaint of fever. The low proportion of persons with malaria purchasing ACTs, and the high proportion of ACTs going to persons without malaria demonstrates a need to better target who receives ACTs in these drug shops. PMID:24732258

Poly(acrylic acid) conjugated hollow mesoporous carbon as a dual-stimuli triggered drug delivery system for chemo-photothermal synergistic therapy

Energy Technology Data Exchange (ETDEWEB)

Li, Xian; Liu, Chang; Wang, Shengyu; Jiao, Jian; Di, Donghua; Jiang, Tongying; Zhao, Qinfu, E-mail: zqf021110505@163.com; Wang, Siling, E-mail: silingwang@syphu.edu.cn

2017-02-01

In this work, we described the development of the redox and pH dual stimuli-responsive drug delivery system and combination of the chemotherapy and photothermal therapy for cancer treatment. The poly(acrylic acid) (PAA) was conjugated on the outlets of hollow mesoporous carbon (HMC) via disulfide bonds. PAA was used as a capping to block drug within the mesopores of HMC for its lots of favorable advantages, such as good biocompatibility, appropriate molecular weight to block the mesopores of HMC, extension of the blood circulation, and the improvement of the dispersity of the nano-carriers in physiological environment. The DOX loaded DOX/HMC-SS-PAA had a high drug loading amount up to 51.9%. The in vitro drug release results illustrated that DOX/HMC-SS-PAA showed redox and pH dual-responsive drug release, and the release rate could be further improved by the near infrared (NIR) irradiation. Cell viability experiment indicated that DOX/HMC-SS-PAA had a synergistic therapeutic effect by combination of chemotherapy and photothermal therapy. This work suggested that HMC-SS-PAA exhibited dual-responsive drug release property and could be used as a NIR-adsorbing drug delivery system for chemo-photothermal synergistic therapy. - Highlights: • Poly(acrylic acid) was grafted on hollow mesoporous carbon (HMC) via disulfide bonds. • The grafted PAA could increase the biocompatibility and stability of HMC. • The DOX-loaded DOX/HMC-SS-PAA had a high drug loading efficiency up to 51.9%. • DOX/HMC-SS-PAA showed redox/pH dual-responsive and NIR-triggered drug release. • DOX/HMC-SS-PAA showed a chemo/photothermal synergistic therapy effect.

Poly(acrylic acid) conjugated hollow mesoporous carbon as a dual-stimuli triggered drug delivery system for chemo-photothermal synergistic therapy

International Nuclear Information System (INIS)

Li, Xian; Liu, Chang; Wang, Shengyu; Jiao, Jian; Di, Donghua; Jiang, Tongying; Zhao, Qinfu; Wang, Siling

2017-01-01

In this work, we described the development of the redox and pH dual stimuli-responsive drug delivery system and combination of the chemotherapy and photothermal therapy for cancer treatment. The poly(acrylic acid) (PAA) was conjugated on the outlets of hollow mesoporous carbon (HMC) via disulfide bonds. PAA was used as a capping to block drug within the mesopores of HMC for its lots of favorable advantages, such as good biocompatibility, appropriate molecular weight to block the mesopores of HMC, extension of the blood circulation, and the improvement of the dispersity of the nano-carriers in physiological environment. The DOX loaded DOX/HMC-SS-PAA had a high drug loading amount up to 51.9%. The in vitro drug release results illustrated that DOX/HMC-SS-PAA showed redox and pH dual-responsive drug release, and the release rate could be further improved by the near infrared (NIR) irradiation. Cell viability experiment indicated that DOX/HMC-SS-PAA had a synergistic therapeutic effect by combination of chemotherapy and photothermal therapy. This work suggested that HMC-SS-PAA exhibited dual-responsive drug release property and could be used as a NIR-adsorbing drug delivery system for chemo-photothermal synergistic therapy. - Highlights: • Poly(acrylic acid) was grafted on hollow mesoporous carbon (HMC) via disulfide bonds. • The grafted PAA could increase the biocompatibility and stability of HMC. • The DOX-loaded DOX/HMC-SS-PAA had a high drug loading efficiency up to 51.9%. • DOX/HMC-SS-PAA showed redox/pH dual-responsive and NIR-triggered drug release. • DOX/HMC-SS-PAA showed a chemo/photothermal synergistic therapy effect.

DANGEROUS AND HYPNOTIC DRUG ACT

Science.gov (United States)

Whelan, William M.

1961-01-01

It is unprofessional conduct within the meaning of the Medical Practice Act to prescribe a dangerous drug without either a medical examination by a physician or other medical indications. Dangerous and hypnotic drugs are specifically defined by both state and federal law and distribution is strictly regulated. A physician may administer to his own patients such amounts of dangerous drugs as are necessary for the immediate needs of the patient. The physician may obtain such needed amounts of these drugs by an order placed with a pharmacist marked “for administration to immediate needs of patients.” A licensed physician may also prescribe dangerous and hypnotic drugs for patients and such prescriptions may be refilled on the specific authorization of the physician. A physician who dispenses dangerous and hypnotic drugs to patients must obtain a hypnotic drug license; he must use specific purchase orders when purchasing; the drugs must be labeled in the manner provided by law; and all records of sale shall be open to inspection by authorized officers of the law and kept for three years. By the Principles of Medical Ethics physicians are bound to limit the source of their professional income to medical services actually rendered. Recent decisions of the Judicial Council answer questions concerning a physician's interest in a corporation which purchases, packages and sells medicines under a corporate name. Also answered are questions as to the measures that exist to prevent physicians from abusing the privilege of owning a pharmacy, and whether a physician can ethically rent space in a building owned by him to a pharmacist with a percentage of the income of the pharmacy as rental. The public welfare of California and the nation as determined by legislation strictly regulates the distribution of dangerous drugs. It is in the best interest of the medical profession and its patients that these laws be understood and carefully observed. PMID:13784776

Design of dual action antibiotics as an approach to search for new promising drugs

International Nuclear Information System (INIS)

Tevyashova, A N; Olsufyeva, E N; Preobrazhenskaya, M N

2015-01-01

The review is devoted to the latest achievements in the design of dual action antibiotics — heterodimeric (chimeric) structures based on antibacterial agents of different classes (fluoroquinolones, anthracyclines, oxazolidines, macrolides and so on). Covalent binding can make the pharmacokinetic characteristics of these molecules more predictable and improve the penetration of each component into the cell. Consequently, not only does the drug efficacy increase owing to inhibition of two targets but also the resistance to one or both antibiotics can be overcome. The theoretical grounds of elaboration, design principles and methods for the synthesis of dual action antibiotics are considered. The structures are classified according to the type of covalent spacer (cleavable or not) connecting the moieties of two agents. Dual action antibiotics with a spacer that can be cleaved in a living cell are considered as dual action prodrugs. Data on the biological action of heterodimeric compounds are presented and structure–activity relationships are analyzed. The bibliography includes 225 references

Computer-Aided Drug Design Applied to Marine Drug Discovery: Meridianins as Alzheimer's Disease Therapeutic Agents.

Science.gov (United States)

Llorach-Pares, Laura; Nonell-Canals, Alfons; Sanchez-Martinez, Melchor; Avila, Conxita

2017-11-27

Computer-aided drug discovery/design (CADD) techniques allow the identification of natural products that are capable of modulating protein functions in pathogenesis-related pathways, constituting one of the most promising lines followed in drug discovery. In this paper, we computationally evaluated and reported the inhibitory activity found in meridianins A-G, a group of marine indole alkaloids isolated from the marine tunicate Aplidium , against various protein kinases involved in Alzheimer's disease (AD), a neurodegenerative pathology characterized by the presence of neurofibrillary tangles (NFT). Balance splitting between tau kinase and phosphate activities caused tau hyperphosphorylation and, thereby, its aggregation and NTF formation. Inhibition of specific kinases involved in its phosphorylation pathway could be one of the key strategies to reverse tau hyperphosphorylation and would represent an approach to develop drugs to palliate AD symptoms. Meridianins bind to the adenosine triphosphate (ATP) binding site of certain protein kinases, acting as ATP competitive inhibitors. These compounds show very promising scaffolds to design new drugs against AD, which could act over tau protein kinases Glycogen synthetase kinase-3 Beta (GSK3β) and Casein kinase 1 delta (CK1δ, CK1D or KC1D), and dual specificity kinases as dual specificity tyrosine phosphorylation regulated kinase 1 (DYRK1A) and cdc2-like kinases (CLK1). This work is aimed to highlight the role of CADD techniques in marine drug discovery and to provide precise information regarding the binding mode and strength of meridianins against several protein kinases that could help in the future development of anti-AD drugs.

(Glyco)-protein drug carriers with an intrinsic therapeutic activity : The concept of dual targeting

NARCIS (Netherlands)

Meijer, D.K F; Molema, Ingrid; Moolenaar, Frits; de Zeeuw, D; Swart, P.J

Dual targeting can in principle be achieved by using intrinsically active carriers that not only deliver the conjugated drug but also otherwise influence the pathological process. Potential carriers of this kind are monoclonal antibodies, certain interferons and interleukins, as well as certain

Review of Drug Quality and Security Act of 2013: The Drug Supply Chain Security Act (DSCSA

Directory of Open Access Journals (Sweden)

Elona Gjini

2016-10-01

Full Text Available The Drug Supply Chain Security Act (DSCSA signed into law in November 27, 2013 by president Obama creates a uniform national standard for tracing drug products through the supply chain. The goal of DQSA is to enhance FDA’s ability to help protect consumers by detecting and removing potential dangerous products from the pharmaceutics distribution supply chain. A new electronic, interoperable system will identify and trace only prescription drugs in the finished form for human use while distributed in the United States. The purpose of this review was to shed light on a complex and complicated process that it will require cooperation between FDA and drug manufactures, wholesale drug distributors, repackagers and dispensers. The implementation of the DSCSA is based on several law requirements and FDA has developed a schedule with time frames for each of them to be executed over a 10-year period. From this review, FDA recommendations are provided through the FDA Guidance on Identifying Suspect Product document to help trading partners and provide information about the risk of suspect drugs entering the supply chain. Moreover, FDA organized on April 5-6, 2016 in Silver Spring, MD a public workshop to gather valuable feedback from stakeholders who shared their input about the implementation of the new electronic system and its requirements. By the end of 2023, a unified system will provide easier data exchange and less errors, and will increase the safety and security of the pharmaceutical distribution supply chain.   Type: Student Project

75 FR 32483 - Prescription Drug User Fee Act; Meetings on Reauthorization; Request for Notification of...

Science.gov (United States)

2010-06-08

.../Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FoodandDrugAdministration... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2010-N-0128] Prescription Drug User Fee Act; Meetings on Reauthorization; Request for Notification of Stakeholder Intention...

Drug-Free Schools and Communities Act Compliance at Michigan Community Colleges

Science.gov (United States)

Custer, Bradley D.

2018-01-01

In 1989, Congress passed the Drug-Free Schools and Communities Act Amendments to address illegal alcohol and drug abuse on college campuses. To receive federal funding, each college must comply by implementing an alcohol and drug prevention program, but the federal government and some colleges have paid little attention to this policy. Recently,…

Dual specificity of activin type II receptor ActRIIb in dorso-ventral patterning during zebrafish embryogenesis.

Science.gov (United States)

Nagaso, H; Suzuki, A; Tada, M; Ueno, N

1999-04-01

Members of the transforming growth factor-beta (TGF-beta) superfamily are thought to regulate specification of a variety of tissue types in early embryogenesis. These effects are mediated through a cell surface receptor complex, consisting of two classes of ser/thr kinase receptor, type I and type II. In the present study, cDNA encoding zebrafish activin type II receptors, ActRIIa and ActRIIb was cloned and characterized. Overexpression of ActRIIb in zebrafish embryos caused dorsalization of embryos, as observed in activin-overexpressing embryos. However, in blastula stage embryos, ActRIIb induced formation of both dorsal and ventro-lateral mesoderm. It has been suggested that these inducing signals from ActRIIb are mediated through each specific type I receptor, TARAM-A and BMPRIA, depending on activin and bone morphogenetic protein (BMP), respectively. In addition, it was shown that a kinase-deleted form of ActRIIb (dnActRIIb) suppressed both activin- and BMP-like signaling pathways. These results suggest that ActRIIb at least has dual roles in both activin and BMP signaling pathways during zebrafish embryogenesis.

Redox and pH dual-responsive PEG and chitosan-conjugated hollow mesoporous silica for controlled drug release

Energy Technology Data Exchange (ETDEWEB)

Jiao, Jian; Li, Xian; Zhang, Sha; Liu, Jie; Di, Donghua [Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning Province 110016 (China); Zhang, Ying [School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, PR China. (China); Zhao, Qinfu, E-mail: zqf021110505@163.com [Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning Province 110016 (China); Wang, Siling, E-mail: silingwang@syphu.edu.cn [Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning Province 110016 (China)

2016-10-01

In this paper, a hollow mesoporous silica nanoparticles (HMSN) was used as the drug vehicle to develop the redox and pH dual stimuli-responsive delivery system, in which the chitosan (CS), a biodegradable cationic polymer, was grafted on the surface of HMSN via the cleavable disulfide bonds. CS was chosen as the gatekeeper mainly due to its appropriate molecular weight as well as possessing abundant amino groups which could be protonated in the acidic condition to achieve pH-responsive drug release. In addition, the PEG was further grafted on the surface of CS to increase the stability and biocompatibility under physiological conditions. The DOX loaded DOX/HMSN-SS-CS@PEG had a relatively high drug loading efficiency up to 32.8%. In vitro release results indicated that DOX was dramatically blocked within the mesopores of HMSN-SS-CS@PEG in pH 7.4 PBS without addition of GSH. However, the release rate of DOX was markedly increased after the addition of 10 mM GSH or in pH 5.0 release medium. Moreover, the release of DOX was further improved in pH 5.0 PBS with 10 mM GSH. The HMSN-SS-CS@PEG could markedly decrease the hemolysis percent and protein adsorption, and increase the biocompatibility and stability of HMSN compared with the HMSN-SS-CS and bare HMSN. This work suggested an exploration about HMSN based stimuli-responsive drug delivery and these results demonstrated that HMSN-SS-CS@PEG exhibited dual-responsive drug release property and could be used as a promising carrier for cancer therapy. - Highlights: • Hollow mesoporous silica nanoparticles (HMSN) were used as a drug carrier. • Chitosan (CS) and PEG were grafted on the surface of HMSN via disulfide bonds. • The DOX loaded DOX/HMSN-SS-CS@PEG had a high drug loading efficiency up to 32.8%. • DOX/HMSN-SS-CS@PEG showed redox/pH dual-responsive drug release property in vitro. • The grafted PEG could increase the biocompatibility and stability of HMSN.

Redox and pH dual-responsive PEG and chitosan-conjugated hollow mesoporous silica for controlled drug release

International Nuclear Information System (INIS)

Jiao, Jian; Li, Xian; Zhang, Sha; Liu, Jie; Di, Donghua; Zhang, Ying; Zhao, Qinfu; Wang, Siling

2016-01-01

In this paper, a hollow mesoporous silica nanoparticles (HMSN) was used as the drug vehicle to develop the redox and pH dual stimuli-responsive delivery system, in which the chitosan (CS), a biodegradable cationic polymer, was grafted on the surface of HMSN via the cleavable disulfide bonds. CS was chosen as the gatekeeper mainly due to its appropriate molecular weight as well as possessing abundant amino groups which could be protonated in the acidic condition to achieve pH-responsive drug release. In addition, the PEG was further grafted on the surface of CS to increase the stability and biocompatibility under physiological conditions. The DOX loaded DOX/HMSN-SS-CS@PEG had a relatively high drug loading efficiency up to 32.8%. In vitro release results indicated that DOX was dramatically blocked within the mesopores of HMSN-SS-CS@PEG in pH 7.4 PBS without addition of GSH. However, the release rate of DOX was markedly increased after the addition of 10 mM GSH or in pH 5.0 release medium. Moreover, the release of DOX was further improved in pH 5.0 PBS with 10 mM GSH. The HMSN-SS-CS@PEG could markedly decrease the hemolysis percent and protein adsorption, and increase the biocompatibility and stability of HMSN compared with the HMSN-SS-CS and bare HMSN. This work suggested an exploration about HMSN based stimuli-responsive drug delivery and these results demonstrated that HMSN-SS-CS@PEG exhibited dual-responsive drug release property and could be used as a promising carrier for cancer therapy. - Highlights: • Hollow mesoporous silica nanoparticles (HMSN) were used as a drug carrier. • Chitosan (CS) and PEG were grafted on the surface of HMSN via disulfide bonds. • The DOX loaded DOX/HMSN-SS-CS@PEG had a high drug loading efficiency up to 32.8%. • DOX/HMSN-SS-CS@PEG showed redox/pH dual-responsive drug release property in vitro. • The grafted PEG could increase the biocompatibility and stability of HMSN.

Mesoporous silicate nanoparticles/3D nanofibrous scaffold-mediated dual-drug delivery for bone tissue engineering.

Science.gov (United States)

Yao, Qingqing; Liu, Yangxi; Selvaratnam, Balaranjan; Koodali, Ranjit T; Sun, Hongli

2018-04-09

Controlled delivery systems play a critical role in the success of bone morphogenetic proteins (i.e., BMP2 and BMP7) for challenged bone repair. Instead of single-drug release that is currently and commonly prevalent, dual-drug delivery strategies are highly desired to achieve effective bone regeneration because natural bone repair process is driven by multiple factors. Particularly, angiogenesis is essential for osteogenesis and requires more than just one factor (e.g., Vascular Endothelial Growth Factor, VEGF). Therefore, we developed a novel mesoporous silicate nanoparticles (MSNs) incorporated-3D nanofibrous gelatin (GF) scaffold for dual-delivery of BMP2 and deferoxamine (DFO). DFO is a hypoxia-mimetic drug that can activate hypoxia-inducible factor-1 alpha (HIF-1α), and trigger subsequent angiogenesis. Sustained BMP2 release system was achieved through encapsulation into large-pored MSNs, while the relative short-term release of DFO was engineered through covalent conjugation with chitosan to reduce its cytotoxicity and elongate its half-life. Both MSNs and DFO were incorporated onto a porous 3D GF scaffold to serve as a biomimetic osteogenic microenvironment. Our data indicated that DFO and BMP2 were released from a scaffold at different release rates (10 vs 28 days) yet maintained their angiogenic and osteogenic ability, respectively. Importantly, our data indicated that the released DFO significantly improved BMP2-induced osteogenic differentiation where the dose/duration was important for its effects in both mouse and human stem cell models. Thus, we developed a novel and tunable MSNs/GF 3D scaffold-mediated dual-drug delivery system and studied the potential application of the both FDA-approved DFO and BMP2 for bone tissue engineering. Copyright © 2018 Elsevier B.V. All rights reserved.

Presence of dual diagnosis between users and non-users of licit and illicit drugs in Brazil

OpenAIRE

Formiga,Mariana Bandeira; Vasconcelos,Selene Cordeiro; Galdino,Melyssa Kellyane Cavalcanti; Lima,Murilo Duarte da Costa

2015-01-01

ABSTRACT Objective Investigate the occurrence of dual diagnosis in users of legal and illegal drugs. Methods It is an analytical, cross-sectional study with a quantitative approach, non-probabilistic intentional sampling, carried out in two centers for drug addiction treatment, by means of individual interviews. A sociodemographic questionnaire, the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) and the Mini-International Neuropsychiatric Interview (MINI) were used. R...

Macromolecular bipill of gemcitabine and methotrexate facilitates tumor-specific dual drug therapy with higher benefit-to-risk ratio

DEFF Research Database (Denmark)

Das, Manasmita; Jain, Roopal; Agrawal, Ashish Kumar

2014-01-01

-PEG-MTX conjugate over all other pharmaceutical preparations including free drugs, physical mixture of GEM and MTX, and PEGylated GEM/MTX. Toxicity studies in tumor bearing rats as well as healthy mice corroborated that dual drug conjugation is an effective means to synergize the therapeutic indices of potential...

Dual antiretroviral therapy for HIV infection.

Science.gov (United States)

Soriano, Vicente; Fernandez-Montero, Jose Vicente; Benitez-Gutierrez, Laura; Mendoza, Carmen de; Arias, Ana; Barreiro, Pablo; Peña, José M; Labarga, Pablo

2017-08-01

For two decades, triple combinations of antiretrovirals have been the standard treatment for HIV infection. The challenges of such lifelong therapy include long-term side effects, high costs and reduced drug adherence. The recent advent of more potent and safer antiretrovirals has renewed the interest for simpler HIV regimens. Areas covered: We discuss the pros and cons of dual antiretroviral therapies in both drug-naïve and in treatment-experienced patients with viral suppression (switch strategy). Expert opinion: Some dual antiretroviral regimens are safe and efficacious, particularly as maintenance therapy. At this time, combinations of dolutegravir plus rilpivirine represent the best dual regimen. Longer follow-up and larger study populations are needed before supporting dolutegravir plus lamivudine. In contrast, dual therapy based on maraviroc is less effective. Although dual regimens with boosted protease inhibitors plus either lamivudine or raltegravir may be effective, they are penalized by metabolic side effects and risk for drug interactions. The newest dual regimens could save money, reduce toxicity and spare drug options for the future. For the first time in HIV therapeutics, less can be more. Dual therapy switching has set up a new paradigm in HIV treatment that uses induction-maintenance.

28 CFR 0.177 - Applications for orders under the Comprehensive Drug Abuse Prevention and Control Act.

Science.gov (United States)

2010-07-01

... Comprehensive Drug Abuse Prevention and Control Act. 0.177 Section 0.177 Judicial Administration DEPARTMENT OF... the Comprehensive Drug Abuse Prevention and Control Act. Notwithstanding the delegation of functions... authorized to exercise the authority vested in the Attorney General by section 514 of the Comprehensive Drug...

Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase Inhibitors.

Science.gov (United States)

Oliveira, Catarina; Cagide, Fernando; Teixeira, José; Amorim, Ricardo; Sequeira, Lisa; Mesiti, Francesco; Silva, Tiago; Garrido, Jorge; Remião, Fernando; Vilar, Santiago; Uriarte, Eugenio; Oliveira, Paulo J; Borges, Fernanda

2018-01-01

Alzheimer's disease (AD) is a multifactorial age-related disease associated with oxidative stress (OS) and impaired cholinergic transmission. Accordingly, targeting mitochondrial OS and restoring cholinergic transmission can be an effective therapeutic strategy toward AD. Herein, we report for the first time dual-target hydroxybenzoic acid (HBAc) derivatives acting as mitochondriotropic antioxidants and cholinesterase (ChE) inhibitors. The studies were performed with two mitochondriotropic antioxidants AntiOxBEN 1 (catechol derivative), and AntiOxBEN 2 (pyrogallol derivative) and compounds 15-18 , which have longer spacers. Compounds AntiOxBEN 1 and 15 , with a shorter carbon chain spacer (six- and eight-carbon) were shown to be potent antioxidants and BChE inhibitors (IC 50 = 85 ± 5 and 106 ± 5 nM, respectively), while compounds 17 and 18 with a 10-carbon chain were more effective AChE inhibitors (IC 50 = 7.7 ± 0.4 and 7.2 ± 0.5 μM, respectively). Interestingly, molecular modeling data pointed toward bifunctional ChEs inhibitors. The most promising ChE inhibitors acted by a non-competitive mechanism. In general, with exception of compounds 15 and 17 , no cytotoxic effects were observed in differentiated human neuroblastoma (SH-SY5Y) and human hepatocarcinoma (HepG2) cells, while Aβ-induced cytotoxicity was significantly prevented by the new dual-target HBAc derivatives. Overall, due to its BChE selectivity, favorable toxicological profile, neuroprotective activity and drug-like properties, which suggested blood-brain barrier (BBB) permeability, the mitochondriotropic antioxidant AntiOxBEN 1 is considered a valid lead candidate for the development of dual acting drugs for AD and other mitochondrial OS-related diseases.

Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase Inhibitors

Directory of Open Access Journals (Sweden)

Catarina Oliveira

2018-04-01

Full Text Available Alzheimer's disease (AD is a multifactorial age-related disease associated with oxidative stress (OS and impaired cholinergic transmission. Accordingly, targeting mitochondrial OS and restoring cholinergic transmission can be an effective therapeutic strategy toward AD. Herein, we report for the first time dual-target hydroxybenzoic acid (HBAc derivatives acting as mitochondriotropic antioxidants and cholinesterase (ChE inhibitors. The studies were performed with two mitochondriotropic antioxidants AntiOxBEN1 (catechol derivative, and AntiOxBEN2 (pyrogallol derivative and compounds 15–18, which have longer spacers. Compounds AntiOxBEN1 and 15, with a shorter carbon chain spacer (six- and eight-carbon were shown to be potent antioxidants and BChE inhibitors (IC50 = 85 ± 5 and 106 ± 5 nM, respectively, while compounds 17 and 18 with a 10-carbon chain were more effective AChE inhibitors (IC50 = 7.7 ± 0.4 and 7.2 ± 0.5 μM, respectively. Interestingly, molecular modeling data pointed toward bifunctional ChEs inhibitors. The most promising ChE inhibitors acted by a non-competitive mechanism. In general, with exception of compounds 15 and 17, no cytotoxic effects were observed in differentiated human neuroblastoma (SH-SY5Y and human hepatocarcinoma (HepG2 cells, while Aβ-induced cytotoxicity was significantly prevented by the new dual-target HBAc derivatives. Overall, due to its BChE selectivity, favorable toxicological profile, neuroprotective activity and drug-like properties, which suggested blood-brain barrier (BBB permeability, the mitochondriotropic antioxidant AntiOxBEN1 is considered a valid lead candidate for the development of dual acting drugs for AD and other mitochondrial OS-related diseases.

Hydroxybenzoic acid derivatives as dual-target ligands: mitochondriotropic antioxidants and cholinesterase inhibitors

Science.gov (United States)

Oliveira, Catarina; Cagide, Fernando; Teixeira, José; Amorim, Ricardo; Sequeira, Lisa; Mesiti, Francesco; Silva, Tiago; Garrido, Jorge; Remião, Fernando; Vilar, Santiago; Uriarte, Eugenio; Oliveira, Paulo J.; Borges, Fernanda

2018-04-01

Alzheimer’s disease (AD) is a multifactorial age-related disease associated with oxidative stress (OS) and impaired cholinergic transmission. Accordingly, targeting mitochondrial OS and restoring cholinergic transmission can be an effective therapeutic strategy towards AD. Herein, we report for the first time dual-target hydroxybenzoic acid (HBAc) derivatives acting as mitochondriotropic antioxidants and cholinesterase (ChE) inhibitors. The studies were performed with two mitochondriotropic antioxidants AntiOxBEN1 (catechol derivative), and AntiOxBEN2 (pyrogallol derivative) and compounds 15-18, which have longer spacers. Compounds AntiOxBEN1 and 15, with a shorter carbon chain spacer (six- and eight-carbon) were shown to be potent antioxidants and BChE inhibitors (IC50 = 85 ± 5 and 106 ± 5 nM, respectively), while compounds 17 and 18 with a ten-carbon chain were more effective AChE inhibitors (IC50 = 7.7 ± 0.4 and 7.2 ± 0.5 nM, respectively). Interestingly, molecular modelling data pointed towards bifunctional ChEs inhibitors. The most promising ChE inhibitors acted by a non-competitive mechanism. In general, with exception of compounds 15 and 17, no cytotoxic effects were observed in differentiated human neuroblastoma (SH-SY5Y) and human hepatocarcinoma (HepG2) cells, while Αβ-induced cytotoxicity was significantly prevented by the new dual-target HBAc derivatives. Overall, due to its BChE selectivity, favourable toxicological profile, neuroprotective activity and drug-like properties, which suggested blood-brain barrier (BBB) permeability, the mitochondriotropic antioxidant AntiOxBEN1 is considered a valid lead candidate for the development of dual acting drugs for AD and other mitochondrial OS-related disease

Phospholipid-Coated Mesoporous Silica Nanoparticles Acting as Lubricating Drug Nanocarriers

Directory of Open Access Journals (Sweden)

Tao Sun

2018-05-01

Full Text Available Osteoarthritis (OA is a severe disease caused by wear and inflammation of joints. In this study, phospholipid-coated mesoporous silica nanoparticles (MSNs@lip were prepared in order to treat OA at an early stage. The phospholipid layer has excellent lubrication capability in aqueous media due to the hydration lubrication mechanism, while mesoporous silica nanoparticles (MSNs act as effective drug nanocarriers. The MSNs@lip were characterized by scanning electron microscope, transmission electron microscope, Fourier transform infrared spectrum, X-ray photoelectron spectrum, thermogravimetric analysis and dynamic light scattering techniques to confirm that the phospholipid layer was coated onto the surface of MSNs successfully. A series of tribological tests were performed under different experimental conditions, and the results showed that MSNs@lip with multi-layers of phospholipids greatly reduced the friction coefficient in comparison with MSNs. Additionally, MSNs@lip demonstrated sustained drug release behavior and were biocompatible based on CCK-8 assay using MC3T3-E1 cells. The MSNs@lip developed in the present study, acting as effective lubricating drug nanocarriers, may represent a promising strategy to treat early stage OA by lubrication enhancement and drug delivery therapy.

Novel bis-(−)-nor-meptazinol derivatives act as dual binding site AChE inhibitors with metal-complexing property

Energy Technology Data Exchange (ETDEWEB)

Zheng, Wei [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China); NPFPC Key Laboratory of Contraceptives and Devices, Shanghai Institute of Planned Parenthood Research, 2140 Xietu Road, Shanghai 200032 (China); Li, Juan [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China); Qiu, Zhuibai [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China); Xia, Zheng [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China); Li, Wei [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China); Yu, Lining; Chen, Hailin; Chen, Jianxing [NPFPC Key Laboratory of Contraceptives and Devices, Shanghai Institute of Planned Parenthood Research, 2140 Xietu Road, Shanghai 200032 (China); Chen, Yan; Hu, Zhuqin; Zhou, Wei; Shao, Biyun; Cui, Yongyao [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China); Xie, Qiong, E-mail: xiejoanxq@gmail.com [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China); Chen, Hongzhuan, E-mail: yaoli@shsmu.edu.cn [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China)

2012-10-01

The strategy of dual binding site acetylcholinesterase (AChE) inhibition along with metal chelation may represent a promising direction for multi-targeted interventions in the pathophysiological processes of Alzheimer's disease (AD). In the present study, two derivatives (ZLA and ZLB) of a potent dual binding site AChE inhibitor bis-(−)-nor-meptazinol (bis-MEP) were designed and synthesized by introducing metal chelating pharmacophores into the middle chain of bis-MEP. They could inhibit human AChE activity with IC{sub 50} values of 9.63 μM (for ZLA) and 8.64 μM (for ZLB), and prevent AChE-induced amyloid-β (Aβ) aggregation with IC{sub 50} values of 49.1 μM (for ZLA) and 55.3 μM (for ZLB). In parallel, molecular docking analysis showed that they are capable of interacting with both the catalytic and peripheral anionic sites of AChE. Furthermore, they exhibited abilities to complex metal ions such as Cu(II) and Zn(II), and inhibit Aβ aggregation triggered by these metals. Collectively, these results suggest that ZLA and ZLB may act as dual binding site AChEIs with metal-chelating potency, and may be potential leads of value for further study on disease-modifying treatment of AD. -- Highlights: ► Two novel bis-(−)-nor-meptazinol derivatives are designed and synthesized. ► ZLA and ZLB may act as dual binding site AChEIs with metal-chelating potency. ► They are potential leads for disease-modifying treatment of Alzheimer's disease.

Novel bis-(−)-nor-meptazinol derivatives act as dual binding site AChE inhibitors with metal-complexing property

International Nuclear Information System (INIS)

Zheng, Wei; Li, Juan; Qiu, Zhuibai; Xia, Zheng; Li, Wei; Yu, Lining; Chen, Hailin; Chen, Jianxing; Chen, Yan; Hu, Zhuqin; Zhou, Wei; Shao, Biyun; Cui, Yongyao; Xie, Qiong; Chen, Hongzhuan

2012-01-01

The strategy of dual binding site acetylcholinesterase (AChE) inhibition along with metal chelation may represent a promising direction for multi-targeted interventions in the pathophysiological processes of Alzheimer's disease (AD). In the present study, two derivatives (ZLA and ZLB) of a potent dual binding site AChE inhibitor bis-(−)-nor-meptazinol (bis-MEP) were designed and synthesized by introducing metal chelating pharmacophores into the middle chain of bis-MEP. They could inhibit human AChE activity with IC 50 values of 9.63 μM (for ZLA) and 8.64 μM (for ZLB), and prevent AChE-induced amyloid-β (Aβ) aggregation with IC 50 values of 49.1 μM (for ZLA) and 55.3 μM (for ZLB). In parallel, molecular docking analysis showed that they are capable of interacting with both the catalytic and peripheral anionic sites of AChE. Furthermore, they exhibited abilities to complex metal ions such as Cu(II) and Zn(II), and inhibit Aβ aggregation triggered by these metals. Collectively, these results suggest that ZLA and ZLB may act as dual binding site AChEIs with metal-chelating potency, and may be potential leads of value for further study on disease-modifying treatment of AD. -- Highlights: ► Two novel bis-(−)-nor-meptazinol derivatives are designed and synthesized. ► ZLA and ZLB may act as dual binding site AChEIs with metal-chelating potency. ► They are potential leads for disease-modifying treatment of Alzheimer's disease.

Poly(L-lactide)/halloysite nanotube electrospun mats as dual-drug delivery systems and their therapeutic efficacy in infected full-thickness burns.

Science.gov (United States)

Zhang, Xiazhi; Guo, Rui; Xu, Jiqing; Lan, Yong; Jiao, Yanpeng; Zhou, Changren; Zhao, Yaowu

2015-11-01

In this study, poly(L-lactide) (PLLA)/halloysite nanotube (HNT) electrospun mats were prepared as a dual-drug delivery system. HNTs were used to encapsulate polymyxin B sulphate (a hydrophilic drug). Dexamethasone (a hydrophobic drug) was directly dissolved in the PLLA solution. The drug-loaded HNTs with optimised encapsulation efficiency were then mixed with the PLLA solution for subsequent electrospinning to form composite dual-drug-loaded fibre mats. The structure, morphology, degradability and mechanical properties of the electrospun composite mats were characterised in detail. The results showed that the HNTs were uniformly distributed in the composite PLLA mats. The HNTs content in the mats could change the morphology and average diameter of the electrospun fibres. The HNTs improved both the tensile strength of the PLLA electrospun mats and their degradation ratio. The drug-release kinetics of the electrospun mats were investigated using ultraviolet-visible spectrophotometry. The HNTs/PLLA ratio could be varied to adjust the release of polymyxin B sulphate and dexamethasone. The antibacterial activity in vitro of the mats was evaluated using agar diffusion and turbidimetry tests, which indicated the antibacterial efficacy of the dual-drug delivery system against Gram-positive and -negative bacteria. Healing in vivo of infected full-thickness burns and infected wounds was investigated by macroscopic observation, histological observation and immunohistochemical staining. The results indicated that the electrospun mats were capable of co-loading and co-delivering hydrophilic and hydrophobic drugs, and could potentially be used as novel antibacterial wound dressings. © The Author(s) 2015.

Clinical assessment of drug-drug interactions of tasimelteon, a novel dual melatonin receptor agonist.

Science.gov (United States)

Ogilvie, Brian W; Torres, Rosarelis; Dressman, Marlene A; Kramer, William G; Baroldi, Paolo

2015-09-01

Tasimelteon ([1R-trans]-N-[(2-[2,3-dihydro-4-benzofuranyl] cyclopropyl) methyl] propanamide), a novel dual melatonin receptor agonist that demonstrates specificity and high affinity for melatonin receptor types 1 and 2 (MT1 and MT2 receptors), is the first treatment approved by the US Food and Drug Administration for Non-24-Hour Sleep-Wake Disorder. Tasimelteon is rapidly absorbed, with a mean absolute bioavailability of approximately 38%, and is extensively metabolized primarily by oxidation at multiple sites, mainly by cytochrome P450 (CYP) 1A2 and CYP3A4/5, as initially demonstrated by in vitro studies and confirmed by the results of clinical drug-drug interactions presented here. The effects of strong inhibitors and moderate or strong inducers of CYP1A2 and CYP3A4/5 on the pharmacokinetics of tasimelteon were evaluated in humans. Coadministration with fluvoxamine resulted in an approximately 6.5-fold increase in tasimelteon's area under the curve (AUC), whereas cigarette smoking decreased tasimelteon's exposure by approximately 40%. Coadministration with ketoconazole resulted in an approximately 54% increase in tasimelteon's AUC, whereas rifampin pretreatment resulted in a decrease in tasimelteon's exposure of approximately 89%. © 2015 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Venetoclax (ABT-199) Might Act as a Perpetrator in Pharmacokinetic Drug-Drug Interactions.

Science.gov (United States)

Weiss, Johanna; Gajek, Thomas; Köhler, Bruno Christian; Haefeli, Walter Emil

2016-02-24

Venetoclax (ABT-199) represents a specific B-cell lymphoma 2 (Bcl-2) inhibitor that is currently under development for the treatment of lymphoid malignancies. So far, there is no published information on its interaction potential with important drug metabolizing enzymes and drug transporters, or its efficacy in multidrug resistant (MDR) cells. We therefore scrutinized its drug-drug interaction potential in vitro. Inhibition of cytochrome P450 enzymes (CYPs) was quantified by commercial kits. Inhibition of drug transporters (P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP), and organic anion transporting polypeptides (OATPs)) was evaluated by the use of fluorescent probe substrates. Induction of drug transporters and drug metabolizing enzymes was quantified by real-time RT-PCR. The efficacy of venetoclax in MDR cells lines was evaluated with proliferation assays. Venetoclax moderately inhibited P-gp, BCRP, OATP1B1, OATP1B3, CYP3A4, and CYP2C19, whereas CYP2B6 activity was increased. Venetoclax induced the mRNA expression of CYP1A1, CYP1A2, UGT1A3, and UGT1A9. In contrast, expression of ABCB1 was suppressed, which might revert tumor resistance towards antineoplastic P-gp substrates. P-gp over-expression led to reduced antiproliferative effects of venetoclax. Effective concentrations for inhibition and induction lay in the range of maximum plasma concentrations of venetoclax, indicating that it might act as a perpetrator drug in pharmacokinetic drug-drug interactions.

Targeting carbonic anhydrase IX by nitroimidazole based sulfamides enhances the therapeutic effect of tumor irradiation: A new concept of dual targeting drugs

International Nuclear Information System (INIS)

Dubois, Ludwig; Peeters, Sarah G.J.A.; Kuijk, Simon J.A. van; Yaromina, Ala; Lieuwes, Natasja G.; Saraya, Ruchi; Biemans, Rianne; Rami, Marouan; Parvathaneni, Nanda Kumar; Vullo, Daniela; Vooijs, Marc; Supuran, Claudiu T.; Winum, Jean-Yves

2013-01-01

Background and purpose: Carbonic anhydrase IX (CAIX) plays an important role in pH regulation processes critical for tumor cell growth and metastasis. We hypothesize that a dual targeting bioreductive nitroimidazole based anti-CAIX sulfamide drug (DH348) will reduce tumor growth and sensitize tumors to irradiation in a CAIX dependent manner. Material and methods: The effect of the dual targeting anti-CAIX (DH348) and its single targeting control drugs on extracellular acidification and radiosensitivity was examined in HT-29 colorectal carcinoma cells. Tumor growth and time to reach 4× start volume (T4×SV) was monitored for animals receiving DH348 (10 mg/kg) combined with tumor single dose irradiation (10 Gy). Results: In vitro, DH348 reduced hypoxia-induced extracellular acidosis, but did not change hypoxic radiosensitivity. In vivo, DH348 monotherapy decreased tumor growth rate and sensitized tumors to radiation (enhancement ratio 1.50) without systemic toxicity only for CAIX expressing tumors. Conclusions: A newly designed nitroimidazole and sulfamide dual targeting drug reduces hypoxic extracellular acidification, slows down tumor growth at nontoxic doses and sensitizes tumors to irradiation all in a CAIX dependent manner, suggesting no “off-target” effects. Our data therefore indicate the potential utility of a dual drug approach as a new strategy for tumor-specific targeting

76 FR 58020 - Prescription Drug User Fee Act IV Information Technology Plan

Science.gov (United States)

2011-09-19

...] Prescription Drug User Fee Act IV Information Technology Plan AGENCY: Food and Drug Administration, HHS. ACTION... information technology (IT) plan entitled ``PDUFA IV Information Technology Plan'' (updated plan) to achieve... Information Technology Plan.'' This plan will meet one of the performance goals agreed to under the 2007...

Development of the generic drug industry in the US after the Hatch-Waxman Act of 1984

Directory of Open Access Journals (Sweden)

Garth Boehm

2013-09-01

Full Text Available The key events in the development of the US generic drug industry after the Hatch-Waxman Act of 1984 are systematically reviewed, including the process of approval for generic drugs, bioequivalence issues including “switchability”, bioequivalence for complicated dosage forms, patent extension, generic drug safety, generic substitution and low-cost generics. The backlog in generic review, generic drug user fees, and “quality by design” for generic drugs is also discussed. The evolution of the US generic drug industry after the Hatch-Waxman Act in 1984 has afforded several lessons of great benefit to other countries wishing to establish or re-establish a domestic generic drug industry.

Peptides with Dual Antimicrobial and Anticancer Activities

Science.gov (United States)

Felício, Mário R.; Silva, Osmar N.; Gonçalves, Sônia; Santos, Nuno C.; Franco, Octávio L.

2017-02-01

In recent years, the number of people suffering from cancer and multi-resistant infections has increased, such that both diseases are already seen as current and future major causes of death. Moreover, chronic infections are one of the main causes of cancer, due to the instability in the immune system that allows cancer cells to proliferate. Likewise, the physical debility associated with cancer or with anticancer therapy itself often paves the way for opportunistic infections. It is urgent to develop new therapeutic methods, with higher efficiency and lower side effects. Antimicrobial peptides (AMPs) are found in the innate immune system of a wide range of organisms. Identified as the most promising alternative to conventional molecules used nowadays against infections, some of them have been shown to have dual activity, both as antimicrobial and anticancer peptides (ACPs). Highly cationic and amphipathic, they have demonstrated efficacy against both conditions, with the number of nature-driven or synthetically designed peptides increasing year by year. With similar properties, AMPs that can also act as ACPs are viewed as future chemotherapeutic drugs, with the advantage of low propensity to resistance, which started this paradigm in the pharmaceutical market. These peptides have already been described as molecules presenting killing mechanisms at the membrane level, but also acting towards intracellular targets, which increases their success comparatively to specific one-target drugs. This review will approach the desirable characteristics of small peptides that demonstrated dual activity against microbial infections and cancer, as well as the peptides engaged in clinical trials.

Dual responsive PNIPAM–chitosan targeted magnetic nanopolymers for targeted drug delivery

Energy Technology Data Exchange (ETDEWEB)

Yadavalli, Tejabhiram, E-mail: tejabhiram@gmail.com [Nanotechnology Research Centre, SRM University, Chennai 603203 (India); Ramasamy, Shivaraman [Nanotechnology Research Centre, SRM University, Chennai 603203 (India); School of Physics, The University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009 (Australia); Chandrasekaran, Gopalakrishnan; Michael, Isaac; Therese, Helen Annal [Nanotechnology Research Centre, SRM University, Chennai 603203 (India); Chennakesavulu, Ramasamy [Department of Pharmacy practice, SRM College of Pharmacy, Chennai 603203 (India)

2015-04-15

A dual stimuli sensitive magnetic hyperthermia based drug delivery system has been developed for targeted cancer treatment. Thermosensitive amine terminated poly-N-isopropylacrylamide complexed with pH sensitive chitosan nanoparticles was prepared as the drug carrier. Folic acid and fluorescein were tagged to the nanopolymer complex via N-hydroxysuccinimide and ethyl-3-(3-dimethylaminopropyl)carbodiimide reaction to form a fluorescent and cancer targeting magnetic carrier system. The formation of the polymer complex was confirmed using infrared spectroscopy. Gadolinium doped nickel ferrite nanoparticles prepared by a hydrothermal method were encapsulated in the polymer complex to form a magnetic drug carrier system. The proton relaxation studies on the magnetic carrier system revealed a 200% increase in the T1 proton relaxation rate. These magnetic carriers were loaded with curcumin using solvent evaporation method with a drug loading efficiency of 86%. Drug loaded nanoparticles were tested for their targeting and anticancer properties on four cancer cell lines with the help of MTT assay. The results indicated apoptosis of cancer cell lines within 3 h of incubation. - Highlights: • The use of gadolinium doped nickel ferrite with the suggested doping level. • The use of PNIPMA–chitosan polymer with folic acid and fluorescein as a drug carrier complex. • Magnetic hyperthermia studies of gadolinium doped nickel ferrites are being reported for the first time. • Proton relaxivity studies which indicate the MRI contrasting properties on the reported system are new. • Use of curcumin, a hydrophobic Indian spice as a cancer killing agent inside the reported magnetic polymer complex.

Mechanical properties and dual drug delivery application of poly(lactic-co-glycolic acid) scaffolds fabricated with a poly(β-amino ester) porogen.

Science.gov (United States)

Clark, Amanda; Milbrandt, Todd A; Hilt, J Zach; Puleo, David A

2014-05-01

Polymeric scaffolds that are biocompatible and biodegradable are widely used for tissue engineering applications. Scaffolds can be further enhanced by enabling the release of one or more drugs to stimulate regeneration or for the treatment of a specific disease or condition. In this study, poly(lactic-co-glycolic acid) (PLGA) microspheres were mixed with poly(β-amino ester) (PBAE) particles to create novel hybrid scaffolds capable of dual release of drug and growth factor. Fast-degrading PBAE particles loaded with the drug ketoprofen acted as porogens that provided a rapid 12h release. The PLGA microspheres were loaded with a growth factor, bone morphogenetic protein 2, and fused together around the porogens to create a slow-degrading matrix that provided sustained release lasting 70days. Drug release was further tailored by varying the amount of porogen added to the scaffold. Bioactivity measurements demonstrated that the scaffold fabrication technique did not damage the drug or protein. The compressive modulus was affected by the amount of porogen added, extending from 50 to 111MPa for loadings from 60 to 40% PBAE, and after 5days of degradation, it decreased to 0.6 to 1.1kPa when the porogen was gone. PLGA containing a quick-degrading porogen can be used to release two drugs while developing a porous microarchitecture for cell ingrowth with in a matrix capable of maintaining a compressive modulus applicable for soft tissue implants. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Dual Cross-Linked Carboxymethyl Sago Pulp-Gelatine Complex Coacervates for Sustained Drug Delivery

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Saravanan Muniyandy

2015-06-01

Full Text Available In the present work, we report for the first time the complex coacervation of carboxymethyl sago pulp (CMSP with gelatine for sustained drug delivery. Toluene saturated with glutaraldehyde and aqueous aluminum chloride was employed as cross-linkers. Measurements of zeta potential confirm neutralization of two oppositely charged colloids due to complexation, which was further supported by infrared spectroscopy. The coacervates encapsulated a model drug ibuprofen and formed microcapsules with a loading of 29%–56% w/w and an entrapment efficiency of 85%–93% w/w. Fresh coacervates loaded with drug had an average diameter of 10.8 ± 1.93 µm (n = 3 ± s.d.. The coacervates could encapsulate only the micronized form of ibuprofen in the absence of surfactant. Analysis through an optical microscope evidenced the encapsulation of the drug in wet spherical coacervates. Scanning electron microscopy revealed the non-spherical geometry and surface roughness of dried drug-loaded microcapsules. X-ray diffraction, differential scanning calorimetry and thermal analysis confirmed intact and crystalline ibuprofen in the coacervates. Gas chromatography indicated the absence of residual glutaraldehyde in the microcapsules. Dual cross-linked microcapsules exhibited a slower release than mono-cross-linked microcapsules and could sustain the drug release over the period of 6 h following Fickian diffusion.

40 CFR 23.10 - Timing of Administrator's action under the Federal Food, Drug, and Cosmetic Act.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Timing of Administrator's action under the Federal Food, Drug, and Cosmetic Act. 23.10 Section 23.10 Protection of Environment ENVIRONMENTAL... action under the Federal Food, Drug, and Cosmetic Act. Unless the Administrator otherwise explicitly...

Fetzima (levomilnacipran), a drug for major depressive disorder as a dual inhibitor for human serotonin transporters and beta-site amyloid precursor protein cleaving enzyme-1.

Science.gov (United States)

Rizvi, Syed Mohd Danish; Shaikh, Sibhghatulla; Khan, Mahiuddin; Biswas, Deboshree; Hameed, Nida; Shakil, Shazi

2014-01-01

Pharmacological management of Major Depressive Disorder includes the use of serotonin reuptake inhibitors which targets serotonin transporters (SERT) to increase the synaptic concentrations of serotonin. Beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1) is responsible for amyloid β plaque formation. Hence it is an interesting target for Alzheimer's disease (AD) therapy. This study describes molecular interactions of a new Food and Drug Administration approved antidepressant drug named 'Fetzima' with BACE-1 and SERT. Fetzima is chemically known as levomilnacipran. The study has explored a possible link between the treatment of Depression and AD. 'Autodock 4.2' was used for docking study. The free energy of binding (ΔG) values for 'levomilnacipran-SERT' interaction and 'levomilnacipran-BACE1' interaction were found to be -7.47 and -8.25 kcal/mol, respectively. Levomilnacipran was found to interact with S438, known to be the most important amino acid residue of serotonin binding site of SERT during 'levomilnacipran-SERT' interaction. In the case of 'levomilnacipran-BACE1' interaction, levomilnacipran interacted with two very crucial aspartic acid residues of BACE-1, namely, D32 and D228. These residues are accountable for the cleavage of amyloid precursor protein and the subsequent formation of amyloid β plaques in AD brain. Hence, Fetzima (levomilnacipran) might act as a potent dual inhibitor of SERT and BACE-1 and expected to form the basis of a future dual therapy against depression and AD. It is an established fact that development of AD is associated with Major Depressive Disorder. Therefore, the design of new BACE-1 inhibitors based on antidepressant drug scaffolds would be particularly beneficial.

Mental Health Service and Drug Treatment Utilization: Adolescents with Substance Use/Mental Disorders and Dual Diagnosis

Science.gov (United States)

Cheng, Tyrone C.; Lo, Celia C.

2010-01-01

This research is a secondary data analysis of the impact of adolescents' mental/substance-use disorders and dual diagnosis on their utilization of drug treatment and mental health services. By analyzing the same teenagers who participated in the NIMH Methods for the Epidemiology of Child and Adolescent Mental Disorders (MECA) study, logistic…

Dual Drug Loaded Biodegradable Nanofibrous Microsphere for Improving Anti-Colon Cancer Activity

Science.gov (United States)

Fan, Rangrang; Li, Xiaoling; Deng, Jiaojiao; Gao, Xiang; Zhou, Liangxue; Zheng, Yu; Tong, Aiping; Zhang, Xiaoning; You, Chao; Guo, Gang

2016-06-01

One of the approaches being explored to increase antitumor activity of chemotherapeutics is to inject drug-loaded microspheres locally to specific anatomic sites, providing for a slow, long term release of a chemotherapeutic while minimizing systemic exposure. However, the used clinically drug carriers available at present have limitations, such as their low stability, renal clearance and residual surfactant. Here, we report docetaxel (DOC) and curcumin (CUR) loaded nanofibrous microspheres (DOC + CUR/nanofibrous microspheres), self-assembled from biodegradable PLA-PEO-PPO-PEO-PLA polymers as an injectable drug carrier without adding surfactant during the emulsification process. The obtained nanofibrous microspheres are composed entirely of nanofibers and have an open hole on the shell without the assistance of a template. It was shown that these DOC + CUR/nanofibrous microspheres could release curcumin and docetaxel slowly in vitro. The slow, sustained release of curcumin and docetaxel in vivo may help maintain local concentrations of active drug. The mechanism by which DOC + CUR/nanofibrous microspheres inhibit colorectal peritoneal carcinomatosis might involve increased induction of apoptosis in tumor cells and inhibition of tumor angiogenesis. In vitro and in vivo evaluations demonstrated efficacious synergistic antitumor effects against CT26 of curcumin and docetaxel combined nanofibrous microspheres. In conclusion, the dual drug loaded nanofibrous microspheres were considered potentially useful for treating abdominal metastases of colorectal cancer.

A Synthetic Dual Drug Sideromycin Induces Gram-Negative Bacteria To Commit Suicide with a Gram-Positive Antibiotic.

Science.gov (United States)

Liu, Rui; Miller, Patricia A; Vakulenko, Sergei B; Stewart, Nichole K; Boggess, William C; Miller, Marvin J

2018-05-10

Many antibiotics lack activity against Gram-negative bacteria because they cannot permeate the outer membrane or suffer from efflux and, in the case of β-lactams, are degraded by β-lactamases. Herein, we describe the synthesis and studies of a dual drug conjugate (1) of a siderophore linked to a cephalosporin with an attached oxazolidinone. The cephalosporin component of 1 is rapidly hydrolyzed by purified ADC-1 β-lactamase to release the oxazolidinone. Conjugate 1 is active against clinical isolates of Acinetobacter baumannii as well as strains producing large amounts of ADC-1 β-lactamase. Overall, the results are consistent with siderophore-mediated active uptake, inherent activity of the delivered dual drug, and in the presence of β-lactamases, intracellular release of the oxazolidinone upon cleavage of the cephalosporin to allow the freed oxazolidinone to inactivate its target. The ultimate result demonstrates that Gram-positive oxazolidinone antibiotics can be made to be effective against Gram-negative bacteria by β-lactamase triggered release.

In silico design and biological evaluation of a dual specificity kinase inhibitor targeting cell cycle progression and angiogenesis.

Science.gov (United States)

Latham, Antony M; Kankanala, Jayakanth; Fearnley, Gareth W; Gage, Matthew C; Kearney, Mark T; Homer-Vanniasinkam, Shervanthi; Wheatcroft, Stephen B; Fishwick, Colin W G; Ponnambalam, Sreenivasan

2014-01-01

Protein kinases play a central role in tumor progression, regulating fundamental processes such as angiogenesis, proliferation and metastasis. Such enzymes are an increasingly important class of drug target with small molecule kinase inhibitors being a major focus in drug development. However, balancing drug specificity and efficacy is problematic with off-target effects and toxicity issues. We have utilized a rational in silico-based approach to demonstrate the design and study of a novel compound that acts as a dual inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2) and cyclin-dependent kinase 1 (CDK1). This compound acts by simultaneously inhibiting pro-angiogenic signal transduction and cell cycle progression in primary endothelial cells. JK-31 displays potent in vitro activity against recombinant VEGFR2 and CDK1/cyclin B proteins comparable to previously characterized inhibitors. Dual inhibition of the vascular endothelial growth factor A (VEGF-A)-mediated signaling response and CDK1-mediated mitotic entry elicits anti-angiogenic activity both in an endothelial-fibroblast co-culture model and a murine ex vivo model of angiogenesis. We deduce that JK-31 reduces the growth of both human endothelial cells and human breast cancer cells in vitro. This novel synthetic molecule has broad implications for development of similar multi-kinase inhibitors with anti-angiogenic and anti-cancer properties. In silico design is an attractive and innovative method to aid such drug discovery.

Portugal's 2001 Drugs Liberalisation Policy: A UK Service Provider's Perspective on the Psychoactive Substances Act (2016)

Science.gov (United States)

Banbury, Samantha; Lusher, Joanne; Guedelha, Francisco

2018-01-01

The Misuse of Drugs Act (1971) and the Psychoactive Substances Act (2016) both reinforce the criminalisation of drug use in the UK. The Psychoactive Substances Act (2016) has been developed to control and monitor the use of legal highs, particularly in institutions. This study aimed to establish drug service providers' viewpoints on how effective…

76 FR 64354 - Burden of Food and Drug Administration Food Safety Modernization Act Fee Amounts on Small...

Science.gov (United States)

2011-10-18

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-N-0529] Burden of Food and Drug Administration Food Safety Modernization Act Fee Amounts on Small Business... amounts on small business, as set forth in the FDA Food Safety Modernization Act (FSMA). In particular...

76 FR 45818 - Burden of Food and Drug Administration Food Safety Modernization Act Fee Amounts on Small...

Science.gov (United States)

2011-08-01

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-N-0529] Burden of Food and Drug Administration Food Safety Modernization Act Fee Amounts on Small Business... burden of fee amounts on small business, as set forth in the FDA Food Safety Modernization Act (FSMA...

Design of Electro-Mechanical Dual-Acting Pulley Continuously Variable Transmission

Directory of Open Access Journals (Sweden)

K.B. Tawi

2015-06-01

Full Text Available Pulley-based continuously variable transmission (CVT with a metal pushing V-belt is fast becoming the preferred choice for global carmakers due to its potential particularly in terms of fuel efficiency thanks to its continuous and wide ratio range. Nevertheless, the existing CVTs still face the issues of high power consumption from the engine because of the application of an electro-hydro-mechanical (EHM actuation system for its ratio changing process and clamping force mechanism. To address this issue, researchers from Universiti Teknologi Malaysia have successfully developed the prototype of an electro-mechanical dual-acting pulley continuously variable transmission (EMDAP CVT for automotive applications. The prototype of EMDAP CVT is developed for a maximum input torque of 160 Nm with the application of a metal pushing V-belt. The results from the testing prove that the prototype can vary its ratio from 2.8 to 0.6 and no continuous power is required to maintain a constant CVT ratio. These results suggest that the prototype is workable and future testing in a real car is possible.

Implications of the Food, Drug, and Cosmetic Act on the quality assurance of radiopharmaceuticals used in the United States

International Nuclear Information System (INIS)

Kishore, R.; Sheinin, E.B.

