Matricellular proteins in drug delivery: Therapeutic targets, active agents, and therapeutic localization.

Science.gov (United States)

Sawyer, Andrew J; Kyriakides, Themis R

2016-02-01

Extracellular matrix is composed of a complex array of molecules that together provide structural and functional support to cells. These properties are mainly mediated by the activity of collagenous and elastic fibers, proteoglycans, and proteins such as fibronectin and laminin. ECM composition is tissue-specific and could include matricellular proteins whose primary role is to modulate cell-matrix interactions. In adults, matricellular proteins are primarily expressed during injury, inflammation and disease. Particularly, they are closely associated with the progression and prognosis of cardiovascular and fibrotic diseases, and cancer. This review aims to provide an overview of the potential use of matricellular proteins in drug delivery including the generation of therapeutic agents based on the properties and structures of these proteins as well as their utility as biomarkers for specific diseases. Copyright © 2016 Elsevier B.V. All rights reserved.

Application of Mesenchymal Stem Cells for Therapeutic Agent Delivery in Anti-tumor Treatment

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Daria S. Chulpanova

2018-03-01

Full Text Available Mesenchymal stem cells (MSCs are non-hematopoietic progenitor cells, which can be isolated from different types of tissues including bone marrow, adipose tissue, tooth pulp, and placenta/umbilical cord blood. There isolation from adult tissues circumvents the ethical concerns of working with embryonic or fetal stem cells, whilst still providing cells capable of differentiating into various cell lineages, such as adipocytes, osteocytes and chondrocytes. An important feature of MSCs is the low immunogenicity due to the lack of co-stimulatory molecules expression, meaning there is no need for immunosuppression during allogenic transplantation. The tropism of MSCs to damaged tissues and tumor sites makes them a promising vector for therapeutic agent delivery to tumors and metastatic niches. MSCs can be genetically modified by virus vectors to encode tumor suppressor genes, immunomodulating cytokines and their combinations, other therapeutic approaches include MSCs priming/loading with chemotherapeutic drugs or nanoparticles. MSCs derived membrane microvesicles (MVs, which play an important role in intercellular communication, are also considered as a new therapeutic agent and drug delivery vector. Recruited by the tumor, MSCs can exhibit both pro- and anti-oncogenic properties. In this regard, for the development of new methods for cancer therapy using MSCs, a deeper understanding of the molecular and cellular interactions between MSCs and the tumor microenvironment is necessary. In this review, we discuss MSC and tumor interaction mechanisms and review the new therapeutic strategies using MSCs and MSCs derived MVs for cancer treatment.

Review of therapeutic agents for burns pruritus and protocols for management in adult and paediatric patients using the GRADE classification

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Goutos Ioannis

2010-10-01

Full Text Available To review the current evidence on therapeutic agents for burns pruritus and use the Grading of Recommendations, Assessment, Development and Evaluation (GRADE classification to propose therapeutic protocols for adult and paediatric patients. All published interventions for burns pruritus were analysed by a multidisciplinary panel of burns specialists following the GRADE classification to rate individual agents. Following the collation of results and panel discussion, consensus protocols are presented. Twenty-three studies appraising therapeutic agents in the burns literature were identified. The majority of these studies (16 out of 23 are of an observational nature, making an evidence-based approach to defining optimal therapy not feasible. Our multidisciplinary approach employing the GRADE classification recommends the use of antihistamines (cetirizine and cimetidine and gabapentin as the first-line pharmacological agents for both adult and paediatric patients. Ondansetron and loratadine are the second-line medications in our protocols. We additionally recommend a variety of non-pharmacological adjuncts for the perusal of clinicians in order to maximise symptomatic relief in patients troubled with postburn itch. Most studies in the subject area lack sufficient statistical power to dictate a ′gold standard′ treatment agent for burns itch. We encourage clinicians to employ the GRADE system in order to delineate the most appropriate therapeutic approach for burns pruritus until further research elucidates the most efficacious interventions. This widely adopted classification empowers burns clinicians to tailor therapeutic regimens according to current evidence, patient values, risks and resource considerations in different medical environments.

Silibinin, dexamethasone, and doxycycline as potential therapeutic agents for treating vesicant-inflicted ocular injuries

International Nuclear Information System (INIS)

Tewari-Singh, Neera; Jain, Anil K.; Inturi, Swetha; Ammar, David A.; Agarwal, Chapla; Tyagi, Puneet; Kompella, Uday B.; Enzenauer, Robert W.; Petrash, J. Mark; Agarwal, Rajesh

2012-01-01

There are no effective and approved therapies against devastating ocular injuries caused by vesicating chemical agents sulfur mustard (SM) and nitrogen mustard (NM). Herein, studies were carried out in rabbit corneal cultures to establish relevant ocular injury biomarkers with NM for screening potential efficacious agents in laboratory settings. NM (100 nmol) exposure of the corneas for 2 h (cultured for 24 h), showed increases in epithelial thickness, ulceration, apoptotic cell death, epithelial detachment microbullae formation, and the levels of VEGF, cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9). Employing these biomarkers, efficacy studies were performed with agent treatments 2 h and every 4 h thereafter, for 24 h following NM exposure. Three agents were evaluated, including prescription drugs dexamethasone (0.1%; anti-inflammatory steroid) and doxycycline (100 nmol; antibiotic and MMP inhibitor) that have been studied earlier for treating vesicant-induced eye injuries. We also examined silibinin (100 μg), a non-toxic natural flavanone found to be effective in treating SM analog-induced skin injuries in our earlier studies. Treatments of doxycycline + dexamethasone, and silibinin were more effective than doxycycline or dexamethasone alone in reversing NM-induced epithelial thickening, microbullae formation, apoptotic cell death, and MMP-9 elevation. However, dexamethasone and silibinin alone were more effective in reversing NM-induced VEGF levels. Doxycycline, dexamethasone and silibinin were all effective in reversing NM-induced COX-2 levels. Apart from therapeutic efficacy of doxycycline and dexamethasone, these results show strong multifunctional efficacy of silibinin in reversing NM-induced ocular injuries, which could help develop effective and safe therapeutics against ocular injuries by vesicants. -- Highlights: ► Established injury biomarkers in rabbit corneal culture with nitrogen mustard (NM) ► This NM model is a cost effective

Silibinin, dexamethasone, and doxycycline as potential therapeutic agents for treating vesicant-inflicted ocular injuries

Energy Technology Data Exchange (ETDEWEB)

Tewari-Singh, Neera, E-mail: Neera.Tewari-Singh@ucdenver.edu [Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045 (United States); Jain, Anil K., E-mail: Anil.Jain@ucdenver.edu [Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045 (United States); Inturi, Swetha, E-mail: Swetha.Inturi@ucdenver.edu [Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045 (United States); Ammar, David A., E-mail: David.Ammar@ucdenver.edu [Department of Ophthalmology, University of Colorado School of Medicine, Aurora, CO 80045 (United States); Agarwal, Chapla, E-mail: Chapla.Agarwal@ucdenver.edu [Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045 (United States); Tyagi, Puneet, E-mail: Puneet.Tyagi@ucdenver.edu [Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045 (United States); Kompella, Uday B., E-mail: Uday.Kompella@ucdenver.edu [Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045 (United States); Enzenauer, Robert W., E-mail: Robert.Enzenauer@ucdenver.edu [Department of Ophthalmology, University of Colorado School of Medicine, Aurora, CO 80045 (United States); Petrash, J. Mark, E-mail: Mark.Petrash@ucdenver.edu [Department of Ophthalmology, University of Colorado School of Medicine, Aurora, CO 80045 (United States); Agarwal, Rajesh, E-mail: Rajesh.Agarwal@ucdenver.edu [Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045 (United States)

2012-10-01

There are no effective and approved therapies against devastating ocular injuries caused by vesicating chemical agents sulfur mustard (SM) and nitrogen mustard (NM). Herein, studies were carried out in rabbit corneal cultures to establish relevant ocular injury biomarkers with NM for screening potential efficacious agents in laboratory settings. NM (100 nmol) exposure of the corneas for 2 h (cultured for 24 h), showed increases in epithelial thickness, ulceration, apoptotic cell death, epithelial detachment microbullae formation, and the levels of VEGF, cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9). Employing these biomarkers, efficacy studies were performed with agent treatments 2 h and every 4 h thereafter, for 24 h following NM exposure. Three agents were evaluated, including prescription drugs dexamethasone (0.1%; anti-inflammatory steroid) and doxycycline (100 nmol; antibiotic and MMP inhibitor) that have been studied earlier for treating vesicant-induced eye injuries. We also examined silibinin (100 μg), a non-toxic natural flavanone found to be effective in treating SM analog-induced skin injuries in our earlier studies. Treatments of doxycycline + dexamethasone, and silibinin were more effective than doxycycline or dexamethasone alone in reversing NM-induced epithelial thickening, microbullae formation, apoptotic cell death, and MMP-9 elevation. However, dexamethasone and silibinin alone were more effective in reversing NM-induced VEGF levels. Doxycycline, dexamethasone and silibinin were all effective in reversing NM-induced COX-2 levels. Apart from therapeutic efficacy of doxycycline and dexamethasone, these results show strong multifunctional efficacy of silibinin in reversing NM-induced ocular injuries, which could help develop effective and safe therapeutics against ocular injuries by vesicants. -- Highlights: ► Established injury biomarkers in rabbit corneal culture with nitrogen mustard (NM) ► This NM model is a cost effective

Functional polymers as therapeutic agents: concept to market place.

Science.gov (United States)

Dhal, Pradeep K; Polomoscanik, Steven C; Avila, Louis Z; Holmes-Farley, S Randall; Miller, Robert J

2009-11-12

Biologically active synthetic polymers have received considerable scientific interest and attention in recent years for their potential as promising novel therapeutic agents to treat human diseases. Although a significant amount of research has been carried out involving polymer-linked drugs as targeted and sustained release drug delivery systems and prodrugs, examples on bioactive polymers that exhibit intrinsic therapeutic properties are relatively less. Several appealing characteristics of synthetic polymers including high molecular weight, molecular architecture, and controlled polydispersity can all be utilized to discover a new generation of therapies. For example, high molecular weight bioactive polymers can be restricted to gastrointestinal tract, where they can selectively recognize, bind, and remove target disease causing substances from the body. The appealing features of GI tract restriction and stability in biological environment render these polymeric drugs to be devoid of systemic toxicity that are generally associated with small molecule systemic drugs. The present article highlights recent developments in the rational design and synthesis of appropriate functional polymers that have resulted in a number of promising polymer based therapies and biomaterials, including some marketed products.

Deoxypodophyllotoxin: a promising therapeutic agent from herbal medicine.

Science.gov (United States)

Khaled, Meyada; Jiang, Zhen-Zhou; Zhang, Lu-Yong

2013-08-26

Recently, biologically active compounds isolated from plants used in herbal medicine have been the center of interest. Deoxypodophyllotoxin (DPT), structurally closely related to the lignan podophyllotoxin, is a potent antitumor and anti-inflammatory agent. However, DPT has not been used clinically yet. Also, DPT from natural sources seems to be unavailable. Hence, it is important to establish alternative resources for the production of such lignan; especially that it is used as a precursor for the semi-synthesis of the cytostatic drugs etoposide phosphate and teniposide. The update paper provides an overview of DPT as an effective anticancer natural compound and a leader for cytotoxic drugs synthesis and development in order to highlight the gaps in our knowledge and explore future research needs. The present review covers the literature available from 1877 to 2012. The information was collected via electronic search using Chinese papers and the major scientific databases including PubMed, Sciencedirect, Web of Science and Google Scholar using the keywords. All abstracts and full-text articles reporting database on the history and current status of DPT were gathered and analyzed. Plants containing DPT have played an important role in traditional medicine. In light of the in vitro pharmacological investigations, DPT is a high valuable medicinal agent that has anti-tumor, anti-proliferative, anti-inflammatory and anti-allergic properties. Further, DPT is an important precursor for the cytotoxic aryltetralin lignan, podophyllotoxin, which is used to obtain semisynthetic derivatives like etoposide and teniposide used in cancer therapy. However, most studies have focused on the in vitro data. Therefore, DPT has not been used clinically yet. DPT has emerged as a potent chemical agent from herbal medicine. Therefore, in vivo studies are needed to carry out clinical trials in humans and enable the development of new anti-cancer agents. In addition, DPT from commercial

Production and evaluation of Lutetium-177 maltolate as a possible therapeutic agent

International Nuclear Information System (INIS)

Hakimi, A.; Jalilian, A. R.; Bahrami Samani, A.; Ghannadi Maragheh, M.

2012-01-01

Development of oral therapeutic radiopharmaceuticals is a new concept in radiopharmacy. Due to the interesting therapeutic properties of 177 Lu and oral bioavailability of maltolate (MAL) metal complexes, 177 Lu-maltolate ( 177 Lu-MAL) was developed as a possible therapeutic compound for ultimate oral administration. The specific activity of 2.6-3 GBq/mg was obtained by irradiation of natural Lu 2 O 3 sample with thermal neutron flux of 4x10 13 n.cm -2 .s -1 for Lu-177. The product was converted into chloride form which was further used for labeling maltol (MAL). At optimized conditions a radiochemical purity of about >99% was obtained for 177 Lu-MAL shown by ITLC (specific activity, 970-1000 Mbq/mmole). The stability of the labeled compound as well as the partition coefficient was determined in the final solution up to 24h. Biodistribution studies of Lu-177 chloride and 177 Lu-MAL were carried out in wild-type rats for post-oral distribution phase data. Lu-MAL is a possible therapeutic agent in human malignancies for the bone palliation therapy so the efficacy of the compound should be tested in various animal models.

Therapeutic efficacy and mechanism of action of ethamsylate, a long-standing hemostatic agent.

Science.gov (United States)

Garay, Ricardo P; Chiavaroli, Carlo; Hannaert, Patrick

2006-01-01

Ethamsylate (2,5-dihydroxy-benzene-sulfonate diethylammonium salt) is a synthetic hemostatic drug indicated in cases of capillary bleeding. This review covers more than 40 years of intensive clinical and fundamental research with ethamsylate. First, we summarize the large medical literature concerning its clinical efficacy. Of these, well-controlled clinical trials clearly showed the therapeutic efficacy of ethamsylate in dysfunctional uterine bleeding, with the magnitude of blood-loss reduction being directly proportional to the severity of the menorrhagia. Other well-controlled clinical trials showed therapeutic efficacy of ethamsylate in periventricular hemorrhage in very low birth weight babies and surgical or postsurgical capillary bleeding. Second, we review the numerous investigations performed to elucidate the mechanism of action of ethamsylate. Ethamsylate acts on the first step of hemostasis by improving platelet adhesiveness and restoring capillary resistance. Recent studies showed that ethamsylate promotes P-selectin-dependent, platelet adhesive mechanisms. Finally, we compare ethamsylate with other recent hemostatic agents. It is suggested that the place of ethamsylate as a hemostatic agent is that of a mild but well-tolerated drug, particularly useful in dysfunctional uterine bleeding when contraception is not needed.

Insights into the Antimicrobial Properties of Hepcidins: Advantages and Drawbacks as Potential Therapeutic Agents

Directory of Open Access Journals (Sweden)

Lisa Lombardi

2015-04-01

Full Text Available The increasing frequency of multi-drug resistant microorganisms has driven research into alternative therapeutic strategies. In this respect, natural antimicrobial peptides (AMPs hold much promise as candidates for the development of novel antibiotics. However, AMPs have some intrinsic drawbacks, such as partial degradation by host proteases or inhibition by host body fluid composition, potential toxicity, and high production costs. This review focuses on the hepcidins, which are peptides produced by the human liver with a known role in iron homeostasis, as well by numerous other organisms (including fish, reptiles, other mammals, and their potential as antibacterial and antifungal agents. Interestingly, the antimicrobial properties of human hepcidins are enhanced at acidic pH, rendering these peptides appealing for the design of new drugs targeting infections that occur in body areas with acidic physiological pH. This review not only considers current research on the direct killing activity of these peptides, but evaluates the potential application of these molecules as coating agents preventing biofilm formation and critically assesses technical obstacles preventing their therapeutic application.