1990-01-01

The drug sections of the Federal Food, Drug, and Cosmetic Act (Title 21 U.S.C.) are intended to assure the consumer that drugs are safe and effective for their intended use. The Act requires that new drugs be approved by the FDA before they go on the market. The regulations for the new drug review process, are contained in the Code of Federal Regulations (CFR) Title 21, sections 312 for Investigational New Drugs (INDs), 314 for New Drug Applications (NDAs). Section 361 deals with radioactive drugs for certain research (RDR) uses. The regulations require that sufficient information be provided on the acceptable limits and the analytical methods used for the assurance of the identity, strength, quality, purity and the stability of the new drug as well as the raw materials used in the preparation of the new drug. The impact of the Act on the control of radiopharmaceutical products will be discussed

Dual stimuli-responsive nano-vehicles for controlled drug delivery: mesoporous silica nanoparticles end-capped with natural chitosan.

Science.gov (United States)

Hakeem, Abdul; Duan, Ruixue; Zahid, Fouzia; Dong, Chao; Wang, Boya; Hong, Fan; Ou, Xiaowen; Jia, Yongmei; Lou, Xiaoding; Xia, Fan

2014-11-11

Herein, we report natural chitosan end-capped MCM-41 type MSNPs as novel, dual stimuli, responsive nano-vehicles for controlled anticancer drug delivery. The chitosan nanovalves tightly close the pores of the MSNPs to control premature cargo release under physiological conditions but respond to lysozyme and acidic media to release the trapped cargo.

Legal Drugs Are Good Drugs And Illegal Drugs Are Bad Drugs

Directory of Open Access Journals (Sweden)

Dina Indrati

2011-07-01

Full Text Available ABSTRACT : Labelling drugs are important issue nowadays in a modern society. Although it is generally believed that legal drugs are good drugs and illegal drugs are bad drugs, it is evident that some people do not aware about the side effects of drugs used. Therefore, a key contention of this philosophical essay is that explores harms minimisation policy, discuss whether legal drugs are good drugs and illegal drugs are bad drugs and explores relation of drugs misuse in a psychiatric nursing setting and dual diagnosis.Key words: Legal, good drugs, illegal, bad drugs.

76 FR 41434 - Removal of Certain Requirements Related to the Prescription Drug Marketing Act; Opportunity for...

Science.gov (United States)

2011-07-14

.... FDA-2011-N-0446] Removal of Certain Requirements Related to the Prescription Drug Marketing Act... Food and Drug Administration (FDA) is proposing to remove a section of the Prescription Drug Marketing... prior sale, purchase, or trade of such drug,'' starting with the manufacturer, and that the identifying...

Comparison of dual-time-constant and fast-acting automatic gain control (AGC) systems in cochlear implants.

Science.gov (United States)

Boyle, Patrick J; Büchner, Andreas; Stone, Michael A; Lenarz, Thomas; Moore, Brian C J

2009-04-01

Cochlear implants usually employ an automatic gain control (AGC) system as a first stage of processing. AGC1 was a fast-acting (syllabic) compressor. AGC2 was a dual-time-constant system; it usually performed as a slow-acting compressor, but incorporated an additional fast-acting system to provide protection from sudden increases in sound level. Six experienced cochlear-implant users were tested in a counterbalanced order, receiving one-month of experience with a given AGC type before switching to the other type. Performance was evaluated shortly after provision of a given AGC type and after one-month of experience with that AGC type. Questionnaires, mainly relating to listening in quiet situations, did not reveal significant differences between the two AGC types. However, fixed-level and roving-level tests of sentence identification in noise both revealed significantly better performance for AGC2. It is suggested that the poorer performance for AGC1 occurred because AGC1 introduced cross-modulation between the target speech and background noise, which made perceptual separation of the target and background more difficult.

NGS combined with phylogenetic analysis to detect HIV-1 dual infection in Romanian people who inject drugs.

Science.gov (United States)

Popescu, Bogdan; Banica, Leontina; Nicolae, Ionelia; Radu, Eugen; Niculescu, Iulia; Abagiu, Adrian; Otelea, Dan; Paraschiv, Simona

2018-04-04

Dual HIV infections are possible and likely in people who inject drugs (PWID). Thirty-eight newly diagnosed patients, 19 PWID and 19 heterosexually HIV infected were analysed. V2-V3 loop of HIV-1 env gene was sequenced on the NGS platform 454 GSJunior (Roche). HIV-1 dual/multiple infections were identified in five PWID. For three of these patients, the reconstructed variants belonged to pure F1 subtype and CRF14_BG strains according to phylogenetic analysis. New recombinant forms between these parental strains were identified in two PWID samples. NGS data can provide, with the help of phylogenetic analysis, important insights about the intra-host sub-population structure. Copyright © 2018. Published by Elsevier Masson SAS.

In silico design and biological evaluation of a dual specificity kinase inhibitor targeting cell cycle progression and angiogenesis.

Directory of Open Access Journals (Sweden)

Antony M Latham

Full Text Available Protein kinases play a central role in tumor progression, regulating fundamental processes such as angiogenesis, proliferation and metastasis. Such enzymes are an increasingly important class of drug target with small molecule kinase inhibitors being a major focus in drug development. However, balancing drug specificity and efficacy is problematic with off-target effects and toxicity issues.We have utilized a rational in silico-based approach to demonstrate the design and study of a novel compound that acts as a dual inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2 and cyclin-dependent kinase 1 (CDK1. This compound acts by simultaneously inhibiting pro-angiogenic signal transduction and cell cycle progression in primary endothelial cells. JK-31 displays potent in vitro activity against recombinant VEGFR2 and CDK1/cyclin B proteins comparable to previously characterized inhibitors. Dual inhibition of the vascular endothelial growth factor A (VEGF-A-mediated signaling response and CDK1-mediated mitotic entry elicits anti-angiogenic activity both in an endothelial-fibroblast co-culture model and a murine ex vivo model of angiogenesis.We deduce that JK-31 reduces the growth of both human endothelial cells and human breast cancer cells in vitro. This novel synthetic molecule has broad implications for development of similar multi-kinase inhibitors with anti-angiogenic and anti-cancer properties. In silico design is an attractive and innovative method to aid such drug discovery.

[Acting out and psychoactive substances: alcohol, drugs, illicit substances].

Science.gov (United States)

Gillet, C; Polard, E; Mauduit, N; Allain, H

2001-01-01

In humans, some psychotropic agents (alcohol, drugs, illicit substances) have been suggested to play a role in the occurrence of major behavioural disorders, mainly due to the suppression of psychomotor inhibition. Behavioural disinhibition is a physiological mechanism which allows humans to behave appropriately according to a given environmental situation. The behavioural disinhibition induced by either therapeutic dosage or misuse involves the loss of restraint over certain types of social behaviour and may increase the risk of auto or hetero-aggression and acting out. The increased use of psychotropic agents in recent years and the occurrence of unwanted effects are worrying and must be detected and evaluated. The objective of the present study was to establish a causal relationship between psychoactive substance use and occurrence of major behavioural disorders, such as paradoxical rage reactions and suicidal behaviour, based on a literature analysis. It consisted of reviewing reports of drug-induced violent reactions in healthy volunteers and demonstrating, where possible, a cause-effect relationship. Patients with schizophrenia and psychopathic personalities were not included in our study since psychiatric comorbidity could influence behavioural responses. Psychotropic agents included drugs, licit and illicit substances already associated with violence in the past. Many reports used the "Go/No Go test" to evaluate the disinhibiting effect of psychotropic substances; this allows the "cognitive mapping" of drugs. The results suggest that only alcohol, antidepressants, benzodiazepines and cocaïne are related to aggressive behaviour. The best known precipitant of behavioural disinhibition is alcohol, which induces aggressive behaviour. However, there are large differences between individuals, and attentional mechanisms are now recognised as being important in mediating the effects of alcohol. Suicidal tendency as an adverse antidepressant reaction is rare

The Medicaid Rebate: Changes in Oncology Drug Prices After the Affordable Care Act.

Science.gov (United States)

Bonakdar Tehrani, Ali; Carroll, Norman V

2017-08-01

Prescription drug spending is a significant component of Medicaid total expenditures. The Affordable Care Act (ACA) includes a provision that increases the Medicaid rebate for both brand-name and generic drugs. This study examines the extent to which oncology drug prices changed after the increase in the Medicaid rebate in 2010. A pre-post study design was used to evaluate the correlation between the Medicaid rebate increase and oncology drug prices after 2010 using 2006-2013 State Drug Utilization Data. The results show that the average annual price of top-selling cancer drugs in 2006, adjusted for inflation and secular changes in drug prices, have increased by US$154 and US$235 for branded and competitive brand drugs, respectively, following the 2010 ACA; however, generic oncology drug prices showed no significant changes. The findings from this study indicate that oncology drug prices have increased after the 2010 ACA, and suggest that pharmaceutical companies may have increased their drug prices to offset increases in Medicaid rebates.

Therapies for inborn errors of metabolism: what has the orphan drug act delivered?

Science.gov (United States)

Talele, Sonali S; Xu, Kui; Pariser, Anne R; Braun, M Miles; Farag-El-Massah, Sheiren; Phillips, M Ian; Thompson, Barry H; Coté, Timothy R

2010-07-01

The 1983 US Orphan Drug Act established a process through which promising therapies are designated as orphan products and, later, with satisfactory safety and efficacy data, receive marketing approval and fiscal incentives. We examined accomplishments in drug development for inborn errors of metabolism (IEMs). Food and Drug Administration data were used to identify orphan product designations and approvals for IEMs, and the trends for the past 26 years were summarized. Individual clinical development times (CDTs) from filing investigational new drug application to marketing approval were determined. We examined 1956 orphan product designations from 1983 through 2008 and found 93 (4.8%) for IEMs. Of those, 24 (25.8%) received marketing approval. This proportion of approval was significantly (P = .036) higher than that for non-IEM orphan products (17%). Among the IEM products, disorders of complex molecules received the most designations and approvals (61 and 11, respectively). Among the subgroups, lysosomal storage diseases received the most designations and approvals (43 and 9, respectively), whereas mitochondrial diseases (other than fatty acid oxidation disorders) received 7 designations with no approvals. We then examined the CDTs for the approved IEM products and found a median of 6.4 years (range: 2.6-25.1 years). Biological products had significantly shorter CDTs than drugs (mean: 4.6 vs 11.0 years; P = .003). For 26 years, the Orphan Drug Act has generated new therapies for IEMs. Why some IEMs have motivated successful drug development and others have not remains enigmatic; yet the needs of IEM patients without treatment are a certainty.

40 CFR 2.308 - Special rules governing certain information obtained under the Federal Food, Drug and Cosmetic Act.

Science.gov (United States)

2010-07-01

... information obtained under the Federal Food, Drug and Cosmetic Act. 2.308 Section 2.308 Protection of... § 2.308 Special rules governing certain information obtained under the Federal Food, Drug and Cosmetic... Cosmetic Act, as amended, 21 U.S.C. 301 et seq. (2) Petition means a petition for the issuance of a...

Synthesis and characterization of novel dual-responsive nanogels and their application as drug delivery systems

Science.gov (United States)

Peng, Jinrong; Qi, Tingting; Liao, Jinfeng; Fan, Min; Luo, Feng; Li, He; Qian, Zhiyong

2012-03-01

In this study, a temperature/pH dual-response nanogel based on NIPAm, MAA, and PEGMA was synthesized via emulsion polymerization and characterized by 1H-NMR, FT-IR, TEM and DLS. By introducing a novel initiator, through which PEG-AIBN-PEG was synthesized, it was revealed that the PEG segments from PEG-AIBN-PEG with a dosage of initiator had a significant influence over the macro-state and stability of the nanogels. In order to optimize the feeding prescription for better application as a drug delivery system, the effect of the co-monomer contents on the response to stimuli (temperature and pH value) and cytotoxicity of the nanogels has been studied in detail. The results demonstrated that the responsiveness, reversibility and volume phase transition critical value of the nanogels could be controlled by adjusting the feeding ratio of the co-monomers in the synthesis process. MTT assay results revealed that nanogels with appropriate compositions showed good biocompatibility and relatively low toxicity. Most importantly, by studying the drug loading behavior, it was found that the dimensions of the drug molecules had a considerable influence on the drug loading efficiency and loading capacity of the nanogels, and that the mechanism by which drug molecule sizes influence the drug loading behavior of nanogels needs further investigation. The results indicated that such PNMP nanogels might have potential applications in drug delivery and other medical applications, but that the drug loading mechanism must be further developed.

75 FR 24967 - Andean Trade Preference Act: Impact on the U.S. Economy and on Andean Drug Crop Eradication

Science.gov (United States)

2010-05-06

... Preference Act: Impact on the U.S. Economy and on Andean Drug Crop Eradication. DATES: June 24, 2010... INTERNATIONAL TRADE COMMISSION [Investigation No. 332-352] Andean Trade Preference Act: Impact on the U.S. Economy and on Andean Drug Crop Eradication AGENCY: United States International Trade...

77 FR 31039 - Andean Trade Preference Act: Impact on the U.S. Economy and on Andean Drug Crop Eradication

Science.gov (United States)

2012-05-24

.... 332-352, Andean Trade Preference Act: Impact on the U.S. Economy and on Andean Drug Crop Eradication... INTERNATIONAL TRADE COMMISSION [Investigation No. 332-352] Andean Trade Preference Act: Impact on the U.S. Economy and on Andean Drug Crop Eradication AGENCY: United States International Trade...

Mulberry-like dual-drug complicated nanocarriers assembled with apogossypolone amphiphilic starch micelles and doxorubicin hyaluronic acid nanoparticles for tumor combination and targeted therapy.

Science.gov (United States)

Li, Ke; Liu, Hao; Gao, Wei; Chen, Mu; Zeng, Yun; Liu, Jiajun; Xu, Liang; Wu, Daocheng

2015-01-01

A comprehensive strategy for the preparation of mulberry-like dual-drug complicated nanocarriers (MLDC NCs) with high drug loading and adjustable dual-drug ratio was developed. First, apogossypolone (ApoG2) amphiphilic starch micelles (AASt MCs) were prepared by self-assembly process, and doxorubicin (DOX) hyaluronic acid nanoparticles (DHA NPs) were prepared by DOX absorption with excess HA by electrostatic absorption. MLDC NCs were obtained by adsorption of 8-9 DHA NPs around one AASt MC via electrostatic interaction. UV-visible and fluorescence spectrophotometers were used to measure the entrapment efficiency and loading efficiency of the two drugs. Transmission electron microscope and dynamic light scattering method were used to observe the size distribution and morphology of the particles. The tumor-targeting feature caused by HA-receptor mediation was confirmed by in vitro cell uptake and in vivo near-infrared fluorescence imaging. MLDC NCs were found to possess a mulberry-like shape with a dynamic size of 83.1 ± 6.6 nm. The final encapsulation efficiencies of ApoG2 and DOX in MLDC NCs were 94 ± 1.7% and 87 ± 5.8% with respect to drug-loading capacities of 13.3 ± 1.2% and 13.1 ± 3.7%, respectively. Almost no ApoG2 release was found within 80 h and less than 30% of DOX was released into the outer phase even after 72 h. In vivo fluorescence imaging revealed that MLDC NCs had highly efficient targeting and accumulation at the tumor in vivo and was maintained for 96 h after being injected intravenously in mice. Low LD50 for the two drugs in MLDC NCs was found after acute toxicity test. One-fifth normal dosage of the two drugs in MLDC NCs exhibited significantly higher anti-tumor efficiency in reducing tumor size compared with free drugs combination or single drug-loaded nanoparticles individually, indicating that the mulberry-like dual-drug nanoplatform has a great potential in tumor therapy. Copyright © 2014 Elsevier Ltd. All rights

Dual turn-on fluorescence signal-based controlled release system for real-time monitoring of drug release dynamics in living cells and tumor tissues.

Science.gov (United States)

Kong, Xiuqi; Dong, Baoli; Song, Xuezhen; Wang, Chao; Zhang, Nan; Lin, Weiying

2018-01-01

Controlled release systems with capabilities for direct and real-time monitoring of the release and dynamics of drugs in living systems are of great value for cancer chemotherapy. Herein, we describe a novel dual turn-on fluorescence signal-based controlled release system ( CDox ), in which the chemotherapy drug doxorubicin ( Dox ) and the fluorescent dye ( CH ) are conjugated by a hydrazone moiety, a pH-responsive cleavable linker. CDox itself shows nearly no fluorescence as the fluorescence of CH and Dox is essentially quenched by the C=N isomerization and N-N free rotation. However, when activated under acidic conditions, CDox could be hydrolyzed to afford Dox and CH , resulting in dual turn-on signals with emission peaks at 595 nm and 488 nm, respectively. Notably, CDox exhibits a desirable controlled release feature as the hydrolysis rate is limited by the steric hindrance effect from both the Dox and CH moieties. Cytotoxicity assays indicate that CDox shows much lower cytotoxicity relative to Dox , and displays higher cell inhibition rate to cancer than normal cells. With the aid of the dual turn-on fluorescence at different wavelengths, the drug release dynamics of CDox in living HepG2 and 4T-1 cells was monitored in double channels in a real-time fashion. Importantly, two-photon fluorescence imaging of CDox in living tumor tissues was also successfully performed by high-definition 3D imaging. We expect that the unique controlled release system illustrated herein could provide a powerful means to investigate modes of action of drugs, which is critical for development of much more robust and effective chemotherapy drugs.

Phospholipid-Coated Mesoporous Silica Nanoparticles Acting as Lubricating Drug Nanocarriers

OpenAIRE

Tao Sun; Yulong Sun; Hongyu Zhang

2018-01-01

Osteoarthritis (OA) is a severe disease caused by wear and inflammation of joints. In this study, phospholipid-coated mesoporous silica nanoparticles (MSNs@lip) were prepared in order to treat OA at an early stage. The phospholipid layer has excellent lubrication capability in aqueous media due to the hydration lubrication mechanism, while mesoporous silica nanoparticles (MSNs) act as effective drug nanocarriers. The MSNs@lip were characterized by scanning electron microscope, transmission el...

A smart upconversion-based light-triggered polymer for synergetic chemo-photodynamic therapy and dual-modal MR/UCL imaging.

Science.gov (United States)

Du, Bin; Han, Shuping; Zhao, Feifei; Lim, Kok Hwa; Xi, Hongwei; Su, Xiangjie; Yao, Hanchun; Zhou, Jie

2016-10-01

We have developed a novel nanocomposite to achieve effective therapy and live surveillance of tumor tissue. In this study, fullerene (C 60 ) with iron oxide (Fe 3 O 4 ) nanoparticles and upconversion nanophosphors (UCNPs) was loaded into N-succinyl-N'-4-(2-nitrobenzyloxy)-succinyl-chitosan micelles (SNSC) with good biocompatibility. In addition, hydrophobic anticancer drug docetaxel (DTX) was also loaded into the nanocomposites. The experiments conducted in vitro and in vivo demonstrated that C 60 /Fe 3 O 4 -UCNPs@DTX@SNSC can act synergistically to kill tumor cells by releasing chemotherapy drugs at specific target site as well as generating reactive oxygen using 980nm. In addition, it can also be used for non-invasive deep magnetic resonance and upconversion fluorescence dual-mode imaging. The results indicated that this system provided an efficient method to surmount the drawback of UV or visible light-responsive polymeric systems for controlled drug release and generated reactive oxygen in deep tissues and ultimately realized the integration of dual-modal imaging and treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

[Dual Pathology in General Population of Itagüí, Colombia].

Science.gov (United States)

Castaño Pérez, Guillermo A; Sierra Hincapié, Gloria Maria

2016-01-01

To study the prevalence of dual diagnosis (presence of a substance use disorder and an associated mental disorder) in the general population of a small town in the department of Antioquia in Colombia, through secondary analysis of survey data on Mental Health held in this city in 2011. With a sample of 415 subjects, the interview Composite International Diagnostic Interview (CIDI), WHO CAPI version, was used and statistical analysis was performed using SPSS v.21. The prevalence of dual diagnosis, considering that the presence of a diagnosis of mental disorder and a disorder snuff use of different substances was 7.2%. Substances with higher prevalence of use in life for individuals with dual diagnosis were alcohol (96.7%), marijuana (80.0%), cocaine and derivatives (33.3%), heroin (23.3%) and finally no prescription tranquilizers (13.3%), finding statistical association between drug use and dual diagnosis. Major depression (40%), oppositional defiant disorder (36.7%), posttraumatic stress (33.3%), specific phobia and attention deficit (26.7%) are the most prevalent disorders in individuals with dual diagnosis of this sample. Alcohol or drugs consumption and fulfilling diagnostic criteria for dual diagnosis have a significant statistical association for consumption of drugs like marijuana, cocaine, heroin and prescription medications (P1.00, very high when the drug is heroin consumed (RD=38.754) or non-prescription medications (RD=29.462). A family history of disease and drug use has a high statistical association with dual diagnosis, with a higher association with a history of mental illness (P<.001; RD=3.677). The study reports on the prevalence of subjects with dual diagnosis in a Colombian population. Alcohol, marijuana, cocaine and heroin are derivatives and substances mostly consumed by these patients and the most prevalent mental disorders are depression, TOD and posttraumatic stress. These findings motivate clinicians to more actively seek the presence of

76 FR 58277 - Animal Generic Drug User Fee Act; Public Meeting; Request for Comments

Science.gov (United States)

2011-09-20

... support for lower-cost alternatives to brand drugs for consumers. Under AGDUFA, FDA agreed to meet review... Parklawn Dr., Element Bldg., Rockville, MD 20857. Dated: September 13, 2011. Leslie Kux, Acting Assistant...

Tragedy, transformation, and triumph: comparing the factors and forces that led to the adoption of the 1860 Adulteration Act in England and the 1906 Pure Food and Drug Act in the United States.

Science.gov (United States)

London, Jillian

2014-01-01

The 1860 Adulteration Act in England and the 1906 Pure Food and Drug Act in the United States were two of the earliest pieces of legislation to provide generalized regulation of food and drugs on a national scale. While significant scholarly attention has been given to explaining the factors and forces that led to the passage of each Act independent of the other, few books or articles have directly compared the similar individuals and events that led to the adoption of both Acts. This paper attempts to fill that gap. Through a comparative examination, this paper reveals that four main components were key to the national pure food and drug movements in both countries: individuals who crusaded for national adulteration legislation; tragedies that shocked the public into calling for reform; press and publicity that was willing and able to bring the evils of adulteration to the forefront of the public mind; and a transformation of the social, political, and economic systems, which created atmospheres conducive to reform. This paper aims to shed new light on the 1860 Adulteration Act and the 1906 Pure Food and Drug Act--two acts that derive their importance not just from the effect that they directly had on the regulation of food and drugs but also as some of the earliest examples of western governments coming to recognize the need for national regulation to protect the public from harm and coming to embrace their changing role as spearheads of modern regulatory states.

Prescription Drug Marketing Act of 1987; Prescription Drug Amendments of 1992; policies, requirements, and administrative procedures; delay of effective date; reopening of administrative record. Food and Drug Administration, HHS. Final rule; delay of effective date; reopening of administrative record.

Science.gov (United States)

2000-05-03

The Food and Drug Administration (FDA) is delaying until October 1, 2001, the effective date and reopening the administrative record to receive additional comments regarding certain requirements of a final rule published in the Federal Register of December 3, 1999 (64 FR 67720). The other provisions of the final rule become effective on December 4, 2000. The final rule implements the Prescription Drug Marketing Act of 1987 (PDMA), as modified by the Prescription Drug Amendments of 1992 (PDA) and the FDA Modernization Act of 1997 (the Modernization Act). FDA is delaying the effective date for certain requirements relating to wholesale distribution of prescription drugs by distributors that are not authorized distributors of record. FDA is also delaying the effective date of another requirement that would prohibit blood centers functioning as "health care entities" to act as wholesale distributors of blood derivatives. The agency is taking this action to address numerous concerns about the provisions raised by affected parties.

Impact of the Pharma Economic Act on Diffusion of Innovation and Reduction of Costs in the Hungarian Prescription Drug Market (2007-2010).

Science.gov (United States)

Hren, Rok

In this study, we examined the impact of the Pharma Economic Act, which was introduced in Hungary in 2007. We used detailed data on the Hungarian prescription drug market, which had been made publicly available by the authorities. We evaluated the effect of the Pharma Economic Act on both dynamic and static efficiencies and also on equity, which has been historically a controversial issue in Hungary. We analyzed the overall prescription drug market and statin and atorvastatin markets; as a proxy for determining dynamic efficiency, we examined the oncology drug market for some specific products (e.g., bortezomib) and the long-acting atypical antipsychotic drugs market. There is no denying that the authorities managed to control the overall prescription drug costs; however, they were still paying excessive rents for off-patent drugs. Examples of oncology and long-acting atypical antipsychotic drugs showed that the diffusion of innovation was on per-capita basis at least comparable to G-5 countries. While the share of out-of-pocket co-payments markedly increased and the reimbursement was lowered, the concurrent price decreases often meant that the co-payment per milligram of a given dispensed drug was actually lower than that before the Act, thereby benefiting the patient. It appears that strong mechanisms to control volume rather than price on the supply side (marketing authorization holders) contained the drug expenditure, while offering enough room to strive for innovation. Making data on prescription drug expenditures and associated co-payments publicly available is an item that should be definitely followed by the surrounding jurisdictions. Copyright © 2013, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc.

Estimating antimalarial drugs consumption in Africa before the switch to artemisinin-based combination therapies (ACTs).

Science.gov (United States)

Kindermans, Jean-Marie; Vandenbergh, Daniel; Vreeke, Ed; Olliaro, Piero; D'Altilia, Jean-Pierre

2007-07-10

Having reliable forecasts is critical now for producers, malaria-endemic countries and agencies in order to adapt production and procurement of the artemisinin-based combination treatments (ACTs), the new first-line treatments of malaria. There is no ideal method to quantify drug requirements for malaria. Morbidity data give uncertain estimations. This study uses drug consumption to provide elements to help estimate quantities and financial requirements of ACTs. The consumption of chloroquine, sulphadoxine/pyrimethamine and quinine both through the private and public sector was assessed in five sub-Saharan Africa countries with different epidemiological patterns (Senegal, Rwanda, Tanzania, Malawi, Zimbabwe). From these data the number of adult treatments per capita was calculated and the volumes and financial implications derived for the whole of Africa. Identifying and obtaining data from the private sector was difficult. The quality of information on drug supply and distribution in countries must be improved. The number of adult treatments per capita and per year in the five countries ranged from 0.18 to 0.50. Current adult treatment prices for ACTs range US$ 1-1.8. Taking the upper range for both volumes and costs, the highest number of adult treatments consumed for Africa was estimated at 314.5 million, corresponding to an overall maximum annual need for financing ACT procurement of US$ 566.1 million. In reality, both the number of cases treated and the cost of treatment are likely to be lower (projections for the lowest consumption estimate with the least expensive ACT would require US $ 113 million per annum). There were substantial variations in the market share between public and private sources among these countries (the public sector share ranging from 98% in Rwanda to 33% in Tanzania). Additional studies are required to build a more robust methodology, and to assess current consumptions more accurately in order to better quantify volumes and finances for

Estimating antimalarial drugs consumption in Africa before the switch to artemisinin-based combination therapies (ACTs

Directory of Open Access Journals (Sweden)

Vreeke Ed

2007-07-01

Full Text Available Abstract Background Having reliable forecasts is critical now for producers, malaria-endemic countries and agencies in order to adapt production and procurement of the artemisinin-based combination treatments (ACTs, the new first-line treatments of malaria. There is no ideal method to quantify drug requirements for malaria. Morbidity data give uncertain estimations. This study uses drug consumption to provide elements to help estimate quantities and financial requirements of ACTs. Methods The consumption of chloroquine, sulphadoxine/pyrimethamine and quinine both through the private and public sector was assessed in five sub-Saharan Africa countries with different epidemiological patterns (Senegal, Rwanda, Tanzania, Malawi, Zimbabwe. From these data the number of adult treatments per capita was calculated and the volumes and financial implications derived for the whole of Africa. Results Identifying and obtaining data from the private sector was difficult. The quality of information on drug supply and distribution in countries must be improved. The number of adult treatments per capita and per year in the five countries ranged from 0.18 to 0.50. Current adult treatment prices for ACTs range US$ 1–1.8. Taking the upper range for both volumes and costs, the highest number of adult treatments consumed for Africa was estimated at 314.5 million, corresponding to an overall maximum annual need for financing ACT procurement of US$ 566.1 million. In reality, both the number of cases treated and the cost of treatment are likely to be lower (projections for the lowest consumption estimate with the least expensive ACT would require US $ 113 million per annum. There were substantial variations in the market share between public and private sources among these countries (the public sector share ranging from 98% in Rwanda to 33% in Tanzania. Conclusion Additional studies are required to build a more robust methodology, and to assess current consumptions

Metal bacteriochlorins which act as dual singlet oxygen and superoxide generators.

Science.gov (United States)

Fukuzumi, Shunichi; Ohkubo, Kei; Zheng, Xiang; Chen, Yihui; Pandey, Ravindra K; Zhan, Riqiang; Kadish, Karl M

2008-03-06

A series of stable free-base, Zn(II) and Pd(II) bacteriochlorins containing a fused six- or five-member diketo- or imide ring have been synthesized as good candidates for photodynamic therapy sensitizers, and their electrochemical, photophysical, and photochemical properties were examined. Photoexcitation of the palladium bacteriochlorin affords the triplet excited state without fluorescence emission, resulting in formation of singlet oxygen with a high quantum yield due to the heavy atom effect of palladium. Electrochemical studies revealed that the zinc bacteriochlorin has the smallest HOMO-LUMO gap of the investigated compounds, and this value is significantly lower than the triplet excited-state energy of the compound in benzonitrile. Such a small HOMO-LUMO gap of the zinc bacteriochlorin enables intermolecular photoinduced electron transfer from the triplet excited state to the ground state to produce both the radical cation and the radical anion. The radical anion thus produced can transfer an electron to molecular oxygen to produce superoxide anion which was detected by electron spin resonance. The same photosensitizer can also act as an efficient singlet oxygen generator. Thus, the same zinc bacteriochlorin can function as a sensitizer with a dual role in that it produces both singlet oxygen and superoxide anion in an aprotic solvent (benzonitrile).

Dual-drug delivery by porous silicon nanoparticles for improved cellular uptake, sustained release, and combination therapy.

Science.gov (United States)

Wang, Chang-Fang; Mäkilä, Ermei M; Kaasalainen, Martti H; Hagström, Marja V; Salonen, Jarno J; Hirvonen, Jouni T; Santos, Hélder A

2015-04-01

Dual-drug delivery of antiangiogenic and chemotherapeutic drugs can enhance the therapeutic effect for cancer therapy. Conjugation of methotrexate (MTX) to porous silicon (PSi) nanoparticles (MTX-PSi) with positively charged surface can improve the cellular uptake of MTX and inhibit the proliferation of cancer cells. Herein, MTX-PSi conjugates sustained the release of MTX up to 96 h, and the released fragments including MTX were confirmed by mass spectrometry. The intracellular distribution of the MTX-PSi nanoparticles was confirmed by transmission electron microscopy. Compared to pure MTX, the MTX-PSi achieved similar inhibition of cell proliferation in folate receptor (FR) over-expressing U87 MG cancer cells, and a higher effect in low FR-expressing EA.hy926 cells. Nuclear fragmentation analysis demonstrated programmed cell apoptosis of MTX-PSi in the high/low FR-expressing cancer cells, whereas PSi alone at the same dose had a minor effect on cell apoptosis. Finally, the porous structure of MTX-PSi enabled a successful concomitant loading of another anti-angiogenic hydrophobic drug, sorafenib, and considerably enhanced the dissolution rate of sorafenib. Overall, the MTX-PSi nanoparticles can be used as a platform for combination chemotherapy by simultaneously enhancing the dissolution rate of a hydrophobic drug and sustaining the release of a conjugated chemotherapeutic drug. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Diagnosis of dual human immunodeficiency virus types 1 & 2 ...

African Journals Online (AJOL)

Background: The presence of dual HlV-l/HIV-2 infection in Ghana and the different drug requirements for the treatment of HlV-1 and HIV-2 presents difficulties for the treatment of dual infections with both viruses. Objectives: To determine the prevalence of the dual sero-positive profile in treatment naive patients at a principal ...

Injectable dual redox responsive diselenide-containing poly(ethylene glycol) hydrogel.

Science.gov (United States)

Gong, Chu; Shan, Meng; Li, Bingqiang; Wu, Guolin

2017-09-01

An injectable dual redox responsive diselenide-containing poly(ethylene glycol) (PEG) hydrogel was successfully developed by combining the conceptions of injectable hydrogels and dual redox responsive diselenides. In the first step, four-armed PEG was modified with N-hydroxysuccinimide (NHS)-activated esters and thereafter, crosslinked by selenocystamine crosslinkers to form injectable hydrogels via the rapid reaction between NHS-activated esters and amino groups. The cross-sectional morphology, mechanical properties, and crosslinking modes of hydrogels were well characterized via scanning electron microscope (SEM), rheological measurements, and Fourier transform infrared spectra, respectively. In addition, the oxidation- and reduction-responsive degradation behaviors of hydrogels were observed and analyzed. The model drug, rhodamine B, was encapsulated in the hydrogel. The drug-loaded hydrogel exhibited a dual redox responsive release profile, which was consistent with the degradation experiments. The results of all experiments indicated that the formulated injectable dual redox responsive diselenide-containing PEG hydrogel can have potential applications in various biomedical fields such as drug delivery and stimuli-responsive drug release. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2451-2460, 2017. © 2017 Wiley Periodicals, Inc.

Knockdown of UbcH10 Enhances the Chemosensitivity of Dual Drug Resistant Breast Cancer Cells to Epirubicin and Docetaxel

Directory of Open Access Journals (Sweden)

Cheng Wang

2015-03-01

Full Text Available Breast cancer is one of the most common and lethal cancers in women. As a hub gene involved in a diversity of tumors, the ubiquitin-conjugating enzyme H10 (UbcH10, may also play some roles in the genesis and development of breast cancer. In the current study, we found that the expression of UbcH10 was up-regulated in some breast cancer tissues and five cell lines. We established a dual drug resistant cell line MCF-7/EPB (epirubicin/TXT (docetaxel and a lentiviral system expressing UbcH10 shRNA to investigate the effects of UbcH10 knockdown on the chemosensitivity of MCF-7/EPB/TXT cells to epirubicin and docetaxel. The knockdown of UbcH10 inhibited the proliferation of both MCF-7 and MCF-7/EPB/TXT cells, due to the G1 phase arrest in cell cycle. Furthermore, UbcH10 knockdown increased the sensitivity of MCF-7/EPB/TXT cells to epirubicin and docetaxel and promoted the apoptosis induced by these two drugs. Protein detection showed that, in addition to inhibiting the expression of Ki67 and cyclin D1, UbcH10 RNAi also impaired the increased BCL-2 and MDR-1 expression levels in MCF-7/EPB/TXT cells, which may contribute to abating the drug resistance in the breast cancer cells. Our research in the current study demonstrated that up-regulation of UbcH10 was involved in breast cancer and its knockdown can inhibit the growth of cancer cells and increase the chemosensitivity of the dual drug resistant breast cancer cells to epirubicin and docetaxel, suggesting that UbcH10 may be a promising target for the therapy of breast cancer.

Stent Thrombosis in Drug-Eluting or Bare-Metal Stents in Patients Receiving Dual Antiplatelet Therapy.

Science.gov (United States)

Kereiakes, Dean J; Yeh, Robert W; Massaro, Joseph M; Driscoll-Shempp, Priscilla; Cutlip, Donald E; Steg, P Gabriel; Gershlick, Anthony H; Darius, Harald; Meredith, Ian T; Ormiston, John; Tanguay, Jean-François; Windecker, Stephan; Garratt, Kirk N; Kandzari, David E; Lee, David P; Simon, Daniel I; Iancu, Adrian Corneliu; Trebacz, Jaroslaw; Mauri, Laura

2015-10-01

This study sought to compare rates of stent thrombosis and major adverse cardiac and cerebrovascular events (MACCE) (composite of death, myocardial infarction, or stroke) after coronary stenting with drug-eluting stents (DES) versus bare-metal stents (BMS) in patients who participated in the DAPT (Dual Antiplatelet Therapy) study, an international multicenter randomized trial comparing 30 versus 12 months of dual antiplatelet therapy in subjects undergoing coronary stenting with either DES or BMS. Despite antirestenotic efficacy of coronary DES compared with BMS, the relative risk of stent thrombosis and adverse cardiovascular events is unclear. Many clinicians perceive BMS to be associated with fewer adverse ischemic events and to require shorter-duration dual antiplatelet therapy than DES. Prospective propensity-matched analysis of subjects enrolled into a randomized trial of dual antiplatelet therapy duration was performed. DES- and BMS-treated subjects were propensity-score matched in a many-to-one fashion. The study design was observational for all subjects 0 to 12 months following stenting. A subset of eligible subjects without major ischemic or bleeding events were randomized at 12 months to continued thienopyridine versus placebo; all subjects were followed through 33 months. Among 10,026 propensity-matched subjects, DES-treated subjects (n = 8,308) had a lower rate of stent thrombosis through 33 months compared with BMS-treated subjects (n = 1,718, 1.7% vs. 2.6%; weighted risk difference -1.1%, p = 0.01) and a noninferior rate of MACCE (11.4% vs. 13.2%, respectively, weighted risk difference -1.8%, p = 0.053, noninferiority p stent thrombosis that are lower than BMS-treated subjects. (The Dual Antiplatelet Therapy Study [DAPT study]; NCT00977938). Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Novel dual small-molecule HIV inhibitors: scaffolds and discovery strategies.

Science.gov (United States)

Song, Anran; Yu, Haiqing; Wang, Changyuan; Zhu, Xingqi; Liu, Kexin; Ma, Xiaodong

2015-01-01

Searching for safe and effective treatments for HIV infection is still a great challenge worldwide in spite of the 27 marketed anti-HIV drugs and the powerful highly active antiretroviral therapy (HAART). As a promising prospect for generation of new HIV therapy drugs, multiple ligands (MDLs) were greatly focused on recently due to their lower toxicity, simplified dosing and patient adherence than single-target drugs. Till now, by disrupting two active sites or steps of HIV replications, a number of HIV dual inhibitors, such as CD4-gssucap120 inhibitors, CXCR4-gp20 inhibitors, RT-CXCR4 inhibitors, RT-protease inhibitors, RT-integrase inhibitors, and RTassociated functions inhibitors have been identified. Generally, these dual inhibitors were discovered mainly through screening approaches and design strategies. Of these compounds, the molecules bearing small skeletons exhibited strong anti-HIV activity and aroused great attention recently. Reviewing the progress of the dual small-molecule HIV inhibitors from the point of view of their scaffolds and discovery strategies will provide valuable information for producing more effective anti-HIV drugs. In this regard, novel dual small-molecule HIV inhibitors were illustrated, and their discovery paradigms as the major contents were also summarized in this manuscript.

A gene expression system offering multiple levels of regulation: the Dual Drug Control (DDC) system.

Science.gov (United States)

Sudomoina, Marina; Latypova, Ekaterina; Favorova, Olga O; Golemis, Erica A; Serebriiskii, Ilya G

2004-04-29

Whether for cell culture studies of protein function, construction of mouse models to enable in vivo analysis of disease epidemiology, or ultimately gene therapy of human diseases, a critical enabling step is the ability to achieve finely controlled regulation of gene expression. Previous efforts to achieve this goal have explored inducible drug regulation of gene expression, and construction of synthetic promoters based on two-hybrid paradigms, among others. In this report, we describe the combination of dimerizer-regulated two-hybrid and tetracycline regulatory elements in an ordered cascade, placing expression of endpoint reporters under the control of two distinct drugs. In this Dual Drug Control (DDC) system, a first plasmid expresses fusion proteins to DBD and AD, which interact only in the presence of a small molecule dimerizer; a second plasmid encodes a cassette transcriptionally responsive to the first DBD, directing expression of the Tet-OFF protein; and a third plasmid encodes a reporter gene transcriptionally responsive to binding by Tet-OFF. We evaluate the dynamic range and specificity of this system in comparison to other available systems. This study demonstrates the feasibility of combining two discrete drug-regulated expression systems in a temporally sequential cascade, without loss of dynamic range of signal induction. The efficient layering of control levels allowed by this combination of elements provides the potential for the generation of complex control circuitry that may advance ability to regulate gene expression in vivo.

A gene expression system offering multiple levels of regulation: the Dual Drug Control (DDC system

Directory of Open Access Journals (Sweden)

Golemis Erica A

2004-04-01

Full Text Available Abstract Background Whether for cell culture studies of protein function, construction of mouse models to enable in vivo analysis of disease epidemiology, or ultimately gene therapy of human diseases, a critical enabling step is the ability to achieve finely controlled regulation of gene expression. Previous efforts to achieve this goal have explored inducible drug regulation of gene expression, and construction of synthetic promoters based on two-hybrid paradigms, among others. Results In this report, we describe the combination of dimerizer-regulated two-hybrid and tetracycline regulatory elements in an ordered cascade, placing expression of endpoint reporters under the control of two distinct drugs. In this Dual Drug Control (DDC system, a first plasmid expresses fusion proteins to DBD and AD, which interact only in the presence of a small molecule dimerizer; a second plasmid encodes a cassette transcriptionally responsive to the first DBD, directing expression of the Tet-OFF protein; and a third plasmid encodes a reporter gene transcriptionally responsive to binding by Tet-OFF. We evaluate the dynamic range and specificity of this system in comparison to other available systems. Conclusion This study demonstrates the feasibility of combining two discrete drug-regulated expression systems in a temporally sequential cascade, without loss of dynamic range of signal induction. The efficient layering of control levels allowed by this combination of elements provides the potential for the generation of complex control circuitry that may advance ability to regulate gene expression in vivo.

Mechanisms and Implications of Dual-Acting Methotrexate in Folate-Targeted Nanotherapeutic Delivery

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Pamela T. Wong

2015-01-01

Full Text Available The rational design of a nanoplatform in drug delivery plays a crucial role in determining its targeting specificity and efficacy in vivo. A conventional approach relies on the surface conjugation of a nanometer-sized particle with two functionally distinct types of molecules, one as a targeting ligand, and the other as a therapeutic agent to be delivered to the diseased cell. However, an alternative simplified approach can be used, in which a single type of molecule displaying dual function as both a targeting ligand and therapeutic agent is conjugated to the nanoparticle. In this review, we evaluate the validity of this new strategy by using methotrexate, which displays multifunctional mechanisms of action. Methotrexate binds to the folate receptor, a surface biomarker frequently overexpressed in tumor cells, and also inhibits dihydrofolate reductase, an enzyme critical for cell survival and division. Thus we describe a series of fifth generation poly(amido amine dendrimers conjugated with methotrexate, and discuss several lines of evidence supporting the efficacy of this new platform strategy based on surface plasmon resonance spectroscopy, enzyme activity assays, and cell-based studies with folate receptor (+ KB cancer cells.

Dual Component Removable Partial Denture shows improved ...

African Journals Online (AJOL)

Dual Component Removable Partial Denture (DuCo RPD) is composed of a double base; lower and upper. The lower base, where the artificial teeth are attached, acts as a support and is in contact with the alveolar ridges and oral mucosa. Clasps are designed on the upper base, which acts towards the retention and ...

Folate decorated dual drug loaded nanoparticle: role of curcumin in enhancing therapeutic potential of nutlin-3a by reversing multidrug resistance.

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Manasi Das

Full Text Available Retinoblastoma is the most common intraocular tumor in children. Malfunctioning of many signaling pathways regulating cell survival or apoptosis, make the disease more vulnerable. Notably, resistance to chemotherapy mediated by MRP-1, lung-resistance protein (LRP is the most challenging aspect to treat this disease. Presently, much attention has been given to the recently developed anticancer drug nutlin-3a because of its non-genotoxic nature and potency to activate tumor suppressor protein p53. However, being a substrate of multidrug resistance protein MRP1 and Pgp its application has become limited. Currently, research has step towards reversing Multi drug resistance (MDR by using curcumin, however its clinical relevance is restricted by plasma instability and poor bioavailability. In the present investigation we tried to encapsulate nutlin-3a and curcumin in PLGA nanoparticle (NPs surface functionalized with folate to enhance therapeutic potential of nutlin-3a by modulating MDR. We document that curcumin can inhibit the expression of MRP-1 and LRP gene/protein in a concentration dependent manner in Y79 cells. In vitro cellular cytotoxicity, cell cycle analysis and apoptosis studies were done to compare the effectiveness of native drugs (single or combined and single or dual drug loaded nanoparticles (unconjugated/folate conjugated. The result demonstrated an augmented therapeutic efficacy of targeted dual drug loaded NPs (Fol-Nut-Cur-NPs over other formulation. Enhanced expression or down regulation of proapoptotic/antiapoptotic proteins respectively and down-regulation of bcl2 and NFκB gene/protein by Fol-Nut-Cur-NPs substantiate the above findings. This is the first investigation exploring the role of curcumin as MDR modulator to enhance the therapeutic potentiality of nutlin-3a, which may opens new direction for targeting cancer with multidrug resistance phenotype.

Bioprinting cell-laden matrigel for radioprotection study of liver by pro-drug conversion in a dual-tissue microfluidic chip

International Nuclear Information System (INIS)

Snyder, J E; Hamid, Q; Wang, C; Chang, R; Sun, W; Emami, K; Wu, H

2011-01-01

The objective of this paper is to introduce a novel cell printing and microfluidic system to serve as a portable ground model for the study of drug conversion and radiation protection of living liver tissue analogs. The system is applied to study behavior in ground models of space stress, particularly radiation. A microfluidic environment is engineered by two cell types to prepare an improved higher fidelity in vitro micro-liver tissue analog. Cell-laden Matrigel printing and microfluidic chips were used to test radiation shielding to liver cells by the pro-drug amifostine. In this work, the sealed microfluidic chip regulates three variables of interest: radiation exposure, anti-radiation drug treatment and single- or dual-tissue culture environments. This application is intended to obtain a scientific understanding of the response of the multi-cellular biological system for long-term manned space exploration, disease models and biosensors.

Bioprinting cell-laden matrigel for radioprotection study of liver by pro-drug conversion in a dual-tissue microfluidic chip

Energy Technology Data Exchange (ETDEWEB)

Snyder, J E; Hamid, Q; Wang, C; Chang, R; Sun, W [Department of Mechanical Engineering, Drexel University, Philadelphia, PA 19104 (United States); Emami, K; Wu, H, E-mail: sunwei@drexel.edu, E-mail: weisun@tsinghua.edu.cn [Radiation Biophysics Lab, NASA Johnson Space Center, Houston, TX 77586 (United States)

2011-09-15

The objective of this paper is to introduce a novel cell printing and microfluidic system to serve as a portable ground model for the study of drug conversion and radiation protection of living liver tissue analogs. The system is applied to study behavior in ground models of space stress, particularly radiation. A microfluidic environment is engineered by two cell types to prepare an improved higher fidelity in vitro micro-liver tissue analog. Cell-laden Matrigel printing and microfluidic chips were used to test radiation shielding to liver cells by the pro-drug amifostine. In this work, the sealed microfluidic chip regulates three variables of interest: radiation exposure, anti-radiation drug treatment and single- or dual-tissue culture environments. This application is intended to obtain a scientific understanding of the response of the multi-cellular biological system for long-term manned space exploration, disease models and biosensors.

Drug discovery and the impact of the safe harbor provision of the Hatch- Waxman Act.

Science.gov (United States)

Goodson, Susanne H

2010-01-01

Many facets of drug discovery involve the use of patented materials and methods, subjecting the researcher to potential liability from infringement of the underlying patents. Enacted in 1984, the Hatch-Waxman Act established a “safe harbor” for activities that would otherwise constitute infringement of a patented invention, if those activities were “solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products”. This article examines the major court decisions interpreting the scope of the safe harbor and their application to various activities in drug development.

Medicare home health care patient case-mix before and after the Balanced Budget Act of 1997: effect on dual eligible beneficiaries.

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Shih, Huai-Che; Temkin-Greener, Helena; Votava, Kathryn; Friedman, Bruce

2014-01-01

The Balanced Budget Act (BBA) of 1997 changed the payment system for Medicare home health care (HHC) from cost-based to prospective reimbursement. We used Medical Expenditure Panel Survey data to assess the impact of the BBA on Medicare HHC patient case-mix measured by the Centers for Medicare and Medicaid Services Hierarchical Condition Categories (CMS-HCC) model. There was a significant increase in Medicare HHC patient case-mix between the pre-BBA and Prospective Payment System (PPS) periods. The increase in the standardized-predicted risk score from the Interim Payment System period to PPS was nearly 4 times greater for the dual eligibles (Medicare-Medicaid) than for the Medicare-only population. This significantly greater rise in the HHC resources required by dual eligibles as compared to nonduals could be due to a shift in HHC payers from Medicare only to Medicaid rather than be an actual increase in case-mix per se.

Dual stimuli polysaccharide nanovesicles for conjugated and physically loaded doxorubicin delivery in breast cancer cells

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Pramod, P. S.; Shah, Ruchira; Jayakannan, Manickam

2015-04-01

The present work reports the development of pH and enzyme dual responsive polysaccharide vesicular nano-scaffolds for the administration of doxorubicin via physical loading and polymer-drug conjugation to breast cancer cells. Dextran was suitably modified with a renewable resource 3-pentadecyl phenol unit through imine and aliphatic ester chemical linkages that acted as pH and esterase enzyme stimuli, respectively. These dual responsive polysaccharide derivatives self-organized into 200 +/- 10 nm diameter nano-vesicles in water. The water soluble anticancer drug doxorubicin (DOX.HCl) was encapsulated in the hydrophilic pocket to produce core-loaded polysaccharide vesicles whereas chemical conjugation produced DOX anchored at the hydrophobic layer of the dextran nano-vesicles. In vitro studies revealed that about 70-80% of the drug was retained under circulatory conditions at pH = 7.4 and 37 °C. At a low pH of 6.0 to 5.0 and in the presence of esterase; both imine and ester linkages were cleaved instantaneously to release 100% of the loaded drugs. Cytotoxicity assays on Wild Type Mouse Embryonic Fibroblasts (WTMEFs) confirmed the non-toxicity of the newly developed dextran derivatives at up to 500 μg mL-1 in PBS. MTT assays on fibroblast cells revealed that DOX.HCl loaded nano-vesicles exhibited better killing abilities than DOX conjugated polymer nano-vesicles. Both DOX loaded and DOX conjugated nano-vesicles were found to show significant killing in breast cancer cells (MCF 7). Confocal microscopy images confirmed the uptake of DOX loaded (or conjugated) nano-vesicles by cells compared to free DOX. Thus, the newly developed pH and enzyme dual responsive polysaccharide vesicular assemblies are potential drug vectors for the administration of DOX in both loaded and chemically conjugated forms for the efficient killing of breast cancer cells.The present work reports the development of pH and enzyme dual responsive polysaccharide vesicular nano-scaffolds for the

Dual Functional Nanocarrier for Cellular Imaging and Drug Delivery in Cancer Cells Based on π-Conjugated Core and Biodegradable Polymer Arms.

Science.gov (United States)

Kulkarni, Bhagyashree; Surnar, Bapurao; Jayakannan, Manickam

2016-03-14

Multipurpose polymer nanoscaffolds for cellular imaging and delivery of anticancer drug are urgently required for the cancer therapy. The present investigation reports a new polymer drug delivery concept based on biodegradable polycaprolactone (PCL) and highly luminescent π-conjugated fluorophore as dual functional nanocarrier for cellular imaging and delivery vehicles for anticancer drug to cancer cells. To accomplish this goal, a new substituted caprolactone monomer was designed, and it was subjected to ring opening polymerization using a blue luminescent bishydroxyloligo-phenylenevinylene (OPV) fluorophore as an initiator. A series of A-B-A triblock copolymer building blocks with a fixed OPV π-core and variable chain biodegradable PCL arm length were tailor-made. These triblocks self-assembled in organic solvents to produce well-defined helical nanofibers, whereas in water they produced spherical nanoparticles (size ∼150 nm) with blue luminescence. The hydrophobic pocket of the polymer nanoparticle was found to be an efficient host for loading water insoluble anticancer drug such as doxorubicin (DOX). The photophysical studies revealed that there was no cross-talking between the OPV and DOX chromophores, and their optical purity was retained in the nanoparticle assembly for cellular imaging. In vitro studies revealed that the biodegradable PCL arm was susceptible to enzymatic cleavage at the intracellular lysosomal esterase under physiological conditions to release the loaded drugs. The nascent nanoparticles were found to be nontoxic to cancer cells, whereas the DOX-loaded nanoparticles accomplished more than 80% killing in HeLa cells. Confocal microscopic analysis confirmed the cell penetrating ability of the blue luminescent polymer nanoparticles and their accumulation preferably in the cytoplasm. The DOX loaded red luminescent polymer nanoparticles were also taken up by the cells, and the drug was found to be accumulated at the perinuclear environment

Venetoclax (ABT-199) Might Act as a Perpetrator in Pharmacokinetic Drug–Drug Interactions

Science.gov (United States)

Weiss, Johanna; Gajek, Thomas; Köhler, Bruno Christian; Haefeli, Walter Emil

2016-01-01

Venetoclax (ABT-199) represents a specific B-cell lymphoma 2 (Bcl-2) inhibitor that is currently under development for the treatment of lymphoid malignancies. So far, there is no published information on its interaction potential with important drug metabolizing enzymes and drug transporters, or its efficacy in multidrug resistant (MDR) cells. We therefore scrutinized its drug–drug interaction potential in vitro. Inhibition of cytochrome P450 enzymes (CYPs) was quantified by commercial kits. Inhibition of drug transporters (P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP), and organic anion transporting polypeptides (OATPs)) was evaluated by the use of fluorescent probe substrates. Induction of drug transporters and drug metabolizing enzymes was quantified by real-time RT-PCR. The efficacy of venetoclax in MDR cells lines was evaluated with proliferation assays. Venetoclax moderately inhibited P-gp, BCRP, OATP1B1, OATP1B3, CYP3A4, and CYP2C19, whereas CYP2B6 activity was increased. Venetoclax induced the mRNA expression of CYP1A1, CYP1A2, UGT1A3, and UGT1A9. In contrast, expression of ABCB1 was suppressed, which might revert tumor resistance towards antineoplastic P-gp substrates. P-gp over-expression led to reduced antiproliferative effects of venetoclax. Effective concentrations for inhibition and induction lay in the range of maximum plasma concentrations of venetoclax, indicating that it might act as a perpetrator drug in pharmacokinetic drug–drug interactions. PMID:26927160

Drug-induced pulmonary arterial hypertension: a recent outbreak

Directory of Open Access Journals (Sweden)

Gérald Simonneau

2013-09-01

Full Text Available Pulmonary arterial hypertension (PAH is a rare disorder characterised by progressive obliteration of the pulmonary microvasculature resulting in elevated pulmonary vascular resistance and premature death. According to the current classification PAH can be associated with exposure to certain drugs or toxins, particularly to appetite suppressant intake drugs, such as aminorex, fenfluramine derivatives and benfluorex. These drugs have been confirmed to be risk factors for PAH and were withdrawn from the market. The supposed mechanism is an increase in serotonin levels, which was demonstrated to act as a growth factor for the pulmonary artery smooth muscle cells. Amphetamines, phentermine and mazindol were less frequently used, but are considered possible risk factors, for PAH. Dasatinib, dual Src/Abl kinase inhibitor, used in the treatment of chronic myelogenous leukaemia was associated with cases of severe PAH, potentially in part reversible after dasatinib withdrawal. Recently, several studies have raised the issue of potential endothelial dysfunction that could be induced by interferon, and a few cases of PAH have been reported with interferon therapy. PAH remains a rare complication of these drugs, suggesting possible individual susceptibility, and further studies are needed to identify patients at risk of drug-induced PAH.

Smart pH- and reduction-dual-responsive folate-PEG-coated polymeric lipid vesicles for tumor-triggered targeted drug delivery

Science.gov (United States)

Wang, Sheng; Wang, Hanjie; Liu, Zhongyun; Wang, Liangliang; Wang, Xiaomin; Su, Lin; Chang, Jin

2014-06-01

To improve their therapeutic index, designed nanocarriers should preferentially accumulate in tumor tissues and then rapidly enter tumor cells to release the encapsulated drugs in a triggered manner. In this article, a new kind of a smart pH- and reduction-dual-responsive drug delivery system based on folate-PEG-coated polymeric lipid vesicles (FPPLVs) formed from amphiphilic dextran derivatives was designed and prepared successfully. PEG chains with pH-sensitive hydrazone bonds, stearyl alcohol (SA) chains with reduction-sensitive disulfide bonds and folate were connected to a dextran main chain. The newly developed FPPLVs had a nano-sized structure (~50 nm) with a PEG coating. The in vitro DOX release profiles showed that the FPPLVs achieved a triggered drug release in response to acidic pH and reducing environments due to the cleavage of hydrazone bonds and disulfide bonds. It has also been demonstrated by an in vitro cellular uptake study that the FPPLVs lose their PEG coating as well as expose the folate in acidic conditions, which allows them to efficiently enter tumor cells through ligand-receptor interactions. In vitro cytotoxicity measurements also confirmed that FPPLVs exhibited pronounced antitumor activity against HeLa cells. These results suggest that FPPLVs are promising carriers for smart antitumor drug delivery applications.To improve their therapeutic index, designed nanocarriers should preferentially accumulate in tumor tissues and then rapidly enter tumor cells to release the encapsulated drugs in a triggered manner. In this article, a new kind of a smart pH- and reduction-dual-responsive drug delivery system based on folate-PEG-coated polymeric lipid vesicles (FPPLVs) formed from amphiphilic dextran derivatives was designed and prepared successfully. PEG chains with pH-sensitive hydrazone bonds, stearyl alcohol (SA) chains with reduction-sensitive disulfide bonds and folate were connected to a dextran main chain. The newly developed FPPLVs had a

Restrictions for reimbursement of interferon-free direct-acting antiviral drugs for HCV infection in Europe

NARCIS (Netherlands)

Marshall, Alison D.; Cunningham, Evan B.; Nielsen, Stine; Aghemo, Alessio; Alho, Hannu; Backmund, Markus; Bruggmann, Philip; Dalgard, Olav; Seguin-Devaux, Carole; Flisiak, Robert; Foster, Graham R.; Gheorghe, Liana; Goldberg, David; Goulis, Ioannis; Hickman, Matthew; Hoffmann, Patrick; Jancorienė, Ligita; Jarcuska, Peter; Kåberg, Martin; Kostrikis, Leondios G.; Makara, Mihály; Maimets, Matti; Marinho, Rui Tato; Matičič, Mojca; Norris, Suzanne; Ólafsson, Sigurður; Øvrehus, Anne; Pawlotsky, Jean-Michel; Pocock, James; Robaeys, Geert; Roncero, Carlos; Simonova, Marieta; Sperl, Jan; Tait, Michele; Tolmane, Ieva; Tomaselli, Stefan; van der Valk, Marc; Vince, Adriana; Dore, Gregory J.; Lazarus, Jeffrey V.; Grebely, Jason

2018-01-01

All-oral direct-acting antiviral drugs (DAAs) for hepatitis C virus, which have response rates of 95% or more, represent a major clinical advance. However, the high list price of DAAs has led many governments to restrict their reimbursement. We reviewed the availability of, and national criteria

Fluorescent carbon dot-gated multifunctional mesoporous silica nanocarriers for redox/enzyme dual-responsive targeted and controlled drug delivery and real-time bioimaging.