RGD-based strategies for selective delivery of therapeutics and imaging agents to the tumour vasculature

NARCIS (Netherlands)

Temming, K; Molema, G; Kok, RJ

2005-01-01

During the past decade, RGD-peptides have become a popular tool for the targeting of drugs and imaging agents to a(v)beta(3)-integrin expressing tumour vasculature. RGD-peptides have been introduced by recombinant means into therapeutic proteins and viruses. Chemical means have been applied to

Effects of treatment with antimicrobial agents on the human colonic microflora

Directory of Open Access Journals (Sweden)

Fatemeh Rafii

2008-12-01

Full Text Available Fatemeh Rafii, John B Sutherland, Carl E CernigliaDivision of Microbiology, National Center for Toxicological Research, FDA, Jefferson, AR, USAAbstract: Antimicrobial agents are the most valuable means available for treating bacterial infections. However, the administration of therapeutic doses of antimicrobial agents to patients is a leading cause of disturbance of the normal gastrointestinal microflora. This disturbance results in diminishing the natural defense mechanisms provided by the colonic microbial ecosystem, making the host vulnerable to infection by commensal microorganisms or nosocomial pathogens. In this minireview, the impacts of antimicrobials, individually and in combinations, on the human colonic microflora are discussed.Keywords: antibiotics, intestinal bacteria

Tetrodotoxin (TTX as a Therapeutic Agent for Pain

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Cruz Miguel Cendán

2012-01-01

Full Text Available Tetrodotoxin (TTX is a potent neurotoxin that blocks voltage-gated sodium channels (VGSCs. VGSCs play a critical role in neuronal function under both physiological and pathological conditions. TTX has been extensively used to functionally characterize VGSCs, which can be classified as TTX-sensitive or TTX-resistant channels according to their sensitivity to this toxin. Alterations in the expression and/or function of some specific TTX-sensitive VGSCs have been implicated in a number of chronic pain conditions. The administration of TTX at doses below those that interfere with the generation and conduction of action potentials in normal (non-injured nerves has been used in humans and experimental animals under different pain conditions. These data indicate a role for TTX as a potential therapeutic agent for pain. This review focuses on the preclinical and clinical evidence supporting a potential analgesic role for TTX. In addition, the contribution of specific TTX-sensitive VGSCs to pain is reviewed.

Tools for predicting the PK/PD of therapeutic proteins.

Science.gov (United States)

Diao, Lei; Meibohm, Bernd

2015-07-01

Assessments of the pharmacokinetic/pharmacodynamic (PK/PD) characteristics are an integral part in the development of novel therapeutic agents. Compared with traditional small molecule drugs, therapeutic proteins possess many distinct PK/PD features that necessitate the application of modified or separate approaches for assessing their PK/PD relationships. In this review, the authors discuss tools that are utilized to describe and predict the PK/PD features of therapeutic proteins and that are valuable additions in the armamentarium of drug development approaches to facilitate and accelerate their successful preclinical and clinical development. A variety of state-of-the-art PK/PD tools is currently being applied and has been adjusted to support the development of proteins as therapeutics, including allometric scaling approaches, target-mediated disposition models, first-in-man dose calculations, physiologically based PK models and empirical and semi-mechanistic PK/PD modeling. With the advent of the next generation of biologics including bioengineered antibody constructs being developed, these tools will need to be further refined and adapted to ensure their applicability and successful facilitation of the drug development process for these novel scaffolds.

Cell targeting peptides as smart ligands for targeting of therapeutic or diagnostic agents: a systematic review.

Science.gov (United States)

Mousavizadeh, Ali; Jabbari, Ali; Akrami, Mohammad; Bardania, Hassan

2017-10-01

Cell targeting peptides (CTP) are small peptides which have high affinity and specificity to a cell or tissue targets. They are typically identified by using phage display and chemical synthetic peptide library methods. CTPs have attracted considerable attention as a new class of ligands to delivery specifically therapeutic and diagnostic agents, because of the fact they have several advantages including easy synthesis, smaller physical sizes, lower immunogenicity and cytotoxicity and their simple and better conjugation to nano-carriers and therapeutic or diagnostic agents compared to conventional antibodies. In this systematic review, we will focus on the basic concepts concerning the use of cell-targeting peptides (CTPs), following the approaches of selecting them from peptide libraries. We discuss several developed strategies for cell-specific delivery of different cargos by CTPs, which are designed for drug delivery and diagnostic applications. Copyright © 2017 Elsevier B.V. All rights reserved.

Anti-SEMA3A Antibody: A Novel Therapeutic Agent to Suppress GBM Tumor Growth.

Science.gov (United States)

Lee, Jaehyun; Shin, Yong Jae; Lee, Kyoungmin; Cho, Hee Jin; Sa, Jason K; Lee, Sang-Yun; Kim, Seok-Hyung; Lee, Jeongwu; Yoon, Yeup; Nam, Do-Hyun

2017-11-10

Glioblastoma (GBM) is classified as one of the most aggressive and lethal brain tumor. Great strides have been made in understanding the genomic and molecular underpinnings of GBM, which translated into development of new therapeutic approaches to combat such deadly disease. However, there are only few therapeutic agents that can effectively inhibit GBM invasion in a clinical framework. In an effort to address such challenges, we have generated anti-SEMA3A monoclonal antibody as a potential therapeutic antibody against GBM progression. We employed public glioma datasets, Repository of Molecular Brain Neoplasia Data and The Cancer Genome Atlas, to analyze SEMA3A mRNA expression in human GBM specimens. We also evaluated for protein expression level of SEMA3A via tissue microarray (TMA) analysis. Cell migration and proliferation kinetics were assessed in various GBM patient-derived cells (PDCs) and U87-MG cell-line for SEMA3A antibody efficacy. GBM patient-derived xenograft (PDX) models were generated to evaluate tumor inhibitory effect of anti-SEMA3A antibody in vivo. By combining bioinformatics and TMA analysis, we discovered that SEMA3A is highly expressed in human GBM specimens compared to non-neoplastic tissues. We developed three different anti-SEMA3A antibodies, in fully human IgG form, through screening phage-displayed synthetic antibody library using a classical panning method. Neutralization of SEMA3A significantly reduced migration and proliferation capabilities of PDCs and U87-MG cell-line in vitro. In PDX models, treatment with anti-SEMA3A antibody exhibited notable tumor inhibitory effect through down-regulation of cellular proliferative kinetics and tumor-associated macrophages recruitment. In present study, we demonstrated tumor inhibitory effect of SEMA3A antibody in GBM progression and present its potential relevance as a therapeutic agent in a clinical framework.

Small Scaffolds, Big Potential: Developing Miniature Proteins as Therapeutic Agents.

Science.gov (United States)

Holub, Justin M

2017-09-01

Preclinical Research Miniature proteins are a class of oligopeptide characterized by their short sequence lengths and ability to adopt well-folded, three-dimensional structures. Because of their biomimetic nature and synthetic tractability, miniature proteins have been used to study a range of biochemical processes including fast protein folding, signal transduction, catalysis and molecular transport. Recently, miniature proteins have been gaining traction as potential therapeutic agents because their small size and ability to fold into defined tertiary structures facilitates their development as protein-based drugs. This research overview discusses emerging developments involving the use of miniature proteins as scaffolds to design novel therapeutics for the treatment and study of human disease. Specifically, this review will explore strategies to: (i) stabilize miniature protein tertiary structure; (ii) optimize biomolecular recognition by grafting functional epitopes onto miniature protein scaffolds; and (iii) enhance cytosolic delivery of miniature proteins through the use of cationic motifs that facilitate endosomal escape. These objectives are discussed not only to address challenges in developing effective miniature protein-based drugs, but also to highlight the tremendous potential miniature proteins hold for combating and understanding human disease. Drug Dev Res 78 : 268-282, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Current progress and future perspectives in the development of anti-polo-like kinase 1 therapeutic agents [version 1; referees: 4 approved

Directory of Open Access Journals (Sweden)

Jung-Eun Park

2017-06-01

Full Text Available Although significant levels of side effects are often associated with their use, microtubule-directed agents that primarily target fast-growing mitotic cells have been considered to be some of the most effective anti-cancer therapeutics. With the hope of developing new-generation anti-mitotic agents with reduced side effects and enhanced tumor specificity, researchers have targeted various proteins whose functions are critically required for mitotic progression. As one of the highly attractive mitotic targets, polo-like kinase 1 (Plk1 has been the subject of an extensive effort for anti-cancer drug discovery. To date, a variety of anti-Plk1 agents have been developed, and several of them are presently in clinical trials. Here, we will discuss the current status of generating anti-Plk1 agents as well as future strategies for designing and developing more efficacious anti-Plk1 therapeutics.

77 FR 62521 - Prospective Grant of Exclusive License: The Development of Therapeutic Agents for the Treatment...

Science.gov (United States)

2012-10-15

... interleukin-10 (IL-10) inhibitor as a dual-biologic therapy to treat metastatic breast cancer, or ii) incorporating a p53 isoform antisense oligonucleotide as a single biologic therapy to treat T- cell lymphoma... Exclusive License: The Development of Therapeutic Agents for the Treatment of Metastatic Breast Cancer and T...

Ultrasound enhanced delivery of molecular imaging and therapeutic agents in Alzheimer's disease mouse models.

Directory of Open Access Journals (Sweden)

Scott B Raymond

Full Text Available Alzheimer's disease is a neurodegenerative disorder typified by the accumulation of a small protein, beta-amyloid, which aggregates and is the primary component of amyloid plaques. Many new therapeutic and diagnostic agents for reducing amyloid plaques have limited efficacy in vivo because of poor transport across the blood-brain barrier. Here we demonstrate that low-intensity focused ultrasound with a microbubble contrast agent may be used to transiently disrupt the blood-brain barrier, allowing non-invasive, localized delivery of imaging fluorophores and immunotherapeutics directly to amyloid plaques. We administered intravenous Trypan blue, an amyloid staining red fluorophore, and anti-amyloid antibodies, concurrently with focused ultrasound therapy in plaque-bearing, transgenic mouse models of Alzheimer's disease with amyloid pathology. MRI guidance permitted selective treatment and monitoring of plaque-heavy anatomical regions, such as the hippocampus. Treated brain regions exhibited 16.5+/-5.4-fold increase in Trypan blue fluorescence and 2.7+/-1.2-fold increase in anti-amyloid antibodies that localized to amyloid plaques. Ultrasound-enhanced delivery was consistently reproduced in two different transgenic strains (APPswe:PSEN1dE9, PDAPP, across a large age range (9-26 months, with and without MR guidance, and with little or no tissue damage. Ultrasound-mediated, transient blood-brain barrier disruption allows the delivery of both therapeutic and molecular imaging agents in Alzheimer's mouse models, which should aid pre-clinical drug screening and imaging probe development. Furthermore, this technique may be used to deliver a wide variety of small and large molecules to the brain for imaging and therapy in other neurodegenerative diseases.

Targeting Potassium Channels for Increasing Delivery of Imaging Agents and Therapeutics to Brain Tumors

OpenAIRE

Nagendra Sanyasihally Ningaraj; Divya eKhaitan

2013-01-01

Every year in the US, 20,000 new primary and nearly 200,000 metastatic brain tumor cases are reported. The cerebral microvessels/ capillaries that form the blood–brain barrier (BBB) not only protect the brain from toxic agents in the blood but also pose a significant hindrance to the delivery of small and large therapeutic molecules. Different strategies have been employed to circumvent the physiological barrier posed by blood-brain tumor barrier (BTB). Studies in our laboratory have identifi...

Vascular-targeted photodynamic therapy with BF2-chelated Tetraaryl-Azadipyrromethene agents: a multi-modality molecular imaging approach to therapeutic assessment.

LENUS (Irish Health Repository)

Byrne, A T

2009-11-03

Photodynamic therapy (PDT) is a treatment modality for a range of diseases including cancer. The BF(2)-chelated tetraaryl-azadipyrromethenes (ADPMs) are an emerging class of non-porphyrin PDT agent, which have previously shown excellent photochemical and photophysical properties for therapeutic application. Herein, in vivo efficacy and mechanism of action studies have been completed for the lead agent, ADMP06.

Frontiers in nano-therapeutics

CERN Document Server

Tasnim, Nishat; Sai Krishna, Katla; Kalagara, Sudhakar; Narayan, Mahesh; Noveron, Juan C; Joddar, Binata

2017-01-01

This brief highlights recent research advances in the area of nano-therapeutics. Nanotechnology holds immense potential for application in a wide range of biological and engineering applications such as molecular sensors for disease diagnosis, therapeutic agents for the treatment of diseases, a vehicle for delivering therapeutics and imaging agents for theranostic applications, both in-vitro and in-vivo. The brief is grouped into the following sections namely, A) Discrete Nanosystems ; B) Anisotropic Nanoparticles; C) Nano-films/coated/layered and D) Nano-composites.

Novel therapeutic uses and formulations of botulinum neurotoxins: a patent review (2012 - 2014).

Science.gov (United States)

Kane, Christopher D; Nuss, Jonathan E; Bavari, Sina

2015-06-01

Botulinum neurotoxins (BoNTs) are among the most toxic of known biological molecules and function as acetylcholine release inhibitors and neuromuscular blocking agents. Paradoxically, these properties also make them valuable therapeutic agents for the treatment of movement disorders, urological conditions and hypersecretory disorders. Greater understanding of their molecular mechanism of action and advances in protein engineering has led to significant efforts to improve and expand their function with a view towards broadening their therapeutic potential. Searches of Espacenet and Google Patent have revealed a number of patents related to BoNTs. This review will focus on novel therapeutic uses and formulations disclosed during 2012 - 2014. The seven patents discussed will include nanoformulations of FDA-approved BoNTs, additional BoNT subtypes and novel BoNT variants and chimeras created through protein engineering. Supporting patents and related publications are also briefly discussed. The clinical and commercial success of BoNTs has prompted investigation into novel BoNTs or BoNT-mediated chimeras with promising in vitro results. Distinct strategies including the use of nanoformulations and targeted delivery have been implemented to identify new indication and improved functionality. Greater understanding of their systemic exposure, efficacy and safety profiles will be required for further development.

New Therapeutic Agent against Arterial Thrombosis: An Iridium(III-Derived Organometallic Compound

Directory of Open Access Journals (Sweden)

Chih-Wei Hsia

2017-12-01

Full Text Available Platelet activation plays a major role in cardio and cerebrovascular diseases, and cancer progression. Disruption of platelet activation represents an attractive therapeutic target for reducing the bidirectional cross talk between platelets and tumor cells. Platinum (Pt compounds have been used for treating cancer. Hence, replacing Pt with iridium (Ir is considered a potential alternative. We recently developed an Ir(III-derived complex, [Ir(Cp*1-(2-pyridyl-3-(2-hydroxyphenylimidazo[1,5-a]pyridine Cl]BF4 (Ir-11, which exhibited strong antiplatelet activity; hence, we assessed the therapeutic potential of Ir-11 against arterial thrombosis. In collagen-activated platelets, Ir-11 inhibited platelet aggregation, adenosine triphosphate (ATP release, intracellular Ca2+ mobilization, P-selectin expression, and OH· formation, as well as the phosphorylation of phospholipase Cγ2 (PLCγ2, protein kinase C (PKC, mitogen-activated protein kinases (MAPKs, and Akt. Neither the adenylate cyclase inhibitor nor the guanylate cyclase inhibitor reversed the Ir-11-mediated antiplatelet effects. In experimental mice, Ir-11 prolonged the bleeding time and reduced mortality associated with acute pulmonary thromboembolism. Ir-11 plays a crucial role by inhibiting platelet activation through the inhibition of the PLCγ2–PKC cascade, and the subsequent suppression of Akt and MAPK activation, ultimately inhibiting platelet aggregation. Therefore, Ir-11 can be considered a new therapeutic agent against either arterial thrombosis or the bidirectional cross talk between platelets and tumor cells.