Science.gov (United States)

Wang, Ying; Cui, Yu; Zhao, Yating; He, Bing; Shi, Xiaoli; Di, Donghua; Zhang, Qiang; Wang, Siling

2017-08-01

A distinctive and personalized nanocarrier is described here for controlled and targeted antitumor drug delivery and real-time bioimaging by combining a redox/enzyme dual-responsive disulfide-conjugated carbon dot with mesoporous silica nanoparticles (MSN-SS-CD HA ). The carbon dot with controlling and targeting abilities was prepared through a polymerizing reaction by applying citric acid and HA as starting materials (named CD HA ). The as-prepared MSN-SS-CD HA exhibited not only superior photostability and excellent biocompatibility, but also the ability to target A549 cells with overexpression of CD44 receptors. Upon loading the antitumor drug, doxorubicin (DOX), into the mesoporous channels of MSN nanoparticles, CD HA with a diameter size of 3nm completely blocked the pore entrance of DOX-encapsulated MSN nanoparticles with a pore size of about 3nm, thus preventing the premature leakage of DOX and increasing the antitumor activity until being triggered by specific stimuli in the tumor environment. The results of the cell imaging and cytotoxicity studies demonstrated that the redox/enzyme dual-responsive DOX-encapsulated MSN-SS-CD HA nanoparticles can selectively deliver and control the release of DOX into tumor cells. Ex vivo fluorescence images showed a much stronger fluorescence of MSN-SS-CD HA -DOX in the tumor site than in normal tissues, greatly facilitating the accumulation of DOX in the target tissue. However, its counterpart, MSN-SH-DOX exhibited no or much lower tumor cytotoxicity and drug accumulation in tumor tissue. In addition, MSN-SS-CD was also used as a control to investigate the ability of MSN-SS-CD HA to target A549 cells. The results obtained indicated that MSN-SS-CD HA possessed a higher cellular uptake through the CD44 receptor-mediated endocytosis compared with MSN-SS-CD in the A549 cells. Such specific redox/enzyme dual-responsive targeted nanocarriers are a useful strategy achieving selective controlled and targeted delivery of

Smart Drug Delivery System-Inspired Enzyme-Linked Immunosorbent Assay Based on Fluorescence Resonance Energy Transfer and Allochroic Effect Induced Dual-Modal Colorimetric and Fluorescent Detection.

Science.gov (United States)

Miao, Luyang; Zhu, Chengzhou; Jiao, Lei; Li, He; Du, Dan; Lin, Yuehe; Wei, Qin

2018-02-06

Numerous analytical techniques have been undertaken for the detection of protein biomarkers because of their extensive and significant applications in clinical diagnosis, whereas there are few strategies to develop dual-readout immunosensors to achieve more accurate results. To the best of our knowledge, inspired by smart drug delivery system (DDS), a novel pH-responsive modified enzyme-linked immunosorbent assay (ELISA) was innovatively developed for the first time, realizing dual-modal colorimetric and fluorescent detection of cardiac troponin I (cTnI). Curcumin (CUR) was elaborately selected as a reporter molecule, which played the same role of drugs in DDS based on the following considerations: (1) CUR can be used as a kind of pH indicator by the inherited allochroic effect induced by basic pH value; (2) the fluorescence of CUR can be quenched by certain nanocarriers as the acceptor because of the occurrence of fluorescence resonance energy transfer (FRET), while recovered by the stimuli of basic pH value, which can produce "signal-on" fluorescence detection. Three-dimensional MoS 2 nanoflowers (3D-MoS 2 NFs) were employed in immobilizing CUR to constitute a nanoprobe for the determination of cTnI by virtue of good biocompatibility, high absorption capacity, and fluorescence quench efficiency toward CUR. The proposed DDS-inspired ELISA offered dual-modal colorimetric and fluorescent detection of cTnI, thereby meeting the reliable and precise analysis requirements. We believe that the developed dual-readout ELISA will create a new avenue and bring innovative inspirations for biological detections.

[Clinical significance of drug resistance-associated mutations in treatment of hepatitis C with direct-acting antiviral agents].

Science.gov (United States)

Li, Z; Chen, Z W; Ren, H; Hu, P

2017-03-20

Direct-acting antiviral agents (DAAs) achieve a high sustained virologic response rate in the treatment of chronic hepatitis C virus infection. However, drug resistance-associated mutations play an important role in treatment failure and have attracted more and more attention. This article elaborates on the clinical significance of drug resistance-associated mutations from the aspects of their definition, association with genotype, known drug resistance-associated mutations and their prevalence rates, the impact of drug resistance-associated mutations on treatment naive and treatment-experienced patients, and the role of clinical detection, in order to provide a reference for clinical regimens with DAAs and help to achieve higher sustained virologic response rates.

Venetoclax (ABT-199 Might Act as a Perpetrator in Pharmacokinetic Drug–Drug Interactions

Directory of Open Access Journals (Sweden)

Johanna Weiss

2016-02-01

Full Text Available Venetoclax (ABT-199 represents a specific B-cell lymphoma 2 (Bcl-2 inhibitor that is currently under development for the treatment of lymphoid malignancies. So far, there is no published information on its interaction potential with important drug metabolizing enzymes and drug transporters, or its efficacy in multidrug resistant (MDR cells. We therefore scrutinized its drug–drug interaction potential in vitro. Inhibition of cytochrome P450 enzymes (CYPs was quantified by commercial kits. Inhibition of drug transporters (P-glycoprotein (P-gp, ABCB1, breast cancer resistance protein (BCRP, and organic anion transporting polypeptides (OATPs was evaluated by the use of fluorescent probe substrates. Induction of drug transporters and drug metabolizing enzymes was quantified by real-time RT-PCR. The efficacy of venetoclax in MDR cells lines was evaluated with proliferation assays. Venetoclax moderately inhibited P-gp, BCRP, OATP1B1, OATP1B3, CYP3A4, and CYP2C19, whereas CYP2B6 activity was increased. Venetoclax induced the mRNA expression of CYP1A1, CYP1A2, UGT1A3, and UGT1A9. In contrast, expression of ABCB1 was suppressed, which might revert tumor resistance towards antineoplastic P-gp substrates. P-gp over-expression led to reduced antiproliferative effects of venetoclax. Effective concentrations for inhibition and induction lay in the range of maximum plasma concentrations of venetoclax, indicating that it might act as a perpetrator drug in pharmacokinetic drug–drug interactions.

Dual-Ligand Modified Polymer-Lipid Hybrid Nanoparticles for Docetaxel Targeting Delivery to Her2/neu Overexpressed Human Breast Cancer Cells.

Science.gov (United States)

Yang, Zhe; Tang, Wenxin; Luo, Xingen; Zhang, Xiaofang; Zhang, Chao; Li, Hao; Gao, Di; Luo, Huiyan; Jiang, Qing; Liu, Jie

2015-08-01

In this study, a dual-ligand polymer-lipid hybrid nanoparticle drug delivery vehicle comprised of an anti-HER2/neu peptide (AHNP) mimic with a modified HIV-1 Tat (mTAT) was established for the targeted treatment of Her2/neu-overexpressing cells. The resultant dual-ligand hybrid nanoparticles (NPs) consisted of a poly(lactide-co-glycolide) core, a near 90% surface coverage of the lipid monolayer, and a 5.7 nm hydrated polyethylene glycol shell. Ligand density optimization study revealed that cellular uptake efficiency of the hybrid NPs could be manipulated by controlling the surface-ligand densities. Furthermore, the cell uptake kinetics and mechanism studies showed that the dual-ligand modifications of hybrid NPs altered the cellular uptake pathway from caveolae-mediated endocytosis (CvME) to the multiple endocytic pathways, which would significantly enhance the NP internalization. Upon the systemic investigation of the cellular uptake behavior of dual-ligand hybrid NPs, docetaxel (DTX), a hydrophobic anticancer drug, was successfully encapsulated into dual-ligand hybrid NPs with high drug loading for Her2/neu-overexpressing SK-BR-3 breast cancer cell treatment. The DTX-loaded dual-ligand hybrid NPs showed a decreased burst release and a more gradual sustained drug release property. Because of the synergistic effect of dual-ligand modification, DTX-loaded dual-ligand hybrid NPs exerted substantially better therapeutic potency against SK-BR-3 cancer cells than other NP formulations and free DTX drugs. These results demonstrate that the dual-ligand hybrid NPs could be a promising vehicle for targeted drug delivery to treat breast cancer.

Dual conformal transformations of smooth holographic Wilson loops

Energy Technology Data Exchange (ETDEWEB)

Dekel, Amit [Nordita, KTH Royal Institute of Technology and Stockholm University, Roslagstullsbacken 23, SE-106 91 Stockholm (Sweden)

2017-01-19

We study dual conformal transformations of minimal area surfaces in AdS{sub 5}×S{sup 5} corresponding to holographic smooth Wilson loops and some other related observables. To act with dual conformal transformations we map the string solutions to the dual space by means of T-duality, then we apply a conformal transformation and finally T-dualize back to the original space. The transformation maps between string solutions with different boundary contours. The boundary contours of the minimal surfaces are not mapped back to the AdS boundary, and the regularized area of the surface changes.

Microemulsion-based synergistic dual-drug codelivery system for enhanced apoptosis of tumor cells.

Science.gov (United States)

Qu, Ding; Ma, Yihua; Sun, Wenjie; Chen, Yan; Zhou, Jing; Liu, Congyan; Huang, Mengmeng

2015-01-01

A microemulsion-based synergistic dual-drug codelivery system was developed for enhanced cell apoptosis by transporting coix seed oil and etoposide into A549 (human lung carcinoma) cells simultaneously. Results obtained by dynamic light scattering showed that an etoposide (VP16)-loaded coix seed oil microemulsion (EC-ME) delivery system had a small size around 35 nm, a narrow polydispersity index, and a slightly negative surface charge. The encapsulating efficiency and total drug loading rate were 97.01% and 45.48%, respectively, by high-performance liquid chromatography. The release profiles at various pH values showed an obvious pH-responsive difference, with the accumulated amount of VP16 released at pH 4.5 (and pH 5.5) being 2.7-fold higher relative to that at pH 7.4. Morphologic alteration (particle swelling) associated with a mildly acidic pH environment was found on transmission electron microscopy. In the cell study, the EC-ME system showed a significantly greater antiproliferative effect toward A549 cells in comparison with free VP16 and the mixture of VP16 and coix seed oil. The half-maximal inhibitory concentration of the EC-ME system was 3.9-fold and 10.4-fold lower relative to that of free VP16 and a mixture of VP16 and coix seed oil, respectively. Moreover, fluorescein isothiocyanate and VP16 (the green fluorescent probe and entrapped drug, respectively) were efficiently internalized into the cells by means of coix seed oil microemulsion through intuitive observation and quantitative measurement. Importantly, an EC-ME system containing 20 μg/mL of VP16 showed a 3.3-fold and 3.5-fold improvement in induction of cell apoptosis compared with the VP-16-loaded microemulsion and free VP16, respectively. The EC-ME combination strategy holds promise as an efficient drug delivery system for induction of apoptosis and treatment of lung cancer.

GLATIRAMER ACETATE IS A FIRST-LINE DUAL-ACTION DRUG FOR THE TREATMENT OF RELAPSING-REMITTING MULTIPLE SCLEROSIS

Directory of Open Access Journals (Sweden)

T. E. Shmidt

2016-01-01

Full Text Available Multiple sclerosis (MS is the most common and potentially disabling disease of the central nervous system in young people. Not only inflammatory, but also neurodegenerative processes are involved in the pathogenesis of MS. The use of MS-modifying drugs (MSMDs  has led to a substantial reduction in the frequency of MS exacerbations and to the slower development of irreversible neurological deficit. Glatiramer acetate is one of the MSMDs of first choice and has a dual (anti-inflammatory and neuroprotective action. The drug has proven to be effective and safe if administered long-term. Therapy with glatiramer acetate has been established to promote the production of anti-inflammatory cytokines and neurotrophic factors, which prevent the development of a degenerative process and stimulate remyelination, and to slow the progression of cerebral atrophy. Experimental findings suggest that the drug improves the processes of neurogenesis.The efficiency of treatment is known to be associated with patient medication adherence. This largely depends on the frequency and route of drug administration and on the development of adverse events (AEs. To improve treatment adherence to glatiramer acetate, its new 40-mg formulation has been designed, which allows it to be administered only thrice weekly. The use of the formulation has demonstrated its efficacy and safety and resulted in a considerable reduction in the incidence rate of AEs.

Reforming the Regulation of Therapeutic Products in Canada: The Protecting of Canadians from Unsafe Drugs Act (Vanessa’s Law

Directory of Open Access Journals (Sweden)

Katherine Fierlbeck

2016-11-01

Full Text Available Enacted November 2014, Vanessa’s Law amends the Food and Drugs Act to give Health Canada greater powers to compel the disclosure of information, recall drugs and devices, impose fines and injunctions, and collect post-market safety information. The Act amends seriously outdated legislation that had been in place since 1954. While the explicit goals of the Act are to improve patient safety and provide transparency, it also establishes a regulatory framework that facilitates investment in the burgeoning field of biotechnology. While regulatory reform was already on the public agenda, public awareness of litigation against large pharmaceutical firms combined with the championing of the legislation by Conservative MP Terence Young, whose daughter Vanessa died from an adverse drug reaction, pushed the legislation through to implementation. Many key aspects of the Act depend upon the precise nature of supporting regulations that are still to be implemented. Despite the new powers conferred by the legislation on the Minister of Health, there is some concern that these discretionary powers may not be exercised, and that Health Canada may not have sufficient resources to take advantage of these new powers. Given experience to date since enactment, the new legislation, designed to provide greater transparency vis-à-vis therapeutic products, may actually have a chilling effect on independent scrutiny.

A dual reporter cell assay for identifying serotype and drug susceptibility of herpes simplex virus.

Science.gov (United States)

Lu, Wen-Wen; Sun, Jun-Ren; Wu, Szu-Sian; Lin, Wan-Hsuan; Kung, Szu-Hao

2011-08-15

A dual reporter cell assay (DRCA) that allows real-time detection of herpes simplex virus (HSV) infection was developed. This was achieved by stable transfection of cells with an expression cassette that contains the dual reporter genes, secreted alkaline phosphatase (SEAP) and enhanced green fluorescent protein (EGFP), under the control of an HSV early gene promoter. Baby hamster kidney (BHK) and Chinese hamster ovary (CHO) cell lines were used as parental cell lines because the former is permissive for both HSV serotypes, HSV-1 and HSV-2, whereas the latter is susceptible to infection only by HSV-2. The DRCA permitted differential detection of HSV-1 and HSV-2 by observation of EGFP-positive cells, as substantiated by screening a total of 35 samples. The BHK-based cell line is sensitive to a viral titer as low as a single plaque-forming unit with a robust assay window as measured by a chemiluminescent assay. Evaluations of the DRCA with representative acyclovir-sensitive and acyclovir-resistant HSV strains demonstrated that their drug susceptibilities were accurately determined by a 48-h format. In summary, this novel DRCA is a useful means for serotyping of HSV in real time as well as a rapid screening method for determining anti-HSV susceptibilities. Copyright © 2011 Elsevier Inc. All rights reserved.

Restricted access magnetic materials prepared by dual surface modification for selective extraction of therapeutic drugs from biological fluids

Energy Technology Data Exchange (ETDEWEB)

Wang Yu; Wang Yuxia; Chen Lei [School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072 (China); Wan Qianhong, E-mail: qhwan@tju.edu.cn [School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072 (China)

2012-02-15

Magnetic porous particles with dual functionality have been prepared by a two-step procedure and evaluated as novel restricted access materials for extraction of therapeutic agents from biological fluids. The magnetic silica particles served as scaffolds were first modified with diol groups, which were then converted to octadecyl esters through reaction with stearoyl chloride. In the second step, the octadecyl esters on the exterior surface were hydrolyzed by the action of lipase to yield magnetic particles with hydrophobic reversed-phase ligands on the inner surface and biocompatible diol groups on the outer surface. The restricted access behavior of the resulting materials was confirmed by differential binding of small molecules such as methotrexate (MTX), leucovorin (LV) and folic acid (FA) relative to bovine serum albumin. While MTX, LV and FA were all bound to the magnetic particles with high affinity, the adsorption of the protein was markedly reduced due to size exclusion effect. The utility of the magnetic particles for sample preparation was tested in solid-phase extraction of MTX, LV and FA from spiked human serum and the effects of the SPE conditions on the recovery of the analytes were systematically studied. Moreover, the magnetic particle-based sample preparation procedure coupled with reversed-phase liquid chromatography analysis was validated in terms of specificity, linearity and reproducibility. The method was shown to be free from interference of endogenous compounds and linear over the concentration range of 0.5-10 {mu}g/mL for the three drugs studied. The limits of detection for the three drugs in serum were in the range of 0.160-0.302 {mu}g/mL. Reproducibility expressed as the RSD of the recovery for ten replicated extractions at three different concentrations was found to be less than 8.93%. With a unique combination of surface functionality with magnetic cores, the restricted access magnetic particles may be adapted in automated and high

Activity of dual SRC-ABL inhibitors highlights the role of BCR/ABL kinase dynamics in drug resistance

Science.gov (United States)

Azam, Mohammad; Nardi, Valentina; Shakespeare, William C.; Metcalf, Chester A.; Bohacek, Regine S.; Wang, Yihan; Sundaramoorthi, Raji; Sliz, Piotr; Veach, Darren R.; Bornmann, William G.; Clarkson, Bayard; Dalgarno, David C.; Sawyer, Tomi K.; Daley, George Q.

2006-01-01

Mutation in the ABL kinase domain is the principal mechanism of imatinib resistance in patients with chronic myelogenous leukemia. Many mutations favor active kinase conformations that preclude imatinib binding. Because the active forms of ABL and SRC resemble one another, we tested two dual SRC-ABL kinase inhibitors, AP23464 and PD166326, against 58 imatinib-resistant (IMR) BCR/ABL kinase variants. Both compounds potently inhibit most IMR variants, and in vitro drug selection demonstrates that active (AP23464) and open (PD166326) conformation-specific compounds are less susceptible to resistance than imatinib. Combinations of inhibitors suppressed essentially all resistance mutations, with the notable exception of T315I. Guided by mutagenesis studies and molecular modeling, we designed a series of AP23464 analogues to target T315I. The analogue AP23846 inhibited both native and T315I variants of BCR/ABL with submicromolar potency but showed nonspecific cellular toxicity. Our data illustrate how conformational dynamics of the ABL kinase accounts for the activity of dual SRC-ABL inhibitors against IMR-mutants and provides a rationale for combining conformation specific inhibitors to suppress resistance. PMID:16754879

AND logic-like pH- and light-dual controlled drug delivery by surface modified mesoporous silica nanoparticles

Energy Technology Data Exchange (ETDEWEB)

Zhao, Junwei; He, Zhaoshuai; Li, Biao; Cheng, Tanyu, E-mail: tycheng@shnu.edu.cn; Liu, Guohua

2017-04-01

Recently, the controlled drug delivery system has become a potential platform for biomedical application. Herein, we developed a pH and light-dual controlled cargo release system exhibiting AND logic based on MCM-41 mesoporous silica nanoparticles, which was surface modified using β-cyclodextrin (β-CD) with imine bond and azobenzene derivative. The complex of β-CD and azobenzene derivative effectively blocked the cargo delivery in pH = 7.0 phosphate buffered saline (PBS) solution without 365 nm UV light irradiation. The cargo was fully released when both factors of acidic environment (pH = 5.0 PBS) and 365 nm UV light irradiation were satisfied, meanwhile only very little cargo was delivered if one factor was satisfied. The result also demonstrates that the opening/closing of the gate and the release of the cargo in small portions can be controlled. - Highlights: • A pH and light-dual controlled cargo release system exhibiting AND logic is developed. • The delivery system can release the cargo in small potions by controlling the opening/closing of the gate. • The delivery system realizes the controlled release in zebrafish.

Dual drug delivery using "smart" liposomes for triggered release of anticancer agents

Science.gov (United States)

Jain, Ankit; Gulbake, Arvind; Jain, Ashish; Shilpi, Satish; Hurkat, Pooja; Jain, Sanjay K.

2013-07-01

Ovarian cancer is one of the most fatal gynecologic cancers. In this debut study, dual approach using synergistically active combination of paclitaxel-topotecan (Pac-Top; 20:1, w/w) is investigated with utilization of characteristic features of tumor micro-environment and additionally overexpressed folate receptors (FR-α) to achieve targeting to tumor site. Various liposomes namely liposomes, PEGylated liposomes, and FR-targeted PEGylated liposomes with lipid compositions viz. DPPC:DMPG (85.5:9.5), DPPC:DMPG:mPEG2000-DSPE (85.5:9.5:5), and DPPC:DMPG:mPEG2000-DSPE:DSPE-PEG-folate (85.5:9.5:4.5:0.5), respectively, were developed using thin film casting method. These were nanometric in size around 200 nm. In vitro drug release study showed initial burst release followed by sustained release for more than 72 h at physiological milieu (37 ± 0.5 °C, pH 7.4) while burst release (i.e., more than 90 %) within 5 min at simulated tumor milieu (41 ± 1 °C, pH 4). SRB cytotoxicity assay in OVCAR-3 cell line revealed Pac-Top free (20:1, w/w) to be more toxic (GI50 = 6.5 μg/ml) than positive control (Adriamycin, GI50 = 9.1 μg/ml) and FR-targeted PEGylated liposomes GI50 (14.7 μg/ml). Moreover, florescence microscopy showed the highest cell uptake of FR-targeted PEGylated liposomes so called "smart liposomes" which has not only mediated effective targeting to FR-α but also triggered release of drugs upon hyperthermia.

Small-scale screening of anticancer drugs acting specifically on neural stem/progenitor cells derived from human-induced pluripotent stem cells using a time-course cytotoxicity test.

Science.gov (United States)

Fukusumi, Hayato; Handa, Yukako; Shofuda, Tomoko; Kanemura, Yonehiro

2018-01-01

Since the development of human-induced pluripotent stem cells (hiPSCs), various types of hiPSC-derived cells have been established for regenerative medicine and drug development. Neural stem/progenitor cells (NSPCs) derived from hiPSCs (hiPSC-NSPCs) have shown benefits for regenerative therapy of the central nervous system. However, owing to their intrinsic proliferative potential, therapies using transplanted hiPSC-NSPCs carry an inherent risk of undesired growth in vivo . Therefore, it is important to find cytotoxic drugs that can specifically target overproliferative transplanted hiPSC-NSPCs without damaging the intrinsic in vivo stem-cell system. Here, we examined the chemosensitivity of hiPSC-NSPCs and human neural tissue-derived NSPCs (hN-NSPCs) to the general anticancer drugs cisplatin, etoposide, mercaptopurine, and methotrexate. A time-course analysis of neurospheres in a microsphere array identified cisplatin and etoposide as fast-acting drugs, and mercaptopurine and methotrexate as slow-acting drugs. Notably, the slow-acting drugs were eventually cytotoxic to hiPSC-NSPCs but not to hN-NSPCs, a phenomenon not evident in the conventional endpoint assay on day 2 of treatment. Our results indicate that slow-acting drugs can distinguish hiPSC-NSPCs from hN-NSPCs and may provide an effective backup safety measure in stem-cell transplant therapies.

49 CFR 40.345 - In what circumstances may a C/TPA act as an intermediary in the transmission of drug and alcohol...

Science.gov (United States)

2010-10-01

... intermediary in the transmission of drug and alcohol testing information to employers? 40.345 Section 40.345 Transportation Office of the Secretary of Transportation PROCEDURES FOR TRANSPORTATION WORKPLACE DRUG AND ALCOHOL... act as an intermediary in the transmission of drug and alcohol testing information to employers? (a...

Novel Dual Mitochondrial and CD44 Receptor Targeting Nanoparticles for Redox Stimuli-Triggered Release

Science.gov (United States)

Wang, Kaili; Qi, Mengjiao; Guo, Chunjing; Yu, Yueming; Wang, Bingjie; Fang, Lei; Liu, Mengna; Wang, Zhen; Fan, Xinxin; Chen, Daquan

2018-02-01

In this work, novel mitochondrial and CD44 receptor dual-targeting redox-sensitive multifunctional nanoparticles (micelles) based on oligomeric hyaluronic acid (oHA) were proposed. The amphiphilic nanocarrier was prepared by (5-carboxypentyl)triphenylphosphonium bromide (TPP), oligomeric hyaluronic acid (oHA), disulfide bond, and curcumin (Cur), named as TPP-oHA-S-S-Cur. The TPP targeted the mitochondria, the antitumor drug Cur served as a hydrophobic core, the CD44 receptor targeting oHA worked as a hydrophilic shell, and the disulfide bond acted as a connecting arm. The chemical structure of TPP-oHA-S-S-Cur was characterized by 1HNMR technology. Cur was loaded into the TPP-oHA-S-S-Cur micelles by self-assembly. Some properties, including the preparation of micelles, morphology, redox sensitivity, and mitochondrial targeting, were studied. The results showed that TPP-oHA-S-S-Cur micelles had a mean diameter of 122.4 ± 23.4 nm, zeta potential - 26.55 ± 4.99 mV. In vitro release study and cellular uptake test showed that TPP-oHA-S-S-Cur micelles had redox sensibility, dual targeting to mitochondrial and CD44 receptor. This work provided a promising smart multifunctional nanocarrier platform to enhance the solubility, decrease the side effects, and improve the therapeutic efficacy of anticancer drugs.

The Cytoplasmic Prolyl-tRNA Synthetase of the Malaria Parasite is a Dual-Stage Target for Drug Development

Science.gov (United States)

Herman, Jonathan D.; Pepper, Lauren R.; Cortese, Joseph F.; Estiu, Guillermina; Galinsky, Kevin; Zuzarte-Luis, Vanessa; Derbyshire, Emily R.; Ribacke, Ulf; Lukens, Amanda K.; Santos, Sofia A.; Patel, Vishal; Clish, Clary B.; Sullivan, William J.; Zhou, Huihao; Bopp, Selina E.; Schimmel, Paul; Lindquist, Susan; Clardy, Jon; Mota, Maria M.; Keller, Tracy L.; Whitman, Malcolm; Wiest, Olaf; Wirth, Dyann F.; Mazitschek, Ralph

2015-01-01

The emergence of drug resistance is a major limitation of current antimalarials. The discovery of new druggable targets and pathways including those that are critical for multiple life cycle stages of the malaria parasite is a major goal for the development of the next-generation of antimalarial drugs. Using an integrated chemogenomics approach that combined drug-resistance selection, whole genome sequencing and an orthogonal yeast model, we demonstrate that the cytoplasmic prolyl-tRNA synthetase (PfcPRS) of the malaria parasite Plasmodium falciparum is a biochemical and functional target of febrifugine and its synthetic derivatives such as halofuginone. Febrifugine is the active principle of a traditional Chinese herbal remedy for malaria. We show that treatment with febrifugine derivatives activated the amino acid starvation response in both P. falciparum and a transgenic yeast strain expressing PfcPRS. We further demonstrate in the P. berghei mouse model of malaria that halofuginol, a new halofuginone analog that we developed, is highly active against both liver and asexual blood stages of the malaria parasite. Halofuginol, unlike halofuginone and febrifugine, is well tolerated at efficacious doses, and represents a promising lead for the development of dual-stage next generation antimalarials. PMID:25995223

Executive functioning in dual-diagnosis

NARCIS (Netherlands)

Duijkers, J.C.L.M.; Vissers, C.T.W.M.; Egger, J.I.M.

2016-01-01

Objectives: In mental health, the term dual-diagnosis (DD) is used for the co-occurrence of Substance Use Disorder (SUD: alcohol/drugs) with another mental disorder. These co-occurring disorders can have a shared cause, and can cause/intensify each other's expression. Forming a threat to health and

Moving Synergistically Acting Drug Combinations to the Clinic by Comparing Sequential versus Simultaneous Drug Administrations.

Science.gov (United States)

Dinavahi, Saketh S; Noory, Mohammad A; Gowda, Raghavendra; Drabick, Joseph J; Berg, Arthur; Neves, Rogerio I; Robertson, Gavin P

2018-03-01

Drug combinations acting synergistically to kill cancer cells have become increasingly important in melanoma as an approach to manage the recurrent resistant disease. Protein kinase B (AKT) is a major target in this disease but its inhibitors are not effective clinically, which is a major concern. Targeting AKT in combination with WEE1 (mitotic inhibitor kinase) seems to have potential to make AKT-based therapeutics effective clinically. Since agents targeting AKT and WEE1 have been tested individually in the clinic, the quickest way to move the drug combination to patients would be to combine these agents sequentially, enabling the use of existing phase I clinical trial toxicity data. Therefore, a rapid preclinical approach is needed to evaluate whether simultaneous or sequential drug treatment has maximal therapeutic efficacy, which is based on a mechanistic rationale. To develop this approach, melanoma cell lines were treated with AKT inhibitor AZD5363 [4-amino- N -[(1 S )-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)piperidine-4-carboxamide] and WEE1 inhibitor AZD1775 [2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1 H -pyrazolo[3,4- d ]pyrimidin-3(2 H )-one] using simultaneous and sequential dosing schedules. Simultaneous treatment synergistically reduced melanoma cell survival and tumor growth. In contrast, sequential treatment was antagonistic and had a minimal tumor inhibitory effect compared with individual agents. Mechanistically, simultaneous targeting of AKT and WEE1 enhanced deregulation of the cell cycle and DNA damage repair pathways by modulating transcription factors p53 and forkhead box M1, which was not observed with sequential treatment. Thus, this study identifies a rapid approach to assess the drug combinations with a mechanistic basis for selection, which suggests that combining AKT and WEE1 inhibitors is needed for maximal efficacy. Copyright © 2018 by The American

Saleability of anti-malarials in private drug shops in Muheza, Tanzania: a baseline study in an era of assumed artemisinin combination therapy (ACT

Directory of Open Access Journals (Sweden)

Ringsted Frank M

2011-08-01

Full Text Available Abstract Background Artemether-lumefantrine (ALu replaced sulphadoxine-pymimethamine (SP as the official first-line anti-malarial in Tanzania in November 2006. So far, artemisinin combination therapy (ACT is contra-indicated during pregnancy by the national malaria treatment guidelines, and pregnant women depend on SP for Intermittent Preventive Treatment (IPTp during pregnancy. SP is still being dispensed by private drug stores, but it is unknown to which extent. If significant, it may undermine its official use for IPTp through induction of resistance. The main study objective was to perform a baseline study of the private market for anti-malarials in Muheza town, an area with widespread anti-malarial drug resistance, prior to the implementation of a provider training and accreditation programme that will allow accredited drug shops to sell subsidized ALu. Methods All drug shops selling prescription-only anti-malarials, in Muheza town, Tanga Region voluntarily participated from July to December 2009. Qualitative in-depth interviews were conducted with owners or shopkeepers on saleability of anti-malarials, and structured questionnaires provided quantitative data on drugs sales volume. Results All surveyed drug shops illicitly sold SP and quinine (QN, and legally amodiaquine (AQ. Calculated monthly sale was 4,041 doses, in a town with a population of 15,000 people. Local brands of SP accounted for 74% of sales volume, compared to AQ (13%, QN (11% and ACT (2%. Conclusions In community practice, the saleability of ACT was negligible. SP was best-selling, and use was not reserved for IPTp, as stipulated in the national anti-malarial policy. It is a major reason for concern that such drug-pressure in the community equals de facto intermittent presumptive treatment. In an area where SP drug resistance remains high, unregulated SP dispensing to people other than pregnant women runs the risk of eventually jeopardizing the effectiveness of the IPTp

Technology, Applications, and Process Challenges of Dual Chamber Systems.

Science.gov (United States)

Werk, Tobias; Ludwig, Imke S; Luemkemann, Joerg; Mahler, Hanns-Christian; Huwyler, Joerg; Hafner, Mathias

2016-01-01

Dual-chamber systems provide an option as a drug and device combination product, when home care and emergency lyophilized products are intended. Nevertheless, until today, there are only a few products on the market, due to the challenges and limitations in manufacturability, product formulation, and product stability in a dual-chamber configuration, as well as economic considerations. This review serves to describe currently available dual-chamber systems and to discuss factors to be considered for appropriate selection and establishing fill-finish processes. Copyright © 2016. Published by Elsevier Inc.

Small-scale screening of anticancer drugs acting specifically on neural stem/progenitor cells derived from human-induced pluripotent stem cells using a time-course cytotoxicity test

Directory of Open Access Journals (Sweden)

Hayato Fukusumi

2018-01-01

Full Text Available Since the development of human-induced pluripotent stem cells (hiPSCs, various types of hiPSC-derived cells have been established for regenerative medicine and drug development. Neural stem/progenitor cells (NSPCs derived from hiPSCs (hiPSC-NSPCs have shown benefits for regenerative therapy of the central nervous system. However, owing to their intrinsic proliferative potential, therapies using transplanted hiPSC-NSPCs carry an inherent risk of undesired growth in vivo. Therefore, it is important to find cytotoxic drugs that can specifically target overproliferative transplanted hiPSC-NSPCs without damaging the intrinsic in vivo stem-cell system. Here, we examined the chemosensitivity of hiPSC-NSPCs and human neural tissue—derived NSPCs (hN-NSPCs to the general anticancer drugs cisplatin, etoposide, mercaptopurine, and methotrexate. A time-course analysis of neurospheres in a microsphere array identified cisplatin and etoposide as fast-acting drugs, and mercaptopurine and methotrexate as slow-acting drugs. Notably, the slow-acting drugs were eventually cytotoxic to hiPSC-NSPCs but not to hN-NSPCs, a phenomenon not evident in the conventional endpoint assay on day 2 of treatment. Our results indicate that slow-acting drugs can distinguish hiPSC-NSPCs from hN-NSPCs and may provide an effective backup safety measure in stem-cell transplant therapies.

A new approach to the self-dual Yang-Mills equations

International Nuclear Information System (INIS)

Takasaki, K.

1984-01-01

Inspired by Sato's new theory for soliton equations, we find a new approach to the self-dual Yang-Mills equations. We first establish a correspondence of solutions between the self-dual Yang-Mills equations and a new system of equations with infinitely many unknown functions. It then turns out that the latter equations can be easily solved by a simple explicit procedure. This leads to an explicit description of a very broad class of solutions to the self-dual Yang-Mills equations, and also to a construction of transformations acting on these solutions. (orig.)

Effectiveness of Inhaled Loxapine in Dual-Diagnosis Patients: A Case Series.

Science.gov (United States)

Roncero, Carlos; Ros-Cucurull, Elena; Grau-López, Lara; Fadeuilhe, Christian; Casas, Miguel

2016-01-01

Episodes of psychotic agitation are frequent in patients with dual diagnosis, that is, in patients with concomitant psychiatric and substance use disorders. Rapid intervention is needed to treat the agitation at a mild stage to prevent the escalation to aggressive behavior. Inhaled loxapine has been demonstrated to rapidly improve symptoms of mild-to-moderate agitation in adults with psychiatric disorders (schizophrenia and bipolar disorder), but data on patients with dual diagnosis are scarce. This study is a retrospective review of data from a case series of patients with dual diagnosis, which were attended for symptoms of agitation while at the emergency room (n = 9), in the outpatient clinic (n = 4), or during hospitalization (n = 1) at 1 center in Spain. All patients received inhaled loxapine for treating the agitation episodes. Data from 14 patients with dual diagnosis were reviewed. All patients had 1 or more psychiatric disorders (schizophrenia, bipolar I disorder, drug-induced psychotic disorder, posttraumatic stress, borderline or antisocial personality disorder, depression, or anxiety) along with a variety of substance use disorders (alcohol, cocaine, cannabis, amphetamines, hypnotics and antianxiety drugs, caffeine, or street drugs). Overall, only 1 dose of inhaled loxapine (9.1 mg) was needed to calm each patient during an acute episode of agitation. Inhaled loxapine was rapid, effective, and well accepted in all dual-pathology patients presenting with acute agitation in the emergency setting. Inhaled loxapine facilitated both patient cooperation and an adequate management of his or her disease.

Differential profile and treatment development of drug-addicted patients depending on violent behaviours and/or criminal acts.

Science.gov (United States)

López-Goñi, José J; Fernández-Montalvo, Javier; Arteaga, Alfonso; Cacho, Raúl

2015-01-01

This study explored the prevalence of violent and/or criminal behaviors in drug-addicted patients. A sample of 252 drug-addicted patients who sought treatment was assessed. Information was collected on violent behaviors, criminal acts, socio-demographic factors, consumption factors, psychopathological factors, and personality variables. The sample was divided into 4 groups according to the presence of violence and/or criminal behaviors. There were significant differences between the groups on some variables. In general, patients associated with both violence and criminal behaviors showed a greater severity in drug consumption and maladjustment variables, as well as a higher rate of treatment dropout and re-entry.

Prescription Drug Marketing Act of 1987; Prescription Drug Amendments of 1992; policies, requirements, and administrative procedures; delay of effective date. Final rule; delay of effective date.

Science.gov (United States)

2004-02-23

The Food and Drug Administration (FDA) is further delaying, until December 1, 2006, the effective date of certain requirements of a final rule published in the Federal Register of December 3, 1999 (64 FR 67720). In the Federal Register of May 3, 2000 (65 FR 25639), the agency delayed until October 1, 2001, the effective date of certain requirements in the final rule relating to wholesale distribution of prescription drugs by distributors that are not authorized distributors of record, and distribution of blood derivatives by entities that meet the definition of a "health care entity" in the final rule. The agency further delayed the effective date of these requirements in three subsequent Federal Register notices. Most recently, in the Federal Register of January 31, 2003 (68 FR 4912), FDA delayed the effective date until April 1, 2004. This action further delays the effective date of these requirements until December 1, 2006. The final rule implements the Prescription Drug Marketing Act of 1987 (PDMA), as modified by the Prescription Drug Amendments of 1992 (PDA), and the Food and Drug Administration Modernization Act of 1997 (the Modernization Act). The agency is taking this action to address concerns about the requirements in the final rule raised by affected parties. As explained in the SUPPLEMENTARY INFORMATION section, FDA is working with stakeholders through its counterfeit drug initiative to facilitate widespread, voluntary adoption of track and trace technologies that will generate a de facto electronic pedigree, including prior transaction history back to the original manufacturer, as a routine course of business. If this technology is widely adopted, it is expected to help fulfill the pedigree requirements of the PDMA and obviate or resolve many of the concerns that have been raised with respect to the final rule by ensuring that an electronic pedigree travels with a drug product at all times. Therefore, it is necessary to delay the effective date of Sec

Chemokine (C-C motif) receptor 5-using envelopes predominate in dual/mixed-tropic HIV from the plasma of drug-naive individuals.

Science.gov (United States)

Irlbeck, David M; Amrine-Madsen, Heather; Kitrinos, Kathryn M; Labranche, Celia C; Demarest, James F

2008-07-31

HIV-1 utilizes CD4 and either chemokine (C-C motif) receptor 5 (CCR5) or chemokine (C-X-C motif) receptor 4 (CXCR4) to gain entry into host cells. Small molecule CCR5 antagonists are currently being developed for the treatment of HIV-1 infection. Because HIV-1 may also use CXCR4 for entry, the use of CCR5 entry inhibitors is controversial for patients harboring CCR5-using and CXCR4-using (dual/mixed-tropic) viruses. The goal of the present study was to determine the proportion of CCR5-tropic and CXCR4-tropic viruses in dual/mixed-tropic virus isolates from drug-naïve patients and the phenotypic and genotypic relationships of viruses that use CCR5 or CXCR4 or both. Fourteen antiretroviral-naive HIV-1-infected patients were identified as having population coreceptor tropism readout of dual/mixed-tropic viruses. Intrapatient comparisons of coreceptor tropism and genotype of env clones were conducted on plasma virus from each patient. Population HIV-1 envelope tropism and susceptibility to the CCR5 entry inhibitor, aplaviroc, were performed using the Monogram Biosciences Trofile Assay. Twelve env clones from each patient were analyzed for coreceptor tropism, aplaviroc sensitivity, genotype, and intrapatient phylogenetic relationships. Viral populations from antiretroviral-naive patients with dual/mixed-tropic virus are composed primarily of CCR5-tropic env clones mixed with those that use both coreceptors (R5X4-tropic) and, occasionally, CXCR4-tropic env clones. Interestingly, the efficiency of CXCR4 use by R5X4-tropic env clones varied with their genetic relationships to CCR5-tropic env clones from the same patient. These data show that the majority of viruses in these dual/mixed-tropic populations use CCR5 and suggest that antiretroviral-naive patients may benefit from combination therapy that includes CCR5 entry inhibitors.

20 CFR 404.1913 - Precluding dual coverage.

Science.gov (United States)

2010-04-01

... precluding dual coverage to avoid inequitable or anomalous coverage situations for certain workers. However... 404.1913 Employees' Benefits SOCIAL SECURITY ADMINISTRATION FEDERAL OLD-AGE, SURVIVORS AND DISABILITY...) General. Employment or self-employment or services recognized as equivalent under the Act or the social...

A dual-targeting strategy for enhanced drug delivery and synergistic therapy based on thermosensitive nanoparticles.

Science.gov (United States)

Wang, Mingxin; You, Chaoqun; Gao, Zhiguo; Wu, Hongshuai; Sun, Baiwang; Zhu, Xiaoli; Chen, Renjie

2018-08-01

The functionalized nanoparticles have been widely studied and reported as carriers of drug transport recently. Furthermore, many groups have focused more on developing novel and efficient treatment methods, such as photodynamic therapy and photothermal therapy, since both therapies have shown inspiring potential in the application of antitumor. The mentioned treatments exhibited the superiority of cooperative manner and showed the ability to compensate for the adverse effects caused by conventional monotherapy in proposed strategies. In view of the above descriptions, we formulated a thermosensitive drug delivery system, which achieved the enhanced delivery of cisplatin and two photosensitizers (ICG and Ce6) by dual-targeting traction. Drawing on the thin film hydration method, cisplatin and photosensitizers were encapsulated inside nanoparticles. Meanwhile, the targeting peptide cRGD and targeting molecule folate can be modified on the surface of nanoparticles to realize the active identification of tumor cells. The measurements of dynamic light scattering showed that the prepared nanoparticles had an ideal dispersibility and uniform particle size of 102.6 nm. On the basis of the results observed from confocal laser scanning microscope, the modified nanoparticles were more efficient endocytosed by MCF-7 cells as a contrast to SGC-7901 cells. Photothermal conversion-triggered drug release and photo-therapies produced a significant apoptosis rate of 85.9% on MCF-7 cells. The distinguished results made it believed that the formulated delivery system had conducted great efforts and innovations for the realization of concise collaboration and provided a promising strategy for the treatment of breast cancer.

DUAL TIMELIKE NORMAL AND DUAL TIMELIKE SPHERICAL CURVES IN DUAL MINKOWSKI SPACE

OpenAIRE

ÖNDER, Mehmet

2009-01-01

Abstract: In this paper, we give characterizations of dual timelike normal and dual timelike spherical curves in the dual Minkowski 3-space and we show that every dual timelike normal curve is also a dual timelike spherical curve. Keywords: Normal curves, Dual Minkowski 3-Space, Dual Timelike curves. Mathematics Subject Classifications (2000): 53C50, 53C40. DUAL MINKOWSKI UZAYINDA DUAL TIMELIKE NORMAL VE DUAL TIMELIKE KÜRESEL EĞRİLER Özet: Bu çalışmada, dual Minkowski 3-...

COMPARATIVE STUDY OF NEW DRUG OF LONG ACTING METOPROLOL TARTRATE - EGILOK RETARD AND ORIGINAL DRUG OF METOPROLOL SUCCINATE – BETALOC ZOK IN PATIENTS WITH MILD TO MODERATE ARTERIAL HYPERTENSION

Directory of Open Access Journals (Sweden)

J. V. Lukina

2015-12-01

Full Text Available Aim. To study efficiency and safety of new drug of long acting metoprolol tartrate, “Egilok retard” (ER in patients with mild to moderate arterial hypertension (AH in comparison with the original drug of metoprolol succinat, “Betaloc ZOK” (BZ, possibility of reaching target blood pressure (BP level with treatment with each drug.Material and methods. 30 patients (11 men and 19 women with mild to moderate AH took part in randomized, open, cross over study. Previous antihypertensive treatment had been canceled for all the patients 10-14 days before the study started. Each patient by turns was treated during 6 weeks with ER and BZ 50-100 mg daily. After cancellation of the previous antihypertensive therapy, BZ and ER were prescribed (according to the randomization table in dose 50 mg daily. Drugs were taken once per day. 29 patients completed therapy with the first drug of randomization, 25 patients – with the second. After 2 weeks efficiency of treatment was assessed by target BP level achievement (< 140/90 mmHg. If efficiency of beta-adrenoblocker (BB was not sufficient, the dose of the drug was doubled to 100 mg daily, if target level was reached – the dose remained unchanged. Treatment with the settled dose was held within next 4 weeks. After 6-week treatment with the first randomized drug antihypertensive therapy was canceled for 10-14 days depending on the BB dose. At each visit office BP and heart rate were assessed, EKG was registered. Side-effects were registered according to the self-control diary, questionnaire results, examination and EKG data.Results. After 6-week treatment with ER and BZ average level of systolic BP reduced by 15,7 and 15,2 mmHg, of diastolic BP – by 8,0 and 4,5 mmHg, heart rate – by 4,1 and 4,3 beat/min respectively. Differences between antihypertensive and heart rate lowering effect of the studied drugs were not significant. Target BP level with treatment with both drugs was reached in approximately

COMPARATIVE STUDY OF NEW DRUG OF LONG ACTING METOPROLOL TARTRATE - EGILOK RETARD AND ORIGINAL DRUG OF METOPROLOL SUCCINATE – BETALOC ZOK IN PATIENTS WITH MILD TO MODERATE ARTERIAL HYPERTENSION

Directory of Open Access Journals (Sweden)

J. V. Lukina

2005-01-01

Full Text Available Aim. To study efficiency and safety of new drug of long acting metoprolol tartrate, “Egilok retard” (ER in patients with mild to moderate arterial hypertension (AH in comparison with the original drug of metoprolol succinat, “Betaloc ZOK” (BZ, possibility of reaching target blood pressure (BP level with treatment with each drug.Material and methods. 30 patients (11 men and 19 women with mild to moderate AH took part in randomized, open, cross over study. Previous antihypertensive treatment had been canceled for all the patients 10-14 days before the study started. Each patient by turns was treated during 6 weeks with ER and BZ 50-100 mg daily. After cancellation of the previous antihypertensive therapy, BZ and ER were prescribed (according to the randomization table in dose 50 mg daily. Drugs were taken once per day. 29 patients completed therapy with the first drug of randomization, 25 patients – with the second. After 2 weeks efficiency of treatment was assessed by target BP level achievement (< 140/90 mmHg. If efficiency of beta-adrenoblocker (BB was not sufficient, the dose of the drug was doubled to 100 mg daily, if target level was reached – the dose remained unchanged. Treatment with the settled dose was held within next 4 weeks. After 6-week treatment with the first randomized drug antihypertensive therapy was canceled for 10-14 days depending on the BB dose. At each visit office BP and heart rate were assessed, EKG was registered. Side-effects were registered according to the self-control diary, questionnaire results, examination and EKG data.Results. After 6-week treatment with ER and BZ average level of systolic BP reduced by 15,7 and 15,2 mmHg, of diastolic BP – by 8,0 and 4,5 mmHg, heart rate – by 4,1 and 4,3 beat/min respectively. Differences between antihypertensive and heart rate lowering effect of the studied drugs were not significant. Target BP level with treatment with both drugs was reached in approximately

Restricted access magnetic materials prepared by dual surface modification for selective extraction of therapeutic drugs from biological fluids

International Nuclear Information System (INIS)

Wang Yu; Wang Yuxia; Chen Lei; Wan Qianhong

2012-01-01

Magnetic porous particles with dual functionality have been prepared by a two-step procedure and evaluated as novel restricted access materials for extraction of therapeutic agents from biological fluids. The magnetic silica particles served as scaffolds were first modified with diol groups, which were then converted to octadecyl esters through reaction with stearoyl chloride. In the second step, the octadecyl esters on the exterior surface were hydrolyzed by the action of lipase to yield magnetic particles with hydrophobic reversed-phase ligands on the inner surface and biocompatible diol groups on the outer surface. The restricted access behavior of the resulting materials was confirmed by differential binding of small molecules such as methotrexate (MTX), leucovorin (LV) and folic acid (FA) relative to bovine serum albumin. While MTX, LV and FA were all bound to the magnetic particles with high affinity, the adsorption of the protein was markedly reduced due to size exclusion effect. The utility of the magnetic particles for sample preparation was tested in solid-phase extraction of MTX, LV and FA from spiked human serum and the effects of the SPE conditions on the recovery of the analytes were systematically studied. Moreover, the magnetic particle-based sample preparation procedure coupled with reversed-phase liquid chromatography analysis was validated in terms of specificity, linearity and reproducibility. The method was shown to be free from interference of endogenous compounds and linear over the concentration range of 0.5-10 μg/mL for the three drugs studied. The limits of detection for the three drugs in serum were in the range of 0.160-0.302 μg/mL. Reproducibility expressed as the RSD of the recovery for ten replicated extractions at three different concentrations was found to be less than 8.93%. With a unique combination of surface functionality with magnetic cores, the restricted access magnetic particles may be adapted in automated and high

Professionals’ perception on the management of patients with dual disorders

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Roncero C

2016-09-01

Full Text Available Carlos Roncero,1,2 Néstor Szerman,3 Antonio Terán,4 Carlos Pino,5 José María Vázquez,6 Elena Velasco,7 Marta García-Dorado,7 Miguel Casas1,2 1Addiction and Dual Diagnosis Unit, CIBERSAM, Hospital Vall Hebron, Barcelona Public Health Agency (ASPB, Barcelona, Spain; 2Department of Psychiatry, Autonomous University of Barcelona, Barcelona, Spain; 3Outpatient Mental Health Clinic El Retiro, Gregorio Marañón University Hospital, Madrid, Spain; 4Outpatient Drug Clinic, Hospital San Juan de Dios, Palencia, Spain; 5Pontevedra City Council Drug Dependence Service, Galician Health Service (Xunta de Galicia, Pontevedra, Spain; 6Outpatient Drug Clinic Sants, Barcelona Public Health Agency (ASPB, Barcelona, Spain; 7Medical Affairs Department, Janssen-Cilag S.A., Madrid, Spain Background: There is a need to evaluate the professionals’ perception about the consequences of the lack of therapeutic adherence in the evolution of patients with co-occurring disorders.Methods: An online survey, released on the Socidrogalcohol [Spanish Scientific Society for Research on Alcohol, Alcoholism and other Drug Addic­tions] and Sociedad Española de Patología Dual [the Spanish Society of Dual Pathology] web pages, was answered by 250 professionals who work in different types of Spanish health centers where dual diagnosis patients are assisted.Results: Most professionals perceived the existence of noncompliance among dual diagnosis patients. Almost all of these professionals (99% perceived that noncompliance leads to a worsening of the progression of the patient’s disorder, in both the exacerbation of mental disorders and the consumption of addictive substances. Most of the professionals (69.2% considered therapeutic alliance as the main aspect to take into account to improve the prognosis in this population. The primary purpose of treatment must be the improvement of psychotic-phase positive symptoms, followed by the control of behavior disorders, reduction of

WAr on DrugS

African Journals Online (AJOL)

2009-04-12

Apr 12, 2009 ... ABStrAct. Since drugs became both a public and social issue in Nigeria, fear about both the real and .... drugs as being morally reprehensible, and ..... tice system (see for instance, Shaw, 1995; ..... A cut throat business:.

Dual drug delivery using “smart” liposomes for triggered release of anticancer agents

International Nuclear Information System (INIS)

Jain, Ankit; Gulbake, Arvind; Jain, Ashish; Shilpi, Satish; Hurkat, Pooja; Jain, Sanjay K.

2013-01-01

Ovarian cancer is one of the most fatal gynecologic cancers. In this debut study, dual approach using synergistically active combination of paclitaxel–topotecan (Pac–Top; 20:1, w/w) is investigated with utilization of characteristic features of tumor micro-environment and additionally overexpressed folate receptors (FR-α) to achieve targeting to tumor site. Various liposomes namely liposomes, PEGylated liposomes, and FR-targeted PEGylated liposomes with lipid compositions viz. DPPC:DMPG (85.5:9.5), DPPC:DMPG:mPEG 2000 –DSPE (85.5:9.5:5), and DPPC:DMPG:mPEG 2000 –DSPE:DSPE–PEG–folate (85.5:9.5:4.5:0.5), respectively, were developed using thin film casting method. These were nanometric in size around 200 nm. In vitro drug release study showed initial burst release followed by sustained release for more than 72 h at physiological milieu (37 ± 0.5 °C, pH 7.4) while burst release (i.e., more than 90 %) within 5 min at simulated tumor milieu (41 ± 1 °C, pH 4). SRB cytotoxicity assay in OVCAR-3 cell line revealed Pac–Top free (20:1, w/w) to be more toxic (GI 50 = 6.5 μg/ml) than positive control (Adriamycin, GI 50 = 9.1 μg/ml) and FR-targeted PEGylated liposomes GI 50 (14.7 μg/ml). Moreover, florescence microscopy showed the highest cell uptake of FR-targeted PEGylated liposomes so called “smart liposomes” which has not only mediated effective targeting to FR-α but also triggered release of drugs upon hyperthermia

Dual-directional regulation of drug permeating amount by combining the technique of ion-pair complexation with chemical enhancers for the synchronous permeation of indapamide and bisoprolol in their compound patch through rabbit skin.

Science.gov (United States)

Song, Wenting; Cun, Dongmei; Quan, Peng; Liu, Nannan; Chen, Yang; Cui, Hongxia; Xiang, Rongwu; Fang, Liang

2015-04-01

To achieve the synchronous skin permeation of indapamide (IND) and bisoprolol (BSP) in their compound patch, the techniques of ion-pair complexation and chemical enhancers were combined to dual-directionally regulate drug permeating amounts. Ion-pair complexes of BSP and various organic acids were formed by the technique of ion-pair complexation. Among the complexes formed, bisoprolol tartrate (BSP.T) down-regulated the permeating amount of BSP to the same extent as that of IND. Then, to simultaneously up-regulate the amounts of the two drugs, an enhancer combination of 15.8% Span80 (SP), 6.0% Azone (AZ) and 2.2% N-methyl pyrrolidone (NMP) was obtained by central composite design and exhibited an outstanding and simultaneous enhancement on IND and BSP with enhancing ratio (ER) of 4.52 and 3.49, respectively. The effect of the dual-directional regulation was evaluated by in vitro permeation experiments and in vivo pharmacokinetic studies. For IND and BSP, their observed permeation profiles were comparable and their MAT (mean absorption time) showed no significant difference, which both demonstrated these two drugs achieved the synchronous skin permeation in their compound patch by the dual-directional regulation strategy of combining the technique of ion-pair complexation with chemical enhancers. Copyright © 2015 Elsevier B.V. All rights reserved.

Dual-Schemata Model

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Taniguchi, Tadahiro; Sawaragi, Tetsuo

In this paper, a new machine-learning method, called Dual-Schemata model, is presented. Dual-Schemata model is a kind of self-organizational machine learning methods for an autonomous robot interacting with an unknown dynamical environment. This is based on Piaget's Schema model, that is a classical psychological model to explain memory and cognitive development of human beings. Our Dual-Schemata model is developed as a computational model of Piaget's Schema model, especially focusing on sensori-motor developing period. This developmental process is characterized by a couple of two mutually-interacting dynamics; one is a dynamics formed by assimilation and accommodation, and the other dynamics is formed by equilibration and differentiation. By these dynamics schema system enables an agent to act well in a real world. This schema's differentiation process corresponds to a symbol formation process occurring within an autonomous agent when it interacts with an unknown, dynamically changing environment. Experiment results obtained from an autonomous facial robot in which our model is embedded are presented; an autonomous facial robot becomes able to chase a ball moving in various ways without any rewards nor teaching signals from outside. Moreover, emergence of concepts on the target movements within a robot is shown and discussed in terms of fuzzy logics on set-subset inclusive relationships.