Development and biological evaluation of {sup 90}Y-BPAMD as a novel bone seeking therapeutic agent

Energy Technology Data Exchange (ETDEWEB)

Rabiei, Ali; Shamsaei, Mojtaba [Amir Kabir University of Technology, Tehran (Iran, Islamic Republic of). Energy Engineering and Physics Dept.; Yousefnia, Hassan; Zolghadri, Samaneh; Jalilian, Amir Reza [Nuclear Science and Technology Research Institute (NSTRI), Tehran (Iran, Islamic Republic of); Enayati, Razieh [Islamic Azad Univ. (IAU), Tehran (Iran, Islamic Republic of). Faculty of Engineering

2016-07-01

Nowadays, the bone-seeking radiopharmaceuticals play an important role in the treatment of the bone-related pathologies. Whereas various phosphonate ligands have already been identified, a DOTA-based bisphosphonate, 4-{[(bis(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl (BPAMD) with better characteristics has recently been synthesized. In this study, {sup 90}Y-BPAMD was developed with radiochemical purity >98% and the specific activity of 3.52 TBq/mmol in the optimized conditions as a new bone-seeking therapeutic agent. The complex demonstrated significant stability at room temperature and in human serum even after 48 h. At even low amount of hydroxyapatite (5 mg), more than 90% binding to hydroxyapatite was observed. Biodistribution studies after injection of the complex into the Syrian rats showed major accumulation of the labelled compound in the bone tissue and an insignificant uptake in the other organs all the times after injection. Generally, {sup 90}Y-BPAMD demonstrated interesting characteristics compared to the other {sup 90}Y bone-seeking agents and even {sup 166}Ho-BPAMD, and can be considered as a new bone-seeking candidate for therapeutic applications.

166Ho-HA evaluation as therapeutic agent for rheumatoid arthritis treatment

International Nuclear Information System (INIS)

Chandia, M.C.; Errazu, X.C.; Pinto, L.N.; Godoy, N.O.; Avila, M.J.; Mendoza, P.; Mendoza, J.; Jofre, J.; Sirraalta, P.

2002-01-01

Aim: Rheumatoid arthritis is a limiting disease having, among its pathological features, the inflammation of synovial tissue with progressive and later destruction of the articulation. This leads to joint deformation and loss of its function, generating pain and reducing the mobility of the affected articulation. The aim was to evaluate 166 Ho-Hydroxyapatite ( 166 Ho-HA) as potential radiopharmaceutical for the symptomatic treatment of chronic and acute arthritis. Materials and Methods: Holmiun-166 was produced by irradiation of Ho 2 O 3 at La Reina Research Reactor, Nuclear Chilean Energy Commission. Hydroxyapatite was in-house synthesized. Its labelling and quality controls follows the internationally accepted procedures. An antigen's arthritis was induced to eight New Zealand rabbits with the 166 Ho-HA radiochemical being administered thereafter in two dosage modalities (single and double). The compound therapeutic efficiency was evaluated based upon clinical improvement and images from the inflamated articulation using 67 Ga citrate before and after 166 Ho-HA injection. Results: The radiochemical purity of the inoculated compound was greater than 98% as measured under sterility conditions. Clinically, an inflammation reduction (2 cm), appetite improvement and general well being was observed. The 166 Ho-HA distribution and localization was monitored using gamma camera images taken at 4 and 24 h. There was no evidence of extra articular leakage. From the 67 Ga citrate imaging, the acute group shows an overall improvement of well being corresponding to a lesser uptake at the inflamated articulation, regarding to the chronic group. The 166 Ho-HA double doses, compared to the single doses, suggest a reduced uptake of 67 Ga citrate at the inflamated tissue, meaning an increased therapeutic effect. Conclusions: 166 Ho-HA is useful as therapeutic agent for the symptomatic treatment of rheumatoid arthritis as shown by imaging and clinical examination

166 Ho-HA Evaluation as therapeutic agent for rheumatoid arthritis treatment

International Nuclear Information System (INIS)

Chandia, M; Errazu, X; Mendoza, P; Troncoso, F; Jofre, J; Sierralta, P

2003-01-01

Aim: Rheumatoid arthritis is a limiting disease having, among its pathological features, the inflammation of synovial tissue with progressive and later destruction of the articulation. This lead to joint deformation and loss of its function, generating pain and reducing the mobility of the affected articulation. The aim was to evaluate 166 Ho-Hydroxyapatite ( 166 Ho-HA) as potential radiopharmaceutical for the syntomatic treatment of chronic and acute arthritis Materials and Methods: 166 Holmiun was produced by irradiation of Ho 2 O 3 at La Reina Research Reactor, Nuclear Chilean Energy Commission. Hydroxyapatite was in-house synthetized. Its labelling and quality controls follows the internationally accepted procedures. An antigen arthritis was induced to eight New Zealand rabbits with the 166 Ho-HA radiochemical being administred thereafter in two dosage modalities (single and double). The compound therapeutic efficiency was evaluated based upon clinical improvement and images from the inflamated articulation using 67 Ga citrate before and after 166 Ho-HA injection. Results: The radiochemical purity of the innoculated compound was greater than 98% as measured under sterility conditions. Clinically, an inflamation reduction (2 cm), appetite improvement and general well being was observed. The 166 Ho-HA distribution and localization was monitored using gamma camera images taken at 4 and 24 h. There was no evidence of extraarticular leakage. From the 67 Ga citrate imaging, the acute group shows an overall improvement of well being corresponding to a lesser uptake at the inflamated articulation, regarding to the chronic group. The 166 Ho-HA double dosis, compared to the single dosis, suggest a reduced uptake of 67 Ga citrate at the inflamated tissue, meaning an increased therapeutic effect. Conclusions: 166 Ho-HA is usefull as therapeutic agent for the syntomatic treatment of rheumatoideal arthritis as shown by imaging and clinical examination (author)

[ManNAc, a new therapeutic agent to reduce Angptl4-induced proteinuria in MCD].

Science.gov (United States)

Clément, Lionel; Macé, Camille

2016-01-01

Current therapies used in minimal change disease (MCD) were originally designed to cure other diseases. They are only partially efficient, and present inconvenient side effects. Therefore, understanding the molecular mechanisms implicated in the pathogenesis of proteinuria in MCD could lead to new therapeutic strategies. A new experimental transgenic rat model of human MCD was generated. These NPHS2-Angptl4 transgenic rats over-express two different forms of the glycoprotein Angptl4 from the podocyte. The majority of the protein shows a lack of sialylation that is implicated in the pathogenesis of proteinuria. Supplementation of ManNAc, a precursor of sialic acid, significantly reduces albuminuria in those rats by increasing sialylation of the hyposialylated form of Angptl4. After treatment of the first episode of MCD with glucocorticoids in patients, ManNAc could be used as a maintenance drug, especially to reduce the frequency and intensity of relapse. ManNAc is a promising therapeutic agent for patients with MCD. © 2016 médecine/sciences – Inserm.

Transport of nanoparticles through the blood-brain barrier for imaging and therapeutic applications

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Shilo, Malka; Motiei, Menachem; Hana, Panet; Popovtzer, Rachela

2014-01-01

A critical problem in the treatment of neurodegenerative disorders and diseases, such as Alzheimer's and Parkinson's, is the incapability to overcome the restrictive mechanism of the blood-brain barrier (BBB) and to deliver important therapeutic agents to the brain. During the last decade, nanoparticles have gained attention as promising drug delivery agents that can transport across the BBB and increase the uptake of appropriate drugs in the brain. In this study we have developed insulin-targeted gold nanoparticles (INS-GNPs) and investigated quantitatively the amount of INS-GNPs that cross the BBB by the receptor-mediated endocytosis process. For this purpose, INS-GNPs and control GNPs were injected into the tail vein of male BALB/c mice. Major organs were then extracted and a blood sample was taken from the mice, and thereafter analyzed for gold content by flame atomic absorption spectroscopy. Results show that two hours post-intravenous injection, the amount of INS-GNPs found in mouse brains is over 5 times greater than that of the control, untargeted GNPs. Results of further experimentation on a rat model show that INS-GNPs can also serve as CT contrast agents to highlight specific brain regions in which they accumulate. Due to the fact that they can overcome the restrictive mechanism of the BBB, this approach could be a potentially valuable tool, helping to confront the great challenge of delivering important imaging and therapeutic agents to the brain for detection and treatment of neurodegenerative disorders and diseases.

Growth/differentiation factor-5: a candidate therapeutic agent for periodontal regeneration? A review of pre-clinical data.

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Moore, Yolanda R; Dickinson, Douglas P; Wikesjö, Ulf M E

2010-03-01

Therapeutic concepts involving the application of matrix, growth and differentiation factors have been advocated in support of periodontal wound healing/regeneration. Growth/differentiation factor-5 (GDF-5), a member of the bone morphogenetic protein family, represents one such factor. The purpose of this review is to provide a background of the therapeutic effects of GDF-5 expressed in various musculoskeletal settings using small and large animal platforms. A comprehensive literature search was conducted to identify all reports in the English language evaluating GDF-5 using the PubMed and Google search engines, and a manual search of the reference lists from the electronically retrieved reports. Two reviewers independently screened the titles and abstracts from a total of 69 reports, 22 of which were identified as pre-clinical (in vivo) evaluations of GDF-5. The full-length article of the 22 pre-clinical reports was then reviewed. Various applications including cranial and craniofacial bone formation, spine fusion, long bone fracture healing, cartilage, and tendon/ligament repair using a variety of small and large animal platforms evaluating GDF-5 as a therapeutic agent were identified. A majority of studies, using biomechanical, radiographic, and histological analysis, demonstrated significant dose-dependent effects of GDF-5. These include increased/enhanced local bone formation, fracture healing/repair, and cartilage and tendon/ligament formation. GDF-5 frequently was shown to accelerate wound maturation. Several studies demonstrated GDF-5 to be a realistic alternative to autograft bone. Studies using pre-clinical models and human histology suggest GDF-5 may also increase/enhance periodontal wound healing/regeneration. GDF-5 appears a promising therapeutic agent for periodontal wound healing/regeneration as GDF-5 supports/accelerates bone and tendon/ligament formation in several musculoskeletal settings including periodontal tissues.

Nerve agent intoxication: Recent neuropathophysiological findings and subsequent impact on medical management prospects

International Nuclear Information System (INIS)

Collombet, Jean-Marc

2011-01-01

This manuscript provides a survey of research findings catered to the development of effective countermeasures against nerve agent poisoning over the past decade. New neuropathophysiological distinctive features as regards organophosphate (OP) intoxication are presented. Such leading neuropathophysiological features include recent data on nerve agent-induced neuropathology, related peripheral or central nervous system inflammation and subsequent angiogenesis process. Hence, leading countermeasures against OP exposure are down-listed in terms of pre-treatment, protection or decontamination and emergency treatments. The final chapter focuses on the description of the self-repair attempt encountered in lesioned rodent brains, up to 3 months after soman poisoning. Indeed, an increased proliferation of neuronal progenitors was recently observed in injured brains of mice subjected to soman exposure. Subsequently, the latter experienced a neuronal regeneration in damaged brain regions such as the hippocampus and amygdala. The positive effect of a cytokine treatment on the neuronal regeneration and subsequent cognitive behavioral recovery are also discussed in this review. For the first time, brain cell therapy and neuronal regeneration are considered as a valuable contribution towards delayed treatment against OP intoxication. To date, efficient delayed treatment was lacking in the therapeutic resources administered to patients contaminated by nerve agents. - Highlights: → This review focuses on neuropathophysiology following nerve agent poisoning in mice. → Extensive data on long-term neuropathology and related inflammation are provided here. → Delayed self-repair attempts encountered in lesioned rodent brains are also described. → Cell therapy is considered as a valuable treatment against nerve agent intoxication.

Preclinical therapeutic potential of a nitrosylating agent in the treatment of ovarian cancer.

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Shailendra Giri

Full Text Available This study examines the role of s-nitrosylation in the growth of ovarian cancer using cell culture based and in vivo approaches. Using the nitrosylating agent, S-nitrosoglutathione (GSNO, a physiological nitric oxide molecule, we show that GSNO treatment inhibited proliferation of chemoresponsive and chemoresistant ovarian cancer cell lines (A2780, C200, SKVO3, ID8, OVCAR3, OVCAR4, OVCAR5, OVCAR7, OVCAR8, OVCAR10, PE01 and PE04 in a dose dependent manner. GSNO treatment abrogated growth factor (HB-EGF induced signal transduction including phosphorylation of Akt, p42/44 and STAT3, which are known to play critical roles in ovarian cancer growth and progression. To examine the therapeutic potential of GSNO in vivo, nude mice bearing intra-peritoneal xenografts of human A2780 ovarian carcinoma cell line (2 × 10(6 were orally administered GSNO at the dose of 1 mg/kg body weight. Daily oral administration of GSNO significantly attenuated tumor mass (p<0.001 in the peritoneal cavity compared to vehicle (phosphate buffered saline treated group at 4 weeks. GSNO also potentiated cisplatin mediated tumor toxicity in an A2780 ovarian carcinoma nude mouse model. GSNO's nitrosylating ability was reflected in the induced nitrosylation of various known proteins including NFκB p65, Akt and EGFR. As a novel finding, we observed that GSNO also induced nitrosylation with inverse relationship at tyrosine 705 phosphorylation of STAT3, an established player in chemoresistance and cell proliferation in ovarian cancer and in cancer in general. Overall, our study underlines the significance of S-nitrosylation of key cancer promoting proteins in modulating ovarian cancer and proposes the therapeutic potential of nitrosylating agents (like GSNO for the treatment of ovarian cancer alone or in combination with chemotherapeutic drugs.

VIP as a potential therapeutic agent in gram negative sepsis.

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Ibrahim, Hiba; Barrow, Paul; Foster, Neil

2012-12-01

Gram negative sepsis remains a high cause of mortality and places a great burden on public health finance in both the developed and developing world. Treatment of sepsis, using antibiotics, is often ineffective since pathology associated with the disease occurs due to dysregulation of the immune system (failure to return to steady state conditions) which continues after the bacteria, which induced the immune response, have been cleared. Immune modulation is therefore a rational approach to the treatment of sepsis but to date no drug has been developed which is highly effective, cheap and completely safe to use. One potential therapeutic agent is VIP, which is a natural peptide and is highly homologous in all vertebrates. In this review we will discuss the effect of VIP on components of the immune system, relevant to gram negative sepsis, and present data from animal models. Furthermore we will hypothesise on how these studies could be improved in future and speculate on the possible different ways in which VIP could be used in clinical medicine.

Quorum Quenching Agents: Resources for Antivirulence Therapy

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Kaihao Tang

2014-05-01

Full Text Available The continuing emergence of antibiotic-resistant pathogens is a concern to human health and highlights the urgent need for the development of alternative therapeutic strategies. Quorum sensing (QS regulates virulence in many bacterial pathogens, and thus, is a promising target for antivirulence therapy which may inhibit virulence instead of cell growth and division. This means that there is little selective pressure for the evolution of resistance. Many natural quorum quenching (QQ agents have been identified. Moreover, it has been shown that many microorganisms are capable of producing small molecular QS inhibitors and/or macromolecular QQ enzymes, which could be regarded as a strategy for bacteria to gain benefits in competitive environments. More than 30 species of marine QQ bacteria have been identified thus far, but only a few of them have been intensively studied. Recent studies indicate that an enormous number of QQ microorganisms are undiscovered in the highly diverse marine environments, and these marine microorganism-derived QQ agents may be valuable resources for antivirulence therapy.

Epigenetics: A novel therapeutic approach for the treatment of Alzheimer’s disease

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Adwan, Lina; Zawia, Nasser H.

2013-01-01

Alzheimer’s disease (AD) is the most common type of dementia in the elderly. It is characterized by the deposition of two forms of aggregates within the brain, the amyloid β plaques and tau neurofibrillary tangles. Currently, no disease-modifying agent is approved for the treatment of AD. Approved pharmacotherapies target the peripheral symptoms but they do not prevent or slow down the progression of the disease. Although several disease-modifying immunotherapeutic agents are in clinical development, many have failed due to lack of efficacy or serious adverse events. Epigenetic changes including DNA methylation and histone modifications are involved in learning and memory and have been recently highlighted for holding promise as potential targets for AD therapeutics. Dynamic and latent epigenetic alterations are incorporated in AD pathological pathways and present valuable reversible targets for AD and other neurological disorders. The approval of epigenetic drugs for cancer treatment has opened the door for the development of epigenetic drugs for other disorders including neurodegenerative diseases. In particular, methyl donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders. This review explores the area of epigenetics for potential AD interventions and presents the most recent findings in this field. PMID:23562602

The influence of polymeric excipients on the process of pharmaceutical availability of therapeutic agents from a model drug form. Part I. In formulations with controlled disintegration and release time.