Treatment in patients with osteoarthritis at different sites: Place of slow-acting drugs

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N. V. Chichasova

2015-01-01

Full Text Available The main goal of osteoarthritis (OA treatment is to perform rational analgesic and anti-inflammatory therapy, to slow down the progression of the disease, and to preserve quality of life in patients. The performance of analgesic therapy in the elderly is impeded by the presence of a concomitant disease, primarily that of the cardiovascular system and gastrointestinal tract. A group of experts has elaborated the algorithm for managing OA patients, which tracks a careful approach to using nonsteroidal anti-inflammatory drugs and confirms the efficacy of slow-acting agents (chondroitin sulfate (CS and glucosamine and intraarticular hyaluronate. The experts have concluded that the use of symptomatic slow-acting drugs for the treatment of OA (SYSADOA, if need be, in combination with short-term paracetanol cycles as basic therapy for this condition is safer and more effective. The 2003 EULAR guidelines identify CS and glucosamine as chondroprotectors. Many studies have shown that CS and glucosamine have a moderate or significant effect on joint pain syndrome and functional mobility in OA; they are safe and characterized by minimal side effects. Long-term qualitative randomized controlled trials have demonstrated that CS and glucosamine are able to slow down the progression of joint space narrowing in OA. It is also shown that the use of a combination of glucosamine and CS allows cartilage loss to be prevented.

Emerging integrated nanoclay-facilitated drug delivery system for papillary thyroid cancer therapy

Science.gov (United States)

Zhang, Yi; Long, Mei; Huang, Peng; Yang, Huaming; Chang, Shi; Hu, Yuehua; Tang, Aidong; Mao, Linfeng

2016-09-01

Nanoclay can be incorporated into emerging dual functional drug delivery systems (DDSs) to promote efficiency in drug delivery and reduce the toxicity of doxorubicin (DOX) used for thyroid cancer treatment. This paper reports the expansion of the basal spacing of kaolinite nanoclay was expanded from 0.72 nm to 0.85 nm, which could provide sufficiently spacious site for hosting doxorubicin molecules and controlling the diffusion rate. A targeted design for papillary thyroid cancer cells was achieved by introducing KI, which is consumed by the sodium-iodide symporter (NIS). As indicated by MTT assays, confocal laser scanning microscopy and bio-TEM observations, methoxy-intercalated kaolinite (KaolinMeOH) exhibited negligible cytotoxicity against papillary thyroid cancer cells. By contrast, DOX-KaolinMeOH showed dose-dependent therapeutic effects in vitro, and KI@DOX-KaolinMeOH was found to act as a powerful targeted therapeutic drug. Furthermore, active and passive targeting strategies played a role in the accumulation of the drug molecules, as verified by an in vivo bio-distribution analysis.

COPD - control drugs

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Chronic obstructive pulmonary disease - control drugs; Bronchodilators - COPD - control drugs; Beta agonist inhaler - COPD - control drugs; Anticholinergic inhaler - COPD - control drugs; Long-acting inhaler - COPD - control drugs; ...

Angiopep-2-conjugated poly(ethylene glycol-co-poly(ε-caprolactone polymersomes for dual-targeting drug delivery to glioma in rats

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Lu F

2017-03-01

Full Text Available Fei Lu,1,2 Zhiyong Pang,2,3 Jingjing Zhao,2 Kai Jin,4 Haichun Li,2 Qiang Pang,2 Long Zhang,2 Zhiqing Pang2 1Department of Pharmacy, Xianju People’s Hospital, Xianju, Zhejiang, 2Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, School of Pharmacy, Fudan University, Shanghai, 3Chongyang Center for Disease Control and Prevention, Xianning, Hubei, 4School of Life Science, Fudan University, Shanghai, People’s Republic of China Abstract: The blood–brain barrier is a formidable obstacle for glioma chemotherapy due to its compact structure and drug efflux ability. In this study, a dual-targeting drug delivery system involving Angiopep-2-conjugated biodegradable polymersomes loaded with doxorubicin (Ang-PS-DOX was developed to exploit transport by the low-density lipoprotein receptor-related protein 1 (LRP1, which is overexpressed in both blood–brain barrier and glioma cells. The polymersomes (PS were prepared using a thin-film hydration method. The PS were loaded with doxorubicin using the pH gradient method (Ang-PS-DOX. The resulting PS were uniformly spherical, with diameters of ~135 nm and with ~159.9 Angiopep-2 molecules on the surface of each PS. The drug-loading capacity and the encapsulation efficiency for doxorubicin were 7.94%±0.17% and 95.0%±1.6%, respectively. Permeability tests demonstrated that the proton diffusion coefficient across the PS membrane was far slower than that across the liposome membrane, and the common logarithm value was linearly dependent on the dioxane content in the external phase. Compared with PS-DOX, Ang-PS-DOX demonstrated significantly higher cellular uptake and stronger cytotoxicity in C6 cells. In vivo pharmacokinetics and brain distribution experiments revealed that Ang-PS-DOX achieved a more extensive distribution and more abundant accumulation in glioma cells than PS-DOX. Moreover, the survival time of glioma-bearing rats treated with Ang-PS-DOX was

The Explicit Determinations Of Dual Plane Curves And Dual Helices In Terms Of Its Dual Curvature And Dual Torsion

OpenAIRE

Lee Jae Won; Choi Jin Ho; Jin Dae Ho

2014-01-01

In this paper, we give the explicit determinations of dual plane curves, general dual helices and dual slant helices in terms of its dual curvature and dual torsion as a fundamental theory of dual curves in a dual 3-space

Comments on the discordant recommendations for the use of symptomatic slow-acting drugs in knee osteoarthritis.

Science.gov (United States)

Reginster, Jean-Yves; Cooper, Cyrus; Hochberg, Marc; Pelletier, Jean-Pierre; Rizzoli, René; Kanis, John; Abadie, Eric; Maheu, Emmanuel; Brandi, Maria Luisa; Devogelaer, Jean-Pierre; Branco, Jaime; Herrero-Beaumont, Gabriel; D'Hooghe, Pieter; Bruyère, Olivier

2015-05-01

Despite the near concurrent publication by influential scientific organizations, there are important differences in interpretation of the evidence base and the conclusions derived from the recent Osteoarthritis Research Society International (OARSI) guidelines for the management of knee osteoarthritis, the American College of Rheumatology (ACR) guidelines (concerning also hip and hand osteoarthritis) and the algorithm recommendations by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). This is particularly evident for the drug class of symptomatic slow-acting drugs in osteoarthritis. In this paper, we highlight these differences and try to understand where they derive from, proposing an evidence-based interpretation.

Stem cells as anticancer drug carrier to reduce the chemotherapy side effect

Science.gov (United States)

Salehi, Hamideh; Al-Arag, Siham; Middendorp, Elodie; Gergley, Csilla; Cuisinier, Frederic

2017-02-01

Chemotherapy used for cancer treatment, due to the lack of specificity of drugs, is associated to various damaging side effects that have severe impact on patients' quality of life. Over the past 30 years, increasing efforts have been placed on optimizing chemotherapy dosing with the main goal of increasing antitumor efficacy while reducing drug-associated toxicity. A novel research shows that stem cells may act as a reservoir for the anticancer agent, which will subsequently release some of the drug's metabolites, or even the drug in its original form, in vicinity of the cancer cells. These cells may play a dual role in controlling drug toxicity depending on their capacity to uptake and release the chemotherapeutic drug. In our study, we show that Dental Pulp Stem Cells DPSCs are able to rapidly uptake Paclitaxel PTX, and to release it in the culture medium in a time-dependent manner. This resulting conditioned culture medium is to be transferred to breast cancer cells, the MCF-7. By applying Confocal Raman Microscopy, the anticancer drug uptake by the MCF-7 was measured. Surprisingly, the cancer cells -without any direct contact with PTX- showed a drug uptake. This proves that the stem cells carried and delivered the anticancer drug without its modification. It could be a revolution in chemotherapy to avoid the drug's side effects and increase its efficacy.

Preparation and characterization of DOX loaded keratin nanoparticles for pH/GSH dual responsive release

Energy Technology Data Exchange (ETDEWEB)

Li, Yanmei; Zhi, Xuelian [Jiangsu Key Laboratory of Biofunctional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023 (China); Lin, Jiantao [Guangdong Medical University, Dongguan 523808 (China); You, Xin [Jiangsu Key Laboratory of Biofunctional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023 (China); Yuan, Jiang, E-mail: jyuan@njnu.edu.cn [Jiangsu Key Laboratory of Biofunctional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023 (China)

2017-04-01

Smart drug carriers are the current need of the hour in controlled drug delivery applications. In this work, pH and redox dual responsive keratin based drug-loaded nanoparticles (KDNPs) were fabricated through two-step strategies. Keratin nanoparticles were first prepared by desolvation method and chemical crosslinking, followed by electrostatic adsorbing doxorubicin (DOX) to afford drug loaded keratin nanoparticles (KDNPs). The size, size distribution, and morphology of the KDNPs were characterized with dynamic light scattering (DLS) and Scan electronic microscope (SEM). Drug delivery profiles showed that KDNPs exhibited pH and glutathione (GSH) dual-responsive characters. Under tumor tissue/cell microenvironments (more acidic and high GSH level), KDNPs tended to accumulate at the tumor region through a potential enhanced permeability and retention (EPR) effect and perform surface negative-to-positive charge conversion. Hemolysis assay indicated that KDNPs had good blood compatibility. Cellular uptake assay demonstrated that KDNPs could be internalized by A 549 cells through endocytosis. Intriguingly, KDNPs were capable of promoting nitric oxide (NO) release from endogenous donor of S-nitrosoglutathione in the presence of GSH. All of these results demonstrated that keratin based drug carriers had potential for drug/NO delivery and cancer therapy in clinical medicine. - Graphical abstract: pH and redox dual responsive keratin based drug-loaded nanoparticles (KDNPs) were fabricated by desolvation with chemical crosslinking, followed by electrostatic adsorbing DOX to afford DOX loaded keratin nanoparticles (KDNPs). Drug delivery profiles showed that KDNPs exhibited pH and GSH dual-responsive characters. Under tumor tissue/cell microenvironments (more acidic and high GSH level), KDNPs tended to accumulate at the tumor region through a potential enhanced permeability and retention (EPR) effect and perform surface negative-to-positive charge conversion. Hemolysis assay

Applicability and safety of dual-frequency ultrasonic treatment for the transdermal delivery of drugs

Science.gov (United States)

Schoellhammer, Carl M.; Srinivasan, Sharanya; Barman, Ross; Mo, Stacy H.; Polat, Baris E.; Langer, Robert; Blankschtein, Daniel

2016-01-01

Low-frequency ultrasound presents an attractive method for transdermal drug delivery. The controlled, yet nonspecific nature of enhancement broadens the range of therapeutics that can be delivered, while minimizing necessary reformulation efforts for differing compounds. Long and inconsistent treatment times, however, have partially limited the attractiveness of this method. Building on recent advances made in this area, the simultaneous use of low- and high-frequency ultrasound is explored in a physiologically relevant experimental setup to enable the translation of this treatment to testing in vivo. Dual-frequency ultrasound, utilizing 20 kHz and 1 MHz wavelengths simultaneously, was found to significantly enhance the size of localized transport regions (LTRs) in both in vitro and in vivo models while decreasing the necessary treatment time compared to 20 kHz alone. Additionally, LTRs generated by treatment with 20 kHz + 1 MHz were found to be more permeable than those generated with 20 kHz alone. This was further corroborated with pore-size estimates utilizing hindered-transport theory, in which the pores in skin treated with 20 kHz + 1 MHz were calculated to be significantly larger than the pores in skin treated with 20 kHz alone. This demonstrates for the first time that LTRs generated with 20 kHz + 1 MHz are also more permeable than those generated with 20 kHz alone, which could broaden the range of therapeutics and doses administered transdermally. With regard to safety, treatment with 20 kHz + 1 MHz both in vitro and in vivo appeared to result in no greater skin disruption than that observed in skin treated with 20 kHz alone, an FDA-approved modality. This study demonstrates that dual-frequency ultrasound is more efficient and effective than single-frequency ultrasound and is well-tolerated in vivo. PMID:25662228

Discovery of Dual ETA/ETB Receptor Antagonists from Traditional Chinese Herbs through in Silico and in Vitro Screening

Directory of Open Access Journals (Sweden)

Xing Wang

2016-03-01

Full Text Available Endothelin-1 receptors (ETAR and ETBR act as a pivotal regulator in the biological effects of ET-1 and represent a potential drug target for the treatment of multiple cardiovascular diseases. The purpose of the study is to discover dual ETA/ETB receptor antagonists from traditional Chinese herbs. Ligand- and structure-based virtual screening was performed to screen an in-house database of traditional Chinese herbs, followed by a series of in vitro bioassay evaluation. Aristolochic acid A (AAA was first confirmed to be a dual ETA/ETB receptor antagonist based intracellular calcium influx assay and impedance-based assay. Dose-response curves showed that AAA can block both ETAR and ETBR with IC50 of 7.91 and 7.40 μM, respectively. Target specificity and cytotoxicity bioassay proved that AAA is a selective dual ETA/ETB receptor antagonist and has no significant cytotoxicity on HEK293/ETAR and HEK293/ETBR cells within 24 h. It is a feasible and effective approach to discover bioactive compounds from traditional Chinese herbs using in silico screening combined with in vitro bioassay evaluation. The structural characteristic of AAA for its activity was especially interpreted, which could provide valuable reference for the further structural modification of AAA.

Long-Acting Antiretrovirals: Where Are We now?

Science.gov (United States)

Nyaku, Amesika N; Kelly, Sean G; Taiwo, Babafemi O

2017-04-01

Current HIV treatment options require daily use of combination antiretroviral drugs. Many persons living with HIV experience treatment fatigue and suboptimal adherence as a result. Long-acting antiretroviral drugs are being developed to expand options for HIV treatment. Here, we review the agents in development, and evaluate data from recent clinical trials. In addition, we anticipate challenges to successful widespread use of long-acting antiretrovirals. Parenteral nanosuspensions of cabotegravir and rilpivirine, and dapivirine vaginal ring are the farthest in clinical development. Long-acting modalities in earlier development stages employ drug-loaded implants, microparticles, or targeted mutagenesis, among other innovations. Long-acting antiretroviral drugs promise new options for HIV prevention and treatment, and ways to address poor adherence and treatment fatigue. Further studies will identify the long-acting agents or combinations that are suitable for routine use. Creative solutions will be needed for anticipated implementation challenges.

The Anabolic Steroid Control Act of 2004: a study in the political economy of drug policy.

Science.gov (United States)

Denham, Bryan E

2006-01-01

This article examines the processes by which the Anabolic Steroid Control Act of 2004, an act that added steroid precursors such as androstenedione to the list of Schedule III Controlled Substances in the United States, came to pass in both the House of Representatives and the Senate. Grounded theoretically in political economy, the article addresses, in the abstract, how the interplay of political pressures and economic influences stands to affect the actions of public officials, and how "tougher" drug policies-those touted to be more substantive and efficacious than existing regulations-often fail to effect change. The article concludes with implications for those involved in the regulation of anabolic steroids and steroid precursors.

Chemoinformatics Profiling of the Chromone Nucleus as a MAO-B/A2AAR Dual Binding Scaffold.

Science.gov (United States)

Cruz-Monteagudo, Maykel; Borges, Fernanda; Cordeiro, M Natalia D S; Helguera, Aliuska Morales; Tejera, Eduardo; Paz-Y-Mino, Cesar; Sanchez-Rodriguez, Aminael; Perera-Sardina, Yunier; Perez-Castillo, Yunierkis

2017-11-14

In the context of the current drug discovery efforts to find disease modifying therapies for Parkinson's disease (PD) the current single target strategy has proved inefficient. Consequently, the search for multi-potent agents is attracting more and more attention due to the multiple pathogenetic factors implicated in PD. Multiple evidences points to the dual inhibition of the monoamine oxidase B (MAO-B), as well as adenosine A2A receptor (A2AAR) blockade, as a promising approach to prevent the neurodegeneration involved in PD. Currently, only two chemical scaffolds has been proposed as potential dual MAO-B inhibitors/A2AAR antagonists (caffeine derivatives and benzothiazinones). In this study, we conduct a series of chemoinformatics analysis in order to evaluate and advance the potential of the chromone nucleus as a MAO-B/A2AAR dual binding scaffold. The information provided by SAR data mining analysis based on network similarity graphs and molecular docking studies support the suitability of the chromone nucleus as a potential MAOB/ A2AAR dual binding scaffold. Additionally, a virtual screening tool based on a group fusion similarity search approach was developed for the prioritization of potential MAO-B/A2AAR dual binder candidates. Among several data fusion schemes evaluated, the MEAN-SIM and MIN-RANK GFSS approaches demonstrated to be efficient virtual screening tools. Then, a combinatorial library potentially enriched with MAO-B/A2AAR dual binding chromone derivatives was assembled and sorted by using the MIN-RANK and then the MEAN-SIM GFSS VS approaches. The information and tools provided in this work represent valuable decision making elements in the search of novel chromone derivatives with a favorable dual binding profile as MAOB inhibitors and A2AAR antagonists with the potential to act as a disease-modifying therapeutic for Parkinson's disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The place of central-acting drugs in the algorithms of treatment of primary obesity

Directory of Open Access Journals (Sweden)

Oksana V. Logvinova

2017-09-01

Full Text Available Pharmacotherapy is an essential component of obesity treatment, as well as efforts focused on changing the lifestyle, correcting the food consumption and increasing the physical activity. The administration of central-acting drugs as pharmacotherapy of obesity is pathogenetically justified and allows improving the effectiveness of treatment. In this article, the use of sibutramine, a serotonin and norepinephrine reuptake inhibitor, is considered in various aspects of endocrinologist’s practice. In addition to aforesaid there is an application of a specific clinical observation.

Animal Modeling and Neurocircuitry of Dual Diagnosis

Science.gov (United States)

Chambers, R. Andrew

2010-01-01

Dual diagnosis is a problem of tremendous depth and scope, spanning many classes of mental disorders and addictive drugs. Animal models of psychiatric disorders studied in addiction paradigms suggest a unitary nature of mental illness and addiction vulnerability both on the neurocircuit and clinical-behavioral levels. These models provide platforms for exploring the interactive roles of biological, environmental and developmental factors on neurocircuits commonly involved in psychiatric and addiction diseases. While suggestive of the artifice of segregated research, training, and clinical cultures between psychiatric and addiction fields, this research may lead to more parsimonious, integrative and preventative treatments for dual diagnosis. PMID:20585464

Dual Drug Targeting of Mutant Bcr-Abl Induces Inactive Conformation: New Strategy for the Treatment of Chronic Myeloid Leukemia and Overcoming Monotherapy Resistance.

Science.gov (United States)

El Rashedy, Ahmed A; Olotu, Fisayo A; Soliman, Mahmoud E S

2018-03-01

Bcr-Abl is an oncogenic fusion protein which expression enhances tumorigenesis, and has been highly associated with chronic myeloid leukemia (CML). Acquired drug resistance in mutant Bcr-Abl has enhanced pathogenesis with the use of single therapy agents such as nilotinib. Moreover, allosteric targeting has been identified to consequentially inhibit Bcr-Abl activity, which led to the recent development of ABL-001 (asciminib) that selectively binds the myristoyl pocket. Experimental studies have revealed that the combination of nilotinib and ABL-001 induced a 'bent' conformation in the C-terminal helix of Bcr-Abl; a benchmark of inhibition, thereby exhibiting a greater potency in the treatment of CML, surmounting the setbacks of drug resistance, disease regression and relapse. Therefore, we report the first account of the dynamics and conformational analysis of oncogenic T334I Bcr-Abl by dual targeting. Our findings revealed that unlike in the Bcr-Abl-Nilotinib complex, dual targeting by both inhibitors induced the bent conformation in the C-terminal helix that varied with time. This was coupled with significant alteration in Bcr-Abl stability, flexibility, and compactness and an overall structural re-orientation inwards towards the hydrophobic core, which reduced the solvent-exposed residues indicative of protein folding. This study will facilitate allosteric targeting and the design of more potent allosteric inhibitors for resistive target proteins in cancer. © 2018 Wiley-VHCA AG, Zurich, Switzerland.

Drugs to be Discontinued

Data.gov (United States)

U.S. Department of Health & Human Services — Companies are required under Section 506C of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (as amended by the Food and Drug Administration Safety and...

Psychiatric disorders are overlooked in patients with drug abuse.

Science.gov (United States)

Kruckow, Line; Linnet, Kristian; Banner, Jytte

2016-03-01

Psychiatric disease is overlooked in drug users. Patients with both drug abuse and a psychiatric disease - dual diagnosis - suffer decreased compliance to treatment and decreased life expectancy compared with single-diagnosis patients. Identifying the patients among either drug addicts or mentally ill patients is difficult. All drug addicts autopsied at the Department of Forensic Medicine, University of Copenhagen, Denmark, in the years 1992, 2002 and 2012 were included. The group was divided into two subpopulations of possible dual diagnosis patients either according to police reports stating mental illness or to psychotropics found in the toxicology screening after autopsy. We found a rise in possible mental illness in both subpopulations in the study period. Drug addicts with psychotropics in the blood at the time of death increased from 3.1% in 1992 to 48.1% in 2012, and this group was significantly younger at the time of death than those without psychotropics in the blood. Suspected dual diagnosis patients have increased in number. They die earlier than their drug addict counterparts. Methadone remains the leading cause of death in all subpopulations. Possible causes are misuse of treatment and/or illegally bought methadone, wrongly assigned cause of death due to unknown tolerance and/or polydrug toxicity in combination with psychotropic medicine. none. not relevant.

Xanthone and Flavone Derivatives as Dual Agents with Acetylcholinesterase Inhibition and Antioxidant Activity as Potential Anti-Alzheimer Agents

Directory of Open Access Journals (Sweden)

Inês Cruz

2017-01-01

Full Text Available Alzheimer’s disease (AD is a multifactorial neurodegenerative disorder that is associated with the elderly. The current therapy that is used to treat AD is based mainly on the administration of acetylcholinesterase (AChE inhibitors. Due to their low efficacy there is a considerable need for other therapeutic strategies. Considering that the malfunctions of different, but interconnected, biochemical complex pathways play an important role in the pathogenesis of this disease, a promising therapy may consist in administration of drugs that act on more than a target on biochemical scenery of AD. In this work, the synthesis and evaluation of xanthone and flavone derivatives as antioxidants with AChE inhibitory activity were accomplished. Among the obtained compounds, Mannich bases 3 and 14 showed capacity to inhibit AChE and antioxidant property, exerting dual activity. Moreover, for the most promising AChE inhibitors, docking studies on the target have been performed aiming to predict the binding mechanism. The results presented here may help to identify new xanthone and flavone derivatives as dual anti-Alzheimer agents with AChE inhibitory and antioxidant activities.

Identification and characterization of a dual-acting antinematodal agent against the pinewood nematode, Bursaphelenchus xylophilus.

Directory of Open Access Journals (Sweden)

Wan-Suk Oh

Full Text Available The pinewood nematode (PWN, Bursaphelenchus xylophilus, is a mycophagous and phytophagous pathogen responsible for the current widespread epidemic of the pine wilt disease, which has become a major threat to pine forests throughout the world. Despite the availability of several preventive trunk-injection agents, no therapeutic trunk-injection agent for eradication of PWN currently exists. In the characterization of basic physiological properties of B. xylophilus YB-1 isolates, we established a high-throughput screening (HTS method that identifies potential hits within approximately 7 h. Using this HTS method, we screened 206 compounds with known activities, mostly antifungal, for antinematodal activities and identified HWY-4213 (1-n-undecyl-2-[2-fluorphenyl] methyl-3,4-dihydro-6,7-dimethoxy-isoquinolinium chloride, a highly water-soluble protoberberine derivative, as a potent nematicidal and antifungal agent. When tested on 4 year-old pinewood seedlings that were infected with YB-1 isolates, HWY-4213 exhibited a potent therapeutic nematicidal activity. Further tests of screening 39 Caenorhabditis elegans mutants deficient in channel proteins and B. xylophilus sensitivity to Ca(2+ channel blockers suggested that HWY-4213 targets the calcium channel proteins. Our study marks a technical breakthrough by developing a novel HTS method that leads to the discovery HWY-4213 as a dual-acting antinematodal and antifungal compound.

Identification and characterization of a dual-acting antinematodal agent against the pinewood nematode, Bursaphelenchus xylophilus.

Science.gov (United States)

Oh, Wan-Suk; Jeong, Pan-Young; Joo, Hyoe-Jin; Lee, Jeong-Eui; Moon, Yil-Seong; Cheon, Hyang-Mi; Kim, Jung-Ho; Lee, Yong-Uk; Shim, Yhong-Hee; Paik, Young-Ki

2009-11-11

The pinewood nematode (PWN), Bursaphelenchus xylophilus, is a mycophagous and phytophagous pathogen responsible for the current widespread epidemic of the pine wilt disease, which has become a major threat to pine forests throughout the world. Despite the availability of several preventive trunk-injection agents, no therapeutic trunk-injection agent for eradication of PWN currently exists. In the characterization of basic physiological properties of B. xylophilus YB-1 isolates, we established a high-throughput screening (HTS) method that identifies potential hits within approximately 7 h. Using this HTS method, we screened 206 compounds with known activities, mostly antifungal, for antinematodal activities and identified HWY-4213 (1-n-undecyl-2-[2-fluorphenyl] methyl-3,4-dihydro-6,7-dimethoxy-isoquinolinium chloride), a highly water-soluble protoberberine derivative, as a potent nematicidal and antifungal agent. When tested on 4 year-old pinewood seedlings that were infected with YB-1 isolates, HWY-4213 exhibited a potent therapeutic nematicidal activity. Further tests of screening 39 Caenorhabditis elegans mutants deficient in channel proteins and B. xylophilus sensitivity to Ca(2+) channel blockers suggested that HWY-4213 targets the calcium channel proteins. Our study marks a technical breakthrough by developing a novel HTS method that leads to the discovery HWY-4213 as a dual-acting antinematodal and antifungal compound.

A new dual injection system for AMS facility

International Nuclear Information System (INIS)

Liu Lin; Zhou Weijian; Cheng Peng; Yu Huagui; Chen Maobai

2007-01-01

In order to measure long-lived radioisotopes such as 10 Be with high sensitivity using an HVEE model 4130 AMS system, as well as to guarantee 14 C measurements of high precision, a new dual injection system for the AMS system is proposed. The proposal is to add a Wien filter located between the ion source system and the recombinator of the HVEE model 4130. When a pulsing voltage is optionally applied to the Wien filter, a sequential injection mode is turned on. The isotopes would alternately pass on different trajectories through the recombinator. When the pulsing voltage and magnetic field are turned off, the Wien filter acts as a field-free drift space and the standard simultaneous injection mode is on. Beam optics calculation show that the new dual injection system will increase the number of radio-nuclides which can be analyzed, keep the high precision capability for radiocarbon dating and achieve high sensitivity for 10 Be and 26 Al measurements, together with simplifying the layout as compared to existing dual-injector and dual high-energy beam line systems

77 FR 28620 - Andean Trade Preference Act: Impact on the U.S. Economy and on Andean Drug Crop Eradication

Science.gov (United States)

2012-05-15

... INTERNATIONAL TRADE COMMISSION [Investigation No. 332-352] Andean Trade Preference Act: Impact on the U.S. Economy and on Andean Drug Crop Eradication AGENCY: United States International Trade... to report biennially to the Congress by September 30 of each reporting year on the economic impact of...

Dual-anticipating, dual and dual-lag synchronization in modulated time-delayed systems

International Nuclear Information System (INIS)

Ghosh, Dibakar; Chowdhury, A. Roy

2010-01-01

In this Letter, dual synchronization in modulated time delay system using delay feedback controller is proposed. Based on Lyapunov stability theory, we suggest a general method to achieve the dual-anticipating, dual, dual-lag synchronization of time-delayed chaotic systems and we find both its existing and sufficient stability conditions. Numerically it is shown that the dual synchronization is also possible when driving system contain two completely different systems. Effect of parameter mismatch on dual synchronization is also discussed. As an example, numerical simulations for the Mackey-Glass and Ikeda systems are conducted, which is in good agreement with the theoretical analysis.

Controllable synthesis of a novel magnetic core-shell nanoparticle for dual-modal imaging and pH-responsive drug delivery

Science.gov (United States)

Xu, Chen; Zhang, Cheng; Wang, Yingxi; Li, Liu; Li, Ling; Whittaker, Andrew K.

2017-12-01

In this study, novel magnetic core-shell nanoparticles Fe3O4@La-BTC/GO have been synthesized by the layer-by-layer self-assembly (LBL) method and further modified by attachment of amino-modified PEG chains. The nanoparticles were thoroughly characterized by x-ray diffraction, FTIR, scanning electron microscopy and transmission electron microscopy. The core-shell structure was shown to be controlled by the LBL method. The drug loading of doxorubicin (DOX) within the Fe3O4@La-BTC/GO-PEG nanoparticles with different numbers of deposited layers was investigated. It was found that DOX loading increased with increasing number of metal organic framework coating layers, indicating that the drug loading can be controlled through the controllable LBL method. Cytotoxicity assays indicated that the Fe3O4@La-BTC/GO-PEG nanoparticles were biocompatible. The DOX was released rapidly at pH 3.8 and pH 5.8, but at pH 7.4 the rate and extent of release was greatly attenuated. The nanoparticles therefore demonstrate an excellent pH-triggered drug release. In addition, the particles could be tracked by magnetic resonance imaging (MRI) and fluorescence optical imaging (FOI). A clear dose-dependent contrast enhancement in T 2-weighted MR images and fluorescence images indicate the potential of these nanoparticles as dual-mode MRI/FOI contrast agents.

Dual Wavelength RP-HPLC Method for Simultaneous Determination of Two Antispasmodic Drugs: An Application in Pharmaceutical and Human Serum

Directory of Open Access Journals (Sweden)

Najmul Hasan

2013-01-01

Full Text Available A reverse phase stability indicating HPLC method for simultaneous determination of two antispasmodic drugs in pharmaceutical parenteral dosage forms (injectable and in serum has been developed and validated. Mobile phase ingredients consist of Acetonitrile : buffer : sulfuric acid 0.1 M (50 : 50 : 0.3 v/v/v, at flow rate 1.0 mL/min using a Hibar μBondapak ODS C18 column monitored at dual wavelength of 266 nm and 205 nm for phloroglucinol and trimethylphloroglucinol, respectively. The drugs were subjected to stress conditions of hydrolysis (oxidation, base, acid, and thermal degradation. Oxidation degraded the molecule drastically while there was not so much significant effect of other stress conditions. The calibration curve was linear with a correlation coefficient of 0.9999 and 0.9992 for PG and TMP, respectively. The drug recoveries fall in the range of 98.56% and 101.24% with 10 pg/mL and 33 pg/mL limit of detection and limit of quantification for both phloroglucinol and trimethylphloroglucinol. The method was validated in accordance with ICH guidelines and was applied successfully to quantify the amount of trimethylphloroglucinol and phloroglucinol in bulk, injectable form and physiological fluid. Forced degradation studies proved the stability indicating abilities of the method.

Dual drug delivery using 'smart' liposomes for triggered release of anticancer agents

Energy Technology Data Exchange (ETDEWEB)

Jain, Ankit; Gulbake, Arvind; Jain, Ashish; Shilpi, Satish; Hurkat, Pooja; Jain, Sanjay K., E-mail: drskjainin@yahoo.com [Dr. Hari Singh Gour Vishwavidyalaya, Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences (India)

2013-07-15

Ovarian cancer is one of the most fatal gynecologic cancers. In this debut study, dual approach using synergistically active combination of paclitaxel-topotecan (Pac-Top; 20:1, w/w) is investigated with utilization of characteristic features of tumor micro-environment and additionally overexpressed folate receptors (FR-{alpha}) to achieve targeting to tumor site. Various liposomes namely liposomes, PEGylated liposomes, and FR-targeted PEGylated liposomes with lipid compositions viz. DPPC:DMPG (85.5:9.5), DPPC:DMPG:mPEG{sub 2000}-DSPE (85.5:9.5:5), and DPPC:DMPG:mPEG{sub 2000}-DSPE:DSPE-PEG-folate (85.5:9.5:4.5:0.5), respectively, were developed using thin film casting method. These were nanometric in size around 200 nm. In vitro drug release study showed initial burst release followed by sustained release for more than 72 h at physiological milieu (37 {+-} 0.5 Degree-Sign C, pH 7.4) while burst release (i.e., more than 90 %) within 5 min at simulated tumor milieu (41 {+-} 1 Degree-Sign C, pH 4). SRB cytotoxicity assay in OVCAR-3 cell line revealed Pac-Top free (20:1, w/w) to be more toxic (GI{sub 50} = 6.5 {mu}g/ml) than positive control (Adriamycin, GI{sub 50} = 9.1 {mu}g/ml) and FR-targeted PEGylated liposomes GI{sub 50} (14.7 {mu}g/ml). Moreover, florescence microscopy showed the highest cell uptake of FR-targeted PEGylated liposomes so called 'smart liposomes' which has not only mediated effective targeting to FR-{alpha} but also triggered release of drugs upon hyperthermia.

Psychiatric disorders are overlooked in patients with drug abuse

DEFF Research Database (Denmark)

Kruckow, Line; Linnet, Kristian; Banner, Jytte

2016-01-01

Introduction: Psychiatric disease is overlooked in drug users. Patients with both drug abuse and a psychiatric disease – dual diagnosis – suffer decreased compliance to treatment and decreased life expectancy compared with single-diagnosis patients. Identifying the patients among ­either drug...... addicts or mentally ill patients is difficult. Methods: All drug addicts autopsied at the Department of Forensic Medicine, University of Copenhagen, Denmark, in the years 1992, 2002 and 2012 were included. The group was divided into two subpopulations of possible dual diagnosis patients either according...... to police reports stating mental illness or to psychotropics found in the toxicology screening after autopsy. Results: We found a rise in possible mental illness in both subpopulations in the study period. Drug addicts with psychotropics in the blood at the time of death increased from 3.1% in 1992 to 48...

Dual localized mitochondrial and nuclear proteins as gene expression regulators in plants?

Directory of Open Access Journals (Sweden)

Philippe eGiegé

2012-09-01

Full Text Available Mitochondria heavily depend on the coordinated expression of both mitochondrial and nuclear genomes because some of their most significant activities are held by multi-subunit complexes composed of both mitochondrial and nuclear encoded proteins. Thus, precise communication and signaling pathways are believed to exist between the two compartments. Proteins dual localized to both mitochondria and the nucleus make excellent candidates for a potential involvement in the envisaged communication. Here, we review the identified instances of dual localized nucleo-mitochondrial proteins with an emphasis on plant proteins and discuss their functions, which are seemingly mostly related to gene expression regulation. We discuss whether dual localization could be achieved by dual targeting and / or by re-localization and try to apprehend the signals required for the respective processes. Finally, we propose that in some instances, dual localized mitochondrial and nuclear proteins might act as retrograde signaling molecules for mitochondrial biogenesis.

Dual Entwining Structures and Dual Entwined Modules

OpenAIRE

Abuhlail, Jawad Y.

2003-01-01

In this note we introduce and investigate the concepts of dual entwining structures and dual entwined modules. This generalizes the concepts of dual Doi-Koppinen structures and dual Doi-Koppinen modules introduced (in the infinite case over rings) by the author is his dissertation.

Large-Scale Off-Target Identification Using Fast and Accurate Dual Regularized One-Class Collaborative Filtering and Its Application to Drug Repurposing.

Directory of Open Access Journals (Sweden)

Hansaim Lim

2016-10-01

Full Text Available Target-based screening is one of the major approaches in drug discovery. Besides the intended target, unexpected drug off-target interactions often occur, and many of them have not been recognized and characterized. The off-target interactions can be responsible for either therapeutic or side effects. Thus, identifying the genome-wide off-targets of lead compounds or existing drugs will be critical for designing effective and safe drugs, and providing new opportunities for drug repurposing. Although many computational methods have been developed to predict drug-target interactions, they are either less accurate than the one that we are proposing here or computationally too intensive, thereby limiting their capability for large-scale off-target identification. In addition, the performances of most machine learning based algorithms have been mainly evaluated to predict off-target interactions in the same gene family for hundreds of chemicals. It is not clear how these algorithms perform in terms of detecting off-targets across gene families on a proteome scale. Here, we are presenting a fast and accurate off-target prediction method, REMAP, which is based on a dual regularized one-class collaborative filtering algorithm, to explore continuous chemical space, protein space, and their interactome on a large scale. When tested in a reliable, extensive, and cross-gene family benchmark, REMAP outperforms the state-of-the-art methods. Furthermore, REMAP is highly scalable. It can screen a dataset of 200 thousands chemicals against 20 thousands proteins within 2 hours. Using the reconstructed genome-wide target profile as the fingerprint of a chemical compound, we predicted that seven FDA-approved drugs can be repurposed as novel anti-cancer therapies. The anti-cancer activity of six of them is supported by experimental evidences. Thus, REMAP is a valuable addition to the existing in silico toolbox for drug target identification, drug repurposing

Large-Scale Off-Target Identification Using Fast and Accurate Dual Regularized One-Class Collaborative Filtering and Its Application to Drug Repurposing.

Science.gov (United States)

Lim, Hansaim; Poleksic, Aleksandar; Yao, Yuan; Tong, Hanghang; He, Di; Zhuang, Luke; Meng, Patrick; Xie, Lei

2016-10-01

Target-based screening is one of the major approaches in drug discovery. Besides the intended target, unexpected drug off-target interactions often occur, and many of them have not been recognized and characterized. The off-target interactions can be responsible for either therapeutic or side effects. Thus, identifying the genome-wide off-targets of lead compounds or existing drugs will be critical for designing effective and safe drugs, and providing new opportunities for drug repurposing. Although many computational methods have been developed to predict drug-target interactions, they are either less accurate than the one that we are proposing here or computationally too intensive, thereby limiting their capability for large-scale off-target identification. In addition, the performances of most machine learning based algorithms have been mainly evaluated to predict off-target interactions in the same gene family for hundreds of chemicals. It is not clear how these algorithms perform in terms of detecting off-targets across gene families on a proteome scale. Here, we are presenting a fast and accurate off-target prediction method, REMAP, which is based on a dual regularized one-class collaborative filtering algorithm, to explore continuous chemical space, protein space, and their interactome on a large scale. When tested in a reliable, extensive, and cross-gene family benchmark, REMAP outperforms the state-of-the-art methods. Furthermore, REMAP is highly scalable. It can screen a dataset of 200 thousands chemicals against 20 thousands proteins within 2 hours. Using the reconstructed genome-wide target profile as the fingerprint of a chemical compound, we predicted that seven FDA-approved drugs can be repurposed as novel anti-cancer therapies. The anti-cancer activity of six of them is supported by experimental evidences. Thus, REMAP is a valuable addition to the existing in silico toolbox for drug target identification, drug repurposing, phenotypic screening, and

Interacting-string picture of dual-resonance models

International Nuclear Information System (INIS)

Mandelstam, S.

1985-01-01

Dual-resonance models are an alyzed by means of operators which act within the physical Hilbert space of positive-metric states. The basis of the method is to extend the relativistic-string picture of a previous study to interacting particles. Functional methods are used, but their relation to the operator is evident, and factorization is maintained. An expression is given for the N-point amplitude in terms of physical-particle operators. For the three-point function the Neumann functions which occur in this expression are evaluated, so that we have a formula for the on- and off-energy-shell vertex. The authors assume that the string has no longitudinal degrees of freedom, and their results are Lorentz invariant and dual only if d=26

Towards holistic dual diagnosis care: physical health screening in a Victorian community-based alcohol and drug treatment service.

Science.gov (United States)

Jackson, Lara; Felstead, Boyce; Bhowmik, Jahar; Avery, Rachel; Nelson-Hearity, Rhonda

2016-01-01

The poorer health outcomes experienced by people with mental illness have led to new directions in policy for routine physical health screening of service users. By contrast, little attention has been paid to the physical health needs of consumers of alcohol and other drug (AOD) services, despite a similar disparity in physical health outcomes compared with the general population. The majority of people with problematic AOD use have comorbid mental illness, known as a dual diagnosis, likely to exacerbate their vulnerability to poor physical health. With the potential for physical health screening to improve health outcomes for AOD clients, a need exists for systematic identification and management of common health conditions. Within the current health service system, those with a dual diagnosis are more likely to have their physical health surveyed and responded to if they present for treatment in the mental health system. In this study, a physical health screening tool was administered to clients attending a community-based AOD service. The tool was administered by a counsellor during the initial phase of treatment, and referrals to health professionals were made as appropriate. Findings are discussed in terms of prevalence, types of problems identified and subsequent rates of referral. The results corroborate the known link between mental and physical ill health, and contribute to developing evidence that AOD clients present with equally concerning physical ill health to that of mental health clients and should equally be screened for such when presenting for AOD treatment.

Coexistence of meningoencephalocele and hippocampal sclerosis: a new type of dual pathology.

Science.gov (United States)

Martinoni, Matteo; Marucci, Gianluca; Gagliardini, Gabriele; Tinuper, Paolo; Michelucci, Roberto; Giulioni, Marco

2017-05-01

Both temporal lobe meningoencephalocele (TE) and hippocampal sclerosis (HS) are causes of drug-resistant temporal lobe epilepsy. Spontaneous TE constitutes a rare but well-known and increasingly recognised cause of refractory epilepsy. It is well known that HS may be associated with another neocortical lesion (dual pathology). Here we report for the first time a new type of dual pathology; namely, the coexistence of temporal pole meningoencephalocele and HS.

National Drug Code Directory

Data.gov (United States)

U.S. Department of Health & Human Services — The Drug Listing Act of 1972 requires registered drug establishments to provide the Food and Drug Administration (FDA) with a current list of all drugs manufactured,...

Tumor-targeted polymeric nanostructured lipid carriers with precise ratiometric control over dual-drug loading for combination therapy in non-small-cell lung cancer.

Science.gov (United States)

Liang, Yan; Tian, Baocheng; Zhang, Jing; Li, Keke; Wang, Lele; Han, Jingtian; Wu, Zimei

2017-01-01

Gemcitabine (GEM) and paclitaxel (PTX) are effective combination anticancer agents against non-small-cell lung cancer (NSCLC). At the present time, a main challenge of combination treatment is the precision of control that will maximize the combined effects. Here, we report a novel method to load GEM (hydrophilic) and PTX (hydrophobic) into simplex tumor-targeted nanostructured lipid carriers (NLCs) for accurate control of the ratio of the two drugs. We covalently preconjugated the dual drugs through a hydrolyzable ester linker to form drug conjugates. N -acetyl-d-glucosamine (NAG) is a glucose receptor-targeting ligand. We added NAG to the formation of NAG-NLCs. In general, synthesis of poly(6- O -methacryloyl-d-galactopyranose)-GEM/PTX (PMAGP-GEM/PTX) conjugates was demonstrated, and NAG-NLCs were prepared using emulsification and solvent evaporation. NAG-NLCs displayed sphericity with an average diameter of 120.3±1.3 nm, a low polydispersity index of 0.233±0.04, and accurate ratiometric control over the two drugs. A cytotoxicity assay showed that the NAG-NLCs had better antitumor activity on NSCLC cells than normal cells. There was an optimal ratio of the two drugs, exhibiting the best cytotoxicity and combinatorial effects among all the formulations we tested. In comparison with both the free-drug combinations and separately nanopackaged drug conjugates, PMAGP-GEM/PTX NAG-NLCs (3:1) exhibited superior synergism. Flow cytometry and confocal laser scanning microscopy showed that NAG-NLCs exhibited higher uptake efficiency in A549 cells via glucose receptor-mediated endocytosis. This combinatorial delivery system settles problems with ratiometric coloading of hydrophilic and hydrophobic drugs for tumor-targeted combination therapy to achieve maximal anticancer efficacy in NSCLC.

Drugs and drug policy in the Netherlands

NARCIS (Netherlands)

Leuw, Ed.

1991-01-01

The Dutch parliament enacted the revised Opium Act in 1976. This penal law is part of the Dutch drug policy framework that includes tolerance for nonconforming lifestyles, risk reduction in regard to the harmful health and social consequences of drug taking, and penal measures directed against

Controlled dual release study of curcumin and a 4-aminoquinoline analog from gum acacia containing hydrogels

CSIR Research Space (South Africa)

Aderibigbe, BA

2014-10-01

Full Text Available The potential of gum acacia containing hydrogels as controlled dual-drug delivery systems for antiprotozoal agents was investigated. 4-Aminoquinoline analog and curcumin were selected as model drugs because they exhibit antiprotozoal activity...

Discovery and Characterization of ACT-451840: an Antimalarial Drug with a Novel Mechanism of Action.

Science.gov (United States)

Boss, Christoph; Aissaoui, Hamed; Amaral, Nathalie; Bauer, Aude; Bazire, Stephanie; Binkert, Christoph; Brun, Reto; Bürki, Cédric; Ciana, Claire-Lise; Corminboeuf, Olivier; Delahaye, Stephane; Dollinger, Claire; Fischli, Christoph; Fischli, Walter; Flock, Alexandre; Frantz, Marie-Céline; Girault, Malory; Grisostomi, Corinna; Friedli, Astrid; Heidmann, Bibia; Hinder, Claire; Jacob, Gael; Le Bihan, Amelie; Malrieu, Sophie; Mamzed, Saskia; Merot, Aurelien; Meyer, Solange; Peixoto, Sabrina; Petit, Nolwenn; Siegrist, Romain; Trollux, Julien; Weller, Thomas; Wittlin, Sergio

2016-09-20

More than 40 % of the world's population is at risk of being infected with malaria. Most malaria cases occur in the countries of sub-Saharan Africa, Central and South America, and Asia. Resistance to standard therapy, including artemisinin combinations, is increasing. There is an urgent need for novel antimalarials with new mechanisms of action. In a phenotypic screen, we identified a series of phenylalanine-based compounds that exhibit antimalarial activity via a new and yet unknown mechanism of action. Our optimization efforts culminated in the selection of ACT-451840 [(S,E)-N-(4-(4-acetylpiperazin-1-yl)benzyl)-3-(4-(tert-butyl)phenyl)-N-(1-(4-(4-cyanobenzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)acrylamide] for clinical development. Herein we describe our optimization efforts from the screening hit to the potential drug candidate with respect to antiparasitic activity, drug metabolism and pharmacokinetics (DMPK) properties, and in vivo pharmacological efficacy. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Adolescents and Dual Diagnosis in a Psychiatric Emergency Service.

Science.gov (United States)

Matali, José Luis; Andión, Oscar; Pardo, Marta; Iniesta, Raquel; Serrano, Eduard; San, Luis

2016-03-02

In recent years, both the prevalence of drug use and related child and adolescent psychiatric emergencies have risen sharply. There are few studies about the impact on child and adolescent emergency services. This study has a twofold aim. The first is to describe the prevalence of substance use disorders, mental disorders and dual diagnosis (substance use problems plus mental disorder) in adolescents in psychiatric emergency service. The second is to analyze clinical and healthcare differences between patients with dual diagnosis and patients with a mental disorder without substance use disorder.We retrospectively reviewed 4012 discharge forms for emergencies treated at the psychiatric emergency department during the period 2007-2009. We obtained a sample of 1795 visits. This sample was divided into two groups: the dual diagnosis group (n = 477) and the psychiatric disorder group (n = 1318).The dual diagnosis group accounted for 26.5% of psychiatric emergencies analyzed. Compared to the psychiatric disorder group,the dual diagnosis group had significantly more conduct disorders, social problems, involuntariness in the visit, less hospital admissions and less connection with the healthcare network.Adolescents with a dual diagnosis account for a high percentage of visits at child and adolescent psychiatric emergency services. This patient group requires specialized care both at emergency services and in specific units. Accordingly, these units should play a triple role when handling dual diagnosis: detection, brief treatment and referral to a specialised unit.

The Creating Hope Act: what is old is new again

Directory of Open Access Journals (Sweden)

Tolbert JA

2014-06-01

Full Text Available Jaszianne A Tolbert,1,2 Jennifer L Goldman,2-4 Ralph E Kauffman,2,4 Susan M Abdel-Rahman2,41Division of Hematology/Oncology, 2Division of Clinical Pharmacology and Therapeutic Innovation, 3Division of Infectious Diseases, Children's Mercy Hospital, Kansas City, MO, USA; 4Department of Pediatrics, University of Missouri-Kansas City, School of Medicine, Kansas City, MO, USAAbstract: The Creating Hope Act, passed as part of the Food and Drug Administration Safety and Innovation Act of 2012, is among the newest laws intended to foster drug development for rare and neglected diseases in children. The act expands the priority review voucher incentive that first appeared in the Food and Drug Administration Amendments Act of 2007 and was intended to stimulate the development of products for the prevention and treatment of tropical diseases. Notably, legislative and regulatory initiatives aimed at enhancing drug development both for use in children and for rare diseases have intermittently emerged over the past 3 decades. This manuscript provides an overview of related legislation that has preceded the Creating Hope Act and examines the potential impact of the new act in the context of the outcomes that have been observed with the earlier initiatives.Keywords: orphan drug, rare disease, pediatric, drug development, priority review voucher

Dual Diagnosis and Suicide Probability in Poly-Drug Users

International Nuclear Information System (INIS)

Youssef, I. M.; Fahmy, M. T.; Haggag, W. L.; Mohamed, K. A.; Baalash, A. A.

2016-01-01

Objective: To determine the frequency of suicidal thoughts and suicidal probability among poly-substance abusers in Saudi population, and to examine the relation between dual diagnosis and suicidal thoughts. Study Design: Case control study. Place and Duration of Study: Al-Baha Psychiatric Hospital, Saudi Arabia, from May 2011 to Jun 2012. Methodology: Participants were 239 subjects, aged 18 - 45 years. We reviewed 122 individuals who fulfilled the DSM-IV-TR criteria of substance abuse for two or more substances, and their data were compared with that collected from 117 control persons. Results: Suicidal cases were highly present among poly-substance abusers 64.75 percentage. Amphetamine and cannabis were the most abused substances, (87.7 percentage and 70.49 percentage, respectively). A statistically significant association with suicidality was found with longer duration of substance abuse (p < 0.001), using alcohol (p=0.001), amphetamine (p=0.007), volatile substances (p=0.034), presence of comorbid psychiatric disorders (dual diagnosis) as substance induced mood disorder (p=0.001), schizo-affective disorder (p=0.017), major depressive disorders (p=0.001), antisocial (p=0.016) and borderline (p=0.005) personality disorder. Suicidal cases showed significant higher scores (p < 0.001) of suicide probability scale and higher scores in Beck depressive inventory (p < 0.001). Conclusion: Abusing certain substances for long duration, in addition to comorbid psychiatric disorders especially with disturbed-mood element, may trigger suicidal thoughts in poly-substance abusers. Depression and suicide probability is common consequences of substance abuse. (author)

The impact of the Food and Drug Administration Modernization Act on the recruitment of children for research.

Science.gov (United States)

Sharav, Vera Hassner

2003-01-01

This article argues that contrary to the claims made by research stakeholders in industry, academia and government, the shift in public policy since the enactment of the Food and Drug Administration Modernization Act (FDAMA) of 1997 and its financial incentives to industry to test drugs on children, has had a deleterious impact on children's dignity, health and welfare. Those lucrative incentives offered an opportunity to accelerate the pace of FDA approval for pediatric drug marketing. FDAMA resulted in a radical shift in federal policy to accommodate an expansion of pediatric trials. Children who are precluded from exercising a human adult's right to informed consent to research are increasingly sought as test subjects even when the trials offer no potential benefit for them. Prior to FDAMA children were protected under federal regulations that prohibited their recruitment for experiments that were not in their best interest. This article discusses eight cases and controversies demonstrating that children have been subjected to experiments that exposed them to pain, discomfort, and serious risks of harm. Babies have died testing a lethal heartburn drug; children have been subjected to "forced dose titration" in antidepressant drug trials that resulted in several suicide attempts. Toddlers are currently being subjected to methylphenidate dose tolerance tests without evidence of any pathological condition. Healthy teenagers are being exposed to antipsychotic drugs known to induce severe pathological side effects in speculative "schizophrenia prevention" experiments.

Outstanding Anti-inflammatory Potential of Selected Asteraceae Species through the Potent Dual Inhibition of Cyclooxygenase-1 and 5-Lipoxygenase.

Science.gov (United States)

Chagas-Paula, Daniela Aparecida; Oliveira, Tiago Branquinho; Faleiro, Danniela Príscylla Vasconcelos; Oliveira, Rejane Barbosa; Costa, Fernando Batista Da

2015-09-01

Cyclooxygenase and 5-lipoxygenase are enzymes that catalyze important inflammatory pathways, suggesting that dual cyclooxygenase/lipoxygenase inhibitors should be more efficacious as anti-inflammatory medicines with lower side effects than the currently available nonsteroidal anti-inflammatory drugs. Many plants from the family Asteraceae have anti-inflammatory activities, which could be exerted by inhibiting the cyclooxygenase-1 and 5-lipoxygenase enzymes. Nevertheless, only a small number of compounds from this family have been directly evaluated for their ability to inhibit the enzymes in cell-free assays. Therefore, this study systematically evaluated 57 Asteraceae extracts in vitro in enzyme activity experiments to determine whether any of these extracts exhibit dual inhibition of cyclooxygenase-1 and 5-lipoxygenase. The chemical profiles of the extracts were obtained by the high-performance liquid chromatography-ultraviolet-diode array detector method, and their major constituents were dereplicated. Of the 57 tested extracts, 13 (26.6 %, IC50 range from 0.03-36.2 µg/mL) of them displayed dual inhibition. Extracts from known anti-inflammatory herbs, food plants, and previously uninvestigated species are among the most active. Additionally, the extract action was found to be specific with IC50 values close to or below those of the standard inhibitors. Thus, the active extracts and active substances of these species are potent inhibitors acting through the mechanism of dual inhibition of cyclooxygenase-1 and 5-lipoxygenase. The extracts were prepared for this study using nontoxic extraction solvents (EtOH-H2O), requiring only a small amount of plant material to carry out the bioassays and the phytochemical analyses. In summary, this study demonstrated the potential of the investigated species as dual inhibitors, revealing their potential as pharmaceuticals or nutraceuticals. Georg Thieme Verlag KG Stuttgart · New York.

Soluble polymeric dual sensor for temperature and pH value

NARCIS (Netherlands)

Pietsch, C.; Hoogenboom, R.; Schubert, U.S.

2009-01-01

Two birds with one stone: A thermoresponsive copolymer (see picture, blue beads) bearing a pH-responsive solvatochromic dye (red beads) acts as the first dual sensor for temperature and pH value (black curve). When the hydrophilicity of the copolymer is increased by using a monomer with more

Synthesis of novel core-shell structured dual-mesoporous silica nanospheres and their application for enhancing the dissolution rate of poorly water-soluble drugs

Energy Technology Data Exchange (ETDEWEB)

Wu, Chao, E-mail: wuchao27@126.com [Department of Pharmaceutics, Liaoning Medical University, 40 Songpo Road, Linghe District, Jinzhou, Liaoning Province 121001 (China); Sun, Xiaohu [Management Center for Experiments, Bohai University, 19 Keji Road, Songshan District, Jinzhou, Liaoning Province 121000 (China); Zhao, Zongzhe; Zhao, Ying; Hao, Yanna; Liu, Ying [Department of Pharmaceutics, Liaoning Medical University, 40 Songpo Road, Linghe District, Jinzhou, Liaoning Province 121001 (China); Gao, Yu, E-mail: gaoyu_1116@163.com [Department of Medical Oncology, First Affiliated Hospital of Liaoning Medical University, 40 Songpo Road, Linghe District, Jinzhou, Liaoning Province 121001 (China)

2014-11-01

Novel core-shell dual-mesoporous silica nanospheres (DMSS) with a tunable pore size were synthesized successfully using a styrene monomer as a channel template for the core and cetyltrimethyl ammonium bromide (CTAB) as a channel template for the shell in order to improve the dissolution rate of poorly water-soluble drugs. Simvastatin was used as a model drug and loaded into DMSS and the mesoporous core without the shell (MSC) by the solvent evaporation method. The drug loading efficiency of DMSS and MSC were determined by thermogravimetric analysis (TGA) and ultraviolet spectroscopy (UV). Characterization, using scanning electron microscopy (SEM), transmission electron microscopy (TEM), nitrogen adsorption, powder X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR) showed that simvastatin adsorbed in DMSS and MSC was in an amorphous state, and in vitro release test results demonstrated that both DMSS and MSC increased the water solubility and dissolution rate of simvastatin. The shell structure of DMSS was able to regulate the release of simvastatin compared with MSC. It is worth noting that DMSS has significant potential as a carrier for improving the dissolution of poorly water-soluble drugs and reducing the rapid release. - Highlights: • A novel core-shell DMSS is prepared for improving the dissolution rate of simvastatin. • The diffusional resistance of the mesoporous shell can delay and regulate drug release. • Simvastatin absorbed in DMSS exists in amorphous form due to spatial confinement.