Science.gov (United States)

Nachajski, Michal Jakub; Zgoda, Marian Mikołaj

2010-01-01

Pre-formulation research was conducted on the application of Ex. Echinaceae aq. siccum in the production of a quickly disintegrating suspension tablet, a lozenge with kariostatic sugar alcohols (mannitol, sorbitol), and, above all, a solid drug form with controlled release of therapeutic agents included in the extract. Morphological parameters of tablets obtained in the course of experiment were estimated and the profiles of the release (diffusion) ofhydrophilic therapeutic agents into model receptor fluids with varying values of osmolarity (0.1 mol HCl approximately 200 mOsm/l, hypotonic hydrating fluid approximately 143 mOsm/l, and compensatory paediatric fluid approximately 272 mOsm/l) were examined. The study focused on the technological problem of determining the effect of hydrogel Carbopol structure on the ordering of diffusion ofhydrophilic therapeutic agents from a model drug form (a tablet) into model fluids with variable osmolarity.

Choline and Geranate Deep Eutectic Solvent as a Broad-Spectrum Antiseptic Agent for Preventive and Therapeutic Applications.

Science.gov (United States)

Zakrewsky, Michael; Banerjee, Amrita; Apte, Sanjana; Kern, Theresa L; Jones, Mattie R; Sesto, Rico E Del; Koppisch, Andrew T; Fox, David T; Mitragotri, Samir

2016-06-01

Antiseptic agents are the primary arsenal to disinfect skin and prevent pathogens spreading within the host as well as into the surroundings; however the Food and Drug Administration published a report in 2015 requiring additional validation of nearly all current antiseptic agents before their continued use can be allowed. This vulnerable position calls for urgent identification of novel antiseptic agents. Recently, the ability of a deep eutectic, Choline And Geranate (CAGE), to treat biofilms of Pseudomonas aeruginosa and Salmonella enterica was demonstrated. Here it is reported that CAGE exhibits broad-spectrum antimicrobial activity against a number of drug-resistant bacteria, fungi, and viruses including clinical isolates of Mycobacterium tuberculosis, Staphylococcus aureus, and Candida albicans as well as laboratory strains of Herpes Simplex Virus. Studies in human keratinocytes and mice show that CAGE affords negligible local or systemic toxicity, and an ≈180-14 000-fold improved efficacy/toxicity ratio over currently used antiseptic agents. Further, CAGE penetrates deep into the dermis and treats pathogens located in deep skin layers as confirmed by the ability of CAGE in vivo to treat Propionibacterium acnes infection. In combination, the results clearly demonstrate CAGE holds promise as a transformative platform antiseptic agent for preventive as well as therapeutic applications. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Therapeutic Hypothermia in Stroke and Traumatic Brain Injury

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Alireza eFaridar

2011-12-01

Full Text Available Therapeutic hypothermia (TH is considered to improve survival with favorable neurological outcome in the case of global cerebral ischemia after cardiac arrest and perinatal asphyxia. The efficacy of hypothermia in acute ischemic stroke (AIS and traumatic brain injury (TBI, however, is not well studied. Induction of TH typically requires a multimodal approach, including the use of both pharmacological agents and physical techniques. To date, clinical outcomes for patients with either AIS or TBI who received TH have yielded conflicting results; thus, no adequate therapeutic consensus has been reached. Nevertheless, it seems that by determining optimal TH parameters and also appropriate applications, cooling therapy still has the potential to become a valuable neuroprotective intervention.Among the various methods for hypothermia induction, intravascular cooling (IVC may have the most promise in the awake patient in terms of clinical outcomes. Currently, the IVC method has the capability of more rapid target temperature attainment and more precise control of temperature. However, this technique requires expertise in endovascular surgery that can preclude its application in the field and/or in most emergency settings. It is very likely that combining neuroprotective strategies will yield better outcomes than utilizing a single approach.

Chelating agents in pharmacology, toxicology and therapeutics

International Nuclear Information System (INIS)

1988-01-01

The proceedings contain 71 abstracts of papers. Fourteen abstracts were inputted in INIS. The topics covered include: the effects of chelating agents on the retention of 63 Ni, 109 Cd, 203 Hg, 144 Ce, 95 Nb and the excretion of 210 Po, 63 Ni, 48 V, 239 Pu, 241 Am, 54 Mn; the applications of tracer techniques for studies of the efficacy of chelation therapy in patients with heart and brain disorders; and the treatment of metal poisoning with chelating agents. (J.P.)

Three Valuable Peptides from Bee and Wasp Venoms for Therapeutic and Biotechnological Use: Melittin, Apamin and Mastoparan

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Moreno, Miguel; Giralt, Ernest

2015-01-01

While knowledge of the composition and mode of action of bee and wasp venoms dates back 50 years, the therapeutic value of these toxins remains relatively unexploded. The properties of these venoms are now being studied with the aim to design and develop new therapeutic drugs. Far from evaluating the extensive number of monographs, journals and books related to bee and wasp venoms and the therapeutic effect of these toxins in numerous diseases, the following review focuses on the three most characterized peptides, namely melittin, apamin, and mastoparan. Here, we update information related to these compounds from the perspective of applied science and discuss their potential therapeutic and biotechnological applications in biomedicine. PMID:25835385

Quercetin as an Emerging Anti-Melanoma Agent: A four-focus area therapeutic development strategy

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Zoey Harris

2016-10-01

Full Text Available Replacing current refractory treatments for melanoma with new prevention and therapeutic approaches is crucial in order to successfully treat this aggressive cancer form. Melanoma develops from neural crest cells, which express tyrosinase -- a key enzyme in the pigmentation pathway. The tyrosinase enzyme is highly active in melanoma cells and metabolizes polyphenolic compounds; tyrosinase expression thus makes a feasible a target for polyphenol-based therapies. For example, quercetin (3,3′,4′,5,7-pentahydroxyflavone is a highly ubiquitous and well-classified dietary polyphenol found in various fruits, vegetables and other plant products including onions, broccoli, kale, oranges, blueberries, apples, and tea. Quercetin has demonstrated anti-proliferative and pro-apoptotic activity in various cancer cell types. Quercetin is readily metabolized by tyrosinase into various compounds that promote anti-cancer activity; additionally, given that tyrosinase expression increases during tumorigenesis, and its activity is associated with pigmentation changes in both early- and late-stage melanocytic lesions, it suggests that quercetin can be used to target melanoma. In this review we explore the potential of Quercetin as an anti-melanoma agent utilizing and extrapolating on evidence from previous in vitro studies in various human malignant cell lines and propose a four-focus area strategy to develop quercetin as a targeted anti-melanoma compound for use as either a preventative or therapeutic agent. The four areas of focus include utilizing quercetin to i modulate cellular bioreduction potential and associated signaling cascades, ii affect transcription of relevant genes, iii regulate epigenetic processes, and iv develop effective combination therapies and delivery modalities/protocols. In general, quercetin could be used to exploit tyrosinase activity to prevent, and/or treat, melanoma with minimal additional side effects.

Protein based therapeutic delivery agents: Contemporary developments and challenges.

Science.gov (United States)

Yin, Liming; Yuvienco, Carlo; Montclare, Jin Kim

2017-07-01

As unique biopolymers, proteins can be employed for therapeutic delivery. They bear important features such as bioavailability, biocompatibility, and biodegradability with low toxicity serving as a platform for delivery of various small molecule therapeutics, gene therapies, protein biologics and cells. Depending on size and characteristic of the therapeutic, a variety of natural and engineered proteins or peptides have been developed. This, coupled to recent advances in synthetic and chemical biology, has led to the creation of tailor-made protein materials for delivery. This review highlights strategies employing proteins to facilitate the delivery of therapeutic matter, addressing the challenges for small molecule, gene, protein and cell transport. Copyright © 2017 Elsevier Ltd. All rights reserved.

Nutraceuticals as therapeutic agents for atherosclerosis.

Science.gov (United States)

Moss, Joe W E; Williams, Jessica O; Ramji, Dipak P

2018-05-01

Atherosclerosis, a chronic inflammatory disorder of medium and large arteries and an underlying cause of cardiovascular disease (CVD), is responsible for a third of all global deaths. Current treatments for CVD, such as optimized statin therapy, are associated with considerable residual risk and several side effects in some patients. The outcome of research on the identification of alternative pharmaceutical agents for the treatment of CVD has been relatively disappointing with many promising leads failing at the clinical level. Nutraceuticals, products from food sources with health benefits beyond their nutritional value, represent promising agents in the prevention of CVD or as an add-on therapy with current treatments. This review will highlight the potential of several nutraceuticals, including polyunsaturated fatty acids, flavonoids and other polyphenols, as anti-CVD therapies based on clinical and pre-clinical mechanism-based studies. Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.

Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles and Their Potential as Novel Immunomodulatory Therapeutic Agents

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Verena Börger

2017-07-01

Full Text Available Extracellular vesicles (EVs, such as exosomes and microvesicles, have been identified as mediators of a newly-discovered intercellular communication system. They are essential signaling mediators in various physiological and pathophysiological processes. Depending on their origin, they fulfill different functions. EVs of mesenchymal stem/stromal cells (MSCs have been found to promote comparable therapeutic activities as MSCs themselves. In a variety of in vivo models, it has been observed that they suppress pro-inflammatory processes and reduce oxidative stress and fibrosis. By switching pro-inflammatory into tolerogenic immune responses, MSC-EVs very likely promote tissue regeneration by creating a pro-regenerative environment allowing endogenous stem and progenitor cells to successfully repair affected tissues. Accordingly, MSC-EVs provide a novel, very promising therapeutic agent, which has already been successfully applied to humans. However, the MSC-EV production process has not been standardized, yet. Indeed, a collection of different protocols has been used for the MSC-EV production, characterization and application. By focusing on kidney, heart, liver and brain injuries, we have reviewed the major outcomes of published MSC-EV in vivo studies.

Interactions of ionic and nonionic contrast agents with thrombolytic agents

International Nuclear Information System (INIS)

Fareed, J.; Moncada, R.; Scanlon, P.; Hoppensteadt, D.; Huan, X.; Walenga, J.M.

1987-01-01

Both the ionic and nonionic intravascular contrast media have been used before and after the administration of thrombolytic agents to evaluate clot lysis during angioplasty and the treatment of myocardial infarction. In experimental animal models, the authors found that the clot lytic efficacy of streptokinase, streptokinase-plasminogen complex, and tissue plasminogen activator (t-PA) is markedly augmented if these agents are administered within 1 hour after the angiographic producers. Furthermore, contrast agents injected after the administration of t-Pa exhibit a synergistic action. In stimulated models administration of one ionic contrast medium (Angiovist, Berlex, Wayne, NJ) and two nonionic contrast agents (Isovue-370, Squibb Diagnostics, New Brunswick, NJ; Omnipaque-350, Winthrop, NY) 15 minutes before the administration of t-PA resulted in marked enhancement of the lytic activity. Although the mechanism of this interaction is unknown at this time, it should be taken into consideration in the treatment of patients with myocardial infarction, in whom contrast agents are continually used to evaluate the therapeutic lysis. Furthermore, this interaction may be partly related to the therapeutic efficacy and/or hemorrhagic actions observed

Potential therapeutic agents for circulatory diseases from Bauhinia glauca Benth.subsp. pernervosa. (Da Ye Guan Men).

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Tang, Yingzhan; Ling, Junhong; Zhang, Peng; Zhang, Xiangrong; Zhang, Na; Wang, Wenli; Li, Jiayuan; Li, Ning

2015-08-15

Because of platelets as critical factor in the formation of pathogenic thrombi, anti-platelet activities have been selected as therapeutic target for various circulatory diseases. In order to find potential therapeutic agents, bioassay-directed separation of Bauhinia glauca Benth.subsp. pernervosa. (called Da Ye Guan Men as a traditional Chinese medicine) was performed to get 29 main components (compounds 1-29) from the bioactive part of this herbal. It was the first time to focus on the composition with anti-platelet aggregation activities for this traditional Chinese medicine. The constituents, characterized from the effective extract, were established on the basis of extensive spectral data analysis. Then their anti-platelet aggregation effects were evaluated systematically. On the basis of the chemical profile and biological assay, it was suggested that the flavonoid composition (5 and 18) should be responsible for the anti-platelet aggregation of the herbal because of their significant activities. The primary structure and activity relationship was also discussed briefly. Copyright © 2015. Published by Elsevier Ltd.

MUCOLYTIC AGENTS IN PEDIATRICS: RATIONAL SELECTION, THERAPEUTIC EFFECTS AND SPECIFIC ASPECTS OF TREATMENT

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O. I. Simonova

2013-01-01

Full Text Available The article deals with the cough treatment options with mucolytic agents administration at the first several days of acute respiratory tract infections in children. Efficacy of treatment with secretolytic and secretomotoric drugs significantly depends on certain factors. The article contains the criteria of therapeutic efficacy of expectorants. A special attention is given to N-acetylcysteine — a direct acting mucolytic agent, which effect is caused by presence of free sulfhydryl groups, disrupting disulfide bonds between molecules of acid mucopolysaccharides and glycoproteins therefore changing the structure of sputum. Acetylcysteine is active against every type of sputum (mucous, muco-purulent, purulent, that is especially important in treatment of bacterial infections, when it is necessary to quickly decrease sputum thickness, eliminate it from the respiratory tract and prevent dissemination of the infection. High efficacy of acetylcysteine is caused by its unique triple action: mucolytic, antioxidant and antitoxic. Mechanism of action of acetylcysteine is discussed in detail. Timely administered treatment will improve sputum discharge and therefore eliminate one of the main factors of bronchial obstruction and decrease the risk of microbial colonization of the respiratory tract. The article also includes indications, contraindications and dosage regimens of acetylcysteine in children. The most common mistakes and specific aspects of mucolytic drugs in pediatrics are listed in the conclusion. 

[Weighing use and safety of therapeutic agents and feed additives (author's transl)].

Science.gov (United States)

van der Wal, P

1982-02-01

(1) The pros and cons of using feed additives and therapeutic agents may be successfully weighed in the light of carefully considered consumer requirements. (2) The socio-economic interests of the producer and the welfare of the animal will also determine the response of the production apparatus to consumer requirements. (3) Consumption of the current amounts of products of animal origin and maintenance of price and quality will only be feasible in the event of rational large-scale production in which constituents used in nutrition, prophylaxis and therapeutics are highly important factors. (4) Using these ingredients should be preceded by accurate evaluation of their use and safety. Testing facilities, conduct of studies and reporting should be such as to make the results nationally and internationally acceptable to all those concerned. (5) In deciding whether feed constituents are acceptable in view of the established use and safety, compliance will have to be sought with those standards which are accepted in other fields of society. Measures which result in raising the price of food without actually helping to reduce the risks to the safety of man, animals and environment, are likely to be rejected by any well-informed consumer who is aware of the facts. (6) For accurate weighing of use and safety at a national level, possibilities are hardly adequate in Europe. Decisions reached within the framework of the European Community, also tuned to U.S.A.- conditions are rightly encouraged. A centrally managed professionally staffed and equipped test system in the European Community would appear to be indispensable.

Therapeutic potential of thiazolidinedione-8 as an antibiofilm agent against Candida albicans.

Directory of Open Access Journals (Sweden)

Mark Feldman

Full Text Available Candida albicans is known as a commensal microorganism but it is also the most common fungal pathogen in humans, causing both mucosal and systemic infections. Biofilm-associated C. albicans infections present clinically important features due to their high levels of resistance to traditional antifungal agents. Quorum sensing is closely associated with biofilm formation and increasing fungal pathogenicity. We investigated the ability of the novel bacterial quorum sensing quencher thiazolidinedione-8 (S-8 to inhibit the formation of, and eradication of mature C. albicans biofilms. In addition, the capability of S-8 to alter fungal adhesion to mammalian cells was checked. S-8 exhibited specific antibiofilm and antiadhesion activities against C. albicans, at four- to eightfold lower concentrations than the minimum inhibitory concentration (MIC. Using fluorescence microscopy, we observed that S-8 dose-dependently reduces C. albicans-GFP binding to RAW macrophages. S-8 at sub-MICs also interfered with fungal morphogenesis by inhibiting the yeast-to-hyphal form transition. In addition, the tested agent strongly affected fungal cell wall characteristics by modulating its hydrophobicity. We evaluated the molecular mode of S-8 antibiofilm and antiadhesion activities using real-time RT-PCR. The expression levels of genes associated with biofilm formation, adhesion and filamentation, HWP1, ALS3 and EAP1, respectively, were dose-dependently downregulated by S-8. Transcript levels of UME6, responsible for long-term hyphal maintenance, were also significantly decreased by the tested agent. Both signaling pathways of hyphal formation-cAMP-PKA and MAPK-were interrupted by S-8. Their upstream general regulator RAS1 was markedly suppressed by S-8. In addition, the expression levels of MAPK cascade components CST20, HST7 and CPH1 were downregulated by S-8. Finally, transcriptional repressors of filament formation, TUP1 and NRG1, were dramatically upregulated by our

Poly-S-Nitrosated Albumin as a Safe and Effective Multifunctional Antitumor Agent: Characterization, Biochemistry and Possible Future Therapeutic Applications

Directory of Open Access Journals (Sweden)

Yu Ishima

2013-01-01

Full Text Available Nitric oxide (NO is a ubiquitous molecule involved in multiple cellular functions. Inappropriate production of NO may lead to disease states. To date, pharmacologically active compounds that release NO within the body, such as organic nitrates, have been used as therapeutic agents, but their efficacy is significantly limited by unwanted side effects. Therefore, novel NO donors with better pharmacological and pharmacokinetic properties are highly desirable. The S-nitrosothiol fraction in plasma is largely composed of endogenous S-nitrosated human serum albumin (Mono-SNO-HSA, and that is why we are testing whether this albumin form can be therapeutically useful. Recently, we developed SNO-HSA analogs such as SNO-HSA with many conjugated SNO groups (Poly-SNO-HSA which were prepared using chemical modification. Unexpectedly, we found striking inverse effects between Poly-SNO-HSA and Mono-SNO-HSA. Despite the fact that Mono-SNO-HSA inhibits apoptosis, Poly-SNO-HSA possesses very strong proapoptotic effects against tumor cells. Furthermore, Poly-SNO-HSA can reduce or perhaps completely eliminate the multidrug resistance often developed by cancer cells. In this review, we forward the possibility that Poly-SNO-HSA can be used as a safe and effective multifunctional antitumor agent.

Inhibiting DNA Polymerases as a Therapeutic Intervention against Cancer

Directory of Open Access Journals (Sweden)

Anthony J. Berdis

2017-11-01

Full Text Available Inhibiting DNA synthesis is an important therapeutic strategy that is widely used to treat a number of hyperproliferative diseases including viral infections, autoimmune disorders, and cancer. This chapter describes two major categories of therapeutic agents used to inhibit DNA synthesis. The first category includes purine and pyrmidine nucleoside analogs that directly inhibit DNA polymerase activity. The second category includes DNA damaging agents including cisplatin and chlorambucil that modify the composition and structure of the nucleic acid substrate to indirectly inhibit DNA synthesis. Special emphasis is placed on describing the molecular mechanisms of these inhibitory effects against chromosomal and mitochondrial DNA polymerases. Discussions are also provided on the mechanisms associated with resistance to these therapeutic agents. A primary focus is toward understanding the roles of specialized DNA polymerases that by-pass DNA lesions produced by DNA damaging agents. Finally, a section is provided that describes emerging areas in developing new therapeutic strategies targeting specialized DNA polymerases.

Cyclic peptides as potential therapeutic agents for skin disorders.

Science.gov (United States)

Namjoshi, Sarika; Benson, Heather A E

2010-01-01

There is an increasing understanding of the role of peptides in normal skin function and skin disease. With this knowledge, there is significant interest in the application of peptides as therapeutics in skin disease or as cosmeceuticals to enhance skin appearance. In particular, antimicrobial peptides and those involved in inflammatory processes provide options for the development of new therapeutic directions in chronic skin conditions such as psoriasis and dermatitis. To exploit their potential, it is essential that these peptides are delivered to their site of action in active form and in sufficient quantity to provide the desired effect. Many polymers permeate the skin poorly and are vulnerable to enzymatic degradation. Synthesis of cyclic peptide derivatives can substantially alter the physicochemical characteristics of the peptide with the potential to improve its skin permeation. In addition, cyclization can stabilize the peptide structure and thereby increase its stability. This review describes the role of cyclic peptides in the skin, examples of current cyclic peptide therapeutic products, and the potential for cyclic peptides as dermatological therapeutics and cosmeceuticals.

A Novel Single-Strand RNAi Therapeutic Agent Targeting the (Pro)renin Receptor Suppresses Ocular Inflammation.

Science.gov (United States)

Kanda, Atsuhiro; Ishizuka, Erdal Tan; Shibata, Atsushi; Matsumoto, Takahiro; Toyofuku, Hidekazu; Noda, Kousuke; Namba, Kenichi; Ishida, Susumu

2017-06-16

The receptor-associated prorenin system (RAPS) refers to the pathogenic mechanism whereby prorenin binding to the (pro)renin receptor [(P)RR] dually activates the tissue renin-angiotensin system (RAS) and RAS-independent intracellular signaling. Here we revealed significant upregulation of prorenin and soluble (P)RR levels in the vitreous fluid of patients with uveitis compared to non-inflammatory controls, together with a positive correlation between these RAPS components and monocyte chemotactic protein-1 among several upregulated cytokines. Moreover, we developed a novel single-strand RNAi agent, proline-modified short hairpin RNA directed against human and mouse (P)RR [(P)RR-PshRNA], and we determined its safety and efficacy in vitro and in vivo. Application of (P)RR-PshRNA in mice caused significant amelioration of acute (uveitic) and chronic (diabetic) models of ocular inflammation with no apparent adverse effects. Our findings demonstrate the significant implication of RAPS in the pathogenesis of human uveitis and the potential usefulness of (P)RR-PshRNA as a therapeutic agent to reduce ocular inflammation. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

The effect of interstitial pressure on therapeutic agent transport: coupling with the tumor blood and lymphatic vascular systems.

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Wu, Min; Frieboes, Hermann B; Chaplain, Mark A J; McDougall, Steven R; Cristini, Vittorio; Lowengrub, John S

2014-08-21

Vascularized tumor growth is characterized by both abnormal interstitial fluid flow and the associated interstitial fluid pressure (IFP). Here, we study the effect that these conditions have on the transport of therapeutic agents during chemotherapy. We apply our recently developed vascular tumor growth model which couples a continuous growth component with a discrete angiogenesis model to show that hypertensive IFP is a physical barrier that may hinder vascular extravasation of agents through transvascular fluid flux convection, which drives the agents away from the tumor. This result is consistent with previous work using simpler models without blood flow or lymphatic drainage. We consider the vascular/interstitial/lymphatic fluid dynamics to show that tumors with larger lymphatic resistance increase the agent concentration more rapidly while also experiencing faster washout. In contrast, tumors with smaller lymphatic resistance accumulate less agents but are able to retain them for a longer time. The agent availability (area-under-the curve, or AUC) increases for less permeable agents as lymphatic resistance increases, and correspondingly decreases for more permeable agents. We also investigate the effect of vascular pathologies on agent transport. We show that elevated vascular hydraulic conductivity contributes to the highest AUC when the agent is less permeable, but to lower AUC when the agent is more permeable. We find that elevated interstitial hydraulic conductivity contributes to low AUC in general regardless of the transvascular agent transport capability. We also couple the agent transport with the tumor dynamics to simulate chemotherapy with the same vascularized tumor under different vascular pathologies. We show that tumors with an elevated interstitial hydraulic conductivity alone require the strongest dosage to shrink. We further show that tumors with elevated vascular hydraulic conductivity are more hypoxic during therapy and that the response

Preparing Students for Future Learning with Teachable Agents

Science.gov (United States)

Chin, Doris B.; Dohmen, Ilsa M.; Cheng, Britte H.; Oppezzo, Marily A.; Chase, Catherine C.; Schwartz, Daniel L.

2010-01-01

One valuable goal of instructional technologies in K-12 education is to prepare students for future learning. Two classroom studies examined whether Teachable Agents (TA) achieves this goal. TA is an instructional technology that draws on the social metaphor of teaching a computer agent to help students learn. Students teach their agent by…

Therapeutic approaches to preventing cell death in Huntington disease.

Science.gov (United States)

Kaplan, Anna; Stockwell, Brent R

2012-12-01

Neurodegenerative diseases affect the lives of millions of patients and their families. Due to the complexity of these diseases and our limited understanding of their pathogenesis, the design of therapeutic agents that can effectively treat these diseases has been challenging. Huntington disease (HD) is one of several neurological disorders with few therapeutic options. HD, like numerous other neurodegenerative diseases, involves extensive neuronal cell loss. One potential strategy to combat HD and other neurodegenerative disorders is to intervene in the execution of neuronal cell death. Inhibiting neuronal cell death pathways may slow the development of neurodegeneration. However, discovering small molecule inhibitors of neuronal cell death remains a significant challenge. Here, we review candidate therapeutic targets controlling cell death mechanisms that have been the focus of research in HD, as well as an emerging strategy that has been applied to developing small molecule inhibitors-fragment-based drug discovery (FBDD). FBDD has been successfully used in both industry and academia to identify selective and potent small molecule inhibitors, with a focus on challenging proteins that are not amenable to traditional high-throughput screening approaches. FBDD has been used to generate potent leads, pre-clinical candidates, and has led to the development of an FDA approved drug. This approach can be valuable for identifying modulators of cell-death-regulating proteins; such compounds may prove to be the key to halting the progression of HD and other neurodegenerative disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.

Bioactive compounds of sea cucumbers and their therapeutic effects

Science.gov (United States)

Shi, Shujuan; Feng, Wenjing; Hu, Song; Liang, Shixiu; An, Nina; Mao, Yongjun

2016-05-01

Sea cucumbers belong to the Class Holothuroidea of marine invertebrates. They are commercially valuable and prized as a food and folk medicine in Asia. Nutritionally, sea cucumbers have an impressive profile of valuable nutrients such as vitamins, minerals and amino acids. A number of unique biological and pharmacological activities/properties, including anticancer, anticoagulant/antithrombotic, antimicrobial, antioxidant, antihyperlipidemic, antihyperglycemic, anti-inflammatory, antihypertension and radioprotective, have been ascribed to various compounds isolated from sea cucumbers. The therapeutic properties and medicinal benefits of sea cucumbers can be linked to the presence of a wide array of bioactives, especially triterpene glycosides, acid mucopolysaccharide, sphingoid bases, glycolipids, fucosylated chondroitin sulfate, polysaccharides, phospholipids, cerebrosides, phosphatidylcholines, and other extracts and hydrolysates. This review highlights the valuable bioactive components as well as the multiple therapeutic properties of sea cucumbers with a view to exploring their potential uses as functional foods and a natural source of new multifunctional drugs.

Formulation and acoustic studies of a new phase-shift agent for diagnostic and therapeutic ultrasound.

Science.gov (United States)

Sheeran, Paul S; Luois, Samantha; Dayton, Paul A; Matsunaga, Terry O

2011-09-06

Recent efforts in the area of acoustic droplet vaporization with the objective of designing extravascular ultrasound contrast agents has led to the development of stabilized, lipid-encapsulated nanodroplets of the highly volatile compound decafluorobutane (DFB). We developed two methods of generating DFB droplets, the first of which involves condensing DFB gas (boiling point from -1.1 to -2 °C) followed by extrusion with a lipid formulation in HEPES buffer. Acoustic droplet vaporization of micrometer-sized lipid-coated droplets at diagnostic ultrasound frequencies and mechanical indices were confirmed optically. In our second formulation methodology, we demonstrate the formulation of submicrometer-sized lipid-coated nanodroplets based upon condensation of preformed microbubbles containing DFB. The droplets are routinely in the 200-300 nm range and yield microbubbles on the order of 1-5 μm once vaporized, consistent with ideal gas law expansion predictions. The simple and effective nature of this methodology allows for the development of a variety of different formulations that can be used for imaging, drug and gene delivery, and therapy. This study is the first to our knowledge to demonstrate both a method of generating ADV agents by microbubble condensation and formulation of primarily submicrometer droplets of decafluorobutane that remain stable at physiological temperatures. Finally, activation of DFB nanodroplets is demonstrated using pressures within the FDA guidelines for diagnostic imaging, which may minimize the potential for bioeffects in humans. This methodology offers a new means of developing extravascular contrast agents for diagnostic and therapeutic applications. © 2011 American Chemical Society

Targeting Potassium Channels for Increasing Delivery of Imaging Agents and Therapeutics to Brain Tumors

Directory of Open Access Journals (Sweden)

Nagendra Sanyasihally Ningaraj

2013-05-01

Full Text Available Every year in the US, 20,000 new primary and nearly 200,000 metastatic brain tumor cases are reported. The cerebral microvessels/ capillaries that form the blood–brain barrier (BBB not only protect the brain from toxic agents in the blood but also pose a significant hindrance to the delivery of small and large therapeutic molecules. Different strategies have been employed to circumvent the physiological barrier posed by blood-brain tumor barrier (BTB. Studies in our laboratory have identified significant differences in the expression levels of certain genes and proteins between normal and brain tumor capillary endothelial cells. In this study, we validated the non-invasive and clinically relevant Dynamic Contrast Enhancing-Magnetic Resonance Imaging (DCE-MRI method with invasive, clinically irrelevant but highly accurate Quantitative Autoradiography (QAR method using rat glioma model. We also showed that DCE-MRI metric of tissue vessel perfusion-permeability is sensitive to changes in blood vessel permeability following administration of calcium-activated potassium (BKCa channel activator NS-1619. Our results show that human gliomas and brain tumor endothelial cells that overexpress BKCa channels can be targeted for increased BTB permeability for MRI enhancing agents to brain tumors. We conclude that monitoring the outcome of increased MRI enhancing agents’ delivery to microsatellites and leading tumor edges in glioma patients would lead to beneficial clinical outcome.

Radiological and physiological studies on the role of some therapeutic agents used for internal decontamination of radionuclides from male albino rats

International Nuclear Information System (INIS)

Mangood, S.A.

2008-01-01

With the earths increasing nuclear arsenal and the growing use of nuclear energy, the possibility of radiological accidents involving release of radioactive materials, internal contamination may consequently occurs via inhalation, ingestion or absorption of radioisotopes.Therefore, the present work was oriented to deal with four topics related to the internal decontamination of two of the most widely used isotopes, namely 134 Cs and 60 Co from contaminated rats:-In vitro study aimed to select agents that can strongly bind the two metal ions and elucidate the best conditions and the factors affecting this binding. The tested agents were bentonite, vermiculite and Prussian blue (PB). The sorption capacity of PB and vermiculite for both metal ions was high and equivalent to more than 10 11 Bq 137 Cs or 60 Co per gram sorbent. As bentonite has lower capacity to both isotopes, further in vivo experiments were performed with PB and vermiculite.-In vivo studies, via 5 groups of rats, devoted to investigate the kinetics of excretion of 134 Cs and/or 60 Co from contaminated rats. The biological half lives of excretion, excretion stages for both isotopes and the effect of route of entry on the excretion were estimated.-In vivo studies aimed to investigate the effectiveness of PB + vermiculite and CaDTPA as therapeutic agents for accelerating the elimination of 134 Cs and/or 60 Co from contaminated rats. The study was performed via 6 groups of rats given different regimes of therapy. The results showed the high efficiency of PB + vermiculite for accelerating elimination of 134 Cs and orally administrated 60 Co while CaDTPA succeeded in accelerating intraperitoneally administrated 60 Co. The study proved that oral administration of PB + vermiculite and injection with CaDTPA at the same time is very effective in accelerating elimination of both contaminants simultaneously.-The physiological studies aimed to evaluate the hazardous effects of 134 Cs and/or 60 Co incorporation and

Bioprospecting the Curculigoside-Cinnamic Acid-Rich Fraction from Molineria latifolia Rhizome as a Potential Antioxidant Therapeutic Agent

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Der Jiun Ooi

2016-06-01

Full Text Available Increasing evidence from both experimental and clinical studies depicts the involvement of oxidative stress in the pathogenesis of various diseases. Specifically, disruption of homeostatic redox balance in accumulated body fat mass leads to obesity-associated metabolic syndrome. Strategies for the restoration of redox balance, potentially by exploring potent plant bioactives, have thus become the focus of therapeutic intervention. The present study aimed to bioprospect the potential use of the curculigoside-cinnamic acid-rich fraction from Molineria latifolia rhizome as an antioxidant therapeutic agent. The ethyl acetate fraction (EAF isolated from M. latifolia rhizome methanolic extract (RME contained the highest amount of phenolic compounds, particularly curculigoside and cinnamic acid. EAF demonstrated glycation inhibitory activities in both glucose- and fructose-mediated glycation models. In addition, in vitro chemical-based and cellular-based antioxidant assays showed that EAF exhibited high antioxidant activities and a protective effect against oxidative damage in 3T3-L1 preadipocytes. Although the efficacies of individual phenolics differed depending on the structure and concentration, a correlational study revealed strong correlations between total phenolic contents and antioxidant capacities. The results concluded that enriched phenolic contents in EAF (curculigoside-cinnamic acid-rich fraction contributed to the overall better reactivity. Our data suggest that this bioactive-rich fraction warrants therapeutic potential against oxidative stress-related disorders.