Synthesis of novel core-shell structured dual-mesoporous silica nanospheres and their application for enhancing the dissolution rate of poorly water-soluble drugs

International Nuclear Information System (INIS)

Wu, Chao; Sun, Xiaohu; Zhao, Zongzhe; Zhao, Ying; Hao, Yanna; Liu, Ying; Gao, Yu

2014-01-01

Novel core-shell dual-mesoporous silica nanospheres (DMSS) with a tunable pore size were synthesized successfully using a styrene monomer as a channel template for the core and cetyltrimethyl ammonium bromide (CTAB) as a channel template for the shell in order to improve the dissolution rate of poorly water-soluble drugs. Simvastatin was used as a model drug and loaded into DMSS and the mesoporous core without the shell (MSC) by the solvent evaporation method. The drug loading efficiency of DMSS and MSC were determined by thermogravimetric analysis (TGA) and ultraviolet spectroscopy (UV). Characterization, using scanning electron microscopy (SEM), transmission electron microscopy (TEM), nitrogen adsorption, powder X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR) showed that simvastatin adsorbed in DMSS and MSC was in an amorphous state, and in vitro release test results demonstrated that both DMSS and MSC increased the water solubility and dissolution rate of simvastatin. The shell structure of DMSS was able to regulate the release of simvastatin compared with MSC. It is worth noting that DMSS has significant potential as a carrier for improving the dissolution of poorly water-soluble drugs and reducing the rapid release. - Highlights: • A novel core-shell DMSS is prepared for improving the dissolution rate of simvastatin. • The diffusional resistance of the mesoporous shell can delay and regulate drug release. • Simvastatin absorbed in DMSS exists in amorphous form due to spatial confinement

Drug-Drug Multicomponent Solid Forms: Cocrystal, Coamorphous and Eutectic of Three Poorly Soluble Antihypertensive Drugs Using Mechanochemical Approach.

Science.gov (United States)

Haneef, Jamshed; Chadha, Renu

2017-08-01

The present study deals with the application of mechanochemical approach for the preparation of drug-drug multicomponent solid forms of three poorly soluble antihypertensive drugs (telmisartan, irbesartan and hydrochlorothiazide) using atenolol as a coformer. The resultant solid forms comprise of cocrystal (telmisartan-atenolol), coamorphous (irbesartan-atenolol) and eutectic (hydrochlorothiazide-atenolol). The study emphasizes that solid-state transformation of drug molecules into new forms is a result of the change in structural patterns, diminishing of dimers and creating new facile hydrogen bonding network based on structural resemblance. The propensity for heteromeric or homomeric interaction between two different drugs resulted into diverse solid forms (cocrystal/coamorphous/eutectics) and become one of the interesting aspects of this research work. Evaluation of these solid forms revealed an increase in solubility and dissolution leading to better antihypertensive activity in deoxycorticosterone acetate (DOCA) salt-induced animal model. Thus, development of these drug-drug multicomponent solid forms is a promising and viable approach to addressing the issue of poor solubility and could be of considerable interest in dual drug therapy for the treatment of hypertension.

Dual pancreas- and lung-targeting therapy for local and systemic complications of acute pancreatitis mediated by a phenolic propanediamine moiety.

Science.gov (United States)

Li, Jianbo; Zhang, Jinjie; Fu, Yao; Sun, Xun; Gong, Tao; Jiang, Jinghui; Zhang, Zhirong

2015-08-28

To inhibit both the local and systemic complications with acute pancreatitis, an effective therapy requires a drug delivery system that can efficiently overcome the blood-pancreas barrier while achieving lung-specific accumulation. Here, we report the first dual pancreas- and lung-targeting therapeutic strategy mediated by a phenolic propanediamine moiety for the treatment of acute pancreatitis. Using the proposed dual-targeting ligand, an anti-inflammatory compound Rhein has been tailored to preferentially accumulate in the pancreas and lungs with rapid distribution kinetics, excellent tissue-penetrating properties and minimum toxicity. Accordingly, the drug-ligand conjugate remarkably downregulated the proinflammatory cytokines in the target organs thus effectively inhibiting local pancreatic and systemic inflammation in rats. The dual-specific targeting therapeutic strategy may help pave the way for targeted drug delivery to treat complicated inflammatory diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

Contingency management for patients with dual disorders in intensive outpatient treatment for addiction.

Science.gov (United States)

Kelly, Thomas M; Daley, Dennis C; Douaihy, Antoine B

2014-01-01

This quality improvement program evaluation investigated the effectiveness of contingency management for improving retention in treatment and positive outcomes among patients with dual disorders in intensive outpatient treatment for addiction. The effect of contingency management was explored among a group of 160 patients exposed to contingency management (n = 88) and not exposed to contingency management (no contingency management, n = 72) in a six-week partial hospitalization program. Patients referred to the partial hospitalization program for treatment of substance use and comorbid psychiatric disorders received diagnoses from psychiatrists and specialist clinicians according to the Diagnostic and Statistical Manual of the American Psychiatric Association. A unique application of the contingency management "fishbowl" method was used to improve the consistency of attendance at treatment sessions, which patients attended 5 days a week. Days attending treatment and drug-free days were the main outcome variables. Other outcomes of interest were depression, anxiety and psychological stress, coping ability, and intensity of drug cravings. Patients in the contingency management group attended more treatment days compared to patients in the no contingency management group; M = 16.2 days (SD = 10.0) versus M = 9.9 days (SD = 8.5), respectively; t = 4.2, df = 158, p contingency management and self-reported drug-free days. Contingency management is a valuable adjunct for increasing retention in treatment among patients with dual disorders in partial hospitalization treatment. Exposure to contingency management increases retention in treatment, which in turn contributes to increased drug-free days. Interventions for coping with psychological stress and drug cravings should be emphasized in intensive dual diagnosis group therapy.

Tumor-targeted polymeric nanostructured lipid carriers with precise ratiometric control over dual-drug loading for combination therapy in non-small-cell lung cancer

Directory of Open Access Journals (Sweden)

Liang Y

2017-03-01

Full Text Available Yan Liang,1 Baocheng Tian,1 Jing Zhang,1 Keke Li,1 Lele Wang,1 Jingtian Han,1,* Zimei Wu2,* 1School of Pharmacy, Binzhou Medical University, 2School of Pharmacy, Yantai University, Yantai, China *These authors contributed equally to this work Abstract: Gemcitabine (GEM and paclitaxel (PTX are effective combination anticancer agents against non-small-cell lung cancer (NSCLC. At the present time, a main challenge of combination treatment is the precision of control that will maximize the combined effects. Here, we report a novel method to load GEM (hydrophilic and PTX (hydrophobic into simplex tumor-targeted nanostructured lipid carriers (NLCs for accurate control of the ratio of the two drugs. We covalently preconjugated the dual drugs through a hydrolyzable ester linker to form drug conjugates. N-acetyl-D-glucosamine (NAG is a glucose receptor-targeting ligand. We added NAG to the formation of NAG-NLCs. In general, synthesis of poly(6-O-methacryloyl-d-galactopyranose–GEM/PTX (PMAGP-GEM/PTX conjugates was demonstrated, and NAG-NLCs were prepared using emulsification and solvent evaporation. NAG-NLCs displayed sphericity with an average diameter of 120.3±1.3 nm, a low polydispersity index of 0.233±0.04, and accurate ratiometric control over the two drugs. A cytotoxicity assay showed that the NAG-NLCs had better antitumor activity on NSCLC cells than normal cells. There was an optimal ratio of the two drugs, exhibiting the best cytotoxicity and combinatorial effects among all the formulations we tested. In comparison with both the free-drug combinations and separately nanopackaged drug conjugates, PMAGP-GEM/PTX NAG-NLCs (3:1 exhibited superior synergism. Flow cytometry and confocal laser scanning microscopy showed that NAG-NLCs exhibited higher uptake efficiency in A549 cells via glucose receptor-mediated endocytosis. This combinatorial delivery system settles problems with ratiometric coloading of hydrophilic and hydrophobic drugs for tumor

Reactive dual magnetron sputtering for large area application

International Nuclear Information System (INIS)

Struempfel, J.

2002-01-01

Production lines for large area coating demand high productivity of reactive magnetron sputtering processes. Increased dynamic deposition rates for oxides and nitrides were already obtained by using of highly powered magnetrons in combination with advanced sputter techniques. However, besides high deposition rates the uniformity of such coatings has to be carefully considered. First the basics of reactive sputtering processes and dual magnetron sputtering are summarized. Different methods for process stabilization and control are commonly used for reactive sputtering. The Plasma Emission Monitor (PE M) offers the prerequisite for fast acting process control derived from the in-situ intensity measurements of a spectral line of the sputtered target material. Combined by multiple Plasma Emission Monitor control loops segmented gas manifolds are able to provide excellent thin film uniformity at high deposition rates. The Dual Magnetron allows a broad range of processing by different power supply modes. Medium frequency, DC and pulsed DC power supplies can be used for high quality layers. Whereas the large area coating of highly isolating layers like TiO 2 or SiO 2 is dominated by MF sputtering best results for coating with transparent conductive oxides are obtained by dual DC powering of the dual magnetron arrangement. (Author)

SMART POLYMERS: INNOVATIONS IN NOVEL DRUG DELIVERY

OpenAIRE

Apoorva Mahajan; Geeta Aggarwal

2011-01-01

Smart polymers are attracting the researchers for development of novel drug delivery systems. Importance of smart polymers is rising day by day as these polymers undergo large reversible, physical or chemical changes in response to small changes in the environmental conditions such as pH, temperature, dual- stimuli, light and phase transition. Smart polymers are representing promising means for targeted drug delivery, enhanced drug delivery, gene therapy, actuator stimuli and protein folders....

Some properties of dual and approximate dual of fusion frames

OpenAIRE

Arefijamaal, Ali Akbar; Neyshaburi, Fahimeh Arabyani

2016-01-01

In this paper we extend the notion of approximate dual to fusion frames and present some approaches to obtain dual and approximate alternate dual fusion frames. Also, we study the stability of dual and approximate alternate dual fusion frames.

Decree of 22 October 1969, Stb. 474, concerning the implementation of Section 58, paragraph 4 of the Nuclear Energy Act (Duties of Food and Drugs Inspectors)

International Nuclear Information System (INIS)

1969-01-01

This Decree defines the responsibilities of municipal and provincial food and drug inspectors appointed under the Nuclear Energy Act. They are required to ascertain that the provisions of the Act concerning the protection of the biological, chemical and physical human environment are observed. Their duties do not include the protection of workers. (NEA) [fr

Distribution of blood derivatives by registered blood establishments that qualify as health care entities; Prescription Drug Marketing Act of 1987; Prescription Drug Amendments of 1992; delay of applicability date. Final rule; delay of applicability date.

Science.gov (United States)

2006-11-13

The Food and Drug Administration (FDA) is further delaying, until December 1, 2008, the applicability date of a certain requirement of a final rule published in the Federal Register of December 3, 1999 (64 FR 67720) (the final rule). The final rule implements the Prescription Drug Marketing Act of 1987 (PDMA), as modified by the Prescription Drug Amendments of 1992 (PDA), and the Food and Drug Administration Modernization Act of 1997 (the Modernization Act). The provisions of the final rule became effective on December 4, 2000, except for certain provisions whose effective or applicability dates were delayed in five subsequent Federal Register notices, until December 1, 2006. The provision with the delayed applicability date would prohibit wholesale distribution of blood derivatives by registered blood establishments that meet the definition of a "health care entity." In the Federal Register of February 1, 2006 (71 FR 5200), FDA published a proposed rule specific to the distribution of blood derivatives by registered blood establishments that qualify as health care entities (the proposed rule). The proposed rule would amend certain limited provisions of the final rule to allow certain registered blood establishments that qualify as health care entities to distribute blood derivatives. In response to the proposed rule, FDA received substantive comments. As explained in the SUPPLEMENTARY INFORMATION section of this document, further delaying the applicability of Sec. 203.3(q) (21 CFR 203.3(q)) to the wholesale distribution of blood derivatives by health care entities is necessary to give the agency additional time to address comments on the proposed rule, consider whether regulatory changes are appropriate, and, if so, to initiate such changes.

Motivating factors for dual-method contraceptive use among adolescents and young women: a qualitative investigation.

Science.gov (United States)

Lemoine, Julie; Teal, Stephanie B; Peters, Marissa; Guiahi, Maryam

2017-11-01

This qualitative study explores how adolescents and young women perceive the need for and describe the use of dual method contraception. We interviewed 20 sexually active women aged 16-24 who attended an adolescent-focused Title X family-planning clinic and were using a non-barrier contraceptive method. We used a semi-structured interview guide that included domains related to sexual activity, knowledge of and use of contraceptives and condoms, and relationship factors. We coded transcripts using grounded theory techniques and used an iterative process to develop overarching themes. Dual method contraceptive users primarily discussed pregnancy prevention as their motivating factor. Many expressed anxieties over an unplanned pregnancy and reported condom use as "back-up" contraception. Risk perception for pregnancy or STI acquisition did not necessarily change as relationship trust increased, but rather, their anxiety regarding the negativity of such outcomes decreased. Dual-method contraception use decreased when participants reported that condoms were not readily available, or when they self-described immaturity. Less frequently, participants reported dual method use for sexually transmitted infection (STI) prevention, and many substituted STI testing for condom use. Contraceptive type (short-acting vs. long-acting) did not influence reported attitudes towards dual method use. Health educators and clinicians encourage condom use in young women due to the significant morbidity associated with STI acquisition. Most participants in our study view condoms as a way to improve pregnancy prevention. Acknowledging and addressing this divergence in motivation will allow caregivers to improve strategies for communicating the importance of dual method use. Young women primarily describe pregnancy prevention as the reason for dual method use, STI protection is less salient. Consideration of this viewpoint by health educators and clinicians will allow us to communicate more

Diffusion of subsidized ACTs in accredited drug shops in Tanzania: determinants of stocking and characteristics of early and late adopters.

Science.gov (United States)

Larson, Peter S; Yadav, Prashant; Alphs, Sarah; Arkedis, Jean; Massaga, Julius; Sabot, Oliver; Cohen, Jessica L

2013-12-18

Many households in sub-Saharan Africa utilize the private sector as a primary source of treatment for malaria episodes. Expanding access to effective treatment in private drug shops may help reduce incidence of severe disease and mortality. This research leveraged a longitudinal survey of stocking of subsidized artemisinin combination therapies (ACTs), an effective anti-malarial, in Accredited Drug Dispensing Outlets (ADDOs) in two regions of Tanzania. This provided a unique opportunity to explore shop and market level determinants of product diffusion in a developing country retail market. 356 ADDOs in the Rukwa and Mtwara regions of Tanzania were surveyed at seven points between Feb 2011 and May 2012. Shop level audits were used to measure the availability of subsidized ACTs at each shop. Data on market and shop level factors were collected during the survey and also extracted from GIS layers. Regression and network based methodologies were used. Shops classified as early and late adopters, following Rogers' model of product diffusion, were compared. The Bass model of product diffusion was applied to determine whether shops stocked ACTs out of a need to imitate market competitors or a desire to satisfy customer needs. Following the introduction of a subsidy for ACTs, stocking increased from 12% to nearly 80% over the seven survey rounds. Stocking was influenced by higher numbers of proximal shops and clinics, larger customer traffic and the presence of a licensed pharmacist. Early adopters were characterized by a larger percentage of customers seeking care for malaria, a larger catchment and sourcing from specific wholesalers/suppliers. The Bass model of product diffusion indicated that shops were adopting products in response to competitor behavior, rather than customer demand. Decisions to stock new pharmaceutical products in Tanzanian ADDOs are influenced by a combination of factors related to both market competition and customer demand, but are particularly

78 FR 23273 - Determination That the OXYCONTIN (Oxycodone Hydrochloride) Drug Products Covered by New Drug...

Science.gov (United States)

2013-04-18

... mitigation strategy (REMS) http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationfor... Blueprint for Prescriber Education for Extended- Release and Long-Acting Opioid Analgesics'' ( http://www...

7 CFR 1710.127 - Drug free workplace.

Science.gov (United States)

2010-01-01

... 7 Agriculture 11 2010-01-01 2010-01-01 false Drug free workplace. 1710.127 Section 1710.127... and Basic Policies § 1710.127 Drug free workplace. Borrowers are required to comply with the Drug Free Workplace Act of 1988 (Pub. L. 100-690, title V, subtitle D) and the Act's implementing regulations (7 CFR...

Brand-name drug, generic drug, orphan drug. Pharmacological therapy with biosimilar drugs - provision of due diligence in the treatment process.

Science.gov (United States)

Zajdel, Justyna; Zajdel, Radosław

2013-01-01

Due diligence in the process of provision of healthcare services refers, among other elements, to the application of pharmacological therapy at a time which offers the greatest chance for a successful outcome of treatment, i.e. for achieving the optimum expected effect understood as an improvement in the patient's health, reduction of health risks or elimination of the disease. However, due diligence may also refer to actions aimed at ensuring that neither the patient nor the healthcare payer is required to incur unreasonable costs in the process of treatment. The validity of that statement stems not only from normative acts but also from ethical standards laid down in the Medical Code of Ethics (Article 57 section 2). It often happens that the provision of optimal treatment calls for deviations from the formal provisions included in Summary Product Characteristics (SPCs), and the application of drugs that are bioequivalent to reference drugs, which translates into a significant reduction of costs. The present study addresses the problem of acceptability of a specific form of drug substitution consisting in the replacement of a reference drug with a generic drug. Also explored are legal aspects associated with the possibility of therapy based on "off-label use". The study reviews normative acts existing in the Polish and EU legislation. It also provides a clear definition of orphan drug, which has made it possible to make a distinction and investigate mutual relations between the concepts of brand-name (reference) drug, orphan drug and generic drug.

A novel antidiabetic drug, fasiglifam/TAK-875, acts as an ago-allosteric modulator of FFAR1.

Directory of Open Access Journals (Sweden)

Chiori Yabuki

Full Text Available Selective free fatty acid receptor 1 (FFAR1/GPR40 agonist fasiglifam (TAK-875, an antidiabetic drug under phase 3 development, potentiates insulin secretion in a glucose-dependent manner by activating FFAR1 expressed in pancreatic β cells. Although fasiglifam significantly improved glycemic control in type 2 diabetes patients with a minimum risk of hypoglycemia in a phase 2 study, the precise mechanisms of its potent pharmacological effects are not fully understood. Here we demonstrate that fasiglifam acts as an ago-allosteric modulator with a partial agonistic activity for FFAR1. In both Ca(2+ influx and insulin secretion assays using cell lines and mouse islets, fasiglifam showed positive cooperativity with the FFAR1 ligand γ-linolenic acid (γ-LA. Augmentation of glucose-induced insulin secretion by fasiglifam, γ-LA, or their combination was completely abolished in pancreatic islets of FFAR1-knockout mice. In diabetic rats, the insulinotropic effect of fasiglifam was suppressed by pharmacological reduction of plasma free fatty acid (FFA levels using a lipolysis inhibitor, suggesting that fasiglifam potentiates insulin release in conjunction with plasma FFAs in vivo. Point mutations of FFAR1 differentially affected Ca(2+ influx activities of fasiglifam and γ-LA, further indicating that these agonists may bind to distinct binding sites. Our results strongly suggest that fasiglifam is an ago-allosteric modulator of FFAR1 that exerts its effects by acting cooperatively with endogenous plasma FFAs in human patients as well as diabetic animals. These findings contribute to our understanding of fasiglifam as an attractive antidiabetic drug with a novel mechanism of action.

Nanocomposites of Polyacrylic Acid Nanogels and Biodegradable Polyhydroxybutyrate for Bone Regeneration and Drug Delivery

Directory of Open Access Journals (Sweden)

Mikael Larsson

2014-01-01

Full Text Available Biodegradable cell scaffolds and local drug delivery to stimulate cell response are currently receiving much scientific attention. Here we present a nanocomposite that combines biodegradation with controlled release of lithium, which is known to enhance bone growth. Nanogels of lithium neutralized polyacrylic acid were synthesized by microemulsion-templated polymerization and were incorporated into a biodegradable polyhydroxybutyrate (PHB matrix. Nanogel size was characterized using dynamic light scattering, and the nanocomposites were characterized with regard to structure using scanning electron microscopy, mechanical properties using tensile testing, permeability using tritiated water, and lithium release in PBS using a lithium specific electrode. The nanogels were well dispersed in the composites and the mechanical properties were good, with a decrease in elastic modulus being compensated by increased tolerance to strain in the wet state. Approximately half of the lithium was released over about three hours, with the remaining fraction being trapped in the PHB for subsequent slow release during biodegradation. The prepared nanocomposites seem promising for use as dual functional scaffolds for bone regeneration. Here lithium ions were chosen as model drug, but the nanogels could potentially act as carriers for larger and more complex drugs, possibly while still carrying lithium.

Dual Credit/Dual Enrollment and Data Driven Policy Implementation

Science.gov (United States)

Lichtenberger, Eric; Witt, M. Allison; Blankenberger, Bob; Franklin, Doug

2014-01-01

The use of dual credit has been expanding rapidly. Dual credit is a college course taken by a high school student for which both college and high school credit is given. Previous studies provided limited quantitative evidence that dual credit/dual enrollment is directly connected to positive student outcomes. In this study, predictive statistics…

Identifying HIV-1 dual infections

Directory of Open Access Journals (Sweden)

Cornelissen Marion

2007-09-01

Full Text Available Abstract Transmission of human immunodeficiency virus (HIV is no exception to the phenomenon that a second, productive infection with another strain of the same virus is feasible. Experiments with RNA viruses have suggested that both coinfections (simultaneous infection with two strains of a virus and superinfections (second infection after a specific immune response to the first infecting strain has developed can result in increased fitness of the viral population. Concerns about dual infections with HIV are increasing. First, the frequent detection of superinfections seems to indicate that it will be difficult to develop a prophylactic vaccine. Second, HIV-1 superinfections have been associated with accelerated disease progression, although this is not true for all persons. In fact, superinfections have even been detected in persons controlling their HIV infections without antiretroviral therapy. Third, dual infections can give rise to recombinant viruses, which are increasingly found in the HIV-1 epidemic. Recombinants could have increased fitness over the parental strains, as in vitro models suggest, and could exhibit increased pathogenicity. Multiple drug resistant (MDR strains could recombine to produce a pan-resistant, transmittable virus. We will describe in this review what is presently known about super- and re-infection among ambient viral infections, as well as the first cases of HIV-1 superinfection, including HIV-1 triple infections. The clinical implications, the impact of the immune system, and the effect of anti-retroviral therapy will be covered, as will as the timing of HIV superinfection. The methods used to detect HIV-1 dual infections will be discussed in detail. To increase the likelihood of detecting a dual HIV-1 infection, pre-selection of patients can be done by serotyping, heteroduplex mobility assays (HMA, counting the degenerate base codes in the HIV-1 genotyping sequence, or surveying unexpected increases in the

6-mercaptopurine and daunorubicin double drug liposomes-preparation, drug-drug interaction and characterization.

Science.gov (United States)

Agrawal, Vineet; Paul, Manash K; Mukhopadhyay, Anup K

2005-01-01

This article addresses and investigates the dual incorporation of daunorubicin (DR) and 6-mercaptopurine (6-MP) in liposomes for better chemotherapy. These drugs are potential candidates for interaction due to the quinone (H acceptor) and hydroxyl (H donor) groups on DR and 6-MP, respectively. Interactions between the two drugs in solution were monitored by UV/Vis and fluorescence spectroscopy. Interaction between the two drugs inside the liposomes was evaluated by HPLC (for 6-MP) and by fluorescence spectroscopy (for daunorubicin) after phospholipase-mediated liposome lysis. Our results provide evidence for the lack of interaction between the two drugs in solution and in liposomes. The entrapment efficiencies of 6-MP in the neutral Phosphatidyl choline (PC):Cholesterol (Chol):: 2:1 and anionic PC:Chol:Cardiolipin (CL) :: 4:5:1 single and double drug liposomes were found to be 0.4% and 1.5% (on average), respectively. The entrapment efficiencies of DR in the neutral and anionic double drug liposomes were found to be 55% and 31%, respectively. The corresponding entrapment of daunorubicin in the single drug liposomes was found to be 62% on average. Our thin layer chromatography (TLC) and transmission electron microscopy (TEM) results suggest stability of lipid and liposomes, thus pointing plausible existence of double drug liposomes. Cytotoxicity experiments were performed by using both single drug and double drug liposomes. By comparing the results of phase contrast and fluorescence microscopy, it was observed that the double drug liposomes were internalized in the jurkat and Hut78 (highly resistant cell line) leukemia cells as viewed by the fluorescence of daunorubicin. The cytotoxicity was dose dependent and had shown a synergistic effect when double drug liposome was used.

Brand-name drug, generic drug, orphan drug. Pharmacological therapy with biosimilar drugs – provision of due diligence in the treatment process

Science.gov (United States)

Zajdel, Justyna

2013-01-01

Due diligence in the process of provision of healthcare services refers, among other elements, to the application of pharmacological therapy at a time which offers the greatest chance for a successful outcome of treatment, i.e. for achieving the optimum expected effect understood as an improvement in the patient's health, reduction of health risks or elimination of the disease. However, due diligence may also refer to actions aimed at ensuring that neither the patient nor the healthcare payer is required to incur unreasonable costs in the process of treatment. The validity of that statement stems not only from normative acts but also from ethical standards laid down in the Medical Code of Ethics (Article 57 section 2). It often happens that the provision of optimal treatment calls for deviations from the formal provisions included in Summary Product Characteristics (SPCs), and the application of drugs that are bioequivalent to reference drugs, which translates into a significant reduction of costs. The present study addresses the problem of acceptability of a specific form of drug substitution consisting in the replacement of a reference drug with a generic drug. Also explored are legal aspects associated with the possibility of therapy based on “off-label use”. The study reviews normative acts existing in the Polish and EU legislation. It also provides a clear definition of orphan drug, which has made it possible to make a distinction and investigate mutual relations between the concepts of brand-name (reference) drug, orphan drug and generic drug. PMID:24592133

Combined Neuropeptide S and D-Cycloserine Augmentation Prevents the Return of Fear in Extinction-Impaired Rodents: Advantage of Dual versus Single Drug Approaches.

Science.gov (United States)

Sartori, Simone B; Maurer, Verena; Murphy, Conor; Schmuckermair, Claudia; Muigg, Patrick; Neumann, Inga D; Whittle, Nigel; Singewald, Nicolas

2016-06-01

Despite its success in treating specific anxiety disorders, the effect of exposure therapy is limited by problems with tolerability, treatment resistance, and fear relapse after initial response. The identification of novel drug targets facilitating fear extinction in clinically relevant animal models may guide improved treatment strategies for these disorders in terms of efficacy, acceleration of fear extinction, and return of fear. The extinction-facilitating potential of neuropeptide S, D-cycloserine, and a benzodiazepine was investigated in extinction-impaired high anxiety HAB rats and 129S1/SvImJ mice using a classical cued fear conditioning paradigm followed by extinction training and several extinction test sessions to study fear relapse. Administration of D-cycloserine improved fear extinction in extinction-limited, but not in extinction-deficient, rodents compared with controls. Preextinction neuropeptide S caused attenuated fear responses in extinction-deficient 129S1/SvImJ mice at extinction training onset and further reduced freezing during this session. While the positive effects of either D-cycloserine or neuropeptide S were not persistent in 129S1/SvImJ mice after 10 days, the combination of preextinction neuropeptide S with postextinction D-cycloserine rendered the extinction memory persistent and context independent up to 5 weeks after extinction training. This dual pharmacological adjunct to extinction learning also protected against fear reinstatement in 129S1/SvImJ mice. By using the potentially nonsedative anxiolytic neuropeptide S and the cognitive enhancer D-cycloserine to facilitate deficient fear extinction, we provide here the first evidence of a purported efficacy of a dual over a single drug approach. This approach may render exposure sessions less aversive and more efficacious for patients, leading to enhanced protection from fear relapse in the long term. © The Author 2015. Published by Oxford University Press on behalf of CINP.

Engineering a segmented dual-reservoir polyurethane intravaginal ring for simultaneous prevention of HIV transmission and unwanted pregnancy.

Directory of Open Access Journals (Sweden)

Justin T Clark

Full Text Available The HIV/AIDS pandemic and its impact on women prompt the investigation of prevention strategies to interrupt sexual transmission of HIV. Long-acting drug delivery systems that simultaneously protect womenfrom sexual transmission of HIV and unwanted pregnancy could be important tools in combating the pandemic. We describe the design, in silico, in vitro and in vivo evaluation of a dual-reservoir intravaginal ring that delivers the HIV-1 reverse transcriptase inhibitor tenofovir and the contraceptive levonorgestrel for 90 days. Two polyether urethanes with two different hard segment volume fractions were used to make coaxial extruded reservoir segments with a 100 µm thick rate controlling membrane and a diameter of 5.5 mm that contain 1.3 wt% levonorgestrel. A new mechanistic diffusion model accurately described the levonorgestrel burst release in early time points and pseudo-steady state behavior at later time points. As previously described, tenofovir was formulated as a glycerol paste and filled into a hydrophilic polyurethane, hollow tube reservoir that was melt-sealed by induction welding. These tenofovir-eluting segments and 2 cm long coaxially extruded levonorgestrel eluting segments were joined by induction welding to form rings that released an average of 7.5 mg tenofovir and 21 µg levonorgestrel per day in vitro for 90 days. Levonorgestrel segments placed intravaginally in rabbits resulted in sustained, dose-dependent levels of levonorgestrel in plasma and cervical tissue for 90 days. Polyurethane caps placed between segments successfully prevented diffusion of levonorgestrel into the tenofovir-releasing segment during storage.Hydrated rings endured between 152 N and 354 N tensile load before failure during uniaxial extension testing. In summary, this system represents a significant advance in vaginal drug delivery technology, and is the first in a new class of long-acting multipurpose prevention drug delivery systems.

Ordinance on radioactive drugs or drugs treated with ionizing rays (AMRadV)

International Nuclear Information System (INIS)

1987-01-01

The ordinance relates to the rules governing the marketing permit (approval) for, and prohibition of, radiosterilized and radioactive drugs (section 1 respectively section 2) according to section 7, subsection 1, of the Drugs Act. It applies also to dental filling materials and artificial denture materials. Excluded are finished drugs. (HP) [de

Republic of Croatia's Experiences in the Implementation of the EU Directive About Dual-Use Items

International Nuclear Information System (INIS)

Vidas, Z.; Orehovec, Z.; Superina, V.

2007-01-01

The Republic of Croatia is undergoing a process of adjusting its own legislation to the legislation of EU. It is one of the most important obligations of the EU-Croatia Stabilization and Association Agreement. It is also a basic prerequisite for the practical realization of the modern, unique and integral Export and Import Control system of the Sensitive Items. At the same time, it is a very important step towards better understanding of real and great danger of the weapons of mass destruction (WMD) proliferation and their possible usage in terrorism. That means that Republic of Croatia will act along with EU in the complex activities to prevent and minimize the WMD proliferation, to participate in antiterrorism activities, and to maintain regional and global security. In the year 2004, along the lines of the EU Legislation, the Croatian Parliament adopted the basic legal act - Act on export of Dual-use Items and its accompanying rules and regulations. The existing act on dual-purpose items in Croatia is mostly in harmony with the 2000 and 2003 EU Decrees which regulate te regime of the dual-purpose items export control. Nevertheless, the EU legislation experiences constant amendments in the field. And the Croatian Government is committed to following the improvements of te system and adjusting its own. However, during this process, a series of vague wordings and inconsistencies were noticed in the WMD nonproliferation policy and in the legislation to control the export of high technology products which could be abused for the WMD development. In addition, there is neither regulation on import control system nor control on the export of knowledge through scientific and professional cooperation. The purpose of this article is to professionally elaborate the value wordings and inconsistencies. It can be done on the basis of Croatia's experiences in the export and import control system of the dual-purpose items and knowledge and experience acquired through the

Structure-Activity Relationships of Truncated C2- or C8-Substituted Adenosine Derivatives as Dual Acting A2A and A3 Adenosine Receptor Ligands

Science.gov (United States)

Hou, Xiyan; Majik, Mahesh S.; Kim, Kyunglim; Pyee, Yuna; Lee, Yoonji; Alexander, Varughese; Chung, Hwa-Jin; Lee, Hyuk Woo; Chandra, Girish; Lee, Jin Hee; Park, Seul-gi; Choi, Won Jun; Kim, Hea Ok; Phan, Khai; Gao, Zhan-Guo; Jacobson, Kenneth A.; Choi, Sun; Lee, Sang Kook; Jeong, Lak Shin

2011-01-01

Truncated N6-substituted-4′-oxo- and 4′-thioadenosine derivatives with C2 or C8 substitution were studied as dual acting A2A and A3 adenosine receptor (AR) ligands. The lithiation-mediated stannyl transfer and palladium-catalyzed cross coupling reactions were utilized for functionalization of the C2 position of 6-chloropurine nucleosides. An unsubstituted 6-amino group and a hydrophobic C2 substituent were required for high affinity at the hA2AAR, but hydrophobic C8 substitution abolished binding at the hA2AAR. However, most of synthesized compounds displayed medium to high binding affinity at the hA3AR, regardless of C2 or C8 substitution, and low efficacy in a functional cAMP assay. Several compounds tended to be full hA2AAR agonists. C2 substitution probed geometrically through hA2AAR-docking, was important for binding in order of hexynyl > hexenyl > hexanyl. Compound 4g was the most potent ligand acting dually as hA2AAR agonist and hA3AR antagonist, which might be useful for treatment of asthma or other inflammatory diseases. PMID:22142423

Microcontroller Based Proportional Derivative Plus Conditional Integral Controller for Electro-Mechanical Dual Acting Pulley Continuously Variable Transmission Ratio Control

International Nuclear Information System (INIS)

Budianto, A; Tawi, K B; Hussein, M; Supriyo, B; Kob, M S Che; Zulkifli, Mohd Ezlamy; Khairuldean A K; Daraoh, Aishah; Ariyono, S

2012-01-01

Electro-Mechanical Dual Acting Pulley (EMDAP) Continuously Variable Transmission (CVT) is a transmission utilized by electro-mechanical actuated system. It has a potential to reduce energy consumption because it only needs power during changing CVT ratio and no power is needed to maintain CVT ratio due to self lock mechanism design. This paper proposed simple proportional derivative plus conditional integral (PDCI) controller to control EMDAP CVT ratio which can be simply implemented on a microcontroller. This proposed controller used Astrom-Hagglund method and Ziegler-Nichols formula to tune PDCI gain. The Proportional Derivative controller is directly activated from the start but Integral controller is only activated when the error value reaches error value setting point. Simulation using Matlab/Simulink software was conducted to evaluate PDCI system performance. The simulation results showed PDCI controller has ability to perform maximum overshoot 0.1%, 0.001 steady state error and 0.5s settling time. For clamping condition, settling time is about 11.46s during changing ratio from 2.0 to 0.7, while for release condition, settling time is about 8.33s during changing ratio from 0.7 to 2.0.

Assessment of the abuse liability of a dual orexin receptor antagonist: a crossover study of almorexant and zolpidem in recreational drug users.

Science.gov (United States)

Cruz, Hans G; Hoever, Petra; Chakraborty, Bijan; Schoedel, Kerri; Sellers, Edward M; Dingemanse, Jasper

2014-04-01

Dual orexin receptor antagonists (DORAs) enable initiation and maintenance of sleep in patients with primary insomnia. Blockade of the orexin system has shown reduction of drug-seeking behavior in animal studies, supporting the role of orexin antagonism as a novel approach for treating substance abuse. Since hypnotics are traditionally associated with misuse, a lack of abuse liability of DORAs would offer significant benefits over current therapies for sleep disorders. In this randomized, crossover, proof-of-concept study, single oral doses of the DORA almorexant (200, 400, and 1,000 mg) were administered to healthy subjects with previous non-therapeutic experience with central nervous system depressants and were compared with placebo and single oral doses of zolpidem (20 and 40 mg), a benzodiazepine-like drug. Subjective measures of abuse potential (visual analog scales [VAS], Addiction Research Center Inventory, and Subjective Drug Value) and objective measures (divided attention [DA]) were evaluated over 24 h post-dose in 33 evaluable subjects. Drug Liking VAS peak effect (E max; primary endpoint) was significantly higher for all doses of almorexant and zolpidem compared with placebo (p<0.001). Almorexant 200 mg showed significantly less 'Drug Liking' than both zolpidem doses (p<0.01), and almorexant 400 mg had smaller effects than zolpidem 20 mg (p<0.05), while almorexant 1,000 mg was not different from either zolpidem dose. Results were similar for other subjective measures, although almorexant generally showed smaller negative and perceptual effects compared with zolpidem. Almorexant also showed less cognitive impairment compared with zolpidem on most DA endpoints. This study in humans investigating single doses of almorexant is the first to explore and show abuse liability of a DORA, a class of compounds that is not only promising for the treatment of sleep disorders, but also of addiction.

N-cinnamoylated chloroquine analogues as dual-stage antimalarial leads.

Science.gov (United States)

Pérez, Bianca C; Teixeira, Cátia; Albuquerque, Inês S; Gut, Jiri; Rosenthal, Philip J; Gomes, José R B; Prudêncio, Miguel; Gomes, Paula

2013-01-24

The control of malaria is challenged by drug resistance, and new antimalarial drugs are needed. New drug discovery efforts include consideration of hybrid compounds as potential multitarget antimalarials. Previous work from our group has demonstrated that hybrid structures resulting from cinnamic acid conjugation with heterocyclic moieties from well-known antimalarials present improved antimalarial activity. Now, we report the synthesis and SAR analysis of an expanded series of cinnamic acid derivatives displaying remarkably high activities against both blood- and liver-stage malaria parasites. Two compounds judged most promising, based on their in vitro activity and druglikeness according to the Lipinski rules and Veber filter, were active in vivo against blood-stage rodent malaria parasites. Therefore, the compounds reported represent a new entry as promising dual-stage antimalarial leads.

Dual drug loaded superparamagnetic iron oxide nanoparticles for targeted cancer therapy.

Science.gov (United States)

Dilnawaz, Fahima; Singh, Abhalaxmi; Mohanty, Chandana; Sahoo, Sanjeeb K

2010-05-01

The primary inadequacy of chemotherapeutic drugs is their relative non-specificity and potential side effects to the healthy tissues. To overcome this, drug loaded multifunctional magnetic nanoparticles are conceptualized. We report here an aqueous based formulation of glycerol monooleate coated magnetic nanoparticles (GMO-MNPs) devoid of any surfactant capable of carrying high payload hydrophobic anticancer drugs. The biocompatibility was confirmed by tumor necrosis factor alpha assay, confocal microscopy. High entrapment efficiency approximately 95% and sustained release of encapsulated drugs for more than two weeks under in vitro conditions was achieved for different anticancer drugs (paclitaxel, rapamycin, alone or combination). Drug loaded GMO-MNPs did not affect the magnetization properties of the iron oxide core as confirmed by magnetization study. Additionally the MNPs were functionalized with carboxylic groups by coating with DMSA (Dimercaptosuccinic acid) for the supplementary conjugation of amines. For targeted therapy, HER2 antibody was conjugated to GMO-MNPs and showed enhanced uptake in human breast carcinoma cell line (MCF-7). The IC(50) doses revealed potential antiproliferative effect in MCF-7. Therefore, antibody conjugated GMO-MNPs could be used as potential drug carrier for the active therapeutic aspects in cancer therapy. Copyright 2010 Elsevier Ltd. All rights reserved.

Drugs acting on amino acid neurotransmitters.

Science.gov (United States)

Meldrum, B S

1986-01-01

The most potent agents currently available for suppressing myoclonic activity in animals and humans act to enhance GABA-mediated inhibition and/or to diminish amino acid-induced excitation. Postsynaptic GABA-mediated inhibition plays an important role at the cortical level, diminishing the effect of augmented afferent activity and preventing pathologically enhanced output. Enhancement of GABAergic inhibition, principally at the cortical level but also at lower levels, by clonazepam and by valproate appears to be a predominant element in their antimyoclonic action. Studies in various animal models, including photically induced myoclonus in the baboon, P papio, indicate the value of other approaches to enhancing GABA-mediated inhibition. Among such approaches meriting evaluation in humans are inhibition of GABA-transaminase activity by gamma-vinyl GABA and action at some of the benzodiazepine receptors to enhance the action of GABA, as by the novel anticonvulsant beta-carbolines. Excitatory transmission mediated by dicarboxylic amino acids appears to play a role in myoclonus, especially at the spinal level, but also in the brainstem, cerebellum, basal ganglia, and cortex. Among various novel agents that act at the postsynaptic receptor site to antagonize such excitation, those specifically blocking excitation induced by aspartate and/or NMDA prevent myoclonic activity in a wide range of animal models. Further research is required before such agents can be evaluated in humans.

Dual delivery systems based on polyamine analog BENSpm as prodrug and gene delivery vectors

Science.gov (United States)

Zhu, Yu

Combination drug and gene therapy shows promise in cancer treatment. However, the success of such strategy requires careful selection of the therapeutic agents, as well as development of efficient delivery vectors. BENSpm (N 1, N11-bisethylnorspermine), a polyamine analogue targeting the intracellular polyamine pathway, draws our special attention because of the following reasons: (1) polyamine pathway is frequently dysregulated in cancer; (2) BENSpm exhibits multiple functions to interfere with the polyamine pathway, such as to up-regulate polyamine metabolism enzymes and down-regulate polyamine biosynthesis enzymes. Therefore BENSpm depletes all natural polyamines and leads to apoptosis and cell growth inhibition in a wide range of cancers; (3) preclinical studies proved that BENSpm can act synergistically with various chemotherapy agents, making it a promising candidate in combination therapy; (4) multiple positive charges in BENSpm enable it as a suitable building block for cationic polymers, which can be further applied to gene delivery. In this dissertation, our goal was to design dual-function delivery vector based on BENSpm that can function as a gene delivery vector and, after intracellular degradation, as an active anticancer agent targeting dysregulated polyamine metabolism. We first demonstrated strong synergism between BENSpm and a potential therapeutic gene product TRAIL. Strong synergism was obtained in both estrogen-dependent MCF-7 breast cancer cells and triple-negative MDA-MB-231 breast cancer cells. Significant dose reduction of TRAIL in combination with BENSpm in MDA-MB-231 cells, together with the fact that BENSpm rendered MCF-7 cells more sensitive to TRAIL treatment verified our rationale of designing BENSpm-based delivery platform. This was expected to be beneficial for overcoming drug resistance in chemotherapy, as well as boosting the therapeutic effect of therapeutic genes. We first designed a lipid-based BENSpm dual vector (Lipo

Using long-acting beta2-agonists safely: What will be the impact of the US Food and Drug Administration's panel recommendations?

Science.gov (United States)

Smart, Brian A

2009-01-01

The US Food and Drug Administration (FDA) has launched an investigation into the safety of long-acting beta(2)-agonists (LABAs). While the impact of this investigation is yet to be seen, clinicians should be circumspect in the use of these agents and prescribe them according to the recommendations of current asthma guidelines, informing patients and their caretakers about potential risks. As clinical trials attempt to address the question of whether LABAs are safe for use in pediatric and adult populations, current data provide no clear answers. A special hearing of the FDA's Pulmonary-Allergy Drugs Advisory Committee, Drug Safety and Risk Management Advisory Committee, and Pediatric Advisory Committee attempted to seek consensus on the matter as it reviewed the results of controlled clinical trials and conducted a benefit:risk assessment of LABAs to make recommendations on their safety.

Caring for clients with dual diagnosis in rural communities in Australia: the experience of mental health professionals.

Science.gov (United States)

Deans, C; Soar, R

2005-06-01

This paper identifies and describes the experiences of 13 rural mental health professionals who care for clients diagnosed with a mental illness and a coexisting alcohol and other drug disorder (dual diagnosis). Dual diagnosis is a common problem which is often poorly understood and managed by mental health professionals. The effect of excessive substance use on a person's mental well-being can present as a diagnostic challenge as each condition may mask symptoms of the other. The authors utilized a phenomenological approach to discover the experiences of a group of mental health professionals working in rural communities in Victoria, Australia. Caring for clients diagnosed with dual diagnosis was found to be a complex and stressful role that involved high levels of skill and knowledge. Despite the fact that health professionals in rural areas are expected to deliver the most appropriate care to individuals with a dual diagnosis, a number of these rural health professionals have limited preparation and experience in dealing with arising clinical diagnosis issues. Clinicians experience frustration, resentment and powerlessness in their attempt to understand their clients' drug misuse whilst simultaneously endeavouring to provide a quality mental health service.

One-step shell polymerization of inorganic nanoparticles and their applications in SERS/nonlinear optical imaging, drug delivery, and catalysis.

Science.gov (United States)

Liu, Tzu-Ming; Yu, Jiashing; Chang, C Allen; Chiou, Arthur; Chiang, Huihua Kenny; Chuang, Yu-Chun; Wu, Cheng-Han; Hsu, Che-Hao; Chen, Po-An; Huang, Chih-Chia

2014-07-07

Surface functionalized nanoparticles have found their applications in several fields including biophotonics, nanobiomedicine, biosensing, drug delivery, and catalysis. Quite often, the nanoparticle surfaces must be post-coated with organic or inorganic layers during the synthesis before use. This work reports a generally one-pot synthesis method for the preparation of various inorganic-organic core-shell nanostructures (Au@polymer, Ag@polymer, Cu@polymer, Fe3O4@polymer, and TiO2@polymer), which led to new optical, magnetic, and catalytic applications. This green synthesis involved reacting inorganic precursors and poly(styrene-alt-maleic acid). The polystyrene blocks separated from the external aqueous environment acting as a hydrophobic depot for aromatic drugs and thus illustrated the integration of functional nanoobjects for drug delivery. Among these nanocomposites, the Au@polymer nanoparticles with good biocompatibility exhibited shell-dependent signal enhancement in the surface plasmon resonance shift, nonlinear fluorescence, and surface-enhanced Raman scattering properties. These unique optical properties were used for dual-modality imaging on the delivery of the aromatic photosensitizer for photodynamic therapy to HeLa cells.

Carboxymethyl cellulose (CMC)-loaded Co-Cu doped manganese ferrite nanorods as a new dual-modal simultaneous contrast agent for magnetic resonance imaging and nanocarrier for drug delivery system

Science.gov (United States)

Abbasi Pour, Sajjad; Shaterian, Hamid Reza; Afradi, Mojgan; Yazdani-Elah-Abadi, Afshin

2017-09-01

We synthesized Co0.25Cu0.25Mn0.5Fe2O4@CMC (CCMFe2O4@CMC) nanorods as a new dual-modal simultaneous for magnetic resonance imaging contrast agent and nanocarrier for drug delivery system. Impact of CCMFe2O4@CMC nanorods were investigated on the longitudinal (T1), transverse (T2) and transverse (T2∗) relaxation times for in vitro MRI contrast agent in water and also for drug delivery system, L-dopa was coated on CCMFe2O4@CMC nanorods and then in vitro drug release test was carried out at three PHs values and different temperatures. In vitro MR imaging demonstrated that r2 value of CCMFe2O4@CMC nanorods is 138.33 mM-1 s-1, CCMFe2O4@CMC is useful as T2 contrast agent relative to other T2 contrast agants. In vitro drug release test shows the amount of released L-dopa from CCMFe2O4@CMC nanorods at medium with pH = 1.2 is more than pH = 5.3 and 7.4.

Patterns of drug dependence in a Queensland (Australia) sample of Indigenous and non-Indigenous people who inject drugs.

Science.gov (United States)

Smirnov, Andrew; Kemp, Robert; Ward, James; Henderson, Suzanna; Williams, Sidney; Dev, Abhilash; Najman, Jake M

2016-09-01

Despite over-representation of Indigenous Australians in sentinel studies of injecting drug use, little is known about relevant patterns of drug use and dependence. This study compares drug dependence and possible contributing factors in Indigenous and non-Indigenous Australians who inject drugs. Respondent-driven sampling was used in major cities and 'peer recruitment' in regional towns of Queensland to obtain a community sample of Indigenous (n = 282) and non-Indigenous (n = 267) injectors. Data are cross sectional. Multinomial models were developed for each group to examine types of dependence on injected drugs (no dependence, methamphetamine-dependent only, opioid-dependent only, dependent on methamphetamine and opioids). Around one-fifth of Indigenous and non-Indigenous injectors were dependent on both methamphetamine and opioids in the previous 12 months. Psychological distress was associated with dual dependence on these drugs for Indigenous [adjusted relative risk (ARR) 4.86, 95% confidence interval (CI) 2.08-11.34] and non-Indigenous (ARR 4.14, 95% CI 1.59-10.78) participants. Unemployment (ARR 8.98, 95% CI 2.25-35.82) and repeated (> once) incarceration as an adult (ARR 3.78, 95% CI 1.43-9.97) were associated with dual dependence for Indigenous participants only. Indigenous participants had high rates of alcohol dependence, except for those dependent on opioids only. The drug dependence patterns of Indigenous and non-Indigenous people who inject drugs were similar, including the proportions dependent on both methamphetamine and opioids. However, for Indigenous injectors, there was a stronger association between drug dependence and contextual factors such as unemployment and incarceration. Expansion of treatment options and community-level programs may be required. [Smirnov A, Kemp R, Ward J, Henderson S, Williams S, Dev A, Najman J M. Patterns of drug dependence in a Queensland (Australia) sample of Indigenous and non-Indigenous people who

Drug metabolism in human brain: high levels of cytochrome P4503A43 in brain and metabolism of anti-anxiety drug alprazolam to its active metabolite.

Directory of Open Access Journals (Sweden)

Varsha Agarwal

2008-06-01

Full Text Available Cytochrome P450 (P450 is a super-family of drug metabolizing enzymes. P450 enzymes have dual function; they can metabolize drugs to pharmacologically inactive metabolites facilitating their excretion or biotransform them to pharmacologically active metabolites which may have longer half-life than the parent drug. The variable pharmacological response to psychoactive drugs typically seen in population groups is often not accountable by considering dissimilarities in hepatic metabolism. Metabolism in brain specific nuclei may play a role in pharmacological modulation of drugs acting on the CNS and help explain some of the diverse response to these drugs seen in patient population. P450 enzymes are also present in brain where drug metabolism can take place and modify therapeutic action of drugs at the site of action. We have earlier demonstrated an intrinsic difference in the biotransformation of alprazolam (ALP in brain and liver, relatively more alpha-hydroxy alprazolam (alpha-OHALP is formed in brain as compared to liver. In the present study we show that recombinant CYP3A43 metabolizes ALP to both alpha-OHALP and 4-hydroxy alprazolam (4-OHALP while CYP3A4 metabolizes ALP predominantly to its inactive metabolite, 4-OHALP. The expression of CYP3A43 mRNA in human brain samples correlates with formation of relatively higher levels of alpha-OH ALP indicating that individuals who express higher levels of CYP3A43 in the brain would generate larger amounts of alpha-OHALP. Further, the expression of CYP3A43 was relatively higher in brain as compared to liver across different ethnic populations. Since CYP3A enzymes play a prominent role in the metabolism of drugs, the higher expression of CYP3A43 would generate metabolite profile of drugs differentially in human brain and thus impact the pharmacodynamics of psychoactive drugs at the site of action.

[Impact Reimbursement Act on the pharmaceutical market in Poland].

Science.gov (United States)

Giermaziak, Wojciech

2014-04-01

According to 12 may 2011 Reimbursement Act, the new regulations were introduced related to changes in so far in force rules on refunds of official prices and margins for drugs, foodstuffs of special purpose and medical products. After year of functioning of this regulation, in evaluation of the government, law gave measurable financial effects for public payer, sometimes through drastic actions, connected the of reduction of existing profits of manufacturers sector and importers drugs, as well wholesale and retail, both in treatment open and closed. Parallel to research and analysis of effects introduction in life act refund, conducted by government, to target current regulation possible negative phenomena can to be after-effects to regulation, systematically there are conducted analogous study to reputable companies specialized in evaluation and updating market Polish pharmaceutical, such as IMS Health Polska, Pharma Expert, Kamsoft, WHO and European a law firm. In their opinion to reimbursement act is the most serious regulation control system to introduced into Polish order legal, and first time for many years on such a large scale. Thoroughly changed policy of drugs State have important influence for all participants Polish pharmaceutical market, both those directly related to the drug trade, as the functioning doctors and health condition and financial Polish patient. Change in the way prices of drugs is determined as flexible to price formation mechanism, combining drugs similar profile pharmacological in so group limits and dependence of the level of refunds from application drug accordingly characteristics medicinal product, adaptation solutions to new law refund to the existing law about health services, gave measurable financial effect for the public payer. Rationalization expenses to NFZ, as main premise introduction refund act, created to broader than so far possibility to use new molecules of drugs, and the latest medical technology, even if in the

NRC drug-free workplace plan. Revision 1

Energy Technology Data Exchange (ETDEWEB)

NONE

1997-11-01

On September 15, 1986, President Reagan signed Executive Order 12564, establishing the goal of a Drug-Free Federal Workplace. The Order made it a condition of employment that all Federal employees refrain from using illegal drugs on or off duty. On July 11, 1987, Congress passed legislation affecting implementation of the Executive Order under Section 503 of the Supplemental Appropriations Act of 1987, Public Law 100-71 (the Act). The Nuclear Regulatory Commission first issued the NRC Drug Testing Plan to set forth objectives, policies, procedures, and implementation guidelines to achieve a drug-free Federal workplace, consistent with the Executive Order and Section 503 of the Act. Revision 1, titled, ``NRC Drug-Free Workplace Plan,`` supersedes the previous version and its supplements and incorporates changes to reflect current guidance from the Department of Justice, the Department of Health and Human Services, as well as other guidance.

NRC drug-free workplace plan. Revision 1

International Nuclear Information System (INIS)

1997-11-01

On September 15, 1986, President Reagan signed Executive Order 12564, establishing the goal of a Drug-Free Federal Workplace. The Order made it a condition of employment that all Federal employees refrain from using illegal drugs on or off duty. On July 11, 1987, Congress passed legislation affecting implementation of the Executive Order under Section 503 of the Supplemental Appropriations Act of 1987, Public Law 100-71 (the Act). The Nuclear Regulatory Commission first issued the NRC Drug Testing Plan to set forth objectives, policies, procedures, and implementation guidelines to achieve a drug-free Federal workplace, consistent with the Executive Order and Section 503 of the Act. Revision 1, titled, ''NRC Drug-Free Workplace Plan,'' supersedes the previous version and its supplements and incorporates changes to reflect current guidance from the Department of Justice, the Department of Health and Human Services, as well as other guidance

Potential beneficial effects of sacubitril-valsartan in renal disease: a new field for a new drug.

Science.gov (United States)

Gervasini, Guillermo; Robles, Nicolas Roberto

2017-05-01

Patients with renal dysfunction are at a higher risk of cardiovascular disease (CVD), which often shares manifestations with heart failure (HF). Last year, the FDA approved the use of sacubitril-valsartan in patients with HF. This dual-acting agent enhances the functions of natriuretic peptides and inhibits the renin-angiotensin system. Areas covered: This review summarizes the existing preclinical and clinical studies carried out with sacubitril-valsartan (and other drugs with similar pharmacological mechanisms) in HF and hypertensive patients. We put the focus on the renal data provided by these studies. Data were obtained from English peer-reviewed articles on PubMed and clinical trials registered in ClinicalTrials.gov. Expert opinion: Overall, sacubitril-valsartan might be a promising therapeutic approach in patients with renal dysfunction. Renal conditions with marked CV risk, such as arterionephrosclerosis, could constitute a particular setting where to evaluate the impact of the drug. Nevertheless, large, randomized trials are needed to confirm the beneficial effects and safety profile of the drug in renal patients, as well as to elucidate some concerns observed in HF trials, such as the slight increase in proteinuria.

Obesity and Pediatric Drug Development.

Science.gov (United States)

Vaughns, Janelle D; Conklin, Laurie S; Long, Ying; Zheng, Panli; Faruque, Fahim; Green, Dionna J; van den Anker, John N; Burckart, Gilbert J

2018-05-01

There is a lack of dosing guidelines for use in obese children. Moreover, the impact of obesity on drug safety and clinical outcomes is poorly defined. The paucity of information needed for the safe and effective use of drugs in obese patients remains a problem, even after drug approval. To assess the current incorporation of obesity as a covariate in pediatric drug development, the pediatric medical and clinical pharmacology reviews under the Food and Drug Administration (FDA) Amendments Act of 2007 and the FDA Safety and Innovation Act (FDASIA) of 2012 were reviewed for obesity studies. FDA labels were also reviewed for statements addressing obesity in pediatric patients. Forty-five drugs studied in pediatric patients under the FDA Amendments Act were found to have statements and key words in the medical and clinical pharmacology reviews and labels related to obesity. Forty-four products were identified similarly with pediatric studies under FDASIA. Of the 89 product labels identified, none provided dosing information related to obesity. The effect of body mass index on drug pharmacokinetics was mentioned in only 4 labels. We conclude that there is little information presently available to provide guidance related to dosing in obese pediatric patients. Moving forward, regulators, clinicians, and the pharmaceutical industry should consider situations in drug development in which the inclusion of obese patients in pediatric trials is necessary to facilitate the safe and effective use of new drug products in the obese pediatric population. © 2018, The American College of Clinical Pharmacology.

Conjugated and Entrapped HPMA-PLA Nano-Polymeric Micelles Based Dual Delivery of First Line Anti TB Drugs: Improved and Safe Drug Delivery against Sensitive and Resistant Mycobacterium Tuberculosis.

Science.gov (United States)

Upadhyay, Seema; Khan, Iliyas; Gothwal, Avinash; Pachouri, Praveen K; Bhaskar, N; Gupta, Umesh D; Chauhan, Devendra S; Gupta, Umesh

2017-09-01

First line antiTB drugs have several physical and toxic manifestations which limit their applications. RIF is a hydrophobic drug and has low water solubility and INH is hepatotoxic. The main objective of the study was to synthesize, characterize HPMA-PLA co-polymeric micelles for the effective dual delivery of INH and RIF. HPMA-PLA co-polymer and HPMA-PLA-INH (HPI) conjugates were synthesized and characterized by FT-IR and 1 H-NMR spectroscopy. Later on RIF loaded HPMA-PLA-INH co-polymeric micelles (PMRI) were formulated and characterized for size, zeta potential and surface morphology (SEM, TEM) as well as critical micellar concentration. The safety was assessed through RBC's interaction study. The prepared PMRI were evaluated through MABA assay against sensitive and resistant strains of M. Tuberculosis. Size, zeta and entrapment efficiency for RIF loaded HPMA-PLA-INH polymeric micelles (PMRI) was 87.64 ± 1.98 nm, -19 ± 1.93 mV and 97.2 ± 1.56%, respectively. In vitro release followed controlled and sustained delivery pattern. Sustained release was also supported by release kinetics. Haemolytic toxicity of HPI and PMRI was 8.57 and 7.05% (p PLA polymeric micelles (PMRI) were more effective against sensitive and resistant M tuberculosis. The developed approach can lead to improved patient compliance and reduced dosing in future, offering improved treatment of tuberculosis.

Neurocircuitry of drug reward

Science.gov (United States)

Ikemoto, Satoshi; Bonci, Antonello

2013-01-01

In recent years, neuroscientists have produced profound conceptual and mechanistic advances on the neurocircuitry of reward and substance use disorders. Here, we will provide a brief review of intracranial drug self-administration and optogenetic self-stimulation studies that identified brain regions and neurotransmitter systems involved in drug- and reward-related behaviors. Also discussed is a theoretical framework that helps to understand the functional properties of the circuitry involved in these behaviors. The circuitry appears to be homeostatically regulated and mediate anticipatory processes that regulate behavioral interaction with the environment in response to salient stimuli. That is, abused drugs or, at least, some may act on basic motivation and mood processes, regulating behavior-environment interaction. Optogenetics and related technologies have begun to uncover detailed circuit mechanisms linking key brain regions in which abused drugs act for rewarding effects. PMID:23664810

Associations Between Medicare Part D and Out-of-Pocket Spending, HIV Viral Load, Adherence, and ADAP Use in Dual Eligibles With HIV.

Science.gov (United States)

Belenky, Nadya; Pence, Brian W; Cole, Stephen R; Dusetzina, Stacie B; Edmonds, Andrew; Oberlander, Jonathan; Plankey, Michael W; Adedimeji, Adebola; Wilson, Tracey E; Cohen, Jennifer; Cohen, Mardge H; Milam, Joel E; Golub, Elizabeth T; Adimora, Adaora A

2018-01-01

The implementation of Medicare part D on January 1, 2006 required all adults who were dually enrolled in Medicaid and Medicare (dual eligibles) to transition prescription drug coverage from Medicaid to Medicare part D. Changes in payment systems and utilization management along with the loss of Medicaid protections had the potential to disrupt medication access, with uncertain consequences for dual eligibles with human immunodeficiency virus (HIV) who rely on consistent prescription coverage to suppress their HIV viral load (VL). To estimate the effect of Medicare part D on self-reported out-of-pocket prescription drug spending, AIDS Drug Assistance Program (ADAP) use, antiretroviral adherence, and HIV VL suppression among dual eligibles with HIV. Using 2003-2008 data from the Women's Interagency HIV Study, we created a propensity score-matched cohort and used a difference-in-differences approach to compare dual eligibles' outcomes pre-Medicare and post-Medicare part D to those enrolled in Medicaid alone. Transition to Medicare part D was associated with a sharp increase in the proportion of dual eligibles with self-reported out-of-pocket prescription drug costs, followed by an increase in ADAP use. Despite the increase in out-of-pocket costs, both adherence and HIV VL suppression remained stable. Medicare part D was associated with increased out-of-pocket spending, although the increased spending did not seem to compromise antiretroviral therapy adherence or HIV VL suppression. It is possible that increased ADAP use mitigated the increase in out-of-pocket spending, suggesting successful coordination between Medicare part D and ADAP as well as the vital role of ADAP during insurance transitions.

A Dual-Sensing Receptor Confers Robust Cellular Homeostasis

Directory of Open Access Journals (Sweden)

Hannah Schramke

2016-06-01

Full Text Available Cells have evolved diverse mechanisms that maintain intracellular homeostasis in fluctuating environments. In bacteria, control is often exerted by bifunctional receptors acting as both kinase and phosphatase to regulate gene expression, a design known to provide robustness against noise. Yet how such antagonistic enzymatic activities are balanced as a function of environmental change remains poorly understood. We find that the bifunctional receptor that regulates K+ uptake in Escherichia coli is a dual sensor, which modulates its autokinase and phosphatase activities in response to both extracellular and intracellular K+ concentration. Using mathematical modeling, we show that dual sensing is a superior strategy for ensuring homeostasis when both the supply of and demand for a limiting resource fluctuate. By engineering standards, this molecular control system displays a strikingly high degree of functional integration, providing a reference for the vast numbers of receptors for which the sensing strategy remains elusive.

Label-free biosensing with high sensitivity in dual-core microstructured polymer optical fibers

DEFF Research Database (Denmark)

Markos, Christos; Yuan, Wu; Vlachos, Kyriakos

2011-01-01

We present experimentally feasible designs of a dual-core microstructured polymer optical fiber (mPOF), which can act as a highly sensitive, label-free, and selective biosensor. An immobilized antigen sensing layer on the walls of the holes in the mPOF provides the ability to selectively capture...

75 FR 59105 - Procedures for Transportation Workplace Drug and Alcohol Testing Programs: Federal Drug Testing...

Science.gov (United States)

2010-09-27

... 2105-AE03 Procedures for Transportation Workplace Drug and Alcohol Testing Programs: Federal Drug... the Federal workplace drug testing program but also pointed out that ``* * * the Department of.... Executive Order 12866 and Regulatory Flexibility Act This Interim Final Rule is not significant for purposes...

Synthesis of Polymer-Lipid Nanoparticles for Image-Guided Delivery of Dual Modality Therapy

NARCIS (Netherlands)

Mieszawska, Aneta J.; Kim, Yongtae; Gianella, Anita; van Rooy, Inge; Priem, Bram; Labarre, Matthew P.; Ozcan, Canturk; Cormode, David P.; Petrov, Artiom; Langer, Robert; Farokhzad, Omid C.; Fayad, Zahi A.; Mulder, Willem J. M.

2013-01-01

For advanced treatment of diseases such as cancer, multicomponent, multifunctional nanoparticles hold great promise. In the current study we report the synthesis of a complex nanoparticle (NP) system with dual drug loading as well as diagnostic properties. To that aim we present a methodology where

Rates of inappropriate antiretroviral prescription among injection drug users

Directory of Open Access Journals (Sweden)

Bonner Simon

2007-01-01

Full Text Available Abstract Background Although the survival benefits of antiretroviral therapy (ART for the treatment of HIV infection are well established, the clinical management of HIV disease continues to present major challenges. There are particular concerns regarding access to appropriate HIV treatment among HIV-infected injection drug users (IDU. Methods In a prospective cohort study of HIV-infected IDU in Vancouver, Canada, we examined initial ART regimens vis-à-vis the provincial government's therapeutic guidelines at the time ART was initiated. Briefly, there have been four sets of guidelines: Era 1 (1992 to November 1995; double-drug (dual NRTIs ART for patients with a CD4 cell count of 350 or less; Era 2 (December 1995 to May 1996; double-drug therapy for patients with a CD4+ cell count of 500 or less; Era 3 (June 1996 to June 1997; triple-drug therapy (dual NRTIs with a PI or NNRTI for patients who had a plasma viral load of > 100,000 HIV-1 RNA copies/mL; dual therapy with two NRTIs for those with a plasma viral load of 5,000 to 100,000 HIV-1 RNA copies/mL; Era 4 (since July 1997; universal use of triple drug therapy as first-line treatment. Results Between May 1996 and May 2003, 431 HIV-infected individuals were enrolled into the cohort. By May 31, 2003, 291 (67.5% individuals had initiated ART. We noted instances of inappropriate antiretroviral prescription in each guideline era, with 9 (53% in Era 1, 3 (12% in Era 2, 22 (28% in Era 3, and 23 (15% in Era 4. Of the 57 subjects who received an inappropriate ART regimen initially, 14 never received the appropriate therapy; among the remaining 43, the median time to the initiation of a guideline-appropriate ART regimen was 12 months (inter-quartile range 5 – 20. Conclusion The present study identified measurable rates of guideline-inappropriate ART prescription for patients who were injection drug users. Rates were highest in the era of dual therapy, although high rates persisted into the triple

Polymer-free Drug-Coated Coronary Stents in Patients at High Bleeding Risk

DEFF Research Database (Denmark)

Urban, Philip; Meredith, Ian T; Abizaid, Alexandre

2015-01-01

BACKGROUND: Patients at high risk for bleeding who undergo percutaneous coronary intervention (PCI) often receive bare-metal stents followed by 1 month of dual antiplatelet therapy. We studied a polymer-free and carrier-free drug-coated stent that transfers umirolimus (also known as biolimus A9......), a highly lipophilic sirolimus analogue, into the vessel wall over a period of 1 month. METHODS: In a randomized, double-blind trial, we compared the drug-coated stent with a very similar bare-metal stent in patients with a high risk of bleeding who underwent PCI. All patients received 1 month of dual...... ratio, 0.50; 95% CI, 0.37 to 0.69; Pbleeding who underwent PCI, a polymer-free umirolimus-coated stent was superior to a bare-metal stent with respect to the primary safety and efficacy end points when used with a 1-month course of dual antiplatelet...

76 FR 53050 - New Animal Drugs; Ampicillin Trihydrate, Bacitracin Methylene Disalicylate, Flunixin...

Science.gov (United States)

2011-08-25

... with the Federal Food, Drug, and Cosmetic Act (the FD&C Act) and to improve the accuracy and... in 21 CFR Parts 520 and 522 Animal drugs. Therefore, under the Federal Food, Drug, and Cosmetic Act...) * * * (c) [Reserved] (d) Conditions of use--(1) Dogs--(i) Amount. Administer 2 to 40 mg (up to 120 mg in...

Professionals’ perception on the management of patients with dual disorders

Science.gov (United States)

Roncero, Carlos; Szerman, Néstor; Terán, Antonio; Pino, Carlos; Vázquez, José María; Velasco, Elena; García-Dorado, Marta; Casas, Miguel

2016-01-01

Background There is a need to evaluate the professionals’ perception about the consequences of the lack of therapeutic adherence in the evolution of patients with co-occurring disorders. Methods An online survey, released on the Socidrogalcohol [Spanish Scientific Society for Research on Alcohol, Alcoholism and other Drug Addictions] and Sociedad Española de Patología Dual [the Spanish Society of Dual Pathology] web pages, was answered by 250 professionals who work in different types of Spanish health centers where dual diagnosis patients are assisted. Results Most professionals perceived the existence of noncompliance among dual diagnosis patients. Almost all of these professionals (99%) perceived that noncompliance leads to a worsening of the progression of the patient’s disorder, in both the exacerbation of mental disorders and the consumption of addictive substances. Most of the professionals (69.2%) considered therapeutic alliance as the main aspect to take into account to improve the prognosis in this population. The primary purpose of treatment must be the improvement of psychotic-phase positive symptoms, followed by the control of behavior disorders, reduction of craving, improvement of social and personal performances, and reduction of psychotic-phase negative symptoms. Conclusion Most professionals perceived low adherence among dual diagnosis patients. This lack of adherence is associated with a worsening of their disease evolution, which is reflected in exacerbations of the psychopathology and relapse in substance use. Therefore, we propose to identify strategies to improve adherence. PMID:27698553

76 FR 24537 - Paperwork Reduction Act; Proposed Collection; Comment Request

Science.gov (United States)

2011-05-02

... President, Office of National Drug Control Policy, Drug-Free Communities (DFC) Support Program, 750 17th... OFFICE OF NATIONAL DRUG CONTROL POLICY Paperwork Reduction Act; Proposed Collection; Comment Request AGENCY: Office of National Drug Control Policy. ACTION: 60-Day notice and request for comments...

Multiple Interference Cancellation Performance for GPS Receivers with Dual-Polarized Antenna Arrays

Directory of Open Access Journals (Sweden)

Moeness G. Amin

2008-11-01

Full Text Available This paper examines the interference cancellation performance in global positioning system (GPS receivers equipped with dual-polarized antenna arrays. In dense jamming environment, different types of interferers can be mitigated by the dual-polarized antennas, either acting individually or in conjunction with other receiver antennas. We apply minimum variance distorntionless response (MVDR method to a uniform circular dual-polarized antenna array. The MVDR beamformer is constructed for each satellite. Analysis of the eigenstructures of the covariance matrix and the corresponding weight vector polarization characteristics are provided. Depending on the number of jammers and jammer polarizations, the array chooses to expend its degrees of freedom to counter the jammer polarization or/and use phase coherence to form jammer spatial nulls. Results of interference cancellations demonstrate that applying multiple MVDR beamformers, each for one satellite, has a superior cancellation performance compared to using only one MVDR beamformer for all satellites in the field of view.

Ionic Copolymer-Magnetite Complexes for Magnetic Resonance Imaging and Drug Delivery

OpenAIRE

Zhang, Rui

2015-01-01

This thesis is focused on the design, synthesis and characterization of magnetite-ionic copolymer complexes as nanocarriers for drug delivery and magnetic resonance imaging. The polymers included phosphonate and carboxylate-containing graft and block copolymers. Oleic-acid coated magnetite nanoparticles (8-nm and 16-nm diameters) were investigated. Cisplatin and carboplatin were used as sample drugs. The potentials of the magnetite-ionomer complexes as dual drug delivery carriers and magneti...

76 FR 54599 - Medicare Program; Medicare Advantage and Prescription Drug Benefit Programs

Science.gov (United States)

2011-09-01

...), prescription drug benefit program (Part D) and section 1876 cost plans including conforming changes to the MA... accounts (MSA) plans, cost-sharing for dual-eligible enrollees in the MA program and prescription drug pricing, coverage, and payment processes in the Part D program, and requirements governing the marketing...

On the quark structure of resonance states in dual models

International Nuclear Information System (INIS)

Volkov, D.V.; Zheltukhin, A.A.; Pashnev, A.I.

1975-01-01

It is shown using as an example the Veneziano dual model, that each particular dual model already contains a certain latent quark structure unambiauously determined by internal properties of the dual model. To prove this degeneration of the resonance state spectrum is studied by introducing an additional disturbing interaction into the model being considered. Induced transitions of particles into a vacuum act as such an additional disturbance. This method complements the known factorization method of Fubini, Gordon and Veneziano and turns out to be free from an essential limitation of the latter connected with implicit assumption about the basence of internal additive laws of conservation in the model. By using the method of induced transitions of particles into a vacuum it has been possible to show that the resonance state spectrum is indeed more degenerated than it should be expected from the factorization theorem, and that the supplementary degeneration corresponds to the quark model with an infinite number of quarks of the increasing mass. Structures of some terms of the dual amplitude expansion over the degrees of the constant of the induced transition of particles to vacuum are considered; it is shown that the summation of this expansion may be reduced to a solution of a certain integral equation. On the basis of the integral equation obtained an integral representation ofr dual amplitudes is established. The problems related with degeneration of resonance states and with determination of additive quantum numbers leading to the quark interpretation of the degeneration being considered are discussed

[Pharmacokinetic interactions of telaprevir with other drugs].

Science.gov (United States)

Berenguer Berenguer, Juan; González-García, Juan

2013-07-01

Telaprevir is a new direct-acting antiviral drug for the treatment of hepatitis C virus (HCV) infection and is both a substrate and an inhibitor of cytochrome P450 (CYP450) isoenzymes. With the introduction of this new drug, assessment of drug-drug interactions has become a key factor in the evaluation of patients under treatment for HCV infection. During the treatment of this infection, many patients require other drugs to mitigate the adverse effects of anti-HCV drugs and to control other comorbidities. Moreover, most patients coinfected with HIV and HCV require antiretroviral therapy during treatment for HCV. Physicians should therefore be familiar with the pharmacokinetic properties of direct-acting antivirals for HCV treatment and their potential drug-drug interactions. The present article reviews the available information to date on the interactions of telaprevir with other drugs and provides recommendations for daily clinical practice. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Acting in solidarity : Testing an extended dual pathway model of collective action by bystander group members

NARCIS (Netherlands)

Saab, Rim; Tausch, Nicole; Spears, Russell; Cheung, Wing-Yee

We examined predictors of collective action among bystander group members in solidarity with a disadvantaged group by extending the dual pathway model of collective action, which proposes one efficacy-based and one emotion-based path to collective action (Van Zomeren, Spears, Fischer, & Leach,

Dual PECCS: a cognitive system for conceptual representation and categorization

Science.gov (United States)

Lieto, Antonio; Radicioni, Daniele P.; Rho, Valentina

2017-03-01

In this article we present an advanced version of Dual-PECCS, a cognitively-inspired knowledge representation and reasoning system aimed at extending the capabilities of artificial systems in conceptual categorization tasks. It combines different sorts of common-sense categorization (prototypical and exemplars-based categorization) with standard monotonic categorization procedures. These different types of inferential procedures are reconciled according to the tenets coming from the dual process theory of reasoning. On the other hand, from a representational perspective, the system relies on the hypothesis of conceptual structures represented as heterogeneous proxytypes. Dual-PECCS has been experimentally assessed in a task of conceptual categorization where a target concept illustrated by a simple common-sense linguistic description had to be identified by resorting to a mix of categorization strategies, and its output has been compared to human responses. The obtained results suggest that our approach can be beneficial to improve the representational and reasoning conceptual capabilities of standard cognitive artificial systems, and - in addition - that it may be plausibly applied to different general computational models of cognition. The current version of the system, in fact, extends our previous work, in that Dual- PECCS is now integrated and tested into two cognitive architectures, ACT-R and CLARION, implementing different assumptions on the underlying invariant structures governing human cognition. Such integration allowed us to extend our previous evaluation.

Self-dual Hopf quivers

International Nuclear Information System (INIS)

Huang Hualin; Li Libin; Ye Yu

2004-07-01

We study pointed graded self-dual Hopf algebras with a help of the dual Gabriel theorem for pointed Hopf algebras. Quivers of such Hopf algebras are said to be self-dual. An explicit classification of self-dual Hopf quivers is obtained. We also prove that finite dimensional coradically graded pointed self-dual Hopf algebras are generated by group-like and skew-primitive elements as associative algebras. This partially justifies a conjecture of Andruskiewitsch and Schneider and may help to classify finite dimensional self-dual pointed Hopf algebras

N-Cinnamoylation of Antimalarial Classics: Effects of Using Acyl Groups Other than Cinnamoyl toward Dual-Stage Antimalarials.

Science.gov (United States)

Gomes, Ana; Machado, Marta; Lobo, Lis; Nogueira, Fátima; Prudêncio, Miguel; Teixeira, Cátia; Gomes, Paula

2015-08-01

In a follow-up study to our reports of N-cinnamoylated chloroquine and quinacrine analogues as promising dual-stage antimalarial leads with high in vitro potency against both blood-stage Plasmodium falciparum and liver-stage Plasmodium berghei, we decided to investigate the effect of replacing the cinnamoyl moiety with other acyl groups. Thus, a series of N-acylated analogues were synthesized, and their activities against blood- and liver-stage Plasmodium spp. were assessed along with their in vitro cytotoxicities. Although the new N-acylated analogues were found to be somewhat less active and more cytotoxic than their N-cinnamoylated counterparts, they equally displayed nanomolar activities in vitro against blood-stage drug-sensitive and drug-resistant P. falciparum, and significant in vitro liver-stage activity against P. berghei. Therefore, it is demonstrated that simple N-acylated surrogates of classical antimalarial drugs are promising dual-stage antimalarial leads. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The dual role of Candida glabrata Drug:H+ Antiporter CgAqr1 (ORF CAGL0J09944g in antifungal drug and acetic acid resistance

Directory of Open Access Journals (Sweden)

Catarina eCosta

2013-06-01

Full Text Available Opportunistic Candida species often have to cope with inhibitory concentrations of acetic acid, in the acidic environment of the vaginal mucosa. Given that the ability of these yeast species to tolerate stress induced by weak acids and antifungal drugs appears to be a key factor in their persistence and virulence, it is crucial to understand the underlying mechanisms.In this study, the Drug:H+ Antiporter CgAqr1 (ORF CAGL0J09944g, from Candida glabrata, was identified as a determinant of resistance to acetic acid, and also to the antifungal agents flucytosine and, less significantly, clotrimazole. These antifungals were found to act synergistically with acetic acid against this pathogen. The action of CgAqr1 in this phenomenon was analyzed. Using a GFP fusion, CgAqr1 was found to localize to the plasma membrane and to membrane vesicles when expressed in C. glabrata or, heterologously, in Saccharomyces cerevisiae. Given its ability to complement the susceptibility phenotype of its S. cerevisiae homolog, ScAqr1, CgAqr1 was proposed to play a similar role in mediating the extrusion of chemical compounds. Significantly, the expression of this gene was found to reduce the intracellular accumulation of 3H-flucytosine and, to a moderate extent, of 3H-clotrimazole, consistent with a direct role in antifungal drug efflux. Interestingly, no effect of CgAQR1 deletion could be found on the intracellular accumulation of 14C-acetic acid, suggesting that its role in acetic acid resistance may be indirect, presumably through the transport of a still unidentified physiological substrate. Although neither of the tested chemicals induces changes in CgAQR1 expression, pre-exposure to flucytosine or clotrimazole was found to make C. glabrata cells more sensitive to acetic acid stress. Results from this study show that CgAqr1 is an antifungal drug resistance determinant and raise the hypothesis that it may play a role in C. glabrata persistent colonization and

Drugs and Crime: The Relationship of Drug Use and Concomitant Criminal Behavior. Research Issues 17.

Science.gov (United States)

Austin, Gregory A., Ed.; Lettieri, Dan J., Ed.

This volume of abstracts of major research and theoretical studies dealing with the relationship between drug use, criminal behavior and the law is concerned with criminal acts other than the possession of, or trafficking in, illicit drugs. Included are 107 selected studies categorized into seven major topic areas: Reviews and Theories, Drug Use…

Dual functions of polyvinyl alcohol (PVA): fabricating particles and electrospinning nanofibers applied in controlled drug release

Science.gov (United States)

Qin, Xiao-Hong; Wu, De-Qun; Chu, Chih-Chang

2013-01-01

The fabrication of submicron size microsphere from 8-Phe-4 poly(ester amide) (PEA) using polyvinyl alcohol (PVA) as the emulsion was reported. The biodegradable microspheres were prepared by an oil-in-water emulsion/solvent evaporation technique, and PVA was used as the emulsion. Furthermore, the emulsion PVA was electrospun into nanofibrous mats, and 8-Phe-4 PEA microspheres were entrapped in the resultant mats. The dual functions of PVA to fabricate ideal nanofibrous mats which can entrap microspheres in them and to obtain 8-Phe-4 microspheres as emulsion in their potential application were demonstrated. The anti-cancer drug doxorubicin (DOX) was encapsulated in the 8-Phe-4 amino acid-based PEA microspheres and the entrapment efficiency is almost 100 %. At the same time, the DOX can be controlled released in PBS solution and in α-chymotrypsin solution. The cytotoxicity of PVA, PVA mats-entrapped 8-Phe-4 microspheres and PVA mats-entrapped DOX-loaded 8-Phe-4 microspheres, was investigated. Hela cells were used to test the cytotoxicity of the DOX that released from the PVA mats-entrapped DOX-loaded 8-Phe-4 microspheres for 2 days, and the cell viability is below 30 % when the 8-Phe-4 microspheres concentration is 1 mg/mL. It demonstrated that the PVA mats-entrapped DOX-loaded 8-Phe-4 microspheres have a potential biomedical application.

Adverse ocular reactions to drugs.

OpenAIRE

Spiteri, M. A.; James, D. G.

1983-01-01

Drugs acting on various parts of the body may also affect the eye insidiously. Increased awareness of such drug toxicity by the prescribing doctor should encourage him to consider effects on the cornea, lens, retina, optic nerve and elsewhere when checking the patient's progress. The following review concerns adverse ocular effects of systemic drug administration.

[Caffeine: a nutrient, a drug or a drug of abuse].

Science.gov (United States)

Pardo Lozano, Ricardo; Alvarez García, Yolanda; Barral Tafalla, Diego; Farré Albaladejo, Magí

2007-01-01

Coffee, tea, chocolate and caffeinated drinks are the main sources of caffeine, which is consumed in almost all ages and socioeconomic levels. Caffeine acts as a non-selective adenosine receptor antagonist in the central nervous system. Its main effects are as psychostimulant, acting in addition on the respiratory, muscular and cardiovascular systems. Basically, caffeine is metabolized by the hepatic cytochrome P-450 1A2 enzymes (CYP1A2). Several drugs can interact with its metabolism. The observed interindividual differences of its effects can be explained by variations in its metabolism. The main therapeutic use of caffeine is bronchodilator in respiratory diseases. Other possible uses are under investigation. Acute or chronic consumption of caffeine can induce several adverse effects, including intoxication that can be lethal. Finally, caffeine can be considered a drug of abuse. It has positive reinforcing actions, produces tolerance, and a withdrawal syndrome after stopping its consumption. Caffeine can cause different mental disorders such as dependence, which is not included in the DSM-IV-R, withdrawal syndrome and intoxication. Depending on its use, caffeine can be considered a nutrient, a drug or a drug of abuse.

Dual Trajectories of Gang Affiliation and Delinquent Peer Association during Adolescence: An Examination of Long-Term Offending Outcomes

Science.gov (United States)

Krohn, Marvin D.

2018-01-01

Prior research has demonstrated that both adolescent gang affiliation and perceived delinquent peer association are important predictors of individual offending. A crucial question is whether and how youth gang affiliation contributes to a spectrum of criminal acts above and beyond the influence of associating with delinquent peers. Using 14 waves of data from the Rochester Youth Developmental Study, an ongoing longitudinal panel study aimed at understanding the causes and consequences of delinquency and drug use in an urban sample of adolescents, the current study employs a relatively new modeling technique—dual trajectory analysis—to illustrate the dynamic relationship between these two measures among 666 male youth. The results suggest that the two measures, while overlapping, may constitute distinct concepts that operate in different ways. The most convincing evidence of gang effects, above and beyond the influence of perceived peer delinquency, is for violent behavior and by extension police arrest. Our findings contribute to developmental research and provide information that informs future gang control efforts. PMID:26748922

Dual Youla parameterization

DEFF Research Database (Denmark)

Niemann, Hans Henrik

2003-01-01

A different aspect of using the parameterisation of all systems stabilised by a given controller, i.e. the dual Youla parameterisation, is considered. The relation between system change and the dual Youla parameter is derived in explicit form. A number of standard uncertain model descriptions...... are considered and the relation with the dual Youla parameter given. Some applications of the dual Youla parameterisation are considered in connection with the design of controllers and model/performance validation....

E-cigarette Use, Cigarette Smoking, Dual Use, and Problem Behaviors Among U.S. Adolescents: Results From a National Survey.

Science.gov (United States)

McCabe, Sean Esteban; West, Brady T; Veliz, Phil; Boyd, Carol J

2017-08-01

There is a need to obtain greater clarity regarding adolescents' e-cigarette use and the associations of use with a wider range of risk behaviors. This study examines the associations among past-month e-cigarette use only, traditional cigarette smoking only, dual use (i.e., concurrent e-cigarette use and cigarette smoking), school-related (i.e., truancy and poor academic performance) risk behaviors, and substance-related (i.e., alcohol use, binge drinking, marijuana use, illicit drug use, and nonmedical prescription drug use) risk behaviors. Data were collected via self-administered questionnaires from a nationally representative sample of 8,696 high school seniors. An estimated 9.9% of U.S. high school seniors reported past-month e-cigarette use only, 6.0% reported past-month cigarette smoking only, and 7.3% reported past-month dual use. School- and substance-related risk behaviors had strong associations with past-month e-cigarette use. Adolescents who only used e-cigarettes had significantly greater odds of all school- and substance-related risk behaviors relative to nonusers. Dual users had significantly greater odds of frequent/daily e-cigarette use as well as all school- and substance-related risk behaviors relative to those who only used e-cigarettes. Finally, adolescents who engaged in frequent/daily e-cigarette use had significantly greater odds of binge drinking, marijuana use, other illicit drug use and nonmedical prescription drug use, relative to experimental e-cigarette users. E-cigarette use is common among U.S. adolescents, and there are robust associations between e-cigarette use and school- and substance-related risk behaviors. There is evidence that e-cigarette use clusters with risk behaviors and appears to represent a problem behavior, especially dual use of e-cigarettes and traditional cigarettes. Copyright © 2017 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

Is the GAIN Act a turning point in new antibiotic discovery?

Science.gov (United States)

Brown, Eric D

2013-03-01

The United States GAIN (Generating Antibiotic Incentives Now) Act is a call to action for new antibiotic discovery and development that arises from a ground swell of concern over declining activity in this therapeutic area in the pharmaceutical sector. The GAIN Act aims to provide economic incentives for antibiotic drug discovery in the form of market exclusivity and accelerated drug approval processes. The legislation comes on the heels of nearly two decades of failure using the tools of modern drug discovery to find new antibiotic drugs. The lessons of failure are examined herein as are the prospects for a renewed effort in antibiotic drug discovery and development stimulated by new investments in both the public and private sector.

75 FR 48625 - Amendment to the International Traffic in Arms Regulations: Dual Nationals and Third-Country...

Science.gov (United States)

2010-08-11

... previous policy regarding the treatment of dual nationals and foreign nationals was reconsidered. The... technology. Regulatory Analysis and Notices Administrative Procedure Act This amendment involves a foreign... amend the International Traffic in Arms Regulations (ITAR) to update the policies regarding end-user...

A low specific on-resistance SOI MOSFET with dual gates and a recessed drain

International Nuclear Information System (INIS)

Luo Xiao-Rong; Hu Gang-Yi; Zhang Zheng-Yuan; Luo Yin-Chun; Fan Ye; Wang Xiao-Wei; Fan Yuan-Hang; Cai Jin-Yong; Wang Pei; Zhou Kun

2013-01-01

A low specific on-resistance (R on,sp ) integrable silicon-on-insulator (SOI) metal-oxide semiconductor field-effect transistor (MOSFET) is proposed and investigated by simulation. The MOSFET features a recessed drain as well as dual gates, which consist of a planar gate and a trench gate extended to the buried oxide layer (BOX) (DGRD MOSFET). First, the dual gates form dual conduction channels, and the extended trench gate also acts as a field plate to improve the electric field distribution. Second, the combination of the trench gate and the recessed drain widens the vertical conduction area and shortens the current path. Third, the P-type top layer not only enhances the drift doping concentration but also modulates the surface electric field distributions. All of these sharply reduce R on,sp and maintain a high breakdown voltage (BV). The BV of 233 V and R on,sp of 4.151 mΩ·cm 2 (V GS = 15 V) are obtained for the DGRD MOSFET with 15-μm half-cell pitch. Compared with the trench gate SOI MOSFET and the conventional MOSFET, R on,sp of the DGRD MOSFET decreases by 36% and 33% with the same BV, respectively. The trench gate extended to the BOX synchronously acts as a dielectric isolation trench, simplifying the fabrication processes. (condensed matter: electronic structure, electrical, magnetic, and optical properties)

Dual Smarandache Curves of a Timelike Curve lying on Unit dual Lorentzian Sphere

OpenAIRE

Kahraman, Tanju; Hüseyin Ugurlu, Hasan

2016-01-01

In this paper, we give Darboux approximation for dual Smarandache curves of time like curve on unit dual Lorentzian sphere. Firstly, we define the four types of dual Smarandache curves of a timelike curve lying on dual Lorentzian sphere.

Dual-targeting hybrid nanoparticles for the delivery of SN38 to Her2 and CD44 overexpressed human gastric cancer

Science.gov (United States)

Yang, Zhe; Luo, Huiyan; Cao, Zhong; Chen, Ya; Gao, Jinbiao; Li, Yingqin; Jiang, Qing; Xu, Ruihua; Liu, Jie

2016-06-01

Gastric cancer (GC), particularly of the type with high expression of both human epidermal growth factor receptor 2 (Her2) and cluster determinant 44 (CD44), is one of the most malignant human tumors which causes a high mortality rate due to rapid tumor growth and metastasis. To develop effective therapeutic treatments, a dual-targeting hybrid nanoparticle (NP) system was designed and constructed to deliver the SN38 agent specifically to human solid gastric tumors bearing excessive Her2 and CD44. The hybrid NPs consist of a particle core made of the biodegradable polymer PLGA and a lipoid shell prepared by conjugating the AHNP peptides and n-hexadecylamine (HDA) to the carboxyl groups of hyaluronic acid (HA). Upon encapsulation of the SN38 agent in the NPs, the AHNP peptides and HA on the NP surface allow preferential delivery of the drug to gastric cancer cells (e.g., HGC27 cells) by targeting Her2 and CD44. Cellular uptake and in vivo biodistribution experiments verified the active targeting and prolonged in vivo circulation properties of the dual-targeting hybrid NPs, leading to enhanced accumulation of the drug in tumors. Furthermore, the anti-proliferation mechanism studies revealed that the inhibition of the growth and invasive activity of HGC27 cells was not only attributed to the enhanced cellular uptake of dual-targeting NPs, but also benefited from the suppression of CD44 and Her2 expression by HA and AHNP moieties. Finally, intravenous administration of the SN38-loaded dual-targeting hybrid NPs induced significant growth inhibition of HGC27 tumor xenografted in nude mice compared with a clinical antitumor agent, Irinotecan (CPT-11), and the other NP formulations. These results demonstrate that the designed dual-targeting hybrid NPs are promising for targeted anti-cancer drug delivery to treat human gastric tumors over-expressing Her2 and CD44.Gastric cancer (GC), particularly of the type with high expression of both human epidermal growth factor receptor

Photo and pH dual-responsive polydiacetylene smart nanocontainer

International Nuclear Information System (INIS)

Li, Jingguo; Yu, Zhiqiang; Jiang, Hao; Zou, Gang; Zhang, Qijin

2012-01-01

Herein, a novel smart nanocontainer was developed by incorporating photo-responsive azobenzene derivative/cyclodextrin (Azo–CD) supramolecular complex into pH-responsive polydiacetylene (PDA) vesicles matrix. The designed nanocontainer exhibited excellent cell-toxicity, and the controlled release property response to external photo and pH stimuli. The photo-controlled inclusion and exclusion reaction between α-cyclodextrin (α-CD) and azobenzene moiety were used to act as the driving force to induce photo-triggered controlled release behavior of the designed nanocontainer. Moreover, the pH-responsive PDA vesicle matrix endowed the designed system with a controlled release property upon pH variation. The facile preparation procedures and their efficiency of response to the external stimuli render the novel smart nanocontainer potential candidate for future applications in remote controlled drug release. -- Graphical abstract: Herein, we developed a novel smart nanocontainer comprising the azobenzene derivative/cyclodextrin supramolecular complex and polydiacetylene vesicles, which exhibited excellent biocompatibility, and controlled release property response to external photo and pH stimuli. Highlights: ► We developed a novel dual-responsive smart polydiacetylene nanocontainer. ► The azobenzene/cyclodextrin complex was introduced into polydiacetylene vesicles. ► The designed nanocontainer exhibited excellent biocompatibility and stability. ► 365 and 435 nm light irradiations are used to realize photo controlled release. ► The smart nanocontainer exhibited controlled release property upon pH variation.

Convergence and divergence, a concept for explaining drug actions.

Science.gov (United States)

Watanabe, Takehiko; Kamisaki, Yoshinori; Timmerman, Henk

2004-10-01

For the teaching and/or learning about drug actions and for the discovery and development of new drugs, it is important to understand how drugs act on living bodies. So far, there has been no clear description on the general principle of drug action in pharmacology textbooks. We propose two principles to depict the action mechanism of drugs. The first is that most, if not all, drugs act on proteins at the molecular level, that is, enzymes, receptors, ion channels, and transporters. The second is that a drug may cause divergent or convergent responses, resulting in changes of a physiological or pathological function of the human body. The concept of divergence and convergence can be used to explain the complex individuality of drug actions.

Indolealkylamines: biotransformations and potential drug-drug interactions.

Science.gov (United States)

Yu, Ai-Ming

2008-06-01

Indolealkylamine (IAA) drugs are 5-hydroxytryptamine (5-HT or serotonin) analogs that mainly act on the serotonin system. Some IAAs are clinically utilized for antimigraine therapy, whereas other substances are notable as drugs of abuse. In the clinical evaluation of antimigraine triptan drugs, studies on their biotransformations and pharmacokinetics would facilitate the understanding and prevention of unwanted drug-drug interactions (DDIs). A stable, principal metabolite of an IAA drug of abuse could serve as a useful biomarker in assessing intoxication of the IAA substance. Studies on the metabolism of IAA drugs of abuse including lysergic acid amides, tryptamine derivatives and beta-carbolines are therefore emerging. An important role for polymorphic cytochrome P450 2D6 (CYP2D6) in the metabolism of IAA drugs of abuse has been revealed by recent studies, suggesting that variations in IAA metabolism, pharmaco- or toxicokinetics and dynamics can arise from distinct CYP2D6 status, and CYP2D6 polymorphism may represent an additional risk factor in the use of these IAA drugs. Furthermore, DDIs with IAA agents could occur additively at the pharmaco/toxicokinetic and dynamic levels, leading to severe or even fatal serotonin toxicity. In this review, the metabolism and potential DDIs of these therapeutic and abused IAA drugs are described.

Implementation of the 2011 Reimbursement Act in Poland: Desired and undesired effects of the changes in reimbursement policy.

Science.gov (United States)

Kawalec, Paweł; Sagan, Anna; Stawowczyk, Ewa; Kowalska-Bobko, Iwona; Mokrzycka, Anna

2016-04-01

The Act of 12 May 2011 on the Reimbursement of Medicines, Foodstuffs Intended for Particular Nutritional Uses and Medical Devices constitutes a major change of the reimbursement policy in Poland. The main aims of this Act were to rationalize the reimbursement policy and to reduce spending on reimbursed drugs. The Act seems to have met these goals: reimbursement policy (including pricing of reimbursed drugs) was overhauled and the expenditure of the National Health Fund on reimbursed drugs saw a significant decrease in the year following the Act's introduction. The annual savings achieved since then (mainly due to the introduction of risk sharing schemes), have made it possible to include new drugs into the reimbursement list and improve access to innovative drugs. However, at the same time, the decrease in prices of reimbursed drugs, that the Act brought about, led to an uncontrolled outflow of some of these drugs abroad and shortages in Poland. This paper analyses the main changes introduced by the Reimbursement Act and their implications. Since the Act came into force relatively recently, its full impact on the reimbursement policy is not yet possible to assess. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Potassium-Based Dual Ion Battery with Dual-Graphite Electrode.

Science.gov (United States)

Fan, Ling; Liu, Qian; Chen, Suhua; Lin, Kairui; Xu, Zhi; Lu, Bingan

2017-08-01

A potassium ion battery has potential applications for large scale electric energy storage systems due to the abundance and low cost of potassium resources. Dual graphite batteries, with graphite as both anode and cathode, eliminate the use of transition metal compounds and greatly lower the overall cost. Herein, combining the merits of the potassium ion battery and dual graphite battery, a potassium-based dual ion battery with dual-graphite electrode is developed. It delivers a reversible capacity of 62 mA h g -1 and medium discharge voltage of ≈3.96 V. The intercalation/deintercalation mechanism of K + and PF 6 - into/from graphite is proposed and discussed in detail, with various characterizations to support. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

America’s Longest War – the War on Drugs

OpenAIRE

Wyrwisz, Anna

2015-01-01

The problem of using illicit drugs in the United States, which is the largest drug consumer in the world, is an important and controversial subject. The prohibition, which aimed to eliminate alcohol from the American society, ended in a failure. In the case of federal drug legislation, the first acts appeared exactly one hundred years ago. The next, intense phase began in 1970 during the presidency of Richard Nixon, when the war on drugs has been declared. Until this day, the number of acts a...

Dual vector multiplet coupled to dual N=1 supergravity in 10D

International Nuclear Information System (INIS)

Nishino, Hitoshi; Rajpoot, Subhash

2005-01-01

We couple in superspace a dual vector multiplet (C m 1 ...m 7 ,λ α ) to the dual version of N=1 supergravity (e m a ,ψ m α ,M m 1 ...m 6 ,χ α ,Φ) in ten dimensions. The 7-form field C has its 8-form field strength H dual to the 2-form field strength F of the conventional vector multiplet. To simplify the computation, we use so-called beta-function-favored superspace constraints for dual supergravity developed for β-function computations. As in a more conventional constraint set, the H-Bianchi identity must have the form N and F, where N is the 7-form field strength in dual supergravity. The potential anomaly for the dual vector multiplet can be cancelled for the particular gauge group U(1) 496 by the Green-Schwarz mechanism. As a by-product, we also give the globally supersymmetric Abelian Dirac-Born-Infeld interactions for the dual vector multiplet for the first time

OrbusNeich fully absorbable coronary stent platform incorporating dual partitioned coatings.

Science.gov (United States)

Cottone, Robert J; Thatcher, G Lawrence; Parker, Sherry P; Hanks, Laurence; Kujawa, David A; Rowland, Stephen M; Costa, Marco; Schwartz, Robert S; Onuma, Yoshinobu

2009-12-15

The field of stent based tissue engineering continues to revolutionise modern medicine by designing novel materials to restore vascular tissue function. Accordingly, the following discussion examines a novel, absorbable, polymeric scaffold engineered in combination with dual therapeutic coating, enabling locally administered temporary scaffolding in the coronary arteries for long term vascular patency and repair. This coronary stent platform consists of an absorbable polymeric material stent structure that incorporates a dual partitioned coating, by means of pro-healing EPC (endothelial progenitor cell) capture technology allowing for rapid endothelial coverage, and an absorbable polymer matrix with sustained elution of sirolimus, a drug controlling neointimal proliferation. This paper provides a brief overview of the various innovations developed by OrbusNeich to create this fully absorbable coronary device platform.

Economic Impacts of the Generic Drug User Fee Act Fee Structure.

Science.gov (United States)

Dong, Ke; Boehm, Garth; Zheng, Qiang

2017-06-01

A Food and Drug Administration (FDA) Generic Drug User system, Generic Drug User Fee Amendment of 2012 (GDUFA), started October 1, 2012, and has been in place for over 3 years. There is controversy about the GDUFA fee structure but no analysis of GDUFA data that we could find. To look at the economic impact of the GDUFA fee structure. We compared the structure of GDUFA with that of other FDA Human Drug User fees. We then, using FDA-published information, analyzed where GDUFA facility and Drug Master File fees are coming from. We used the Orange Book to identify the sponsors of all approved Abbreviated New Drug Applications (ANDAs) and the S&P Capital IQ database to find the ultimate parent companies of sponsors of approved ANDAs. The key differences between the previous structure for Human Drug User fees and the GDUFA are as follows: GDUFA has no approved product fee and no first-time or small business fee exemptions and GDUFA charges facility fees from the time of filing and charges a foreign facility levy. Most GDUFA fees are paid by or on behalf of foreign entities. The top 10 companies hold nearly 50% of all approved ANDAs but pay about 14% of GDUFA facility fees. We conclude that the regressive nature of the GDUFA fee structure penalizes small, new, and foreign firms while benefiting the large established firms. A progressive fee structure in line with other human drug user fees is needed to ensure a healthy generic drug industry. Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Deployment of ACT antimalarials for treatment of malaria: challenges and opportunities

Directory of Open Access Journals (Sweden)

Leslie Toby

2008-12-01

Full Text Available Abstract Following a long period when the effectiveness of existing mono-therapies for antimalarials was steadily declining with no clear alternative, most malaria-endemic countries in Africa and Asia have adopted artemisinin combination therapy (ACT as antimalarial drug policy. Several ACT drugs exist and others are in the pipeline. If properly targeted, they have the potential to reduce mortality from malaria substantially. The major challenge now is to get the drugs to the right people. Current evidence suggests that most of those who need the drugs do not get them. Simultaneously, a high proportion of those who are given antimalarials do not in fact have malaria. Financial and other barriers mean that, in many settings, the majority of those with malaria, particularly the poorest, do not access formal healthcare, so the provision of free antimalarials via this route has only limited impact. The higher cost of ACT creates a market for fake drugs. Addressing these problems is now a priority. This review outlines current evidence, possible solutions and research priorities.

Dual Diagnosis and Suicide Probability in Poly-Drug Users.

Science.gov (United States)

Youssef, Ismail M; Fahmy, Magda T; Haggag, Wafaa L; Mohamed, Khalid A; Baalash, Amany A

2016-02-01

To determine the frequency of suicidal thoughts and suicidal probability among poly-substance abusers in Saudi population, and to examine the relation between dual diagnosis and suicidal thoughts. Case control study. Al-Baha Psychiatric Hospital, Saudi Arabia, from May 2011 to June 2012. Participants were 239 subjects, aged 18 - 45 years. We reviewed 122 individuals who fulfilled the DSM-IV-TR criteria of substance abuse for two or more substances, and their data were compared with that collected from 117 control persons. Suicidal cases were highly present among poly-substance abusers 64.75%. Amphetamine and cannabis were the most abused substances, (87.7% and 70.49%, respectively). Astatistically significant association with suicidality was found with longer duration of substance abuse (p Suicidal cases showed significant higher scores (p suicide probability scale and higher scores in Beck depressive inventory (p Abusing certain substances for long duration, in addition to comorbid psychiatric disorders especially with disturbed-mood element, may trigger suicidal thoughts in poly-substance abusers. Depression and suicide probability is common consequences of substance abuse.

Managing dual use technology: it takes two to tango.

Science.gov (United States)

Kant, Lalit; Mourya, D T

2010-03-01

Like nuclear energy, most technologies could have dual use-for health and well being and disaster and terror. Some research publications have brought to the forefront the tragic consequences of the latter potential through their possible use. Monitoring life science research and development (R&D) to prevent possible misuse is a challenging task globally, more so in developing economies like India, which are emerging as major biotech hubs. As a signatory to the Biological and Toxin Weapons Convention, India has put in motion a process of evolving a series of measures to manage dual-use technology. The Indian Council of Medical Research (ICMR) has taken a lead in drafting model codes of conduct, ethics and practice for use by other S&T agencies to tailor them as per their requirements. Taking cue from the discussions held by the editors of the various medical and science journals in the developed world, the Indian Journal of Medical Research, the official publication of the ICMR, is working on policy and uniform practice of publication of dual-use research results. The Government of India too has promulgated legal provisions to minimize the risks of misuse of technology, like the Weapons of Mass Destruction Act. Clearly, no single agency would be able to manage the dual-use of technology effectively. Multiple agencies have to come together to work in tandem for effective implementation of various measure and also like Janus, ensure that they are neither too restrictive nor intrusive to discourage the development of science.

A graphene quantum dot@Fe3O4@SiO2 based nanoprobe for drug delivery sensing and dual-modal fluorescence and MRI imaging in cancer cells.

Science.gov (United States)

Su, Xiaoqian; Chan, Chunyu; Shi, Jingyu; Tsang, Ming-Kiu; Pan, Yi; Cheng, Changming; Gerile, Oudeng; Yang, Mo

2017-06-15

A novel graphene quantum dot (GQD)@Fe 3 O 4 @SiO 2 based nanoprobe was reported for targeted drug delivery, sensing, dual-modal imaging and therapy. Carboxyl-terminated GQD (C-GQD) was firstly conjugated with Fe 3 O 4 @SiO 2 and then functionalized with cancer targeting molecule folic acid (FA). DOX drug molecules were then loaded on GQD surface of Fe 3 O 4 @SiO 2 @GQD-FA nanoprobe via pi-pi stacking, which resulted in Fe 3 O 4 @SiO 2 @GQD-FA/DOX conjugates based on a FRET mechanism with GQD as donor molecules and DOX as acceptor molecules. Meanwhile, we successfully performed in vitro MRI and fluorescence imaging of living Hela cells and monitored intracellular drug release process using this Fe 3 O 4 @SiO 2 @GQD-FA/DOX nanoprobe. Cell viability study demonstrated the low cytotoxicity of Fe 3 O 4 @SiO 2 @GQD-FA nanocarrier and the enhanced therapeutic efficacy of Fe 3 O 4 @SiO 2 @GQD-FA/DOX nanoprobe for cancer cells. This luminomagnetic nanoprobe will be a potential platform for cancer accurate diagnosis and therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

The US Food and Drug Administration’s drug safety recommendations and long-acting beta2-agonist dispensing pattern changes in adult asthma patients: 2003–2012

Directory of Open Access Journals (Sweden)

Zhou EH

2017-03-01

Full Text Available Esther H Zhou,1 Sally Seymour,2 Margie R Goulding,1 Elizabeth M Kang,1 Jacqueline M Major,1 Solomon Iyasu1 1Division of Epidemiology, Office of Surveillance and Epidemiology, 2Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA Background: Emerging safety issues associated with long-acting beta2-agonist (LABA have led to multiple regulatory activities by the US Food and Drug Administration (FDA since 2003, including Drug Safety Communications (DSCs in 2010. These DSCs had three specific recommendations for the safe use of LABA products in adult asthma treatment. Methods: We examined the initiation of LABA-containing products for adult asthma treatment using an intermittent time series approach in a claims database from 2003 to 2012. We assessed the alignment of dispensing patterns with the following 2010 FDA recommendations: 1 contraindicated use of single-ingredient (SI-LABA without an asthma controller medication (ACM; 2 a LABA should only be used when asthma is not adequately controlled on inhaled corticosteroids (ICSs or ACM; and 3 step-down asthma therapy (e.g., discontinue LABA when asthma control is achieved. Results: There were 477,922 adults (18–64 years old dispensed a new LABA during 2003–2012. Among LABA initiators, patients who initiated an SI-LABA and who did “not” have an ACM dispensed on the same date decreased from >9% in 2003 (the initial labeling change to <2% post 2010 DSCs (p-value <0.0001 in the segmented regression model. The proportion of asthma patients dispensed an ICS in 6 months prior to initiating LABA treatment did not increase. The proportion of patients with longer than 4 months of continuous treatment did not decrease over the study period. Conclusion: Although the decrease in SI-LABA initiation is consistent with FDA’s recommendations, low ICS dispensing before initiating a LABA and LABA continuation practices require further efforts

Photoacoustic/ultrasound dual-modality contrast agent and its application to thermotherapy.

Science.gov (United States)

Wang, Yu-Hsin; Liao, Ai-Ho; Chen, Jui-Hao; Wang, Churng-Ren Chris; Li, Pai-Chi

2012-04-01

This study investigates a photoacoustic/ultrasound dual-modality contrast agent, including extending its applications from image-contrast enhancement to combined diagnosis and therapy with site-specific targeting. The contrast agent comprises albumin-shelled microbubbles with encapsulated gold nanorods (AuMBs). The gas-filled microbubbles, whose diameters range from submicrometer to several micrometers, are not only echogenic but also can serve as drug-delivery vehicles. The gold nanorods are used to enhance the generation of both photoacoustic and photothermal signals. The optical absorption peak of the gold nanorods is tuned to 760 nm and is invariant after microbubble encapsulation. Dual-modality contrast enhancement is first described here, and the applications to cellular targeting and laser-induced thermotherapy in a phantom are demonstrated. Photoacoustic imaging can be used to monitor temperature increases during the treatment. The targeting capability of AuMBs was verified, and the temperature increased by 26°C for a laser power of 980 mW, demonstrating the potential of combined diagnosis and therapy with the dual-modality agent. Targeted photo- or acoustic-mediated delivery is also possible.

Dual Loyalty in Prison Health Care

Science.gov (United States)

Stöver, Heino; Wolff, Hans

2012-01-01

Despite the dissemination of principles of medical ethics in prisons, formulated and advocated by numerous international organizations, health care professionals in prisons all over the world continue to infringe these principles because of perceived or real dual loyalty to patients and prison authorities. Health care professionals and nonmedical prison staff need greater awareness of and training in medical ethics and prisoner human rights. All parties should accept integration of prison health services with public health services. Health care workers in prison should act exclusively as caregivers, and medical tasks required by the prosecution, court, or security system should be carried out by medical professionals not involved in the care of prisoners. PMID:22390510

Dual Income Taxes

DEFF Research Database (Denmark)

Sørensen, Peter Birch

This paper discusses the principles and practices of dual income taxation in the Nordic countries. The first part of the paper explains the rationale and the historical background for the introduction of the dual income tax and describes the current Nordic tax practices. The second part...... of the paper focuses on the problems of taxing income from small businesses and the issue of corporate-personal tax integration under the dual income tax, considering alternative ways of dealing with these challenges. In the third and final part of the paper, I briefly discuss whether introducing a dual income...

Dual Diagnosis - Multiple Languages

Science.gov (United States)

... National Library of Medicine Comorbidity or dual diagnosis - Opioid addiction, part 9 - English PDF Comorbidity or dual diagnosis - Opioid addiction, part 9 - español (Spanish) PDF Comorbidity or dual ...

Multimodal Theranostic Nanoformulations Permit Magnetic Resonance Bioimaging of Antiretroviral Drug Particle Tissue-Cell Biodistribution

Science.gov (United States)

Kevadiya, Bhavesh D.; Woldstad, Christopher; Ottemann, Brendan M.; Dash, Prasanta; Sajja, Balasrinivasa R.; Lamberty, Benjamin; Morsey, Brenda; Kocher, Ted; Dutta, Rinku; Bade, Aditya N.; Liu, Yutong; Callen, Shannon E.; Fox, Howard S.; Byrareddy, Siddappa N.; McMillan, JoEllyn M.; Bronich, Tatiana K.; Edagwa, Benson J.; Boska, Michael D.; Gendelman, Howard E.

2018-01-01

RATIONALE: Long-acting slow effective release antiretroviral therapy (LASER ART) was developed to improve patient regimen adherence, prevent new infections, and facilitate drug delivery to human immunodeficiency virus cell and tissue reservoirs. In an effort to facilitate LASER ART development, “multimodal imaging theranostic nanoprobes” were created. These allow combined bioimaging, drug pharmacokinetics and tissue biodistribution tests in animal models. METHODS: Europium (Eu3+)- doped cobalt ferrite (CF) dolutegravir (DTG)- loaded (EuCF-DTG) nanoparticles were synthesized then fully characterized based on their size, shape and stability. These were then used as platforms for nanoformulated drug biodistribution. RESULTS: Folic acid (FA) decoration of EuCF-DTG (FA-EuCF-DTG) nanoparticles facilitated macrophage targeting and sped drug entry across cell barriers. Macrophage uptake was higher for FA-EuCF-DTG than EuCF-DTG nanoparticles with relaxivities of r2 = 546 mM-1s-1 and r2 = 564 mM-1s-1 in saline, and r2 = 850 mM-1s-1 and r2 = 876 mM-1s-1 in cells, respectively. The values were ten or more times higher than what was observed for ultrasmall superparamagnetic iron oxide particles (r2 = 31.15 mM-1s-1 in saline) using identical iron concentrations. Drug particles were detected in macrophage Rab compartments by dual fluorescence labeling. Replicate particles elicited sustained antiretroviral responses. After parenteral injection of FA-EuCF-DTG and EuCF-DTG into rats and rhesus macaques, drug, iron and cobalt levels, measured by LC-MS/MS, magnetic resonance imaging, and ICP-MS were coordinate. CONCLUSION: We posit that these theranostic nanoprobes can assess LASER ART drug delivery and be used as part of a precision nanomedicine therapeutic strategy. PMID:29290806

The implementation and evaluation of cognitive milieu therapy for dual diagnosis inpatients: A pragmatic clinical trial

DEFF Research Database (Denmark)

Lykke, Jørn; Oestrich, I.; Austin, Stephen

2010-01-01

milieu therapy (CMT) among a group of dual diagnosis inpatients. CMT is an integrated treatment for both mental illness and substance abuse based on cognitive behavioral principles and carried out within a supportive inpatient environment. A convenience sample of dual diagnosis inpatients (N = 136......) was assessed pre- and post-intervention from an inpatient setting where CMT was the mode of treatment. Psychopathology was measured using the Brief Psychiatric Rating Scale and substance abuse measured with the DrugCheck scale, breath/urine samples, and the Severity of Dependence Scale. Functioning...

Dual Targeting of the Insulin-Like Growth Factor and Collateral Pathways in Cancer: Combating Drug Resistance

Energy Technology Data Exchange (ETDEWEB)

Ludwig, Joseph A., E-mail: jaludwig@mdanderson.org; Lamhamedi-Cherradi, Salah-Eddine [Departments of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 (United States); Lee, Ho-Young [Departments of Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 (United States); Naing, Aung [Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 (United States); Benjamin, Robert [Departments of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 (United States)

2011-07-26

The insulin-like growth factor pathway, regulated by a complex interplay of growth factors, cognate receptors, and binding proteins, is critically important for many of the hallmarks of cancer such as oncogenesis, cell division, growth, and antineoplastic resistance. Naturally, a number of clinical trials have sought to directly abrogate insulin-like growth factor receptor 1 (IGF-1R) function and/or indirectly mitigate its downstream mediators such as mTOR, PI3K, MAPK, and others under the assumption that such therapeutic interventions would provide clinical benefit, demonstrable by impaired tumor growth as well as prolonged progression-free and overall survival for patients. Though a small subset of patients enrolled within phase I or II clinical trials revealed dramatic clinical response to IGF-1R targeted therapies (most using monoclonal antibodies to IGF-1R), in toto, the anticancer effect has been underwhelming and unsustained, as even those with marked clinical responses seem to rapidly acquire resistance to IGF-1R targeted agents when used alone through yet to be identified mechanisms. As the IGF-1R receptor is just one of many that converge upon common intracellular signaling cascades, it is likely that effective IGF-1R targeting must occur in parallel with blockade of redundant signaling paths. Herein, we present the rationale for dual targeting of IGF-1R and other signaling molecules as an effective strategy to combat acquired drug resistance by carcinomas and sarcomas.