Folic acid tagged nanoceria as a novel therapeutic agent in ovarian cancer

International Nuclear Information System (INIS)

Hijaz, Miriana; Das, Soumen; Mert, Ismail; Gupta, Ankur; Al-Wahab, Zaid; Tebbe, Calvin; Dar, Sajad; Chhina, Jasdeep; Giri, Shailendra; Munkarah, Adnan; Seal, Sudipta; Rattan, Ramandeep

2016-01-01

Nanomedicine is a very promising field and nanomedical drugs have recently been used as therapeutic agents against cancer. In a previous study, we showed that Nanoceria (NCe), nanoparticles of cerium oxide, significantly inhibited production of reactive oxygen species, cell migration and invasion of ovarian cancer cells in vitro, without affecting cell proliferation and significantly reduced tumor growth in an ovarian cancer xenograft nude model. Increased expression of folate receptor-α, an isoform of membrane-bound folate receptors, has been described in ovarian cancer. To enable NCe to specifically target ovarian cancer cells, we conjugated nanoceria to folic acid (NCe-FA). Our aim was to investigate the pre-clinical efficacy of NCe-FA alone and in combination with Cisplatin. Ovarian cancer cell lines were treated with NCe or NCe-FA. Cell viability was assessed by MTT and colony forming units. In vivo studies were carried in A2780 generated mouse xenografts treated with 0.1 mg/Kg NCe, 0.1 mg/Kg; NCe-FA and cisplatinum, 4 mg/Kg by intra-peritoneal injections. Tumor weights and burden scores were determined. Immunohistochemistry and toxicity assays were used to evaluate treatment effects. We show that folic acid conjugation of NCe increased the cellular NCe internalization and inhibited cell proliferation. Mice treated with NCe-FA had a lower tumor burden compared to NCe, without any vital organ toxicity. Combination of NCe-FA with cisplatinum decreased the tumor burden more significantly. Moreover, NCe-FA was also effective in reducing proliferation and angiogenesis in the xenograft mouse model. Thus, specific targeting of ovarian cancer cells by NCe-FA holds great potential as an effective therapeutic alone or in combination with standard chemotherapy. The online version of this article (doi:10.1186/s12885-016-2206-4) contains supplementary material, which is available to authorized users

Dendrimer advances for the central nervous system delivery of therapeutics.

Science.gov (United States)

Xu, Leyuan; Zhang, Hao; Wu, Yue

2014-01-15

The effectiveness of noninvasive treatment for central nervous system (CNS) diseases is generally limited by the poor access of therapeutic agents into the CNS. Most CNS drugs cannot permeate into the brain parenchyma because of the blood-brain barrier (BBB), and overcoming this has become one of the most significant challenges in the development of CNS therapeutics. Rapid advances in nanotechnology have provided promising solutions to this challenge. This review discusses the latest applications of dendrimers in the treatment of CNS diseases with an emphasis on brain tumors. Dendrimer-mediated drug delivery, imaging, and diagnosis are also reviewed. The toxicity, biodistribution, and transport mechanisms in dendrimer-mediated delivery of CNS therapeutic agents bypassing or crossing the BBB are also discussed. Future directions and major challenges of dendrimer-mediated delivery of CNS therapeutic agents are included.

TRAIL: A Novel Therapeutic Agent for Prostate Cancer

National Research Council Canada - National Science Library

Li, Honglin

2002-01-01

This study aims to elucidate the signaling pathway of TRAIL-mediated apoptosis in prostate cancer cells, and to examine the therapeutic effect of TRAIL on prostate cancer cells in vitro and in vivo...

TRAIL: A Novel Therapeutic Agent for Prostate Cancer

National Research Council Canada - National Science Library

Li, Honglin

2004-01-01

This study aims to elucidate the signaling pathway of TRAIL-mediated apoptosis in prostate cancer cells, and to examine the therapeutic effect of TRAIL on prostate cancer cells in vitro and in vivo...

TRAIL: A Novel Therapeutic Agent for Prostate Cancer

National Research Council Canada - National Science Library

Li, Honglin

2003-01-01

This study aims to elucidate the signaling pathway of TRAIL-mediated apoptosis in prostate cancer cells, and to examine the therapeutic effect of TRAIL on prostate cancer cells in vitro and in vivo...

Technical cooperation for the wider uses of Ho-166 therapeutic agents in European countries

CERN Document Server

Park, K B; Choi, S M; Han, K H; Hong, Y D; Park, W W; Shin, B C

2002-01-01

Czech has put their priority in developing the radiopharmaceuticals based on reactor produced Ho-166 and a related fabrication will be extended to other EU conturies including Germany, France, etc after a development of project. The collaboration will be based on the mutual agreement for developing the between research institutes, industries and academic institutes and further researches should be followed by the issue of developing radiopharmaceuticals using Ho-166. To strengthen the collaboration, detailed discussions for the practical collaboration have been made through the visitation to the research institution of each counter part. For implementing the collaboration between NPI and KAERI, an institutional basis technical cooperation agreement(TCA) will be concluded. Furthermore, agreement for the substantial collaboration on Ho-166 related researches will be made after the conclusion of the TCA. It will accelerate the commercialization of KAERI developed Ho-166 therapeutic agents into other European cou...

In-silico analysis of heat shock protein 47 for identifying the novel therapeutic agents in the management of oral submucous fibrosis

Directory of Open Access Journals (Sweden)

Jayasankar P Pillai

2014-01-01

Conclusion: HSP47 can be a potential candidate to target, in order to control the production of abundance collagen in OSF. Hence, the binding sites of HSP47 with collagen are identified and some natural compounds with a potential to bind with these binding receptors are also recognized. These natural compounds might act as anti-HSP47 lead molecules in designing novel therapeutic agents for OSF, which are so far unavailable.

PYTHIOSIS: A THERAPEUTIC APPROACH

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C. M. C. Falcão

2015-10-01

Full Text Available Pythiosis, a disease caused by the oomycete Pythium insidiosum, often presents inefficient response to chemotherapy. It is a consensus that, in spite the several therapeutic protocols, a combination of surgery, chemotherapy and immunotherapy should be used. Surgical excision requires the removal of the entire affected area, with a wide margin of safety. The use of antifungal drugs has resulted in variable results, both in vitro and in vivo, and presents low therapeutic efficiency due to differences in the agent characteristics, which differ from true fungi. Immunotherapy is a non-invasive alternative for the treatment of pythiosis, which aims at modifying the immune response of the host, thereby producing an effective response to the agent. Photodynamic therapy has emerged as a promising technique, with good activity against P. insidiosum in vitro and in vivo. However, more studies are necessary to increase the efficiency of the current treatment protocols and consequently improve the cure rates. This paper aims to conduct a review covering the conventional and recent therapeutic methods against P. insidiosum infections

Pharmacokinetics of cotinine in rats: a potential therapeutic agent for disorders of cognitive function.

Science.gov (United States)

Li, Pei; Beck, Wayne D; Callahan, Patrick M; Terry, Alvin V; Bartlett, Michael G

2015-06-01

Attention has been paid to cotinine (COT), one of the major metabolites of nicotine (NIC), for its pro-cognitive effects and potential therapeutic activities against Alzheimer's disease (AD) and other types of cognitive impairment. In order to facilitate pharmacological and toxicological studies on COT for its pro-cognitive activities, we conducted a pharmacokinetic (PK) study of COT in rats, providing important oral and intravenously (iv) PK information. In this study, plasma samples were obtained up to 48 h after COT was dosed to rats orally and iv at a dose of 3mg/kg. Plasma samples were prepared and analyzed using a sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) bioanalytical method, providing concentration profiles of COT and metabolites after oral and iv administrations. The data were fitted into a one-compartment model and a two-compartment model for the oral and iv groups, respectively, providing important PK information for COT including PK profiles, half-life, clearance and bioavailability. The results suggested fast absorption, slow elimination and high bioavailability of COT in rats. Several important facts about the PK properties in rats suggested COT could be a potential pro-cognitive agent. Information about the pharmacokinetics of COT in rats revealed in this study is of great importance for the future studies on COT or potential COT analogs as agents for improving cognition. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Dendrimer Advances for the Central Nervous System Delivery of Therapeutics

Science.gov (United States)

2013-01-01

The effectiveness of noninvasive treatment for central nervous system (CNS) diseases is generally limited by the poor access of therapeutic agents into the CNS. Most CNS drugs cannot permeate into the brain parenchyma because of the blood-brain barrier (BBB), and overcoming this has become one of the most significant challenges in the development of CNS therapeutics. Rapid advances in nanotechnology have provided promising solutions to this challenge. This review discusses the latest applications of dendrimers in the treatment of CNS diseases with an emphasis on brain tumors. Dendrimer-mediated drug delivery, imaging, and diagnosis are also reviewed. The toxicity, biodistribution, and transport mechanisms in dendrimer-mediated delivery of CNS therapeutic agents bypassing or crossing the BBB are also discussed. Future directions and major challenges of dendrimer-mediated delivery of CNS therapeutic agents are included. PMID:24274162

Recent trends in the transdermal delivery of therapeutic agents used for the management of neurodegenerative diseases.

Science.gov (United States)

Ita, Kevin

2017-06-01

With the increasing proportion of the global geriatric population, it becomes obvious that neurodegenerative diseases will become more widespread. From an epidemiological standpoint, it is necessary to develop new therapeutic agents for the management of Alzheimer's disease, Parkinson's disease, multiple sclerosis and other neurodegenerative disorders. An important approach in this regard involves the use of the transdermal route. With transdermal drug delivery systems (TDDS), it is possible to modulate the pharmacokinetic profiles of these medications and improve patient compliance. Transdermal drug delivery has also been shown to be useful for drugs with short half-life and low or unpredictable bioavailability. In this review, several transdermal drug delivery enhancement technologies are being discussed in relation to the delivery of medications used for the management of neurodegenerative disorders.

Biomedical and therapeutic applications of biosurfactants

OpenAIRE

Rodrigues, L. R.; Teixeira, J. A.

2010-01-01

During the last years, several applications of biosurfactants with medical purposes have been reported. Biosurfactants are considered relevant molecules for applications in combating many diseases and as therapeutic agents due to their antibacterial, antifungal and antiviral activities. Furthermore, their role as anti-adhesive agents against several pathogens illustrate their utility as suitable anti-adhesive coating agents for medical insertional materials leading to a reduction of a large n...

Canabinoides: análogos y perspectivas terapéuticas II Cannabinoids: analogues and therapeutical perspectivas II

Directory of Open Access Journals (Sweden)

Juan E. Tacoronte Morales

2008-12-01

Full Text Available Actualmente se han generado valiosísimas fuentes de información que correlacionan la especie botánica Cannabis sativa L y sus metabolitos secundarios con la medicina (tratamiento terapéutico, farmacología (modelos experimentales y química sintética (diseño y generación de nuevas estructuras y análogos bioisósteres, que avalan la significación del estudio de esta planta, sus extractos, metabolitos, precursores y análogos naturales y sintéticos como fuente de agentes terapéuticos. Por tal motivo se presenta una revisión de la información existente sobre las potenciales implicaciones terapéuticas de sistemas moleculares canabinoidales (endógenos, naturales y sintéticos en el tratamiento de diversas afecciones del sistema nervioso central, que incluye: conceptos de tipos de canabinoides; sistemas de receptores canabinoides CB1 y CB2 y sus ligandos así como evidencias preclínicas de los efectos terapéuticos de canabinoides desde 1970 hasta el 2006.At present, a great amount of valuable information and experimental data has been generated that correlate Cannabis sativa and its secondary metabolites with medicine (therapeutic treatment, pharmacology (experimental animal models and synthetic chemistry (design and generation of new structures and biososteric analogues, showing the importance of the study about this plant, its extracts, metabolite precursors and natural and synthetic analogues as therapeutic agents. Taking theses points into consideration, this article reviews the therapeutic implications of cannabinoid systems (endogenous, natural, and synthetic on several pathologies of central nervous system, including: cannabinoid type concepts, cannabinoid receptor systems CB1 and CB2 and preclinical studies devoted to therapeutic effects of the cannabinoids since 1970 until 2006

The nitric oxide prodrug JS-K and its structural analogues as cancer therapeutic agents.

Science.gov (United States)

Maciag, Anna E; Saavedra, Joseph E; Chakrapani, Harinath

2009-09-01

Nitric oxide (NO) prodrugs of the diazeniumdiolate class are routinely used as reliable sources of nitric oxide in chemical and biological laboratory settings. O(2)-(2,4-dinitrophenyl) diazeniumdiolates, which are derivatized forms of ionic diazeniumdiolates, have been found to show potent anti-proliferative activity in a variety of cancer cells, presumably through the effects of NO. One important member of this class of diazeniumdiolates, O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K), has shown promise as a novel cancer therapeutic agent in a number of animal models. This review describes the developments in chemical and biochemical characterization and structure-activity relationship of JS-K and its analogues. In addition, some molecular mechanistic insights into the observed anti-proliferative activity of JS-K are discussed. Finally, a structural motif is presented for O(2)-(aryl) diazeniumdiolate nitric oxide prodrugs that show potency comparable with that of JS-K.

MCM-41 mesoporous silica nanoparticles functionalized with aptamer and radiolabelled with 90Y and 159Gd as a potential therapeutic agent against colorectal cancer

International Nuclear Information System (INIS)

Ferreira, Carolina de Aguiar

2014-01-01

Colorectal cancer (CRC) is a malignancy that affects large intestine and rectum, and it is the most common malignancy of the gastrointestinal tract, the third most commonly diagnosed type of cancer in the world and the second leading cause of cancer-related death in the United States. Nowadays, available therapeutic procedures for this type of cancer are limited and ineffective. Conventional radiotherapy is not an often used approach in the treatment of CRC due to the fact that peristaltic movements hamper the targeting of ionizing radiation and this type of treatment is used as adjuvant and palliative to control symptoms. Therefore, surgical intervention is the primary therapeutic choice against this disease. Researches based on the combination of radioisotopes and nanostructured carriers systems have demonstrated significant results in improving the selectivity action as well as reducing the radiation dose into healthy tissues. MCM-41 mesoporous silica nanoparticles have unique characteristics such as high surface area and well-defined pore diameters making these nanoparticles an ideal candidate of therapeutic agent carrier. Thus, the objective of this work is to synthesize and characterize MCM-41 mesoporous silica nanoparticles conjugated with yttrium-90 and gadolinium-159 and evaluate this system as a potential therapeutic agent. The nanoparticles were synthesized via sol-gel method. The sample was characterized using FTIR, SAXS, PCS, Zeta Potential analysis, Thermal analysis, CHN elemental analysis, nitrogen adsorption, scanning and transmission electron microscopy. The ability to incorporate Y +3 and Gd +3 ion was determined in vitro using different ratios (1:1, 1:3, 1:5 v/v) of YCL 3 and Gd 2 O 3 and silica nanoparticles dispersed in saline, pH 7.4. The non-incorporated Y +3 and Gd +3 ions were removed by ultracentrifugation procedure and the concentration of ions in the supernatant was determined by ICP-AES. Cell viability was assessed by colorimetric MTT

Therapeutic improvement of colonic anastomotic healing under complicated conditions

DEFF Research Database (Denmark)

Nerstrøm, Malene; Krarup, Peter-Martin; Jørgensen, Lars Nannestad

2016-01-01

AIM: To identify therapeutic agents for the prophylaxis of gastrointestinal anastomotic leakage (AL) under complicated conditions. METHODS: The PubMed and EMBASE databases were searched for English articles published between January 1975 and September 2014. Studies with the primary purpose of imp...... controls in experimental chemotherapeutic models. CONCLUSION: This systematic review identified potential therapeutic agents, but more studies are needed before concluding that any of these are useful for AL prophylaxis....