Dual Targeting of the Insulin-Like Growth Factor and Collateral Pathways in Cancer: Combating Drug Resistance

International Nuclear Information System (INIS)

Ludwig, Joseph A.; Lamhamedi-Cherradi, Salah-Eddine; Lee, Ho-Young; Naing, Aung; Benjamin, Robert

2011-01-01

The insulin-like growth factor pathway, regulated by a complex interplay of growth factors, cognate receptors, and binding proteins, is critically important for many of the hallmarks of cancer such as oncogenesis, cell division, growth, and antineoplastic resistance. Naturally, a number of clinical trials have sought to directly abrogate insulin-like growth factor receptor 1 (IGF-1R) function and/or indirectly mitigate its downstream mediators such as mTOR, PI3K, MAPK, and others under the assumption that such therapeutic interventions would provide clinical benefit, demonstrable by impaired tumor growth as well as prolonged progression-free and overall survival for patients. Though a small subset of patients enrolled within phase I or II clinical trials revealed dramatic clinical response to IGF-1R targeted therapies (most using monoclonal antibodies to IGF-1R), in toto, the anticancer effect has been underwhelming and unsustained, as even those with marked clinical responses seem to rapidly acquire resistance to IGF-1R targeted agents when used alone through yet to be identified mechanisms. As the IGF-1R receptor is just one of many that converge upon common intracellular signaling cascades, it is likely that effective IGF-1R targeting must occur in parallel with blockade of redundant signaling paths. Herein, we present the rationale for dual targeting of IGF-1R and other signaling molecules as an effective strategy to combat acquired drug resistance by carcinomas and sarcomas

Dual Targeting of the Insulin-Like Growth Factor and Collateral Pathways in Cancer: Combating Drug Resistance

Directory of Open Access Journals (Sweden)

Aung Naing

2011-07-01

Full Text Available The insulin-like growth factor pathway, regulated by a complex interplay of growth factors, cognate receptors, and binding proteins, is critically important for many of the hallmarks of cancer such as oncogenesis, cell division, growth, and antineoplastic resistance. Naturally, a number of clinical trials have sought to directly abrogate insulin-like growth factor receptor 1 (IGF-1R function and/or indirectly mitigate its downstream mediators such as mTOR, PI3K, MAPK, and others under the assumption that such therapeutic interventions would provide clinical benefit, demonstrable by impaired tumor growth as well as prolonged progression-free and overall survival for patients. Though a small subset of patients enrolled within phase I or II clinical trials revealed dramatic clinical response to IGF-1R targeted therapies (most using monoclonal antibodies to IGF-1R, in toto, the anticancer effect has been underwhelming and unsustained, as even those with marked clinical responses seem to rapidly acquire resistance to IGF-1R targeted agents when used alone through yet to be identified mechanisms. As the IGF-1R receptor is just one of many that converge upon common intracellular signaling cascades, it is likely that effective IGF-1R targeting must occur in parallel with blockade of redundant signaling paths. Herein, we present the rationale for dual targeting of IGF-1R and other signaling molecules as an effective strategy to combat acquired drug resistance by carcinomas and sarcomas.

78 FR 21613 - Prescription Drug User Fee Act Patient-Focused Drug Development; Announcement of Disease Areas...

Science.gov (United States)

2013-04-11

... Availability. SUMMARY: The Food and Drug Administration (FDA) is announcing the selection of disease areas to... selection criteria, which were published in the September 24, 2012, Federal Register notice: Disease areas... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-N-0967...

Enzyme-guided plasmonic biosensor based on dual-functional nanohybrid for sensitive detection of thrombin.

Science.gov (United States)

Yan, Jing; Wang, Lida; Tang, Longhua; Lin, Lei; Liu, Yang; Li, Jinghong

2015-08-15

Rapid and sensitive methodologies for the detection of protein are in urgent requirement for clinic diagnostics. Localized surface plasmon resonance (LSPR) of metal nanostructures has the potential to circumvent this problem due to its sensitive optical properties and strong electromagnetic near-field enhancements. In this work, an enzyme mediated plasmonic biosensor on the basis of a dual-functional nanohybrid was developed for the detection of thrombin. By utilizing LSPR-responsive nanohybrid and anaptamer-enzyme conjugated reporting probe, the sensing platform brings enhanced signal, stability as well as simplicity. Enzymatic reaction catalyzed the reduction of Au(3+) to Au° in situ, further leading to the rapid crystal growth of gold nanoparticles (AuNPs). The LSPR absorbance band and color changed company with the nanoparticle generation, which can be real-time monitoring by UV-visible spectrophotometer and naked eye. Nanohybrid constructed by gold and magnetic nanoparticles acts as a dual functional plasmonic unit, which not only plays the role of signal production, but also endows the sensor with the function of magnetic separation. Simultaneously, the introduction of enzyme effectively regulates the programming crystal growth of AuNPs. In addition, enzyme also serves as signal amplifier owing to its high catalysis efficiency. The response of the plasmonic sensor varies linearly with the logarithmic thrombin concentration up to 10nM with a limit of detection of 200 pM. The as-proposed strategy shows good analytical performance for thrombin determination. This simple, disposable method is promising in developing universal platforms for protein monitoring, drug discovery and point-of-care diagnostics. Copyright © 2015 Elsevier B.V. All rights reserved.

Abbreviated New Drug Applications (ANDAS): Future trend in radiopharmaceuticals

International Nuclear Information System (INIS)

Kishore, R.

1990-01-01

The Drug Price Competition and Patent Term Restoration Act (commonly called Waxman Hatch Amendment) of 1984, to the Federal Food, Drug, and Cosmetic Act provided for abbreviated new drug applications (ANDAs) if the conditions specified in the Code of Federal Regulations (CFR) Title 21, subsection 312.55 are met. Under this subsection, reports of nonclinical laboratory studies and clinical investigations can be omitted. New drugs approved under these regulations are so called generic drugs as opposed to listed or pioneer (innovator) drugs. As the patents on more and more radiopharmaceuticals reach their expiration, the radiopharmaceutical industry is likely to produce more of these generic versions of innovator drugs. The ANDAs are required to contain information specified under subsections 314.50(a), (b), (d)(1) and (3), (e), and (g)

Self-dual metrics with self-dual Killing vectors

International Nuclear Information System (INIS)

Tod, K.P.; Ward, R.S.

1979-01-01

Twistor methods are used to derive a class of solutions to Einstein's vacuum equations, with anti-self dual Weyl tensor. In particular, all metrics with a Killing vector whose derivative is anti-self-dual and which admit a real positive-definite section are exhibited and shown to coincide with the metrics of Hawking. (author)

Evaluating Drug Cost per Response with SGLT2 Inhibitors in Patients with Type 2 Diabetes Mellitus.

Science.gov (United States)

Lopez, Janice M S; Macomson, Brian; Ektare, Varun; Patel, Dipen; Botteman, Marc

2015-09-01

The sodium-glucose cotransporter 2 (SGLT2) inhibitors, which include canagliflozin, dapagliflozin, and empagliflozin, represent a new class of antihyperglycemic agents. Few studies have assessed their cost per response, with "cost per response" being the total cost of a select drug, divided by the resulting change in glycated hemoglobin (HbA1c) levels. To examine the drug cost of SGLT2 inhibitors per a reduction in placebo-adjusted 1% HbA1c in patients with type 2 diabetes mellitus who received treatment during 26 weeks with canagliflozin, dapagliflozin, or empagliflozin. The drug cost per response for each of the 3 agents individually was assessed based on data from a subset of clinical trials discussed in the prescribing information for each drug that were all placebo-controlled studies evaluating each drug as monotherapy, dual therapy (combined with metformin), and triple therapy (combined with metformin and a sulfonylurea) in patients with uncontrolled, type 2 diabetes mellitus. The US 2015 wholesale acquisition cost for each drug was used to calculate each drug's treatment costs over 26 weeks. The average cost per response for each drug was defined as the prescription drug cost of each SGLT2 inhibitor, divided by the average, placebo-adjusted HbA1c reduction at 26 weeks. The drug cost per unit dose was the same for canagliflozin (100 mg or 300 mg), dapagliflozin (5 mg or 10 mg), and empagliflozin (10 mg or 25 mg), at $11.43. The drug cost per placebo-adjusted 1% HbA1c reduction varied by agent and by dose, as a result of the differences in the treatment responses for each of the 3 drugs. The costs per response for canagliflozin 100 mg as monotherapy, dual therapy, and triple therapy regimens ranged from $2286 to $3355, and for canagliflozin 300 mg, from $1793 to $2702. The costs per response for dapagliflozin 5 mg as monotherapy and dual therapy (triple therapy was not available at the time of the study) ranged from $4161 to $5201; the cost for dapagliflozin

Dual tumor-targeted poly(lactic-co-glycolic acid–polyethylene glycol–folic acid nanoparticles: a novel biodegradable nanocarrier for secure and efficient antitumor drug delivery

Directory of Open Access Journals (Sweden)

Chen J

2017-08-01

Full Text Available Jia Chen,1,2,* Qi Wu,1,* Li Luo,1 Yi Wang,1 Yuan Zhong,1 Han-Bin Dai,1 Da Sun,1,3 Mao-Ling Luo,4 Wei Wu,1 Gui-Xue Wang1 1Key Laboratory for Biorheological Science and Technology, Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College, Chongqing University, Chongqing, 2Institute of Laboratory Animals, Sichuan Academy of Medical Science, Sichuan Provincial People’s Hospital, Chengdu, 3Institute of Life Sciences, Wenzhou University, Wenzhou, 4School of Medicine, Wuhan University, Wuhan, China *These authors contributed equally to this work Abstract: Further specific target-ability development of biodegradable nanocarriers is extremely important to promote their security and efficiency in antitumor drug-delivery applications. In this study, a facilely prepared poly(lactic-co-glycolic acid (PLGA–polyethylene glycol (PEG–folic acid (FA copolymer was able to self-assemble into nanoparticles with favorable hydrodynamic diameters of around 100 nm and negative surface charge in aqueous solution, which was expected to enhance intracellular antitumor drug delivery by advanced dual tumor-target effects, ie, enhanced permeability and retention induced the passive target, and FA mediated the positive target. Fluorescence-activated cell-sorting and confocal laser-scanning microscopy results confirmed that doxorubicin (model drug loaded into PLGA-PEG-FA nanoparticles was able to be delivered efficiently into tumor cells and accumulated at nuclei. In addition, all hemolysis, 3-(4,5-dimethylthiazol-2-yl-5-(3-carboxymethoxyphenyl-2-(4-sulfophenyl-2H-tetrazolium, and zebrafish-development experiments demonstrated that PLGA-PEG-FA nanoparticles were biocompatible and secure for biomedical applications, even at high polymer concentration (0.1 mg/mL, both in vitro and in vivo. Therefore, PLGA-PEG-FA nanoparticles provide a feasible controlled-release platform for secure and efficient antitumor drug

Multifunctional quantum dots and liposome complexes in drug delivery.

Science.gov (United States)

Wang, Qi; Chao, Yi-Min

2017-09-03

Incorporating both diagnostic and therapeutic functions into a single nanoscale system is an effective modern drug delivery strategy. Combining liposomes with semiconductor quantum dots (QDs) has great potential to achieve such dual functions, referred to in this review as a liposomal QD hybrid system (L-QD). Here we review the recent literature dealing with the design and application of L-QD for advances in bio-imaging and drug delivery. After a summary of L-QD synthesis processes and evaluation of their properties, we will focus on their multifunctional applications, ranging from in vitro cell imaging to theranostic drug delivery approaches.

Multifunctional quantum dots and liposome complexes in drug delivery

Science.gov (United States)

Wang, Qi; Chao, Yimin

2018-01-01

Incorporating both diagnostic and therapeutic functions into a single nanoscale system is an effective modern drug delivery strategy. Combining liposomes with semiconductor quantum dots (QDs) has great potential to achieve such dual functions, referred to in this review as a liposomal QD hybrid system (L-QD). Here we review the recent literature dealing with the design and application of L-QD for advances in bio-imaging and drug delivery. After a summary of L-QD synthesis processes and evaluation of their properties, we will focus on their multifunctional applications, ranging from in vitro cell imaging to theranostic drug delivery approaches. PMID:28866655

A comparative study of five centrally acting drugs on the pharmacological treatment of obesity.

Science.gov (United States)

Suplicy, H; Boguszewski, C L; dos Santos, C M C; do Desterro de Figueiredo, M; Cunha, D R; Radominski, R

2014-08-01

No long-term studies have compared centrally acting drugs for treating obesity. To compare the efficacy and safety of diethylpropion (DEP), fenproporex (FEN), mazindol (MZD), fluoxetine (FXT) and sibutramine (SIB) in promoting weight loss. A prospective, randomized, placebo (PCB)-controlled study conducted at a single academic institution. A total of 174 obese premenopausal women. Participants randomly received DEP 75 mg (n=28), FEN 25 mg (n=29), MZD 2 mg (n=29), SIB 15 mg (n=30), FXT 20 mg (n=29) or PCB (n=29) daily over 52 weeks. Diet and physical activity were encouraged. The primary endpoints were changes in body weight and the proportion of women who achieved at least 5% weight loss by week 52 in the intent-to-treat population. Other measurements included anthropometry, safety, metabolic and cardiovascular parameters. Weight loss was greater than PCB (-3.1±4.3 kg) with DEP (-10.0±6.4 kg; Pobese premenopausal women, with a satisfactory benefit-risk profile.

Investigation of naphthofuran moiety as potential dual inhibitor against BACE-1 and GSK-3β: molecular dynamics simulations, binding energy, and network analysis to identify first-in-class dual inhibitors against Alzheimer's disease.

Science.gov (United States)

Kumar, Akhil; Srivastava, Gaurava; Srivastava, Swati; Verma, Seema; Negi, Arvind S; Sharma, Ashok

2017-08-01

BACE-1 and GSK-3β are potential therapeutic drug targets for Alzheimer's disease. Recently, both the targets received attention for designing dual inhibitors for Alzheimer's disease. Until now, only two-scaffold triazinone and curcumin have been reported as BACE-1 and GSK-3β dual inhibitors. Docking, molecular dynamics, clustering, binding energy, and network analysis of triazinone derivatives with BACE-1 and GSK-3β was performed to get molecular insight into the first reported dual inhibitor. Further, we designed and evaluated a naphthofuran series for its ability to inhibit BACE-1 and GSK-3β with the computational approaches. Docking study of naphthofuran series showed a good binding affinity towards both the targets. Molecular dynamics, binding energy, and network analysis were performed to compare their binding with the targets and amino acids responsible for binding. Naphthofuran series derivatives showed good interaction within the active site residues of both of the targets. Hydrogen bond occupancy and binding energy suggested strong binding with the targets. Dual-inhibitor binding was mostly governed by the hydrophobic interactions for both of the targets. Per residue energy decomposition and network analysis identified the key residues involved in the binding and inhibiting BACE-1 and GSK-3β. The results indicated that naphthofuran series derivative 11 may be a promising first-in-class dual inhibitor against BACE-1 and GSK-3β. This naphthofuran series may be further explored to design better dual inhibitors. Graphical abstract Naphthofuran derivative as a dual inhibitor for BACE-1 and GSK-3β.

Orphan drugs: trends and issues in drug development.

Science.gov (United States)

Rana, Proteesh; Chawla, Shalini

2018-04-12

Research in rare diseases has contributed substantially toward the current understanding in the pathophysiology of the common diseases. However, medical needs of patients with rare diseases have always been neglected by the society and pharmaceutical industries based on their small numbers and unprofitability. The Orphan Drug Act (1983) was the first serious attempt to address the unmet medical needs for patients with rare diseases and to provide impetus for the pharmaceutical industry to promote orphan drug development. The process of drug development for rare diseases is no different from common diseases but involves significant cost and infrastructure. Further, certain aspect of drug research may not be feasible for the rare diseases. The drug-approving authority must exercise their scientific judgment and ensure due flexibility while evaluating data at various stages of orphan drug development. The emergence of patent cliff combined with the government incentives led the pharmaceutical industry to realize the good commercial prospects in developing an orphan drug despite the small market size. Indeed, many drugs that were given orphan designation ended up being blockbusters. The orphan drug market is projected to reach $178 billion by 2020, and the prospects of research and development in rare diseases appears to be quite promising and rewarding.

Dual antagonists of integrins.

Science.gov (United States)

Nadrah, K; Dolenc, M Sollner

2005-01-01

The roles of integrins in pathologies have been studied intensively and only partially explained. This has resulted in the development of several nanomolar antagonists to certain integrins. In most cases, the aim was to produce compounds which are highly selective towards specific integrins. This paradigm has recently shifted a little. Targeting two or more integrins with one compound has become a very attractive concept, especially since it has become clear that several severe disorders, such as pathological angiogenesis, cannot be treated just with highly specific integrin antagonists. This review is aimed to elucidate some aspects regarding the design of drugs with dual activity towards integrins. Integrin structure and tissue distribution will first be described, in order to provide the basis for their functions in various pathologies which will follow. Inhibitors of several pairs of integrins will be described.

Glutamatergic transmission in drug reward: implications for drug addiction.

Science.gov (United States)

D'Souza, Manoranjan S

2015-01-01

Individuals addicted to drugs of abuse such as alcohol, nicotine, cocaine, and heroin are a significant burden on healthcare systems all over the world. The positive reinforcing (rewarding) effects of the above mentioned drugs play a major role in the initiation and maintenance of the drug-taking habit. Thus, understanding the neurochemical mechanisms underlying the reinforcing effects of drugs of abuse is critical to reducing the burden of drug addiction in society. Over the last two decades, there has been an increasing focus on the role of the excitatory neurotransmitter glutamate in drug addiction. In this review, pharmacological and genetic evidence supporting the role of glutamate in mediating the rewarding effects of the above described drugs of abuse will be discussed. Further, the review will discuss the role of glutamate transmission in two complex heterogeneous brain regions, namely the nucleus accumbens (NAcc) and the ventral tegmental area (VTA), which mediate the rewarding effects of drugs of abuse. In addition, several medications approved by the Food and Drug Administration that act by blocking glutamate transmission will be discussed in the context of drug reward. Finally, this review will discuss future studies needed to address currently unanswered gaps in knowledge, which will further elucidate the role of glutamate in the rewarding effects of drugs of abuse.

Dual affine isoperimetric inequalities

Directory of Open Access Journals (Sweden)

Bin Xiong

2006-01-01

Full Text Available We establish some inequalities for the dual -centroid bodies which are the dual forms of the results by Lutwak, Yang, and Zhang. Further, we establish a Brunn-Minkowski-type inequality for the polar of dual -centroid bodies.

Indolealkylamines: Biotransformations and Potential Drug–Drug Interactions

OpenAIRE

Yu, Ai-Ming

2008-01-01

Indolealkylamine (IAA) drugs are 5-hydroxytryptamine (5-HT or serotonin) analogs that mainly act on the serotonin system. Some IAAs are clinically utilized for antimigraine therapy, whereas other substances are notable as drugs of abuse. In the clinical evaluation of antimigraine triptan drugs, studies on their biotransformations and pharmacokinetics would facilitate the understanding and prevention of unwanted drug–drug interactions (DDIs). A stable, principal metabolite of an IAA drug of ab...

Controlling type I error rate for fast track drug development programmes.

Science.gov (United States)

Shih, Weichung J; Ouyang, Peter; Quan, Hui; Lin, Yong; Michiels, Bart; Bijnens, Luc

2003-03-15

The U.S. Food and Drug Administration (FDA) Modernization Act of 1997 has a Section (No. 112) entitled 'Expediting Study and Approval of Fast Track Drugs' (the Act). In 1998, the FDA issued a 'Guidance for Industry: the Fast Track Drug Development Programs' (the FTDD programmes) to meet the requirement of the Act. The purpose of FTDD programmes is to 'facilitate the development and expedite the review of new drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs'. Since then many health products have reached patients who suffered from AIDS, cancer, osteoporosis, and many other diseases, sooner by utilizing the Fast Track Act and the FTDD programmes. In the meantime several scientific issues have also surfaced when following the FTDD programmes. In this paper we will discuss the concept of two kinds of type I errors, namely, the 'conditional approval' and the 'final approval' type I errors, and propose statistical methods for controlling them in a new drug submission process. Copyright 2003 John Wiley & Sons, Ltd.

Orphan Drug Debate: A Cheat Sheet.

Science.gov (United States)

Patel, Krishna R

2017-06-01

In some respects, the 1983 Orphan Drug Act is a success story. But high prices and allegations that some drug companies have twisted the law to their advantage have made it controversial. Here are some of the main points in the debate.

78 FR 29748 - Privacy Act of 1974; Computer Matching Program Between the Department of Education and the...

Science.gov (United States)

2013-05-21

... the Higher Education Act of 1965, as amended (HEA)) to individuals convicted of drug trafficking or... drug trafficking or possession of a controlled substance who have been denied Federal benefits by..., which was originally enacted as section 5301 of the Anti-Drug Abuse Act of 1988, and which was amended...

Acting in solidarity: Testing an extended dual pathway model of collective action by bystander group members.

Science.gov (United States)

Saab, Rim; Tausch, Nicole; Spears, Russell; Cheung, Wing-Yee

2015-09-01

We examined predictors of collective action among bystander group members in solidarity with a disadvantaged group by extending the dual pathway model of collective action, which proposes one efficacy-based and one emotion-based path to collective action (Van Zomeren, Spears, Fischer, & Leach, 2004). Based on two proposed functions of social identity performance (Klein, Spears, & Reicher, 2007), we distinguished between the efficacy of collective action at consolidating the identity of a protest movement and its efficacy at achieving social change (political efficacy). We expected identity consolidation efficacy to positively predict collective action tendencies directly and indirectly via political efficacy. We also expected collective action tendencies to be positively predicted by moral outrage and by sympathy in response to disadvantaged outgroup's suffering. These hypotheses were supported in two surveys examining intentions to protest for Palestine in Britain (Study 1), and intentions to attend the June 4th vigil in Hong Kong to commemorate the Tiananmen massacre among a sample of Hong Kong citizens (Study 2). The contributions of these findings to research on the dual pathway model of collective action and the different functions of collective action are discussed. © 2014 The British Psychological Society.

Clopidogrel discontinuation within the first year after coronary drug-eluting stent implantation

DEFF Research Database (Denmark)

Thim, Troels; Johansen, Martin Berg; Chisholm, Gro Egholm

2014-01-01

BACKGROUND: The impact of adherence to the recommended duration of dual antiplatelet therapy after first generation drug-eluting stent implantation is difficult to assess in real-world settings and limited data are available. METHODS: We followed 4,154 patients treated with coronary drug-eluting ......BACKGROUND: The impact of adherence to the recommended duration of dual antiplatelet therapy after first generation drug-eluting stent implantation is difficult to assess in real-world settings and limited data are available. METHODS: We followed 4,154 patients treated with coronary drug......-eluting stents in Western Denmark for 1 year and obtained data on redeemed clopidogrel prescriptions and major adverse cardiovascular events (MACE, i.e., cardiac death, myocardial infarction, or stent thrombosis) from medical databases. RESULTS: Discontinuation of clopidogrel within the first 3 months after...... stent implantation was associated with a significantly increased rate of MACE at 1-year follow-up (hazard ratio (HR) 2.06; 95% confidence interval (CI): 1.08-3.93). Discontinuation 3-6 months (HR 1.29; 95% CI: 0.70-2.41) and 6-12 months (HR 1.29; 95% CI: 0.54-3.07) after stent implantation were...

Combined use of drugs inhibiting the renin-angiotensin system: prescribing patterns and risk of acute kidney injury in German nursing home residents.

Science.gov (United States)

Dörks, Michael; Herget-Rosenthal, Stefan; Hoffmann, Falk; Jobski, Kathrin

2018-01-01

In 2012, the European Medicines Agency reviewed the safety of dual renin-angiotensin system (RAS) blockade because of potentially increased risks for inter alia acute kidney injury (AKI). Since residents of nursing homes are particularly vulnerable to adverse drug outcomes, the aims of our study were to describe RAS-inhibiting drug use in German nursing home residents and examine the risk of AKI associated with dual RAS blockade. Based on claims data, a nested case-control study within a cohort of RAS-inhibiting drug users was conducted. Using conditional logistic regression, confounder-adjusted odds ratios (aORs) and 95% confidence intervals (CI) were obtained for the risk of AKI associated with dual RAS blockade. Subgroup analyses were performed in patients with diabetes or chronic kidney disease and both comorbidities. Of all 127,227 nursing home residents, the study cohort included 64,567 (50.7%) who were treated with at least one RAS-inhibiting drug. More than three quarters of the study population were female (77.1%). Mean age was 86.0 ± 6.8 years. Most residents were treated with angiotensin-converting enzyme inhibitors (77.8%), followed by angiotensin II receptor blockers (21.6%) and aliskiren (0.2%). Annual prevalence of dual RAS blockade declined from 9.6 (95% CI 7.8-11.8) in 2010 to 4.7 (95% CI 4.0-5.4) per 1,000 users in 2014. In the overall cohort, AKI was not significantly associated with dual RAS blockade (aOR 1.99; 0.77-5.17). However, significantly increased aORs were observed when considering patients with diabetes (3.47; 1.27-9.47), chronic kidney disease (4.74; 1.24-18.13) or both (11.17; 2.65-47.15). Prescribing of drugs inhibiting the RAS is common in German nursing homes. Though the prevalence of dual RAS blockade declined, our study showed an increased risk of AKI in patients with diabetes and/or chronic kidney disease. Therefore, cautious use is warranted in these vulnerable patients.

Conceptualizing the impacts of dual practice on the retention of public sector specialists - evidence from South Africa.

Science.gov (United States)

Ashmore, John; Gilson, Lucy

2015-01-19

'Dual practice', or multiple job holding, generally involves public sector-based health workers taking additional work in the private sector. This form of the practice is purported to help retain public health care workers in low and middle-income countries' public sectors through additional wage incentives. There has been little conceptual or empirical development of the relationship between dual practice and retention. This article helps begin to fill this gap, drawing on empirical evidence from a qualitative study focusing on South African specialists. Fifty-one repeat, in-depth interviews were carried out with 28 doctors (predominantly specialists) with more than one job, in one public and one private urban hospital. Findings suggest dual practice can impact both positively and negatively on specialists' intention to stay in the public sector. This is through multiple conceptual channels including those previously identified in the literature such as dual practice acting as a 'stepping stone' to private practice by reducing migration costs. Dual practice can also lead specialists to re-evaluate how they compare public and private jobs, and to overworking which can expedite decisions on whether to stay in the public sector or leave. Numerous respondents undertook dual practice without official permission. The idea that dual practice helps retain public specialists in South Africa may be overstated. Yet banning the practice may be ineffective, given many undertake it without permission in any case. Regulation should be better enforced to ensure dual practice is not abused. The conceptual framework developed in this article could form a basis for further qualitative and quantitative inquiry.

Evaluation of γ-cyclodextrin effect on permeation of lipophilic drugs: application of cellophane/fused octanol membrane.

Science.gov (United States)

Muankaew, Chutimon; Jansook, Phatsawee; Loftsson, Thorsteinn

2017-06-01

According to the Biopharmaceutics Classification System, oral bioavailability of drugs is determined by their aqueous solubility and the ability of the dissolved drug molecules to permeate lipophilic biological membranes. Similarly topical bioavailability of ophthalmic drugs is determined by their solubility in the aqueous tear fluid and their ability to permeate the lipophilic cornea. Enabling pharmaceutical excipients such as cyclodextrins can have profound effect on the drug bioavailability. However, to fully appreciate such enabling excipients, the relationship between their effects and the physicochemical properties of the permeating drug needs to be known. In this study, the permeation enhancing effect of γ-cyclodextrin (γCD) on saturated drug solutions containing hydrocortisone (HC), irbesartan (IBS), or telmisartan (TEL) was evaluated using cellophane and fused cellulose-octanol membranes in a conventional Franz diffusion cell system. The flux (J), the flux ratio (J R ) and the apparent permeability coefficients (P app ) demonstrate that γCD increases drug permeability. However, its efficacy depends on the drug properties. Addition of γCD increased P app of HC (unionized) and IBS (partially ionized) through the dual membrane but decreased the P app of TEL (fully ionized) that displays low complexation efficacy. The dual cellophane-octanol membrane system was simple to use and gave reproducible results.

Identification of dual-tropic HIV-1 using evolved neural networks.

Science.gov (United States)

Fogel, Gary B; Lamers, Susanna L; Liu, Enoch S; Salemi, Marco; McGrath, Michael S

2015-11-01

Blocking the binding of the envelope HIV-1 protein to immune cells is a popular concept for development of anti-HIV therapeutics. R5 HIV-1 binds CCR5, X4 HIV-1 binds CXCR4, and dual-tropic HIV-1 can bind either coreceptor for cellular entry. R5 viruses are associated with early infection and over time can evolve to X4 viruses that are associated with immune failure. Dual-tropic HIV-1 is less studied; however, it represents functional antigenic intermediates during the transition of R5 to X4 viruses. Viral tropism is linked partly to the HIV-1 envelope V3 domain, where the amino acid sequence helps dictate the receptor a particular virus will target; however, using V3 sequence information to identify dual-tropic HIV-1 isolates has remained difficult. Our goal in this study was to elucidate features of dual-tropic HIV-1 isolates that assist in the biological understanding of dual-tropism and develop an approach for their detection. Over 1559 HIV-1 subtype B sequences with known tropisms were analyzed. Each sequence was represented by 73 structural, biochemical and regional features. These features were provided to an evolved neural network classifier and evaluated using balanced and unbalanced data sets. The study resolved R5X4 viruses from R5 with an accuracy of 81.8% and from X4 with an accuracy of 78.8%. The approach also identified a set of V3 features (hydrophobicity, structural and polarity) that are associated with tropism transitions. The ability to distinguish R5X4 isolates will improve computational tropism decisions for R5 vs. X4 and assist in HIV-1 research and drug development efforts. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Regulatory considerations concerning IND radiopharmaceutical drug products

International Nuclear Information System (INIS)

Nissel, M.

1985-01-01

The Food and Drug Administration is charged by the Food, Drug, and Cosmetic Act, as presently amended, to assure that any drug introduced into interstate commerce is safe and effective for the purposes for which it is labeled. A radiopharmaceutical is, by definition, a new drug unless there is in effect an approved New Drug Application (NDA) for it. Before the data for the NDA are compiled, investigative studies have to be done. Before such studies can be performed in humans, an exemption from the Act is necessary. This exemption, technically the Claimed Exemption for an Investigational New Drug, is termed the IND. Both the scientific and the administrative requirements for an IND are discussed. For radiopharmaceutical drug products (RDP's), the radiation hazards, as well as the pharmacological ones, must be documented. Should the early studies demonstrate a potential for efficacy in a certain condition or disease state, an investigative protocol for an extended clinical trial is presented. The necessary requirements for Institutional Review Board (IRB) approval and consent forms are discussed. For certain research purposes, uniquely for radioactive drugs, an IND is not required for certain specific studies; the requirements for such a research study, conducted under the auspices of an approved radioactive drug research committee, are outlined

Permanent Discontinuance or Interruption in Manufacturing of Certain Drug or Biological Products. Final rule.

Science.gov (United States)

2015-07-08

The Food and Drug Administration (FDA or the Agency) is amending its regulations to implement certain drug shortages provisions of the Federal Food, Drug, and Cosmetic Act (the FD&C Act), as amended by the Food and Drug Administration Safety and Innovation Act (FDASIA). The rule requires all applicants of covered approved drugs or biological products--including certain applicants of blood or blood components for transfusion and all manufacturers of covered drugs marketed without an approved application--to notify FDA electronically of a permanent discontinuance or an interruption in manufacturing of the product that is likely to lead to a meaningful disruption in supply (or a significant disruption in supply for blood or blood components) of the product in the United States.

A P-N Sequence Generator Using LFSR with Dual Edge Trigger Technique

Directory of Open Access Journals (Sweden)

Naghwal Nitin Kumar

2016-01-01

Full Text Available This paper represents the design and implementation of a low power 4-bit LFSR using Dual edge triggered flip flop. A linear feedback shift register (LFSR is assembled by N number of flip flops connected in series and a combinational logic generally xor gate. An LFSR can generate random number sequence which acts as cipher in cryptography. A known text encrypted over long PN sequence, in order to improve security sequence made longer ie 128 bit; require long chain of flip flop leads to more power consumption. In this paper a novel circuit of random sequence generator using dual edge triggered flip flop has been proposed. Data has been generated on every edge of flip flop instead of single edge. A DETFF-LFSR can generate random number require with less number of clock cycle, it minimizes the number of flip flop result in power saving. In this paper we concentrates on the designing of power competent Test Pattern Generator (TPG using four dual edge triggered flip-flops as the basic building block, overall there is reduction of power around 25% by using these techniques.

Glutamatergic transmission in drug reward: Implications for drug addiction

Directory of Open Access Journals (Sweden)

Manoranjan S Dsouza

2015-11-01

Full Text Available Individuals addicted to drugs of abuse such as alcohol, nicotine, cocaine, and heroin are a significant burden on healthcare systems all over the world. The positive reinforcing (rewarding effects of the above mentioned drugs play a major role in the initiation and maintenance of the drug-taking habit. Thus, understanding the neurochemical mechanisms underlying the reinforcing effects of drugs of abuse is critical to reducing the burden of drug addiction in society. Over the last two decades, there has been an increasing focus on the role of the excitatory neurotransmitter glutamate in drug addiction. In this review, pharmacological and genetic evidence supporting the role of glutamate in mediating the rewarding effects of the above described drugs of abuse will be discussed. Further, the review will discuss the role of glutamate transmission in two complex heterogeneous brain regions, namely the nucleus accumbens (NAcc and the ventral tegmental area (VTA, which mediate the rewarding effects of drugs of abuse. In addition, several medications approved by the Food and Drug Administration that act by blocking glutamate transmission will be discussed in the context of drug reward. Finally, this review will discuss future studies needed to address currently unanswered gaps in knowledge, which will further elucidate the role of glutamate in the rewarding effects of drugs of abuse.

Enhanced therapeutic efficacy of budesonide in experimental colitis with enzyme/pH dual-sensitive polymeric nanoparticles

Directory of Open Access Journals (Sweden)

Naeem M

2015-07-01

Full Text Available Muhammad Naeem, Jiafu Cao, Moonjeong Choi, Woo Seong Kim, Hyung Ryong Moon, Bok Luel Lee, Min-Soo Kim, Yunjin Jung, Jin-Wook Yoo College of Pharmacy, Pusan National University, Busan, South Korea Abstract: Current colon-targeted drug-delivery approaches for colitis therapy often utilize single pH-triggered systems, which are less reliable due to the variation of gut pH in individuals and in disease conditions. Herein, we prepared budesonide-loaded dual-sensitive nanoparticles using enzyme-sensitive azo-polyurethane and pH-sensitive methacrylate copolymer for the treatment of colitis. The therapeutic potential of the enzyme/pH dual-sensitive nanoparticles was evaluated using a rat colitis model and compared to single pH-triggered nanoparticles. Clinical activity scores, colon/body weight ratios, myeloperoxidase activity, and proinflammatory cytokine levels were markedly decreased by dual-sensitive nanoparticles compared to single pH-triggered nanoparticles and budesonide solution. Moreover, dual-sensitive nanoparticles accumulated selectively in inflamed segments of the colon. In addition, dual-sensitive nanoparticle plasma concentrations were lower than single pH-triggered nanoparticles, and no noticeable in vitro or in vivo toxicity was observed. Our results demonstrate that enzyme/pH dual-sensitive nanoparticles are an effective and safe colon-targeted delivery system for colitis therapy. Keywords: azo-polyurethane, methacrylate copolymer, budesonide, colon-targeted nanoparticles, colitis

Lp-dual affine surface area

Science.gov (United States)

Wei, Wang; Binwu, He

2008-12-01

According to the notion of Lp-affine surface area by Lutwak, in this paper, we introduce the concept of Lp-dual affine surface area. Further, we establish the affine isoperimetric inequality and the Blaschke-Santaló inequality for Lp-dual affine surface area. Besides, the dual Brunn-Minkowski inequality for Lp-dual affine surface area is presented.

Dual symmetry in gauge theories

International Nuclear Information System (INIS)

Koshkarov, A.L.

1997-01-01

Continuous dual symmetry in electrodynamics, Yang-Mills theory and gravitation is investigated. Dual invariant which leads to badly nonlinear motion equations is chosen as a Lagrangian of the pure classical dual nonlinear electrodynamics. In a natural manner some dual angle which is determined by the electromagnetic strengths at the point of the time-space appears in the model. Motion equations may well be interpreted as the equations of the standard Maxwell theory with source. Alternative interpretation is the quasi-Maxwell linear theory with magnetic charge. Analogous approach is possible in the Yang-Mills theory. In this case the dual-invariant non-Abelian theory motion equations possess the same instanton solutions as the conventional Yang-Mills equations have. An Abelian two-parameter dual group is found to exist in gravitation. Irreducible representations have been obtained: the curvature tensor was expanded into the sum of twice anti-self-dual and self-dual parts. Gravitational instantons are defined as (real )solutions to the usual duality equations. Central symmetry solutions to these equations are obtained. The twice anti-self-dual part of the curvature tensor may be used for introduction of new gravitational equations generalizing Einstein''s equations. However, the theory obtained reduces to the conformal-flat Nordstroem theory

Co-delivery of doxorubicin and arsenite with reduction and pH dual-sensitive vesicle for synergistic cancer therapy

Science.gov (United States)

Zhang, Lu; Xiao, Hong; Li, Jingguo; Cheng, Du; Shuai, Xintao

2016-06-01

Drug resistance is the underlying cause for therapeutic failure in clinical cancer chemotherapy. A prodrug copolymer mPEG-PAsp(DIP-co-BZA-co-DOX) (PDBD) was synthesized and assembled into a nanoscale vesicle comprising a PEG corona, a reduction and pH dual-sensitive hydrophobic membrane and an aqueous lumen encapsulating doxorubicin hydrochloride (DOX.HCl) and arsenite (As). The dual stimulation-sensitive design of the vesicle gave rise to rapid release of the physically entrapped DOX.HCl and arsenite inside acidic lysosomes, and chemically conjugated DOX inside the cytosol with high glutathione (GSH) concentration. In the optimized concentration range, arsenite previously recognized as a promising anticancer agent from traditional Chinese medicine can down-regulate the expressions of anti-apoptotic and multidrug resistance proteins to sensitize cancer cells to chemotherapy. Consequently, the DOX-As-co-loaded vesicle demonstrated potent anticancer activity. Compared to the only DOX-loaded vesicle, the DOX-As-co-loaded one induced more than twice the apoptotic ratio of MCF-7/ADR breast cancer cells at a low As concentration (0.5 μM), due to the synergistic effects of DOX and As. The drug loading strategy integrating chemical conjugation and physical encapsulation in stimulation-sensitive carriers enabled efficient drug loading in the formulation.Drug resistance is the underlying cause for therapeutic failure in clinical cancer chemotherapy. A prodrug copolymer mPEG-PAsp(DIP-co-BZA-co-DOX) (PDBD) was synthesized and assembled into a nanoscale vesicle comprising a PEG corona, a reduction and pH dual-sensitive hydrophobic membrane and an aqueous lumen encapsulating doxorubicin hydrochloride (DOX.HCl) and arsenite (As). The dual stimulation-sensitive design of the vesicle gave rise to rapid release of the physically entrapped DOX.HCl and arsenite inside acidic lysosomes, and chemically conjugated DOX inside the cytosol with high glutathione (GSH) concentration. In the

77 FR 58849 - Prescription Drug User Fee Act Patient-Focused Drug Development; Public Meeting and Request for...

Science.gov (United States)

2012-09-24

... disease areas to consider. FDA also welcomes public comment on the criteria for disease area selection... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-N-0967...: Food and Drug Administration, HHS. ACTION: Notice of public meeting; request for comments. SUMMARY: The...

Computational methods in drug discovery

OpenAIRE

Sumudu P. Leelananda; Steffen Lindert

2016-01-01

The process for drug discovery and development is challenging, time consuming and expensive. Computer-aided drug discovery (CADD) tools can act as a virtual shortcut, assisting in the expedition of this long process and potentially reducing the cost of research and development. Today CADD has become an effective and indispensable tool in therapeutic development. The human genome project has made available a substantial amount of sequence data that can be used in various drug discovery project...

Dual energy CT

DEFF Research Database (Denmark)

Al-Najami, Issam; Drue, Henrik Christian; Steele, Robert

2017-01-01

and inaccurate with existing methods. Dual Energy Computed Tomography (DECT) enables qualitative tissue differentiation by simultaneous scanning with different levels of energy. We aimed to assess the feasibility of DECT in quantifying tumor response to neoadjuvant therapy in loco-advanced rectal cancer. METHODS...... to determine the average quantitative parameters; effective-Z, water- and iodine-concentration, Dual Energy Index (DEI), and Dual Energy Ratio (DER). These parameters were compared to the regression in the resection specimen as measured by the pathologist. RESULTS: Changes in the quantitative parameters...

Dual Smarandache Curves and Smarandache Ruled Surfaces

OpenAIRE

Tanju KAHRAMAN; Mehmet ÖNDER; H. Hüseyin UGURLU

2013-01-01

In this paper, by considering dual geodesic trihedron (dual Darboux frame) we define dual Smarandache curves lying fully on dual unit sphere S^2 and corresponding to ruled surfaces. We obtain the relationships between the elements of curvature of dual spherical curve (ruled surface) x(s) and its dual Smarandache curve (Smarandache ruled surface) x1(s) and we give an example for dual Smarandache curves of a dual spherical curve.

77 FR 16239 - Medical Device User Fee Act; Public Meeting

Science.gov (United States)

2012-03-20

... different stakeholder interest groups (such as patient advocates, consumer advocates, industry, health... consultations with public stakeholders, the Federal Food, Drug, and Cosmetic Act (FD&C Act) directs FDA to...: FDA is holding this public meeting to hear stakeholders' views on the draft recommendations for the...

Single-transducer dual-frequency ultrasound generation to enhance acoustic cavitation.

Science.gov (United States)

Liu, Hao-Li; Hsieh, Chao-Ming

2009-03-01

Dual- or multiple-frequency ultrasound stimulation is capable of effectively enhancing the acoustic cavitation effect over single-frequency ultrasound. Potential application of this sonoreactor design has been widely proposed such as on sonoluminescence, sonochemistry enhancement, and transdermal drug release enhancement. All currently available sonoreactor designs employed multiple piezoelectric transducers for generating single-frequency ultrasonic waves separately and then these waves were mixed and interfered in solutions. The purpose of this research is to propose a novel design of generating dual-frequency ultrasonic waves with single piezoelectric elements, thereby enhancing acoustic cavitation. Macroscopic bubbles were detected optically, and they were quantified at either a single-frequency or for different frequency combinations for determining their efficiency for enhancing acoustic cavitation. Visible bubbles were optically detected and hydrogen peroxide was measured to quantify acoustic cavitation. Test water samples with different gas concentrations and different power levels were used to determine the efficacy of enhancing acoustic cavitation of this design. The spectrum obtained from the backscattered signals was also recorded and examined to confirm the occurrence of stable cavitation. The results confirmed that single-element dual-frequency ultrasound stimulation can enhance acoustic cavitation. Under certain testing conditions, the generation of bubbles can be enhanced up to a level of five times higher than the generation of bubbles in single-frequency stimulation, and can increase the hydrogen peroxide production up to an increase of one fold. This design may serve as a useful alternative for future sonoreactor design owing to its simplicity to produce dual- or multiple-frequency ultrasound.

Restricted access magnetic materials prepared by dual surface modification for selective extraction of therapeutic drugs from biological fluids

Science.gov (United States)

Wang, Yu; Wang, Yuxia; Chen, Lei; Wan, Qian-Hong

2012-02-01

Magnetic porous particles with dual functionality have been prepared by a two-step procedure and evaluated as novel restricted access materials for extraction of therapeutic agents from biological fluids. The magnetic silica particles served as scaffolds were first modified with diol groups, which were then converted to octadecyl esters through reaction with stearoyl chloride. In the second step, the octadecyl esters on the exterior surface were hydrolyzed by the action of lipase to yield magnetic particles with hydrophobic reversed-phase ligands on the inner surface and biocompatible diol groups on the outer surface. The restricted access behavior of the resulting materials was confirmed by differential binding of small molecules such as methotrexate (MTX), leucovorin (LV) and folic acid (FA) relative to bovine serum albumin. While MTX, LV and FA were all bound to the magnetic particles with high affinity, the adsorption of the protein was markedly reduced due to size exclusion effect. The utility of the magnetic particles for sample preparation was tested in solid-phase extraction of MTX, LV and FA from spiked human serum and the effects of the SPE conditions on the recovery of the analytes were systematically studied. Moreover, the magnetic particle-based sample preparation procedure coupled with reversed-phase liquid chromatography analysis was validated in terms of specificity, linearity and reproducibility. The method was shown to be free from interference of endogenous compounds and linear over the concentration range of 0.5-10 μg/mL for the three drugs studied. The limits of detection for the three drugs in serum were in the range of 0.160-0.302 μg/mL. Reproducibility expressed as the RSD of the recovery for ten replicated extractions at three different concentrations was found to be less than 8.93%. With a unique combination of surface functionality with magnetic cores, the restricted access magnetic particles may be adapted in automated and high

Dual-cycle dielectrophoretic collection rates for probing the dielectric properties of nanoparticles.

Science.gov (United States)

Bakewell, David J; Holmes, David

2013-04-01

A new DEP spectroscopy method and supporting theoretical model is developed to systematically quantify the dielectric properties of nanoparticles using continuously pulsed DEP collection rates. Initial DEP collection rates, that are dependent on the nanoparticle dielectric properties, are an attractive alternative to the crossover frequency method for determining dielectric properties. The new method introduces dual-cycle amplitude modulated and frequency-switched DEP (dual-cycle DEP) where the first collection rate with a fixed frequency acts as a control, and the second collection rate frequency is switched to a chosen value, such that, it can effectively probe the dielectric properties of the nanoparticles. The application of the control means that measurement variation between DEP collection experiments is reduced so that the frequency-switched probe collection is more effective. A mathematical model of the dual-cycle method is developed that simulates the temporal dynamics of the dual-cycle DEP nanoparticle collection system. A new statistical method is also developed that enables systematic bivariate fitting of the multifrequency DEP collection rates to the Clausius-Mossotti function, and is instrumental for determining dielectric properties. A Monte-Carlo simulation validates that collection rates improve estimation of the dielectric properties, compared with the crossover method, by exploiting a larger number of independent samples. Experiments using 200 nm diameter latex nanospheres suspended in 0.2 mS/m KCl buffer yield a nanoparticle conductivity of 26 mS/m that lies within 8% of the expected value. The results show that the dual-frequency method has considerable promise particularly for automated DEP investigations and associated technologies. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Regulatory challenges in developing long-acting antiretrovirals for treatment and prevention of HIV infection.

Science.gov (United States)

Arya, Vikram; Au, Stanley; Belew, Yodit; Miele, Peter; Struble, Kimberly

2015-07-01

To outline some of the regulatory challenges inherent to the development of long-acting antiretrovirals (ARVs) for the treatment or prevention of HIV infection. Despite advances in drug development that have reduced ARV dosing to once daily, suboptimal drug adherence remains an obstacle to successful HIV treatment. Further, large randomized trials of once daily oral ARVs for preexposure prophylaxis (PrEP) have shown that drug adherence correlates strongly with prophylactic effect and study outcomes. Thus, the prospect of developing long-acting ARVs, which may mitigate drug adherence issues, has attracted considerable attention lately. Because of their pharmacokinetic properties, the development of long-acting ARVs can present novel regulatory challenges. Chief among them is determining the appropriate dosing regimen, the need for an oral lead-in, and whether existing data with an approved oral agent, if available, can be leveraged for a treatment or prevention indication. For PrEP, because validated biomarkers are lacking, additional nonclinical studies and evaluation of tissue concentrations in multiple compartments may be necessary to identify optimal dosages. Study design and choice of controls for registrational trials of new long-acting PrEP agents might also prove challenging following the availability of an oral PrEP drug.

Demonstration and evaluation of dual-fuel technology; Demonstration och utvaerdering av dual-fuel-tekniken

Energy Technology Data Exchange (ETDEWEB)

Staalhammar, Per; Erlandsson, Lennart; Willner, Kristina (AVL MTC Motortestcenter AB (Sweden)); Johannesson, Staffan (Ecoplan AB (Sweden))

2011-06-15

There is an increased interest for Dual Fuel (methane-Diesel) applications in Sweden since this technology is seen as one of the more interesting options for a fast and cost effective introduction of biomethane as fuel for HD engines. The Dual Fuel technology has been used for many years, mainly for stationary purpose (generators, pumps and ships) while the Spark Ignited (SI) 'Otto' technology has been used for trucks and busses. One obstacle for introducing Dual Fuel technology for busses and trucks is the EU legislation that don't allow for HD on road certification of Dual Fuel applications. Challenges with the Dual Fuel technology is to develop cost effective applications that is capable of reaching low emissions (especially CH{sub 4} and NO{sub x}) in combination with high Diesel replacement in the test cycles used for on road applications. AVL MTC Motortestcenter AB (hereinafter called AVL) has on commission by SGC (Swedish Gas technical Centre) carried out this project with the objectives to analyze the Dual Fuel (Diesel-methane) technology with focus on emissions, fuel consumption and technical challenges. One important part of this project was to carry out emission tests on selected Dual Fuel applications in Sweden and to compile experiences from existing Dual Fuel technology. This report also summarizes other commonly used technologies for methane engines and compares the Dual Fuel with conventional Diesel and Otto technologies. The major challenges with Dual Fuel applications for on road vehicles will be to develop robust and cost effective solutions that meet the emission legislations (with aged catalysts) and to increase the Diesel replacement to achieve reasonable reduction of green house gases (GHG). This is especially important when biomethane is available as fuel but not Bio-Diesel. It will probably be possible to reach EURO V emission limits with advanced Dual Fuel systems but none of the tested systems reached EURO V emission levels

Prevalence and impact of high platelet reactivity in chronic kidney disease: results from the Assessment of Dual Antiplatelet Therapy with Drug-Eluting Stents registry.

Science.gov (United States)

Baber, Usman; Mehran, Roxana; Kirtane, Ajay J; Gurbel, Paul A; Christodoulidis, Georgios; Maehara, Akiko; Witzenbichler, Bernhard; Weisz, Giora; Rinaldi, Michael J; Metzger, D Christopher; Henry, Timothy D; Cox, David A; Duffy, Peter L; Mazzaferri, Ernest L; Xu, Ke; Parise, Helen; Brodie, Bruce R; Stuckey, Thomas D; Stone, Gregg W

2015-06-01

Chronic kidney disease (CKD) is associated with increased rates of adverse events after percutaneous coronary intervention. We sought to determine the impact of CKD on platelet reactivity in clopidogrel-treated patients and whether high platelet reactivity (HPR) confers a similar or differential risk for adverse events among patients with CKD and non-CKD. We performed a post hoc analysis of the Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents (ADAPT-DES) registry, which included 8582 patients undergoing percutaneous coronary intervention with drug-eluting stents and platelet function testing using the VerifyNow assay. We compared HPR and its impact on ischemic and bleeding events >2 years among patients with CKD and non-CKD. Patients with CKD (n=1367) were older, more often female, diabetic, and had lower ejection fraction compared with their non-CKD counterparts (n=7043). Although HPR prevalence increased with worsening renal function in unadjusted analyses, these associations were no longer present after adjustment. Major adverse cardiac event rates at 2 years among those without CKD or HPR, HPR alone, CKD alone, and both CKD and HPR were 9.0%, 11.2%, 13.3%, and 17.5%, respectively (Pimpact of HPR on ischemic and bleeding events is similar irrespective of CKD status. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00638794. © 2015 American Heart Association, Inc.

Dual Regression

OpenAIRE

Spady, Richard; Stouli, Sami

2012-01-01

We propose dual regression as an alternative to the quantile regression process for the global estimation of conditional distribution functions under minimal assumptions. Dual regression provides all the interpretational power of the quantile regression process while avoiding the need for repairing the intersecting conditional quantile surfaces that quantile regression often produces in practice. Our approach introduces a mathematical programming characterization of conditional distribution f...

How Do Dual Long-acting Bronchodilators Prevent Exacerbations of Chronic Obstructive Pulmonary Disease?

DEFF Research Database (Denmark)

Beeh, Kai M; Burgel, Pierre-Regis; Franssen, Frits M E

2017-01-01

that combinations of long-acting β2-adrenergic agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) provide greater reductions in exacerbation frequency than either their monocomponents or LABA/inhaled corticosteroids (LABA/ICS) combinations in patients at low and high risk for these events....... In this review, small groups of experts critically evaluated mechanisms potentially responsible for the increased benefit of LABA/LAMA combinations over single LABDs or LABA/ICS in decreasing exacerbation. These included effects on lung hyperinflation and mechanical stress, inflammation, excessive mucus...... production with impaired mucociliary clearance, and symptom severity. The data assembled and analyzed by each group were reviewed by all authors and combined into this manuscript. Available clinical results support the possibility that effects of LABA/LAMA combinations on hyperinflation, mucociliary...

Dual Orlicz geominimal surface area

Directory of Open Access Journals (Sweden)

Tongyi Ma

2016-02-01

Full Text Available Abstract The L p $L_{p}$ -geominimal surface area was introduced by Lutwak in 1996, which extended the important concept of the geominimal surface area. Recently, Wang and Qi defined the p-dual geominimal surface area, which belongs to the dual Brunn-Minkowski theory. In this paper, based on the concept of the dual Orlicz mixed volume, we extend the dual geominimal surface area to the Orlicz version and give its properties. In addition, the isoperimetric inequality, a Blaschke-Santaló type inequality, and the monotonicity inequality for the dual Orlicz geominimal surface areas are established.

20 CFR 638.511 - Drug use and abuse.

Science.gov (United States)

2010-04-01

... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Drug use and abuse. 638.511 Section 638.511... TITLE IV-B OF THE JOB TRAINING PARTNERSHIP ACT Center Operations § 638.511 Drug use and abuse. The Job... and education programs related to drug and alcohol use and abuse. ...

Analysis of U.S. Food and Drug Administration food allergen recalls after implementation of the food allergen labeling and consumer protection act.

Science.gov (United States)

Gendel, Steven M; Zhu, Jianmei

2013-11-01

To avoid potentially life-threatening reactions, food allergic consumers rely on information on food labels to help them avoid exposure to a food or ingredient that could trigger a reaction. To help consumers in the United States obtain the information that they need, the Food Allergen Labeling and Consumer Protection Act of 2004 defined a major food allergen as being one of eight foods or food groups and any ingredient that contains protein from one of these foods or food groups. A food that contains an undeclared major food allergen is misbranded under the U.S. Food, Drug, and Cosmetic Act and is subject to recall. Food allergen labeling problems are the most common cause of recalls for U.S. Food and Drug Administration (FDA)-regulated food products. To help understand why food allergen recalls continue to occur at a high rate, information on each food allergen recall that occurred in fiscal years 2007 through 2012 was obtained from the FDA recall database. This information was analyzed to identify the food, allergen, root cause, and mode of discovery for each food allergen recall. Bakery products were the most frequently recalled food type, and milk was the most frequently undeclared major food allergen. Use of the wrong package or label was the most frequent problem leading to food allergen recalls. These data are the first reported that indicate the importance of label and package controls as public health measures.

Dual-band dual-polarized array for WLAN applications

CSIR Research Space (South Africa)

Steyn, JM

2009-01-01

Full Text Available dual-band dual-polarized (DBDP) antenna design for WLAN applications. The antenna is in the form of an array consisting of four double-dipole radiators. The basic radiating element consists of a rhombus shaped dipole above a planar ground plane... the ground planes and the respective feedlines. Substrate cuts and difierent heights for the horizontal feedlines were necessary to achieve the latter. The 2nd conflguration (for vertical polarization) has a slightly difierent feeding network layout...

77 FR 60125 - Generic Drug Facilities, Sites and Organizations

Science.gov (United States)

2012-10-02

...] Generic Drug Facilities, Sites and Organizations AGENCY: Food and Drug Administration, HHS. ACTION: Notice..., and certain sites and organizations identified in a generic drug submission, that they must provide... and Innovation Act (FDASIA). This notice is intended to help organizations ascertain if they need to...

El anillo de los números duales

OpenAIRE

Jiménez, Haydee; Luque, Carlos Julio

2007-01-01

Se inicia con una presentación de la estructura de * - Álgebra de los números duales; se muestran diferentes representaciones que permiten la definición de potencias racionales de números duales, lo que exige una extensión de su estructura a un anillo de números duales con coeficientes complejos. Seguidamente se estudian la función exponencial dual y la función logaritmo dual que permiten la definición de potencias duales de un número dual; luego se estudian ecuaciones en los números duales h...

Federal Strategy for Prevention of Drug Abuse and Drug Trafficking, 1982. Prepared for the President Pursuant to the Drug Abuse Office and Treatment Act of 1972.

Science.gov (United States)

Office of Policy Development, Washington, DC.

This document describes the Federal response to drug abuse and drug trafficking. The actions of President Reagan, in Executive Order 12368, establishing an official advisor on drug abuse policy matters, and the priorities, issues, and objectives (international cooperation, drug law enforcement, education and prevention, detoxification and…

Drug-loaded poly (ε-caprolactone)/Fe3O4 composite microspheres for magnetic resonance imaging and controlled drug delivery

Science.gov (United States)

Wang, Guangshuo; Zhao, Dexing; Li, Nannan; Wang, Xuehan; Ma, Yingying

2018-06-01

In this study, poly (ε-caprolactone) (PCL) microspheres loading magnetic Fe3O4 nanoparticles and anti-cancer drug of doxorubicin hydrochloride (DOX) were successfully prepared by a modified solvent-evaporation method. The obtained magnetic composite microspheres exhibited dual features of magnetic resonance imaging and controlled drug delivery. The morphology, structure, thermal behavior and magnetic properties of the drug-loaded magnetic microspheres were investigated in detail by SEM, XRD, DSC and SQUID. The obtained composite microspheres showed superparamagnetic behavior and T2-weighted enhancement effect. The drug loading, encapsulation efficiency, releasing behavior and in vitro cytotoxicity of the drug-loaded composite microspheres were systematically investigated. It was found that the values of drug loading and encapsulation efficiency were 36.7% and 25.8%, respectively. The composite microspheres were sensitive to pH and released in a sustained way, and both the release curves under various pH conditions (4.0 and 7.4) were well satisfied with the biphase kinetics function. In addition, the magnetic response of the drug-loaded microspheres was studied and the results showed that the composite microspheres had a good magnetic stability and strong targeting ability.