Evolution of hemostatic agents in surgical practice

Directory of Open Access Journals (Sweden)

Chandru P Sundaram

2010-01-01

Conclusions : A review of the evolution of topical hemostatic agents highlights opportunities for potential novel research. Fibrin sealants may have the most opportunity for advancement, and understanding the history of these products is useful. With the drive in urology for minimally invasive surgical techniques, adaptation of topical hemostatic agents to this surgical approach would be valuable and offers an opportunity for novel contributions.

Evaluation of 188Re-labeled PEGylated nanoliposome as a radionuclide therapeutic agent in an orthotopic glioma-bearing rat model

Directory of Open Access Journals (Sweden)

Huang FYJ

2015-01-01

Full Text Available Feng-Yun J Huang,1 Te-Wei Lee,2 Chih-Hsien Chang,2 Liang-Cheng Chen,2 Wei-Hsin Hsu,2 Chien-Wen Chang,1 Jem-Mau Lo1 1Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan; 2Institute of Nuclear Energy Research, Longtan, Taiwan Purpose: In this study, the 188Re-labeled PEGylated nanoliposome (188Re-liposome was prepared and evaluated as a therapeutic agent for glioma.Materials and methods: The reporter cell line, F98luc was prepared via Lentivector expression kit system and used to set up the orthotopic glioma-bearing rat model for non-invasive bioluminescent imaging. The maximum tolerated dose applicable in Fischer344 rats was explored via body weight monitoring of the rats after single intravenous injection of 188Re-liposome with varying dosages before the treatment study. The OLINDA/EXM 1.1 software was utilized for estimating the radiation dosimetry. To assess the therapeutic efficacy, tumor-bearing rats were intravenously administered 188Re-liposome or normal saline followed by monitoring of the tumor growth and animal survival time. In addition, the histopathological examinations of tumors were conducted on the 188Re-liposome-treated rats.Results: By using bioluminescent imaging, the well-established reporter cell line (F98luc showed a high relationship between cell number and its bioluminescent intensity (R2=0.99 in vitro; furthermore, it could also provide clear tumor imaging for monitoring tumor growth in vivo. The maximum tolerated dose of 188Re-liposome in Fischer344 rats was estimated to be 333 MBq. According to the dosimetry results, higher equivalent doses were observed in spleen and kidneys while very less were in normal brain, red marrow, and thyroid. For therapeutic efficacy study, the progression of tumor growth in terms of tumor volume and/or tumor weight was significantly slower for the 188Re-liposome-treated group than the control group (P<0.05. As a result, the

New and exploratory therapeutic agents for asthma

National Research Council Canada - National Science Library

Yeadon, Michael; Diamant, Zuzana

2000-01-01

... been accomplished. It is well recognized that new drugs are essentially the result of basic and applied research. Early in this century, the advent of a chemical approach to medicine led to many extraordinary developments. The past few decades have been characterized by a search to understand the mechanisms of disease- a quest spurred by the recognition that if pathogenic processes were known, new therapeutic opportunities would ensue. The validity of this concept is beautifully illustrated in the case of asthma. Here is a d...

Challenging and valuable

NARCIS (Netherlands)

Van Hal, J.D.M.

2008-01-01

Challenging and valuable Inaugural speech given on May 7th 2008 at the occasion of the acceptance of the position of Professor Sustainable Housing Transformation at the faculty of Architeeture of the Delft University of Technology by Prof. J.D.M. van Hal MSc PhD.

Therapeutic efficacy of a therapeutic cooking group from the patients' perspective.

Science.gov (United States)

Hill, Kimberly H; O'Brien, Kimberly A; Yurt, Roger W

2007-01-01

The purpose of this study was to evaluate the therapeutic efficacy of the cooking group from the burn survivors' perspective. By incorporating concepts of kitchen skills, energy conservation, and desensitization techniques, the cooking group can assist patients with the functional use of their hands, standing tolerance, return to former vocational activities, and socialization with other patients. A questionnaire was developed based on commonly expressed benefits of cooking group. Areas of interest included decreasing anxiety in the kitchen, distraction from their burns, socializing with other burn survivors, and the physical benefits of participating in the group. The results of this study indicate that participants regard the therapeutic cooking group as a valuable treatment modality that effectively combines functional activities with socialization to decrease burn related anxiety and increase motion in a supportive environment for patients with burns.

Bacterial agents and sensitivity pattern of neonatal conjuctivitis in ...

African Journals Online (AJOL)

Introduction: In Africa alone, between 1000 – 4000 children are blinded annually by conjunctivitis. In view of the changing aetiological agents documented in other parts of the world and evolving resistance of infective agents to therapeutic agents, the present study was designed to define the bacterial agents, their antibiotic ...

Therapeutic response assessment of percutaneous radiofrequency ablation for hepatocellular carcinoma: Utility of contrast-enhanced agent detection imaging

International Nuclear Information System (INIS)

Kim, Chan Kyo; Choi, Dongil; Lim, Hyo K.; Kim, Seung Hoon; Lee, Won Jae; Kim, Min Ju; Lee, Ji Yeon; Jeon, Yong Hwan; Lee, Jongmee; Lee, Soon Jin; Lim, Jae Hoon

2005-01-01

Purpose: To assess the utility of contrast-enhanced agent detection imaging (ADI) in the assessment of the therapeutic response to percutaneous radiofrequency (RF) ablation in patients with hepatocellular carcinoma (HCC). Materials and methods: Ninety patients with a total of 97 nodular HCCs (mean, 2.1 ± 1.3 cm; range, 1.0-5.0 cm) treated with percutaneous RF ablation under the ultrasound guidance were evaluated with contrast-enhanced ADI after receiving an intravenous bolus injection of a microbubble contrast agent (SH U 508A). We obtained serial contrast-enhanced ADI images during the time period from 15 to 90 s after the initiation of the bolus contrast injection. All of the patients underwent a follow-up four-phase helical CT at 1 month after RF ablation, which was then repeated at 2-4 month intervals during a period of at least 12 months. The results of the contrast-enhanced ADI were compared with those of the follow-up CT in terms of the presence or absence of residual unablated tumor and local tumor progression in the treated lesions. Results: On contrast-enhanced ADI, technical success was obtained in 94 (97%) of the 97 HCCs, while residual unablated tumors were found in three HCCs (3%). Two of the three tumors that were suspicious (was not proven) for incomplete ablation were subjected to additional RF ablation. The remaining one enhancing lesion that was suspicious of a residual tumor on contrast-enhanced ADI was revealed to be reactive hyperemia at the 1-month follow-up CT. Therefore; the diagnostic concordance between the contrast-enhanced ADI and 1-month follow-up CT was 99%. Of the 94 ablated HCCs without residual tumors on both the contrast-enhanced ADI and 1-month follow-up CT after the initial RF ablation, five (5%) had CT findings of local tumor progression at a subsequent follow-up CT. Conclusion: Despite its limitations in predicting local tumor progression in the treated tumors, contrast-enhanced ADI is potentially useful for evaluating the

Recovery and utilization of valuable metals from spent nuclear fuel. 3: Mutual separation of valuable metals

International Nuclear Information System (INIS)

Kirishima, K.; Shibayama, H.; Nakahira, H.; Shimauchi, H.; Myochin, M.; Wada, Y.; Kawase, K.; Kishimoto, Y.

1993-01-01

In the project ''Recovery and Utilization of Valuable Metals from Spent Fuel,'' mutual separation process of valuable metals recovered from spent fuel has been studied by using the simulated solution contained Pb, Ru, Rh, Pd and Mo. Pd was separated successfully by DHS (di-hexyl sulfide) solvent extraction method, while Pb was recovered selectively from the raffinate by neutralization precipitation of other elements. On the other hand, Rh was roughly separated by washing the precipitate with alkaline solution, so that Rh was refined by chelate resin CS-346. Outline of the mutual separation process flow sheet has been established of the combination of these techniques. The experimental results and the process flow sheet of mutual separation of valuable metals are presented in this paper

Selective estrogen receptor modulators as brain therapeutic agents

OpenAIRE

Arévalo, María Ángeles; Santos-Galindo, María; Lagunas, Natalia; Azcoitia, I.; García-Segura, Luis M.

2011-01-01

Selective estrogen receptor modulators (SERMs), used for the treatment of breast cancer, osteoporosis, and menopausal symptoms, affect the nervous system. Some SERMs trigger neuroprotective mechanisms and reduce neural damage in different experimental models of neural trauma, brain inflammation, neurodegenerative diseases, cognitive impairment, and affective disorders. New SERMs with specific actions on neurons and glial cells may represent promising therapeutic tools for the brain. © 2011 So...

Use of flubendazole as a therapeutic agent against rotifers (Brachionus plicatilis) in intensive cultures of the harpacticoid copepod Tisbe holothuriae

DEFF Research Database (Denmark)

Steenfeldt, Svend Jørgen; Nielsen, Johan W.

2010-01-01

down production and subsequently use a therapeutic agent to eliminate all zooplankton in the system before restart with a stock culture free of rotifers. We tested flubendazole as a mean of controlling rotifers (Brachionus plicatilis) in intensive laboratory cultures of the harpacticoid copepod (Tisbe...... holothuria). Flubendazole was lethal to rotifers in concentrations as low as 0.05 mg L−1. There was no significant effect on the concentration of copepods, even at the highest concentration tested, i.e. 5.0 mg L−1 flubendazole. We conclude that flubendazole is an effective drug for control of B. plicatilis...

Targeted Anticancer Immunotoxins and Cytotoxic Agents with Direct Killing Moieties

Directory of Open Access Journals (Sweden)

Koji Kawakami

2006-01-01

Full Text Available Despite the progress of the bioinformatics approach to characterize cell-surface antigens and receptors on tumor cells, it remains difficult to generate novel cancer vaccines or neutralizing monoclonal antibody therapeutics. Among targeted cancer therapeutics, biologicals with targetable antibodies or ligands conjugated or fused to toxins or chemicals for direct cell-killing ability have been developed over the last 2 decades. These conjugated or fused chimeric proteins are termed immunotoxins or cytotoxic agents. Two agents, DAB389IL-2 (ONTAKTM targeting the interleukin-2 receptor and CD33-calicheamicin (Mylotarg®, have been approved by the FDA for cutaneous T-cell lymphoma (CTCL and relapsed acute myeloid leukemia (AML, respectively. Such targetable agents, including RFB4(dsFv-PE38 (BL22, IL13-PE38QQR, and Tf-CRM107, are being tested in clinical trials. Several agents using unique technology such as a cleavable adapter or immunoliposomes with antibodies are also in the preclinical stage. This review summarizes the generation, mechanism, and development of these agents. In addition, possible future directions of this therapeutic approach are discussed.

Nanoparticles for therapeutic and diagnostic applications

OpenAIRE

Chiu, Yin To

2014-01-01

Nanomedicine focuses on the development and engineering of novel and unique therapeutic and diagnostic agents that can overcome the challenges associated with using traditional modalities. Nanoparticles (NPs) in the size range between 1 and 1000 nm have many advantages for use in these applications, such as, low polydispersity, established characterization methodologies, and the ability to be loaded with therapeutics for diseases, conjugated to targeting ligands to enhance specificity, and co...

Topical antifungal agents: an update.

Science.gov (United States)

Diehl, K B

1996-10-01

So many topical antifungal agents have been introduced that it has become very difficult to select the proper agent for a given infection. Nonspecific agents have been available for many years, and they are still effective in many situations. These agents include Whitfield's ointment, Castellani paint, gentian violet, potassium permanganate, undecylenic acid and selenium sulfide. Specific antifungal agents include, among others, the polyenes (nystatin, amphotericin B), the imidazoles (metronidazole, clotrimazole) and the allylamines (terbinafine, naftifine). Although the choice of an antifungal agent should be based on an accurate diagnosis, many clinicians believe that topical miconazole is a relatively effective agent for the treatment of most mycotic infections. Terbinafine and other newer drugs have primary fungicidal effects. Compared with older antifungal agents, these newer drugs can be used in lower concentrations and shorter therapeutic courses. Studies are needed to evaluate the clinical efficacies and cost advantages of both newer and traditional agents.

New 68Ga-PhenA bisphosphonates as potential bone imaging agents

International Nuclear Information System (INIS)

Wu, Zehui; Zha, Zhihao; Choi, Seok Rye; Plössl, Karl; Zhu, Lin; Kung, Hank F.

2016-01-01

Introduction: In vivo positron emission tomography (PET) imaging of the bone using [ 68 Ga]bisphosphonates may be a valuable tool for cancer diagnosis and monitoring therapeutic treatment. We have developed new [ 68 Ga]bisphosphonates based on the chelating group, AAZTA (6-[bis(hydroxycarbonyl-methyl)amino]-1,4-bis(hydroxycarbonyl methyl)-6-methylperhydro-1,4-diazepine). Method: Phenoxy derivative of AAZTA (2,2′-(6-(bis(carboxymethyl)amino)-6-((4-(2-carboxyethyl)phenoxy) methyl)-1,4-diazepane-1,4-diyl)diacetic acid), PhenA, 2, containing a bisphosphonate group (PhenA-BPAMD, 3, and PhenA-HBP, 4) was prepared. Labeling of these chelating agents with 68 Ga was evaluated. Results: The ligands reacted rapidly in a sodium acetate buffer with [ 68 Ga]GaCl 3 eluted from a commercially available 68 Ge/ 68 Ga generator (pH 4, > 95% labeling at room temperature in 5 min) to form [ 68 Ga]PhenA-BPAMD, 3, and [ 68 Ga]PhenA-HBP, 4. The improved labeling condition negates the need for further purification. The 68 Ga bisphosphonate biodistribution and autoradiography of bone sections in normal mice after an iv injection showed excellent bone uptake. Conclusion: New 68 Ga labeled bisphosphonates may be useful as in vivo bone imaging agents in conjunction with positron emission tomography (PET).

New therapeutic agent for radiation synovectomy - preparation of 166Ho-EDTMP-HA particle

International Nuclear Information System (INIS)

Bai, H.; Jin, X.; Du, J.; Wang, F.; Chen, D.; Fan, H.; Cheng, Z.; Zhang, J.

1997-01-01

In order to prepare new therapeutical agent for radiation synovectomy, Hydroxyapatite (HA) was labelled with 166 Ho by EDTMP that had high affinity to HA particles. Radiolabelling of HA particles was divided into two steps, 166 Ho-EDTMP was prepared first; then mixed with HA particles completely and vibrated for 15 minutes on the micromixer at room temperature, washed 3 times with deionized water. Radiolabelling particle was separated from free 166 Ho via centrifugation to determine its radiolabelling efficiency. 166 Ho-EDTMP-HA and 166 Ho-EDTMP were injected into knee joint of normal rabbits respectively, every group was killed at different time postinjection, took out major organ and collected urine and blood, then weighted and determined their radio counts. HA particles, as a natural component of bone was known to have good compatibility with soft tissue and biodegrade into calcium and phosphate in vivo. It was readily prepared from common chemical and formed into particles of desired size range in a controlled process, it had high stability in vitro and vivo. Radiolabelling of HA particle with 166 Ho by EDTMP was simple to perform and provides an excellent labelling yield that was more than 95% under the optimal labelling condition. The optimal labelling condition at room temperature was pH 6.0-8.0 and vibration time 15 minutes. The absorbed capacity of HA particle was 5 mg Ho/g HA particle and size of radiolabelling particle was at range of 2-5,μm that is suitable for therapy of radiation synovectomy. 166 Ho-EDTMP-HA particle demonstrated high in vitro stability in either normal saline or 1% BSA solution, but instability under extremely acidic condition (pH 1-2). The control studies performed with 166 Ho-EDTMP not bound to HA particle provided information on the distribution of radioactivity that would occur upon leakage of the radiochemical compound from joint. Its short half-life, its extremely low leakage from the joint and its even distribution throughout

Therapeutic strategies to improve control of hypertension.

Science.gov (United States)

Armario, Pedro; Waeber, Bernard

2013-03-01

Blood pressure is poorly controlled in most European countries and the control rate is even lower in high-risk patients such as patients with chronic kidney disease, diabetic patients or previous coronary heart disease. Several factors have been associated with poor control, some of which involve the characteristic of the patients themselves, such as socioeconomic factors, or unsuitable life-styles, other factors related to hypertension or to associated comorbidity, but there are also factors directly associated with antihypertensive therapy, mainly involving adherence problems, therapeutic inertia and therapeutic strategies unsuited to difficult-to-control hypertensive patients. It is common knowledge that only 30% of hypertensive patients can be controlled using monotherapy; all the rest require a combination of two or more antihypertensive drugs, and this can be a barrier to good adherence and log-term persistence in patients who also often need to use other drugs, such as antidiabetic agents, statins or antiplatelet agents. The fixed combinations of three antihypertensive agents currently available can facilitate long-term control of these patients in clinical practice. If well tolerated, a long-term therapeutic regimen that includes a diuretic, an ACE inhibitor or an angiotensin receptor blocker, and a calcium channel blocker is the recommended optimal triple therapy.