Combined use of drugs inhibiting the renin–angiotensin system: prescribing patterns and risk of acute kidney injury in German nursing home residents

Directory of Open Access Journals (Sweden)

Dörks M

2018-05-01

Full Text Available Michael Dörks,1 Stefan Herget-Rosenthal,2 Falk Hoffmann,1 Kathrin Jobski1 1Department of Health Services Research, Carl von Ossietzky University Oldenburg, Oldenburg, Germany; 2Department of Medicine, Rotes Kreuz Krankenhaus, Bremen, Germany Background/aims: In 2012, the European Medicines Agency reviewed the safety of dual renin–angiotensin system (RAS blockade because of potentially increased risks for inter alia acute kidney injury (AKI. Since residents of nursing homes are particularly vulnerable to adverse drug outcomes, the aims of our study were to describe RAS-inhibiting drug use in German nursing home residents and examine the risk of AKI associated with dual RAS blockade.Methods: Based on claims data, a nested case-control study within a cohort of RAS-inhibiting drug users was conducted. Using conditional logistic regression, confounder-adjusted odds ratios (aORs and 95% confidence intervals (CI were obtained for the risk of AKI associated with dual RAS blockade. Subgroup analyses were performed in patients with diabetes or chronic kidney disease and both comorbidities.Results: Of all 127,227 nursing home residents, the study cohort included 64,567 (50.7% who were treated with at least one RAS-inhibiting drug. More than three quarters of the study population were female (77.1%. Mean age was 86.0 ± 6.8 years. Most residents were treated with angiotensin-converting enzyme inhibitors (77.8%, followed by angiotensin II receptor blockers (21.6% and aliskiren (0.2%. Annual prevalence of dual RAS blockade declined from 9.6 (95% CI 7.8–11.8 in 2010 to 4.7 (95% CI 4.0–5.4 per 1,000 users in 2014. In the overall cohort, AKI was not significantly associated with dual RAS blockade (aOR 1.99; 0.77–5.17. However, significantly increased aORs were observed when considering patients with diabetes (3.47; 1.27–9.47, chronic kidney disease (4.74; 1.24–18.13 or both (11.17; 2.65–47.15.Conclusions: Prescribing of drugs inhibiting the RAS is

Nonword Reading: Comparing Dual-Route Cascaded and Connectionist Dual-Process Models with Human Data

Science.gov (United States)

Pritchard, Stephen C.; Coltheart, Max; Palethorpe, Sallyanne; Castles, Anne

2012-01-01

Two prominent dual-route computational models of reading aloud are the dual-route cascaded (DRC) model, and the connectionist dual-process plus (CDP+) model. While sharing similarly designed lexical routes, the two models differ greatly in their respective nonlexical route architecture, such that they often differ on nonword pronunciation. Neither…

Dual-Recycling Channel Decision in a Closed-Loop Supply Chain with Cost Disruptions

Directory of Open Access Journals (Sweden)

Yanting Huang

2017-11-01

Full Text Available This paper investigates cost disruptions of new and remanufactured products in a closed-loop supply chain where a manufacturer and a third-party collector recycle used products through online-recycling and offline-recycling channels, respectively. We use a Stackelberg game to acquire the equilibrium decisions of dual-recycling and single-recycling channels and analyze how cost disruptions affect the manufacturer’ production and collection strategies. We show that, cost disruption of new products produces a positive impact whilst the remanufacturing cost disruption has a negative impact on collection quantity of used products and negative cost disruptions of both new and remanufactured products could be profitable to the manufacturer. As for the manufacturer’s channel choice, the dual-recycling channel dominates single-recycling channels when new product cost faces positive disruption, because the manufacturer acts as both a buyer and a competitor to the collector and can determine an appropriate acquisition price and transfer price to coordinate the online-offline recycling channel. While if cost disruption of new products is negative, the manufacturer prefers the dual-recycling channel instead of single-recycling channels only if the remanufacturing cost faces large size of negative disruption.

Dual-Functional Nanoparticles Targeting CXCR4 and Delivering Antiangiogenic siRNA Ameliorate Liver Fibrosis.

Science.gov (United States)

Liu, Chun-Hung; Chan, Kun-Ming; Chiang, Tsaiyu; Liu, Jia-Yu; Chern, Guann-Gen; Hsu, Fu-Fei; Wu, Yu-Hsuan; Liu, Ya-Chi; Chen, Yunching

2016-07-05

The progression of liver fibrosis, an intrinsic response to chronic liver injury, is associated with hepatic hypoxia, angiogenesis, abnormal inflammation, and significant matrix deposition, leading to the development of cirrhosis and hepatocellular carcinoma (HCC). Due to the complex pathogenesis of liver fibrosis, antifibrotic drug development has faced the challenge of efficiently and specifically targeting multiple pathogenic mechanisms. Therefore, CXCR4-targeted nanoparticles (NPs) were formulated to deliver siRNAs against vascular endothelial growth factor (VEGF) into fibrotic livers to block angiogenesis during the progression of liver fibrosis. AMD3100, a CXCR4 antagonist that was incorporated into the NPs, served dual functions: it acted as a targeting moiety and suppressed the progression of fibrosis by inhibiting the proliferation and activation of hepatic stellate cells (HSCs). We demonstrated that CXCR4-targeted NPs could deliver VEGF siRNAs to fibrotic livers, decrease VEGF expression, suppress angiogenesis and normalize the distorted vessels in the fibrotic livers in the carbon tetrachloride (CCl4) induced mouse model. Moreover, blocking SDF-1α/CXCR4 by CXCR4-targeted NPs in combination with VEGF siRNA significantly prevented the progression of liver fibrosis in CCl4-treated mice. In conclusion, the multifunctional CXCR4-targeted NPs delivering VEGF siRNAs provide an effective antifibrotic therapeutic strategy.

Spinning self-dual particles

International Nuclear Information System (INIS)

Gamboa, J.; Rivelles, V.O.

1989-02-01

We study spinning self-dual particles in two dimensions. They are obtained from the chiral bosonic particle through the square root technique. We show that the resulting field theory can be either fermionic or bosonic and that the associated self-dual field reveals its Lorentz tensor structure which remains hidden in the usual formulations. We also calculate the spinning self-dual particle propagators using the BFV formalism. (author) [pt

Assessment of Dual Life Stage Antiplasmodial Activity of British Seaweeds

Directory of Open Access Journals (Sweden)

Deniz Tasdemir

2013-10-01

Full Text Available Terrestrial plants have proven to be a prolific producer of clinically effective antimalarial drugs, but the antimalarial potential of seaweeds has been little explored. The main aim of this study was to assess the in vitro chemotherapeutical and prophylactic potential of the extracts of twenty-three seaweeds collected from the south coast of England against blood stage (BS and liver stage (LS Plasmodium parasites. The majority (14 of the extracts were active against BS of P. falciparum, with brown seaweeds Cystoseira tamariscifolia, C. baccata and the green seaweed Ulva lactuca being the most active (IC50s around 3 μg/mL. The extracts generally had high selectivity indices (>10. Eight seaweed extracts inhibited the growth of LS parasites of P. berghei without any obvious effect on the viability of the human hepatoma (Huh7 cells, and the highest potential was exerted by U. lactuca and red seaweeds Ceramium virgatum and Halopitys incurvus (IC50 values 14.9 to 28.8 μg/mL. The LS-active extracts inhibited one or more key enzymes of the malarial type-II fatty acid biosynthesis (FAS-II pathway, a drug target specific for LS. Except for the red seaweed Halopitys incurvus, all LS-active extracts showed dual activity versus both malarial intracellular stage parasites. This is the first report of LS antiplasmodial activity and dual stage inhibitory potential of seaweeds.

[Drugs use in pregnancy in the Valencia Region and the risk of congenital anomalies].

Science.gov (United States)

Cavero-Carbonell, Clara; Gimeno-Martos, Silvia; Páramo-Rodríguez, Lucía; Rabanaque-Hernández, María José; Martos-Jiménez, Carmen; Zurriaga, Óscar

2017-09-01

Despite the potential risks of drug use during pregnancy, consumption has increased in recent decades. To identify the risk of congenital anomalies (CA) associated with the use of drugs in primary care in pregnant women residents in the Valencia Region. A case-control study, considering a case as a less than one year old live birth in 2009-2010, diagnosed with a CA and resident in the Valencia Region, obtained from the CA population-based registry. Controls were selected from the Metabolic Disease Registry, and the drugs prescribed and dispensed from the Integral Management of Pharmaceutical Services. Crude odds ratio (OR) was calculated with its 95% confidence intervals and adjusted OR was calculated using logistic regression. A total of 1,913 cases and 3,826 controls were identified. The most frequently used drug groups were those acting on the musculoskeletal, nervous and respiratory systems, on the blood and blood forming organs, and anti-infection drugs. The most common drugs used were ibuprofen, dexketoprofen, paracetamol, amoxicillin, ferrous sulphate, and a combination of folic acid. A significantly increased risk of CA was identified for drugs acting on the musculoskeletal system (adjusted OR 1.14 [95% confidence interval 1.02-1.28]). A significantly decreased risk was observed for drugs acting on the blood and blood forming organs (adjusted OR 0.87 [95% confidence interval 0.78-0.98]). Associations between drugs and CA in pregnant women resident in the Valencia Region have been identified for drugs that act as risk factors of CA, and for drugs that act as protective factors of CA. Copyright © 2016 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

Reconstructed Living Lab: supporting drug users and families ...

African Journals Online (AJOL)

based organisations are discussed. Data on relatives of drug users using the system are included. Conclusion: The use of mobile phone technology has advantages for community-based organisations acting as a first point of contact to drug ...

Dietary flavonoid fisetin: A novel dual inhibitor of PI3K/Akt and mTOR for prostate cancer management

Science.gov (United States)

Adhami, Vaqar Mustafa; Syed, Deeba; Khan, Naghma; Mukhtar, Hasan

2013-01-01

Epidemiologic and case control population based studies over the past few decades have identified diet as an important determinant of cancer risk. This evidence has kindled an interest into research on bioactive food components and has till date resulted in the identification of many compounds with cancer preventive and therapeutic potential. Among such compounds has been fisetin (3,7,3’,4’-tetrahydroxyflavone), a flavonol and a member of the flavonoid polyphenols that also include quercetin, myricetin and kaempferol. Fisetin is commonly found in many fruits and vegetables such as apples, persimmons, grapes, kiwis, strawberries, onions and cucumbers. We evaluated the effects of fisetin against melanoma and cancers of the prostate, pancreas and the lungs. Using prostate and lung adenocarcinoma cells, we observed that fisetin acts as a dual inhibitor of the PI3K/Akt and the mTOR pathways. This is a significant finding considering the fact that mTOR is phosphorylated and its activation is more frequent in tumors with overexpression of PI3K/Akt. Dual inhibitors of PI3K/Akt and mTOR signaling have been suggested as valuable agents for treating such cancers. Here, we summarize our findings on the dietary flavonoid fisetin and its effects on cancer with particular focus on prostate cancer. Our observations and findings from other laboratories suggest that fisetin could be a useful chemotherapeutic agent that could be used either alone or as an adjuvant with conventional chemotherapeutic drugs for the management of prostate and other cancers. PMID:22842629

Dual-targeting immunoliposomes using angiopep-2 and CD133 antibody for glioblastoma stem cells.

Science.gov (United States)

Kim, Jung Seok; Shin, Dae Hwan; Kim, Jin-Seok

2018-01-10

Glioblastoma stem cells (GSCs), which are identified as subpopulation of CD133 + /ALDH1 + , are known to show resistance to the most of chemotherapy and radiation therapy, leading to the recurrence of tumor in glioblastoma multiforme (GBM) patients. Also, delivery of temozolomide (TMZ), a mainline treatment of GBM, to the GBM site is hampered by various barriers including the blood-brain barrier (BBB). A dual-targeting immunoliposome encapsulating TMZ (Dual-LP-TMZ) was developed by using angiopep-2 (An2) and anti-CD133 monoclonal antibody (CD133 mAb) for BBB transcytosis and specific delivery to GSCs, respectively. The size, zeta potential and drug encapsulation efficiency of Dual-LP-TMZ were 203.4nm in diameter, -1.6mV and 99.2%, respectively. The in vitro cytotoxicity of Dual-LP-TMZ against U87MG GSCs was increased by 425- and 181-folds when compared with that of free TMZ and non-targeted TMZ liposome (LP-TMZ) (10.3μM vs. 4380μM and 1869μM in IC 50 , respectively). Apoptosis and anti-migration ability of Dual-LP-TMZ in U87MG GSCs were also significantly enhanced comparing with those of free TMZ or LP-TMZ. In vivo study clearly showed a significant reduction in tumor size after intravenous administrations of Dual-LP-TMZ to the orthotopically-implanted brain tumor mice when compared with free TMZ or LP-TMZ. Increased life span (ILS) and median survival time (MST) of tumor-bearing mice were also increased when treated with Dual-LP-TMZ (211.2% in ILS and 49.2days in MST) than with free TMZ (0% in ILS and 23.3day in MST). These data indicate that conjugation of both An2 peptide and CD133 mAb to TMZ-encapsulating liposome is very effective in delivering the TMZ to GSCs via BBB, suggesting a potential use of Dual-LP-TMZ as a therapeutic modality for GBM. Copyright © 2017 Elsevier B.V. All rights reserved.

Dual-responsive surfaces modified with phenylboronic acid-containing polymer brush to reversibly capture and release cancer cells.

Science.gov (United States)

Liu, Hongliang; Li, Yingying; Sun, Kang; Fan, Junbing; Zhang, Pengchao; Meng, Jingxin; Wang, Shutao; Jiang, Lei

2013-05-22

Artificial stimuli-responsive surfaces that can mimic the dynamic function of living systems have attracted much attention. However, there exist few artificial systems capable of responding to dual- or multistimulation as the natural system does. Herein, we synthesize a pH and glucose dual-responsive surface by grafting poly(acrylamidophenylboronic acid) (polyAAPBA) brush from aligned silicon nanowire (SiNW) array. The as-prepared surface can reversibly capture and release targeted cancer cells by precisely controlling pH and glucose concentration, exhibiting dual-responsive AND logic. In the presence of 70 mM glucose, the surface is pH responsive, which can vary from a cell-adhesive state to a cell-repulsive state by changing the pH from 6.8 to 7.8. While keeping the pH at 7.8, the surface becomes glucose responsive--capturing cells in the absence of glucose and releasing cells by adding 70 mM glucose. Through simultaneously changing the pH and glucose concentration from pH 6.8/0 mM glucose to pH 7.8/70 mM glucose, the surface is dual responsive with the capability to switch between cell capture and release for at least 5 cycles. The cell capture and release process on this dual-responsive surface is noninvasive with cell viability higher than 95%. Moreover, topographical interaction between the aligned SiNW array and cell protrusions greatly amplifies the responsiveness and accelerates the response rate of the dual-responsive surface between cell capture and release. The responsive mechanism of the dual-responsive surface is systematically studied using a quartz crystal microbalance, which shows that the competitive binding between polyAAPBA/sialic acid and polyAAPBA/glucose contributes to the dual response. Such dual-responsive surface can significantly impact biomedical and biological applications including cell-based diagnostics, in vivo drug delivery, etc.

Exploring drug-target interaction networks of illicit drugs.

Science.gov (United States)

Atreya, Ravi V; Sun, Jingchun; Zhao, Zhongming

2013-01-01

Drug addiction is a complex and chronic mental disease, which places a large burden on the American healthcare system due to its negative effects on patients and their families. Recently, network pharmacology is emerging as a promising approach to drug discovery by integrating network biology and polypharmacology, allowing for a deeper understanding of molecular mechanisms of drug actions at the systems level. This study seeks to apply this approach for investigation of illicit drugs and their targets in order to elucidate their interaction patterns and potential secondary drugs that can aid future research and clinical care. In this study, we extracted 188 illicit substances and their related information from the DrugBank database. The data process revealed 86 illicit drugs targeting a total of 73 unique human genes, which forms an illicit drug-target network. Compared to the full drug-target network from DrugBank, illicit drugs and their target genes tend to cluster together and form four subnetworks, corresponding to four major medication categories: depressants, stimulants, analgesics, and steroids. External analysis of Anatomical Therapeutic Chemical (ATC) second sublevel classifications confirmed that the illicit drugs have neurological functions or act via mechanisms of stimulants, opioids, and steroids. To further explore other drugs potentially having associations with illicit drugs, we constructed an illicit-extended drug-target network by adding the drugs that have the same target(s) as illicit drugs to the illicit drug-target network. After analyzing the degree and betweenness of the network, we identified hubs and bridge nodes, which might play important roles in the development and treatment of drug addiction. Among them, 49 non-illicit drugs might have potential to be used to treat addiction or have addictive effects, including some results that are supported by previous studies. This study presents the first systematic review of the network

Cocaine abuse or dependency and other pyschiatric disorders. Madrid study on dual pathology.

Science.gov (United States)

Arias, Francisco; Szerman, Nestor; Vega, Pablo; Mesias, Beatriz; Basurte, Ignacio; Morant, Consuelo; Ochoa, Enriqueta; Poyo, Félix; Babin, Francisco

2013-01-01

The main objective of this study was to analyse the cocaine addict subgroup from the Madrid study of prevalence of dual disorders in community mental health and substance misuse services. The sample consisted of 837 outpatients from Madrid, Spain. We compared 488 subjects who had a lifetime diagnosis of cocaine abuse or dependence, and 222 subjects who did not have a cocaine substance use disorder. We used the Mini International Neuropsychiatric Interview to evaluate axis I mental disorders, and the Personality Disorder Questionnaire to evaluate personality disorders. Almost three-quarters (73.4%) of cocaine addicts had a current dual disorder. Most prevalent were mood and anxiety disorders. Almost half (49.6%) had a personality disorder. Most of them (94.9%) had other substance use disorders. Cocaine addicts did not have higher prevalence rates of dual pathology than addicts with no cocaine abuse or dependence. Cocaine addicts were associated to a diagnosis of antisocial personality disorder, agoraphobia, and post-traumatic stress disorder, and they had an early age of onset of alcohol and cannabis use. Dual pathology is no higher in cocaine addicts in treatment than in addicts who do not use cocaine, however cocaine addicts started other drugs earlier, and were associated with specific mental disorders. Copyright © 2012 SEP y SEPB. Published by Elsevier Espana. All rights reserved.

Stimuli-Responsive Mesoporous Silica NPs as Non-viral Dual siRNA/Chemotherapy Carriers for Triple Negative Breast Cancer

Directory of Open Access Journals (Sweden)

Behrad Darvishi

2017-06-01

Full Text Available Triple negative breast cancer (TNBC is the most aggressive and lethal subtype of breast cancer. It is associated with a very poor prognosis and intrinsically resistant to several conventional and targeted chemotherapy agents and has a 5-year survival rate of less than 25%. Because the treatment options for TNBC are very limited and not efficient enough for achieving minimum desired goals, shifting toward a new generation of anti-cancer agents appears to be very critical. Among recent alternative approaches being proposed, small interfering RNA (siRNA gene therapy can potently suppress Bcl-2 proto-oncogene and p-glycoprotein gene expression, the most important chemotherapy resistance inducers in TNBC. When resensitized, primarily ineffective chemotherapy drugs turn back into valuable sources for further intensive chemotherapy. Regrettably, siRNA’s poor stability, rapid clearance in the circulatory system, and poor cellular uptake mostly hampers the beneficial outcomes of siRNA therapy. Considering these drawbacks, dual siRNA/chemotherapy drug encapsulation in targeted delivery vehicles, especially mesoporous silica nanoparticles (MSNs appears to be the most reasonable solution. The literature is full of reports of successful treatments of multi-drug-resistant cancer cells by administration of dual drug/siRNA-loaded MSNs. Here we tried to answer the question of whether application of a similar approach with identical delivery devices in TNBC is rational.

Knowing "and" Acting in the Clinical Workplace: Trainees' Perspectives on Modelling and Feedback

Science.gov (United States)

Stegeman, J. H.; Schoten, E. J.; Terpstra, O. T.

2013-01-01

In this article we discuss clinical workplace learning using a dual approach: a theoretical one and an empirical one. Drawing on the philosophical work of Aristotle, Polanyi and Schön we posit that the "knowing 'and' acting" underpinning day-to-day medical practice is personal and embraces by nature a tacit dimension.…

Construction of dual-functional polymer nanomaterials with near-infrared fluorescence imaging and polymer prodrug by RAFT-mediated aqueous dispersion polymerization.

Science.gov (United States)

Tian, Chun; Niu, Jinyun; Wei, Xuerui; Xu, Yujie; Zhang, Lifen; Cheng, Zhenping; Zhu, Xiulin

2018-05-31

The performance of functional polymer nanomaterials is a vigorously discussed topic in polymer science. We devoted ourselves to investigating polymer nanomaterials based on near-infrared (NIR) fluorescence imaging and polymer prodrug in this study. Aza-boron dipyrromethene (BODIPY) is an important organic dye, having characteristics such as environmental resistance, light resistance, high molar extinction coefficient, and fluorescence quantum yield. We incorporated it into our target monomer, which can be polymerized without changing its parent structure in a polar solvent and copolymerized with water-soluble monomer to improve the solubility of the dye in an aqueous solution. At the same time, the hydrophobic drug camptothecin (CPT) was designed as a prodrug monomer, and the polymeric nanoparticles (NPs) with NIR fluorescence imaging and prodrug were synthesized in situ in reversible addition-fragmentation chain transfer (RAFT)-mediated aqueous dispersion polymerization. The dynamic light scattering (DLS) and transmission electron microscopy (TEM) revealed the final uniform size of the dual-functional polymeric NPs morphology. The dual-functional polymeric NPs had a strong absorption and emission signal in the NIR region (>650 nm) based on the fluorescence tests. In consideration of the long-term biological toxicity, confocal laser scanning microscopy (CLSM) results indicated that the dual-functional NPs with controlled drug content exhibited effective capability of killing HeLa cells. In addition, in vivo imaging of the dual-functional NPs was observed in real time, and the fluorescent signals clearly demonstrated the dynamic process of prodrug transfer.

Dual thyroid ectopia

International Nuclear Information System (INIS)

Al-Akeely, Mohammed H.

2003-01-01

Ectopic thyroid gland is a rare embryological fault of thyroid development .Dual ectopic thyroid is more rare and only 8 cases have been reported in the literature. The author presents a case of dual ectopic thyroid in a 16 year old boy with an anterior red neck mass, which is gradually growing in size particularly in last 2 years. The initial diagnosis was thyroglossal duct cyst. Thyroid function test revealed elevated thyroid-stimulating hormone. Ultrasound of the neck did not show thyroid gland in its normal pre tracheal position. Thyroid scan (Technetium 99)revealed the diagnosis of dual thyroid ectopia(lingual and subhyoid). (author)

The DNP/MPH Dual Degree: An Innovative Graduate Education Program for Advanced Public Health Nursing.

Science.gov (United States)

Shaw, Kathy; Harpin, Scott; Steinke, Geraldine; Stember, Marilyn; Krajicek, Marilyn

2017-03-01

Strong professional priorities, evolving Affordable Care Act requirements, and a significantly limited public health nursing workforce prompted the University of Colorado College of Nursing to collaborate with the School of Public Health to implement one of the first Doctor of Nursing Practice/Master of Public Health dual degree programs in the nation. Federal grant funding supported the development, implementation, and evaluation of this unique post-baccalaureate dual degree program, for which there were no roadmaps, models, or best practices to follow. Several key issues emerged that serve as lessons learned in creating a new, novel higher education pathway for Advanced Public Health Nursing. This paper highlights two of those: (1) marketing, admission, and matriculation across two programs, and (2) enhancing curricula through distance coursework and interprofessional education. When collaboration with a school of public health is possible, the Doctor of Nursing Practice/Master of Public Health dual degree is an efficient way to prepare public health nurses' with the highest level of public health knowledge, practice, and leadership expertise. © 2016 Wiley Periodicals, Inc.

Dual-functional transdermal drug delivery system with controllable drug loading based on thermosensitive poloxamer hydrogel for atopic dermatitis treatment

Science.gov (United States)

Wang, Wenyi; Wat, Elaine; Hui, Patrick C. L.; Chan, Ben; Ng, Frency S. F.; Kan, Chi-Wai; Wang, Xiaowen; Hu, Huawen; Wong, Eric C. W.; Lau, Clara B. S.; Leung, Ping-Chung

2016-04-01

The treatment of atopic dermatitis (AD) has long been viewed as a problematic issue by the medical profession. Although a wide variety of complementary therapies have been introduced, they fail to combine the skin moisturizing and drug supply for AD patients. This study reports the development of a thermo-sensitive Poloxamer 407/Carboxymethyl cellulose sodium (P407/CMCs) composite hydrogel formulation with twin functions of moisture and drug supply for AD treatment. It was found that the presence of CMCs can appreciably improve the physical properties of P407 hydrogel, which makes it more suitable for tailored drug loading. The fabricated P407/CMCs composite hydrogel was also characterized in terms of surface morphology by field emission scanning electron microscopy (FE-SEM), rheological properties by a rheometer, release profile in vitro by dialysis method and cytotoxicity test. More importantly, the findings from transdermal drug delivery behavior revealed that P407/CMCs showed desirable percutaneous performance. Additionally, analysis of cytotoxicity test suggested that P407/CMCs composite hydrogel is a high-security therapy for clinical trials and thus exhibits a promising way to treat AD with skin moisturizing and medication.

Crime Control Act of 1990 [29 November 1990]. [Summary].

Science.gov (United States)

1990-01-01

In the US, the Crime Control Act of 1990 was approved on November 29, 1990. This various titles of this Act include provisions relating to the following: 1) international money laundering; 2) child abuse; 3) child pornography; 4) kidnapping, abducting, or unlawfully restraining a child; 5) the protection of crime victims; 6) funding for local law enforcement agencies; 7) funding for federal law enforcement; 8) rural drug enforcement assistance; 9) mandatory detention for certain criminals; 10) juvenile justice; 11) penalties for use of certain firearms; 12) improvements in miscellaneous criminal law; 13) disability benefits for public safety officers; 14) money laundering; 15) drug-free school zones; 16) miscellaneous amendments to the federal judicial and criminal codes; 17) general provisions; 18) grants for correctional options; 19) control of anabolic steroids; 20) asset forfeiture; 21) student loan cancellation for law enforcement officers; 22) firearms provisions; 23) chemical diversion and trafficking; 24) drug paraphernalia; 25) banking law enforcement; 26) licit opium imports; 27) sentencing for methamphetamine offenses; 28) drug enforcement grants; 29) prisons; 30) shock incarceration (prison boot camps); 31) bankruptcy and restitution; 32) appropriations for law and drug enforcement agencies; 33) anti-drug programs; 34) support of law enforcement; 35) technical and minor substantive amendments to the federal criminal code; 36) federal debt collection; and 37) national child search assistance (for missing children).

The Dual Orlicz-Brunn-Minkowski Theory

OpenAIRE

Gardner, Richard J.; Hug, Daniel; Weil, Wolfgang; Ye, Deping

2014-01-01

This paper introduces the dual Orlicz-Brunn-Minkowski theory for star sets. A radial Orlicz addition of two or more star sets is proposed and a corresponding dual Orlicz-Brunn-Minkowski inequality is established. Based on a radial Orlicz linear combination of two star sets, a formula for the dual Orlicz mixed volume is derived and a corresponding dual Orlicz-Minkowski inequality proved. The inequalities proved yield as special cases the precise duals of the conjectured log-Brunn-Minkowski and...

Dual centrifugation - A new technique for nanomilling of poorly soluble drugs and formulation screening by an DoE-approach.

Science.gov (United States)

Hagedorn, Martin; Bögershausen, Ansgar; Rischer, Matthias; Schubert, Rolf; Massing, Ulrich

2017-09-15

The development of nanosuspensions of poorly soluble APIs takes a lot of time and high amount of active material is needed. In this publication the use of dual centrifugation (DC) for an effective and rapid API-nanomilling is described for the first time. DC differs from normal centrifugation by an additional rotation of the samples during centrifugation, resulting in a very fast and powerful movement of the samples inside the vials, which - in combination with milling beads - result in effective milling. DC-nanomilling was compared to conventional wet ball milling and results in same or even smaller particle sizes. Also drug concentrations up to 40% can be processed. The process is fast (typical 90min) and the temperature can be controlled. DC-nanomilling appears to be very gentle, experiments showed no change of the crystal structure during milling. Since batch sizes are very small (100-1000mg) and since 40 sample vials can be processed in parallel, DC is ideal for the screening of suitable polymer/surfactant combinations. Fenofibrate was used to investigate DC-nanomilling for formulation screening by applying a DoE-approach. The presented data also show that the results of DC-nanomilling experiments are highly comparable to the results obtained by common agitator mills. Copyright © 2017 Elsevier B.V. All rights reserved.

78 FR 36711 - Food and Drug Administration Safety and Innovation Act Title VII-Drug Supply Chain; Standards for...

Science.gov (United States)

2013-06-19

... inspections, and drive safety and quality throughout the supply chain. Implementation of these authorities... authorities granted to FDA under Title VII and their importance in ensuring drug safety, effectiveness, and.... FDA-2013-N-0683, FDA-2013-N-0684, and FDA-2013-N-0685] Food and Drug Administration Safety and...

Prostate stem cell antigen-targeted nanoparticles with dual functional properties: in vivo imaging and cancer chemotherapy

Directory of Open Access Journals (Sweden)

Gao X

2012-07-01

Full Text Available Xin Gao,1,* Yun Luo,1,* Yuanyuan Wang,1,* Jun Pang,1 Chengde Liao,2 Hanlun Lu,3 Youqiang Fang11Department of Urology, The Third Affiliated Hospital, 2Department of Radiology, The Second Affiliated Hospital, Sun Yat-Sen University, 3Materials Science Institute of Zhongshan University, Guangzhou, China*These authors contributed equally to this workBackground: We designed dual-functional nanoparticles for in vivo application using a modified electrostatic and covalent layer-by-layer assembly strategy to address the challenge of assessment and treatment of hormone-refractory prostate cancer.Methods: Core-shell nanoparticles were formulated by integrating three distinct functional components, ie, a core constituted by poly(D,L-lactic-co-glycolic acid, docetaxel, and hydrophobic superparamagnetic iron oxide nanocrystals (SPIONs, a multilayer shell formed by poly(allylamine hydrochloride and two different sized poly(ethylene glycol molecules, and a single-chain prostate stem cell antigen antibody conjugated to the nanoparticle surface for targeted delivery.Results: Drug release profiles indicated that the dual-function nanoparticles had a sustained release pattern over 764 hours, and SPIONs could facilitate the controlled release of the drug in vitro. The nanoparticles showed increased antitumor efficiency and enhanced magnetic resonance imaging in vitro through targeted delivery of docetaxel and SPIONs to PC3M cells. Moreover, in nude mice bearing PC3M xenografts, the nanoparticles provided MRI negative contrast enhancement, as well as halting and even reversing tumor growth during the 76-day study duration, and without significant systemic toxicity. The lifespan of the mice treated with these targeted dual-function nanoparticles was significantly increased (Chi-square = 22.514, P < 0.0001.Conclusion: This dual-function nanomedical platform may be a promising candidate for tumor imaging and targeted delivery of chemotherapeutic agents in vivo

White organic light-emitting devices based on blue fluorescent dye combined with dual sub-monolayer

Energy Technology Data Exchange (ETDEWEB)

Yang, Huishan, E-mail: yanghuishan1697@163.com

2013-10-15

White organic light-emitting devices have been realized by using highly blue fluorescent dye 4,4′-Bis(2,2-diphenyl-ethen-1-yl)-4,4′-di-(tert-butyl)phenyl(p-TDPVBi) and [2-methyl-6-[2-(2, 3,6,7-tetrahydro-1H, red fluorescent dye 5H-benzo[ij] quinolizin-9-yl) ethenyl]-4H-pyran-4-ylidene] propane-dinitrile(DCM2), together with well known green fluorescent dye quinacridone (QAD). The fabrication of multilayer WOLEDs did not involve the hard-to-control doping process. The structure of the device is ITO/m-MTDATA (45 nm)/NPB(8 nm)/p-TDPVBi(15 nm)/DCM2(x nm)/Alq{sub 3} (5 nm)/QAD(y nm)/Alq{sub 3}(55 nm)/LiF(1 nm)/Al, where 4,4′,4′′-tris{N,-(3-methylphenyl)-N-phenylamine}triphenylamine (m-MTDATA) acts as a hole injection layer, N,N′-bis-(1-naphthyl)-N, N′-diphenyl-1, 1′-biph-enyl-4, 4′-diamine (NPB) acts as a hole transport layer, p-TDPVBi acts as a blue emitting layer, DCM2 acts as a red emitting layer, QAD acts as a green emitting layer, tris-(8-hydroxyquinoline) aluminum (Alq{sub 3}) acts as an electron transport layer, and WOLEDs of devices A, B, C and D are different in layer thickness of DCM2 and QAD, respectively. To change the thickness of dual sub-monolayer DCM2 and QAD, the WOLEDs were obtained. When x, y=0.05, 0.1, the Commission Internationale de 1’Eclairage (CIE) coordinates of the device change from (0.4458, 0.4589) at 3 V to (0.3137, 0.3455) at 12 V that are well in the white region, and the color temperature and color rendering index were 5348 K and 85 at 8 V, respectively. Its maximum luminance was 35260 cd/m{sup 2} at 12 V, and maximum current efficiency and maximum power efficiency were 13.54 cd/A at 12 V and 6.68 lm/W at 5 V, respectively. Moreover, the current efficiency is largely insensitive to the applied voltage. The electroluminescence intensity of white EL devices varied only little at deferent dual sub-monolayer. Device D exhibited relatively high color rendering index (CRI) in the range of 88–90, which was essentially

Mass thickness measurement of dual-sample by dual-energy X-rays

International Nuclear Information System (INIS)

Chen Mincong; Li Hongmei; Chen Ziyu; Shen Ji

2008-01-01

X-ray equivalent energy can be used to measure mass thicknesses of materials. Based on this, a method of mass thickness measurement of dual-sample was discussed. It was found that in the range of sample mass thickness under investigation, the equivalent mass attenuation coefficient of a component could be used to compute mass thicknesses of a dual-sample, with relative errors of less than 5%. Mass thickness measurement of a fish sample was performed, and the fish bone and flesh could be displayed separately and clearly by their own mass thicknesses. This indicates that the method is effective in mass thickness measurement of dual-sample of suitable thicknesses. (authors)

New Fukui, dual and hyper-dual kernels as bond reactivity descriptors.

Science.gov (United States)

Franco-Pérez, Marco; Polanco-Ramírez, Carlos-A; Ayers, Paul W; Gázquez, José L; Vela, Alberto

2017-06-21

We define three new linear response indices with promising applications for bond reactivity using the mathematical framework of τ-CRT (finite temperature chemical reactivity theory). The τ-Fukui kernel is defined as the ratio between the fluctuations of the average electron density at two different points in the space and the fluctuations in the average electron number and is designed to integrate to the finite-temperature definition of the electronic Fukui function. When this kernel is condensed, it can be interpreted as a site-reactivity descriptor of the boundary region between two atoms. The τ-dual kernel corresponds to the first order response of the Fukui kernel and is designed to integrate to the finite temperature definition of the dual descriptor; it indicates the ambiphilic reactivity of a specific bond and enriches the traditional dual descriptor by allowing one to distinguish between the electron-accepting and electron-donating processes. Finally, the τ-hyper dual kernel is defined as the second-order derivative of the Fukui kernel and is proposed as a measure of the strength of ambiphilic bonding interactions. Although these quantities have never been proposed, our results for the τ-Fukui kernel and for τ-dual kernel can be derived in zero-temperature formulation of the chemical reactivity theory with, among other things, the widely-used parabolic interpolation model.

Dual Credit Report

Science.gov (United States)

Light, Noreen

2016-01-01

In 2015, legislation to improve access to dual-credit programs and to reduce disparities in access and completion--particularly for low income and underrepresented students--was enacted. The new law focused on expanding access to College in the High School but acknowledged issues in other dual-credit programs and reinforced the notion that cost…

NEOGLYCOPROTEINS AS CARRIERS FOR ANTIVIRAL DRUGS - SYNTHESIS AND ANALYSIS OF PROTEIN DRUG CONJUGATES

NARCIS (Netherlands)

Molema, Grietje; Jansen, Robert W.; Visser, Jan; Herdewijn, Piet; Moolenaar, Frits; Meijer, Dirk K.F.

In order to investigate whether neoglycoproteins can potentially act as carriers for targeting of antiviral drugs to certain cell types in the body, various neoglycoproteins were synthesized using thiophosgene-activated p-aminophenyl sugar derivatives. These neoglycoproteins were conjugated with the

A high-performance dual-scale porous electrode for vanadium redox flow batteries

Science.gov (United States)

Zhou, X. L.; Zeng, Y. K.; Zhu, X. B.; Wei, L.; Zhao, T. S.

2016-09-01

In this work, we present a simple and cost-effective method to form a dual-scale porous electrode by KOH activation of the fibers of carbon papers. The large pores (∼10 μm), formed between carbon fibers, serve as the macroscopic pathways for high electrolyte flow rates, while the small pores (∼5 nm), formed on carbon fiber surfaces, act as active sites for rapid electrochemical reactions. It is shown that the Brunauer-Emmett-Teller specific surface area of the carbon paper is increased by a factor of 16 while maintaining the same hydraulic permeability as that of the original carbon paper electrode. We then apply the dual-scale electrode to a vanadium redox flow battery (VRFB) and demonstrate an energy efficiency ranging from 82% to 88% at current densities of 200-400 mA cm-2, which is record breaking as the highest performance of VRFB in the open literature.

Dual QCD thermodynamics and quark–gluon plasma

International Nuclear Information System (INIS)

Chandola, H.C.; Punetha, Garima; Dehnen, H.

2016-01-01

Using grand canonical ensemble formulation of a multi-particle statistical system, the thermodynamical description of dual QCD based on magnetic symmetry has been presented and analyzed for the quark–gluon plasma phase of hadronic matter. The dual QCD based bag construction has been shown to lead to the radial pressure on bag surface in terms of the vector glueball masses of magnetically condensed QCD vacuum. Constructing the grand canonical partition function, the energy density and plasma pressure have been derived and used to compute the critical temperatures for QGP–hadron phase transition along with its dynamics. A comparison of the values of critical temperatures for QGP–hadron phase transition with those obtained for the deconfinement-phase transition, has been shown to lead to either the relaxation of the system via a mixed phase of QGP and hot hadron gas or go through a crossover. The associated profiles of the normalized energy density and specific heat have been shown to lead to a large latent heat generation and indicate the onset of a first-order QGP phase transition which turns into a rapid crossover for the case of temperature dependent bag parameter. The squared speed of sound has been shown to act as a physical measure of large thermodynamical fluctuations near transition point. The possible implications of trace anomaly and conformal measure on QGP formation have also been discussed.

Surface bioengineering of diatomite based nanovectors for efficient intracellular uptake and drug delivery

Science.gov (United States)

Terracciano, Monica; Shahbazi, Mohammad-Ali; Correia, Alexandra; Rea, Ilaria; Lamberti, Annalisa; de Stefano, Luca; Santos, Hélder A.

2015-11-01

Diatomite is a natural porous silica material of sedimentary origin. Due to its peculiar properties, it can be considered as a valid surrogate of synthetic porous silica for nano-based drug delivery. In this work, we exploit the potential of diatomite nanoparticles (DNPs) for drug delivery with the aim of developing a successful dual-biofunctionalization method by polyethylene glycol (PEG) coverage and cell-penetrating peptide (CPP) bioconjugation, to improve the physicochemical and biological properties of the particles, to enhance the intracellular uptake in cancer cells, and to increase the biocompatibility of 3-aminopropyltriethoxysilane (APT) modified-DNPs. DNPs-APT-PEG-CPP showed hemocompatibility for up to 200 μg mL-1 after 48 h of incubation with erythrocytes, with a hemolysis value of only 1.3%. The cytotoxicity of the modified-DNPs with a concentration up to 200 μg mL-1 and incubation with MCF-7 and MDA-MB-231 breast cancer cells for 24 h, demonstrated that PEGylation and CPP-bioconjugation can strongly reduce the cytotoxicity of DNPs-APT. The cellular uptake of the modified-DNPs was also evaluated using the above mentioned cancer cell lines, showing that the CPP-bioconjugation can considerably increase the DNP cellular uptake. Moreover, the dual surface modification of DNPs improved both the loading of a poorly water-soluble anticancer drug, sorafenib, with a loading degree up to 22 wt%, and also enhanced the drug release profiles in aqueous solutions. Overall, this work demonstrates that the biofunctionalization of DNPs is a promising platform for drug delivery applications in cancer therapy as a result of its enhanced stability, biocompatibility, cellular uptake, and drug release profiles.Diatomite is a natural porous silica material of sedimentary origin. Due to its peculiar properties, it can be considered as a valid surrogate of synthetic porous silica for nano-based drug delivery. In this work, we exploit the potential of diatomite nanoparticles

spinning self-dual particles

International Nuclear Information System (INIS)

Gamboa, J.; Rivelles, V.O.

1989-01-01

Self-dual particles in two-dimensions are presented. They were obtained from chiral boson particle by square root technique. The propagator of spinning self-dual particle is calculated using the BFV formalism. (M.C.K.)

49 CFR 40.281 - Who is qualified to act as a SAP?

Science.gov (United States)

2010-10-01

... 49 Transportation 1 2010-10-01 2010-10-01 false Who is qualified to act as a SAP? 40.281 Section... § 40.281 Who is qualified to act as a SAP? To be permitted to act as a SAP in the DOT drug and alcohol.... (2) You must be knowledgeable about the SAP function as it relates to employer interests in safety...

pH and temperature dual-sensitive liposome gel based on novel cleavable mPEG-Hz-CHEMS polymeric vaginal delivery system

Directory of Open Access Journals (Sweden)

Chen D

2012-05-01

Full Text Available Daquan Chen,1,2 Kaoxiang Sun,1,2 Hongjie Mu,1 Mingtan Tang,3 Rongcai Liang,1,2 Aiping Wang,1,2 Shasha Zhou,1 Haijun Sun,1 Feng Zhao,1 Jianwen Yao,1 Wanhui Liu1,21School of Pharmacy, Yantai University, 2State Key Laboratory of Longacting and Targeting Drug Delivery Systems, Yantai, 3School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of ChinaBackground: In this study, a pH and temperature dual-sensitive liposome gel based on a novel cleavable hydrazone-based pH-sensitive methoxy polyethylene glycol 2000-hydrazone-cholesteryl hemisuccinate (mPEG-Hz-CHEMS polymer was used for vaginal administration.Methods: The pH-sensitive, cleavable mPEG-Hz-CHEMS was designed as a modified pH-sensitive liposome that would selectively degrade under locally acidic vaginal conditions. The novel pH-sensitive liposome was engineered to form a thermogel at body temperature and to degrade in an acidic environment.Results: A dual-sensitive liposome gel with a high encapsulation efficiency of arctigenin was formed and improved the solubility of arctigenin characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry. The dual-sensitive liposome gel with a sol-gel transition at body temperature was degraded in a pH-dependent manner, and was stable for a long period of time at neutral and basic pH, but cleavable under acidic conditions (pH 5.0. Arctigenin encapsulated in a dual-sensitive liposome gel was more stable and less toxic than arctigenin loaded into pH-sensitive liposomes. In vitro drug release results indicated that dual-sensitive liposome gels showed constant release of arctigenin over 3 days, but showed sustained release of arctigenin in buffers at pH 7.4 and pH 9.0.Conclusion: This research has shed some light on a pH and temperature dual-sensitive liposome gel using a cleavable mPEG-Hz-CHEMS polymer for vaginal delivery.Keywords: mPEG-Hz-CHEMS polymer, pH-sensitive liposomes, thermosensitive

Building the Bridge as You Walk on It: Didactic Behaviors of Elementary Teachers in a Dual Language Program

Science.gov (United States)

Ray, Juliet M.

2008-01-01

While there is evidence that the dual language model has the potential to raise the academic achievement of English language learners (ELLs), the policies mandated through the No Child Left Behind Act do not support maintenance of the student's heritage language which is an integral part of the model. Using symbolic interactionism as a framework,…

In vitro differentiation of renal stone composition using dual-source, dual-energy CT

International Nuclear Information System (INIS)

Zhou Changsheng; Zhang Longjiang; Xu Feng; Qi Li; Zhao Yan'e; Zheng Ling; Huang Wei; Liu Youhuang; Lu Guangming

2012-01-01

Objective: To evaluate the ability of dual-source. dual-energy CT in differentiating uric acid stones from non-uric acid stones with infrared spectroscopy as reference standard. Materials and Methods: Urinary calculus from 308 patients were scanned in first generation dual-source CT with dual-energy mode between July 2011 and June 2012. Renal Stone application was used to analyze their composition. The uric acid stones color were coded red and non-uric acid stones were blue. CT values were measured in 60 selective urinary calculus including 30 uric acid stones and 30 non-uric acid stones. The accuracy of dual energy CT to differentiate uric acid and no-uric acid stones was calculated. Results: Of 308 patients, 60 patients had uric acid stones and 248 non-uric acid stones. No difference was found for uric acid stone at 80 kV and 140 kV (375.8±69.2 HU vs. 374.1±69.4 HU; t=-0.217, P=0.830), while CT values of non-uric acid stones were higher at 80 kV than those at 140 kV (1455.1±312.4 HU vs. 1039.6±194.4 HU; t=-12.16. P<0.001). CT values of non-uric acid stones at 80 kV, 140 kV, and average weighted images (1455.1±312.4 HU, 1 039.6±194.4 HU, and 882.0±176.4 HU, respectively) were higher than those of uric acid stones (375.8±69.2 HU, 374.1±69.4 HU, and 366.3±80.1 HU, respectively; P<0.001). With infrared spectrum findings as reference standard, the accuracy of dual energy CT in differentiating uric acid stones from non-uric acid stones was 100%. Conclusions: Dual-source, dual-energy CT can accurately differentiate uric acid stones from non-uric acid stones, and plays an important role in treatment planning of renal stones. (authors)

Dual coil ignition system

Energy Technology Data Exchange (ETDEWEB)

Huberts, Garlan J.; Qu, Qiuping; Czekala, Michael Damian

2017-03-28

A dual coil ignition system is provided. The dual coil ignition system includes a first inductive ignition coil including a first primary winding and a first secondary winding, and a second inductive ignition coil including a second primary winding and a second secondary winding, the second secondary winding connected in series to the first secondary winding. The dual coil ignition system further includes a diode network including a first diode and a second diode connected between the first secondary winding and the second secondary winding.

Inhibition of HIV Virus by Neutralizing Vhh Attached to Dual Functional Liposomes Encapsulating Dapivirine.

Science.gov (United States)

Wang, Scarlet Xiaoyan; Michiels, Johan; Ariën, Kevin K; New, Roger; Vanham, Guido; Roitt, Ivan

2016-12-01

Although highly active antiretroviral therapy (HAART) has greatly improved the life expectancy of HIV/AIDS patients, the treatment is not curative. It is a global challenge which fosters an urgent need to develop an effective drug or neutralizing antibody delivery approach for the prevention and treatment of this disease. Due to the low density of envelope spikes with restricted mobility present on the surface of HIV virus, which limit the antibody potency and allow virus mutation and escape from the immune system, it is important for a neutralizing antibody to form bivalent or multivalent bonds with the virus. Liposome constructs could fulfil this need due to the flexible mobility of the membrane with its attached antibodies and the capacity for drug encapsulation. In this study, we evaluated the neutralization activity of a range of liposome formulations in different sizes coated with anti-gp120 llama antibody fragments (Vhhs) conjugated via either non-covalent metal chelation or a covalent linkage. The non-covalent construct demonstrated identical binding affinity to HIV-1 envelope glycoprotein gp120 and neutralizing ability for HIV virus as free Vhh. Although covalently linked Vhh showed significant binding affinity to gp120, it unexpectedly had a lower neutralization potency. This may be due to the comparability in size of the viral and liposome particles restricting the number which can be bound to the liposome surface so involving only a fraction of the antibodies, whereas non-covalently attached antibodies dissociate from the surface after acting with gp120 and free the remainder to bind further viruses. Covalently conjugated Vhh might also trigger the cellular uptake of a liposome-virion complex. To explore the possible ability of the antibody-coated liposomes to have a further function, we encapsulated the hydrophobic antiviral drug dapivirine into both of the non-covalently and covalently conjugated liposome formulations, both of which revealed high

Inhibition of HIV Virus by Neutralizing Vhh Attached to Dual Functional Liposomes Encapsulating Dapivirine

Science.gov (United States)

Wang, Scarlet Xiaoyan; Michiels, Johan; Ariën, Kevin K.; New, Roger; Vanham, Guido; Roitt, Ivan

2016-07-01

Although highly active antiretroviral therapy (HAART) has greatly improved the life expectancy of HIV/AIDS patients, the treatment is not curative. It is a global challenge which fosters an urgent need to develop an effective drug or neutralizing antibody delivery approach for the prevention and treatment of this disease. Due to the low density of envelope spikes with restricted mobility present on the surface of HIV virus, which limit the antibody potency and allow virus mutation and escape from the immune system, it is important for a neutralizing antibody to form bivalent or multivalent bonds with the virus. Liposome constructs could fulfil this need due to the flexible mobility of the membrane with its attached antibodies and the capacity for drug encapsulation. In this study, we evaluated the neutralization activity of a range of liposome formulations in different sizes coated with anti-gp120 llama antibody fragments (Vhhs) conjugated via either non-covalent metal chelation or a covalent linkage. The non-covalent construct demonstrated identical binding affinity to HIV-1 envelope glycoprotein gp120 and neutralizing ability for HIV virus as free Vhh. Although covalently linked Vhh showed significant binding affinity to gp120, it unexpectedly had a lower neutralization potency. This may be due to the comparability in size of the viral and liposome particles restricting the number which can be bound to the liposome surface so involving only a fraction of the antibodies, whereas non-covalently attached antibodies dissociate from the surface after acting with gp120 and free the remainder to bind further viruses. Covalently conjugated Vhh might also trigger the cellular uptake of a liposome-virion complex. To explore the possible ability of the antibody-coated liposomes to have a further function, we encapsulated the hydrophobic antiviral drug dapivirine into both of the non-covalently and covalently conjugated liposome formulations, both of which revealed high

Treatment of a solid tumor using engineered drug-resistant immunocompetent cells and cytotoxic chemotherapy.

Science.gov (United States)

Dasgupta, Anindya; Shields, Jordan E; Spencer, H Trent

2012-07-01

Multimodal therapy approaches, such as combining chemotherapy agents with cellular immunotherapy, suffers from potential drug-mediated toxicity to immune effector cells. Overcoming such toxic effects of anticancer cellular products is a potential critical barrier to the development of combined therapeutic approaches. We are evaluating an anticancer strategy that focuses on overcoming such a barrier by genetically engineering drug-resistant variants of immunocompetent cells, thereby allowing for the coadministration of cellular therapy with cytotoxic chemotherapy, a method we refer to as drug-resistant immunotherapy (DRI). The strategy relies on the use of cDNA sequences that confer drug resistance and recombinant lentiviral vectors to transfer nucleic acid sequences into immunocompetent cells. In the present study, we evaluated a DRI-based strategy that incorporates the immunocompetent cell line NK-92, which has intrinsic antitumor properties, genetically engineered to be resistant to both temozolomide and trimetrexate. These immune effector cells efficiently lysed neuroblastoma cell lines, which we show are also sensitive to both chemotherapy agents. The antitumor efficacy of the DRI strategy was demonstrated in vivo, whereby neuroblastoma-bearing NOD/SCID/γ-chain knockout (NSG) mice treated with dual drug-resistant NK-92 cell therapy followed by dual cytotoxic chemotherapy showed tumor regression and significantly enhanced survival compared with animals receiving either nonengineered cell-based therapy and chemotherapy, immunotherapy alone, or chemotherapy alone. These data show there is a benefit to using drug-resistant cellular therapy when combined with cytotoxic chemotherapy approaches.

Magnetic Graphene Oxide for Dual Targeted Delivery of Doxorubicin and Photothermal Therapy

Directory of Open Access Journals (Sweden)

Yu-Jen Lu

2018-03-01

Full Text Available To develop a pH-sensitive dual targeting magnetic nanocarrier for chemo-phototherapy in cancer treatment, we prepared magnetic graphene oxide (MGO by depositing Fe3O4 magnetic nanoparticles on graphene oxide (GO through chemical co-precipitation. MGO was modified with polyethylene glycol (PEG and cetuximab (CET, an epidermal growth factor receptor (EGFR monoclonal antibody to obtain MGO-PEG-CET. Since EGFR was highly expressed on the tumor cell surface, MGO-PEG-CET was used for dual targeted delivery an anticancer drug doxorubicin (DOX. The physico-chemical properties of MGO-PEG-CET were fully characterized by dynamic light scattering, transmission electron microscopy, X-ray diffraction, Fourier transform Infrared spectroscopy, thermogravimetric analysis, and superconducting quantum interference device. Drug loading experiments revealed that DOX adsorption followed the Langmuir isotherm with a maximal drug loading capacity of 6.35 mg/mg, while DOX release was pH-dependent with more DOX released at pH 5.5 than pH 7.4. Using quantum-dots labeled nanocarriers and confocal microscopy, intracellular uptakes of MGO-PEG-CET by high EGFR-expressing CT-26 murine colorectal cells was confirmed to be more efficient than MGO. This cellular uptake could be inhibited by pre-incubation with CET, which confirmed the receptor-mediated endocytosis of MGO-PEG-CET. Magnetic targeted killing of CT-26 was demonstrated in vitro through magnetic guidance of MGO-PEG-CET/DOX, while the photothermal effect could be confirmed in vivo and in vitro after exposure of MGO-PEG-CET to near-infrared (NIR laser light. In addition, the biocompatibility tests indicated MGO-PEG-CET showed no cytotoxicity toward fibroblasts and elicited minimum hemolysis. In vitro cytotoxicity tests showed the half maximal inhibitory concentration (IC50 value of MGO-PEG-CET/DOX toward CT-26 cells was 1.48 µg/mL, which was lower than that of MGO-PEG/DOX (2.64 µg/mL. The IC50 value could be further

Drug-induced regulation of target expression

DEFF Research Database (Denmark)

Iskar, Murat; Campillos, Monica; Kuhn, Michael

2010-01-01

Drug perturbations of human cells lead to complex responses upon target binding. One of the known mechanisms is a (positive or negative) feedback loop that adjusts the expression level of the respective target protein. To quantify this mechanism systems-wide in an unbiased way, drug......-induced differential expression of drug target mRNA was examined in three cell lines using the Connectivity Map. To overcome various biases in this valuable resource, we have developed a computational normalization and scoring procedure that is applicable to gene expression recording upon heterogeneous drug treatments....... In 1290 drug-target relations, corresponding to 466 drugs acting on 167 drug targets studied, 8% of the targets are subject to regulation at the mRNA level. We confirmed systematically that in particular G-protein coupled receptors, when serving as known targets, are regulated upon drug treatment. We...

Colon-targeted delivery of budesonide using dual pH- and time-dependent polymeric nanoparticles for colitis therapy

Directory of Open Access Journals (Sweden)

Naeem M

2015-07-01

Full Text Available Muhammad Naeem,1 Moonjeong Choi,1 Jiafu Cao,1 Yujeong Lee,1 Muhammad Ikram,2 Sik Yoon,2 Jaewon Lee,1 Hyung Ryong Moon,1 Min-Soo Kim,1 Yunjin Jung,1 Jin-Wook Yoo11College of Pharmacy, Pusan National University, Busan, 2Pusan National University School of Medicine, Yangsan, South KoreaAbstract: Single pH-dependent drug delivery systems have been widely used for colon-targeted delivery, but their efficiency is often hampered by the variation in gut pH. To overcome the limitation of single pH-dependent delivery systems, in this study, we developed and evaluated the therapeutic potential of budesonide-loaded dual pH/time-dependent nanoparticles (NPs for the treatment of colitis. Eudragit FS30D was used as a pH-dependent polymer, and Eudragit RS100 as a time-dependent controlled release polymer. Single pH-dependent NPs (pH_NPs, single time-dependent NPs (Time_NPs, and dual pH/time-dependent NPs (pH/Time_NPs were prepared using the oil-in-water emulsion method. The physicochemical properties and drug release profiles of these NPs in gastrointestinal (GI tract conditions were investigated. The therapeutic potential and in vivo distribution of the NPs were evaluated in a dextran sulfate sodium (DSS-induced colitis mice model. The pH/Time_NPs prevented a burst drug release in acidic pH conditions and showed sustained release at a colonic pH. The in vivo distribution study in the mice GI tract demonstrated that pH/Time_NPs were more efficiently delivered to the inflamed colon than pH_NPs were. Compared to the single pH_NPs-treated group, the pH/Time_NPs-treated group showed increased body weight and colon length and markedly decreased disease activity index, colon weight/length ratios, histological damage, and inflammatory cell infiltration in colon tissue. Our results demonstrate that the dual pH/time-dependent NPs are an effective oral colon-targeted delivery system for colitis therapy.Keywords: colon-specific delivery, dual-sensitive delivery

Microwave Activation of Drug Release