An agent-based intelligent environmental monitoring system

OpenAIRE

Athanasiadis, Ioannis N; Mitkas, Pericles A

2004-01-01

Fairly rapid environmental changes call for continuous surveillance and on-line decision making. There are two main areas where IT technologies can be valuable. In this paper we present a multi-agent system for monitoring and assessing air-quality attributes, which uses data coming from a meteorological station. A community of software agents is assigned to monitor and validate measurements coming from several sensors, to assess air-quality, and, finally, to fire alarms to appropriate recipie...

Orexin receptor antagonists as therapeutic agents for insomnia

Directory of Open Access Journals (Sweden)

Ana Clementina Equihua

2013-12-01

Full Text Available Insomnia is a common clinical condition characterized by difficulty initiating or maintaining sleep, or non-restorative sleep with impairment of daytime functioning.Currently, treatment for insomnia involves a combination of cognitive behavioral therapy and pharmacological therapy. Among pharmacological interventions, the most evidence exists for benzodiazepine receptor agonist drugs (GABAA receptor, although concerns persist regarding their safety and their limited efficacy. The use of these hypnotic medications must be carefully monitored for adverse effects.Orexin (hypocretin neuropeptides have been shown to regulate transitions between wakefulness and sleep by promoting cholinergic/monoaminergic neural pathways. This has led to the development of a new class of pharmacological agents that antagonize the physiological effects of orexin. The development of these agents may lead to novel therapies for insomnia without the side effect profile of hypnotics (e.g. impaired cognition, disturbed arousal, and motor balance difficulties. However, antagonizing a system that regulates the sleep-wake cycle may create an entirely different side effect profile. In this review, we discuss the role of orexin and its receptors on the sleep-wake cycle and that of orexin antagonists in the treatment of insomnia.

Topical Botanical Agents for the Treatment of Psoriasis: A Systematic Review.

Science.gov (United States)

Farahnik, Benjamin; Sharma, Divya; Alban, Joseph; Sivamani, Raja K

2017-08-01

Patients with psoriasis often enquire about the use of numerous botanical therapeutics. It is important for dermatologists to be aware of the current evidence regarding these agents. We conducted a systematic literature search using the PubMed, MEDLINE, and EMBASE databases for controlled and uncontrolled clinical trials that assessed the use of topical botanical therapeutics for psoriasis. The search included the following keywords: 'psoriasis' and 'plant' or 'herbal' or 'botanical'. We also reviewed citations within articles to identify additional relevant sources. We then further refined the results by route of administration and the topical botanical agents are reviewed herein. A total of 27 controlled and uncontrolled clinical trials addressing the use of topical botanical agents for psoriasis were assessed in this review. We found that the most highly studied and most efficacious topical botanical therapeutics were Mahonia aquifolium, indigo naturalis, aloe vera, and, to a lesser degree, capsaicin. The most commonly reported adverse effects were local skin irritation, erythema, pruritus, burning, and pain. However, the overall evidence for these therapeutics remains limited in quantity and quality. The literature addresses a large number of studies in regard to botanicals for the treatment of psoriasis. While most agents appear to be safe, further research is necessary before topical botanical agents can be consistently recommended to patients.

[New agents for hypercholesterolemia].

Science.gov (United States)

Pintó, Xavier; García Gómez, María Carmen

2016-02-19

An elevated proportion of high cardiovascular risk patients do not achieve the therapeutic c-LDL goals. This owes to physicians' inappropriate or insufficient use of cholesterol lowering medications or to patients' bad tolerance or therapeutic compliance. Another cause is an insufficient efficacy of current cholesterol lowering drugs including statins and ezetimibe. In addition, proprotein convertase subtilisin kexin type 9 inhibitors are a new cholesterol lowering medications showing safety and high efficacy to reduce c-LDL in numerous already performed or underway clinical trials, potentially allowing an optimal control of hypercholesterolemia in most patients. Agents inhibiting apolipoprotein B synthesis and microsomal transfer protein are also providing a new potential to decrease cholesterol in patients with severe hypercholesterolemia and in particular in homozygote familial hypercholesterolemia. Last, cholesteryl ester transfer protein inhibitors have shown powerful effects on c-HDL and c-LDL, although their efficacy in cardiovascular prevention and safety has not been demonstrated yet. We provide in this article an overview of the main characteristics of therapeutic agents for hypercholesterolemia, which have been recently approved or in an advanced research stage. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

Trypanosoma cruzi benznidazole susceptibility in vitro does not predict the therapeutic outcome of human Chagas disease

Directory of Open Access Journals (Sweden)

Margoth Moreno

2010-11-01

Full Text Available Therapeutic failure of benznidazole (BZ is widely documented in Chagas disease and has been primarily associated with variations in the drug susceptibility of Trypanosoma cruzi strains. In humans, therapeutic success has been assessed by the negativation of anti-T. cruzi antibodies, a process that may take up to 10 years. A protocol for early screening of the drug resistance of infective strains would be valuable for orienting physicians towards alternative therapies, with a combination of existing drugs or new anti-T. cruzi agents. We developed a procedure that couples the isolation of parasites by haemoculture with quantification of BZ susceptibility in the resultant epimastigote forms. BZ activity was standardized with reference strains, which showed IC50 to BZ between 7.6-32 µM. The assay was then applied to isolates from seven chronic patients prior to administration of BZ therapy. The IC50 of the strains varied from 15.6 ± 3-51.4 ± 1 µM. Comparison of BZ susceptibility of the pre-treatment isolates of patients considered cured by several criteria and of non-cured patients indicates that the assay does not predict therapeutic outcome. A two-fold increase in BZ resistance in the post-treatment isolates of two patients was verified. Based on the profile of nine microsatellite loci, sub-population selection in non-cured patients was ruled out.

Concanavalin A: A potential anti-neoplastic agent targeting apoptosis, autophagy and anti-angiogenesis for cancer therapeutics

International Nuclear Information System (INIS)

Li, Wen-wen; Yu, Jia-ying; Xu, Huai-long; Bao, Jin-ku

2011-01-01

Highlights: → ConA induces cancer cell death targeting apoptosis and autophagy. → ConA inhibits cancer cell angiogenesis. → ConA is utilized in pre-clinical and clinical trials. -- Abstract: Concanavalin A (ConA), a Ca 2+ /Mn 2+ -dependent and mannose/glucose-binding legume lectin, has drawn a rising attention for its remarkable anti-proliferative and anti-tumor activities to a variety of cancer cells. ConA induces programmed cell death via mitochondria-mediated, P73-Foxo1a-Bim apoptosis and BNIP3-mediated mitochondrial autophagy. Through IKK-NF-κB-COX-2, SHP-2-MEK-1-ERK, and SHP-2-Ras-ERK anti-angiogenic pathways, ConA would inhibit cancer cell survival. In addition, ConA stimulates cell immunity and generates an immune memory, resisting to the same genotypic tumor. These biological findings shed light on new perspectives of ConA as a potential anti-neoplastic agent targeting apoptosis, autophagy and anti-angiogenesis in pre-clinical or clinical trials for cancer therapeutics.

Cisplatin encapsulated nanoparticle as a therapeutic agent for anticancer treatment

Science.gov (United States)

Eka Putra, Gusti Ngurah Putu; Huang, Leaf; Hsu, Yih-Chih

2016-03-01

The knowledge of manipulating size of biomaterials encapsulated drug into nano-scale particles has been researched and developed in treating cancer. Cancer is the second worldwide cause of death, therefore it is critical to treat cancers challenging with therapeutic modality of various mechanisms. Our preliminary investigation has studied cisplatin encapsulated into lipid-based nanoparticle and examined the therapeutic effect on xenografted animal model. We used mice with tumor volume ranging from 195 to 214 mm3 and then few mice were grouped into three groups including: control (PBS), lipid platinum chloride (LPC) nanoparticles and CDDP (cis-diamminedichloroplatinum(II) at dose of 3mg cisplatin /kg body weight. The effect of the treatment was observed for 12 days post-injection. It showed that LPC NPs demonstrated a better therapeutic effect compared to CDDP at same 3mg cisplatin/kg drug dose of tumor size reduction, 96.6% and 11.1% respectively. In addition, mouse body weight loss of LPC, CDDP and PBS treated group are 12.1%, 24.3% and 1.4%. It means that by compared to CDDP group, LPC group demonstrated less side effect as not much reduction of body weight have found. Our findings have shown to be a potential modality to further investigate as a feasible cancer therapy modality.

Therapeutic benefit in patients switching tolterodine to other novel antimuscarinic agents.

Science.gov (United States)

Sánchez-Ballester, F; Miranda, P; Lizarraga, I; Rejas, J; Arumi, D

2014-04-01

To explore in the daily clinical practice setting that antimuscarinic, Fesoterodine or Solifenacin, provides a greater clinical benefit after changing their prior Overactive Bladder (OAB) therapy with tolterodine extended-release (ER) to other novel antimuscarinic agents. A post-hoc analysis of data from an observational multicenter, cross-sectional, retrospective study. Adult patients of both sexes, with OAB and OAB-V8 score≥8, who switched to fesoterodine or solifenacin within the 3-4 months before study visit from their prior tolterodine-ER-based therapy due to poor response were included. 92 patients were selected for each treatment group, matched (1:1) according to conditioned probability using the propensity score. Benefit of treatment change perceived by the physician and patient was evaluated by means of the Clinical Global Impression of Improvement subscale (CGI-I) and Treatment Benefit Scale (TBS), respectively. Degree of worry, bother and interference with daily living activities due to urinary symptoms, level of satisfaction, and preference for current treatment were also assessed. Fesoterodine provided a significantly greater improvement than solifenacina in terms of therapeutic benefit perceived by the physician according to ICG-I. 96.7% of the patients on fesoterodine treatment vs. 81.6% of the solifenacin group showed a score of improvement in TBS (P<.05). Fesoterodine was also better rated than solifenacin with regard to satisfaction and preference for the new treatment (93.4 vs. 78.2% P<.05). In daily clinical practice the switch from tolterodine LP to fesoterodine seems to provide greater benefits both from the physician's and the patient's point of view compared with those provided by solifenacin. Copyright © 2013 AEU. Published by Elsevier Espana. All rights reserved.

Gallium a unique anti-resorptive agent in bone: Preclinical studies on its mechanisms of action

International Nuclear Information System (INIS)

Bockman, R.; Adelman, R.; Donnelly, R.; Brody, L.; Warrell, R.; Jones, K.W.

1990-01-01

The discovery of gallium as a new and unique agent for the treatment of metabolic bone disorders was in part fortuitous. Gallium is an exciting new therapeutic agent for the treatment of pathologic states characterized by accelerated bone resorption. Compared to other therapeutic metal compounds containing platinum or germanium, gallium affects its antiresorptive action without any evidence of a cytotoxic effect on bone cells. Gallium is unique amongst all therapeutically available antiresorptive agents in that it favors bone formation. 18 refs., 1 fig

Beyond Needs Assessments: Marketing as Change Agent.

Science.gov (United States)

Piland, William E.

1984-01-01

Views marketing techniques as agents of change providing valuable assistance to community college decision makers. Discusses the importance of a balance among the four P's of marketing (i.e., promotion, price, place, and product); and seven procedural steps in developing a sound marketing strategy. (DMM)

Epigenetic Modulating Agents as a New Therapeutic Approach in Multiple Myeloma

International Nuclear Information System (INIS)

Maes, Ken; Menu, Eline; Van Valckenborgh, Els; Van Riet, Ivan; Vanderkerken, Karin; De Bruyne, Elke

2013-01-01

Multiple myeloma (MM) is an incurable B-cell malignancy. Therefore, new targets and drugs are urgently needed to improve patient outcome. Epigenetic aberrations play a crucial role in development and progression in cancer, including MM. To target these aberrations, epigenetic modulating agents, such as DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi), are under intense investigation in solid and hematological cancers. A clinical benefit of the use of these agents as single agents and in combination regimens has been suggested based on numerous studies in pre-clinical tumor models, including MM models. The mechanisms of action are not yet fully understood but appear to involve a combination of true epigenetic changes and cytotoxic actions. In addition, the interactions with the BM niche are also affected by epigenetic modulating agents that will further determine the in vivo efficacy and thus patient outcome. A better understanding of the molecular events underlying the anti-tumor activity of the epigenetic drugs will lead to more rational drug combinations. This review focuses on the involvement of epigenetic changes in MM pathogenesis and how the use of DNMTi and HDACi affect the myeloma tumor itself and its interactions with the microenvironment

The botulinum toxin as a therapeutic agent: molecular and pharmacological insights

Directory of Open Access Journals (Sweden)

Kukreja R

2015-12-01

Full Text Available Roshan Kukreja,1 Bal Ram Singh2 1Department of Chemistry and Biochemistry, University of Massachusetts, 2Botulinum Research Center, Institute of Advanced Sciences, Dartmouth, MA, USA Abstract: Botulinum neurotoxins (BoNTs, the most potent toxins known to mankind, are metalloproteases that act on nerve–muscle junctions to block exocytosis through a very specific and exclusive endopeptidase activity against soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE proteins of presynaptic vesicle fusion machinery. This very ability of the toxins to produce flaccid muscle paralysis through chemical denervation has been put to good use, and these potentially lethal toxins have been licensed to treat an ever expanding list of medical disorders and more popularly in the field of esthetic medicine. In most cases, therapeutic BoNT preparations are high-molecular-weight protein complexes consisting of BoNT, complexing proteins, and excipients. There is at least one isolated BoNT, which is free of complexing proteins in the market (Xeomin®. Each commercially available BoNT formulation is unique, differing mainly in molecular size and composition of complexing proteins, biological activity, and antigenicity. BoNT serotype A is marketed as Botox®, Dysport®, and Xeomin®, while BoNT type B is commercially available as Myobloc®. Nerve terminal intoxication by BoNTs is completely reversible, and the duration of therapeutic effects of BoNTs varies for different serotypes. Depending on the target tissue, BoNTs can block the cholinergic neuromuscular or cholinergic autonomic innervation of exocrine glands and smooth muscles. Therapeutic BoNTs exhibit a high safety and very limited adverse effects profile. Despite their established efficacy, the greatest concern with the use of therapeutic BoNTs is their propensity to elicit immunogenic reactions that might render the patient unresponsive to subsequent treatments, particularly in chronic

Tracking of multimodal therapeutic nanocomplexes targeting breast cancer in vivo.

Science.gov (United States)

Bardhan, Rizia; Chen, Wenxue; Bartels, Marc; Perez-Torres, Carlos; Botero, Maria F; McAninch, Robin Ward; Contreras, Alejandro; Schiff, Rachel; Pautler, Robia G; Halas, Naomi J; Joshi, Amit

2010-12-08

Nanoparticle-based therapeutics with local delivery and external electromagnetic field modulation holds extraordinary promise for soft-tissue cancers such as breast cancer; however, knowledge of the distribution and fate of nanoparticles in vivo is crucial for clinical translation. Here we demonstrate that multiple diagnostic capabilities can be introduced in photothermal therapeutic nanocomplexes by simultaneously enhancing both near-infrared fluorescence and magnetic resonance imaging (MRI). We track nanocomplexes in vivo, examining the influence of HER2 antibody targeting on nanocomplex distribution over 72 h. This approach provides valuable, detailed information regarding the distribution and fate of complex nanoparticles designed for specific diagnostic and therapeutic functions.

Kinase inhibitors of the IGF-1R as a potential therapeutic agent for rheumatoid arthritis.

Science.gov (United States)

Tsushima, Hiroshi; Morimoto, Shinji; Fujishiro, Maki; Yoshida, Yuko; Hayakawa, Kunihiro; Hirai, Takuya; Miyashita, Tomoko; Ikeda, Keigo; Yamaji, Ken; Takamori, Kenji; Takasaki, Yoshinari; Sekigawa, Iwao; Tamura, Naoto

2017-08-01

We have previously shown that the inhibition of connective tissue growth factor (CTGF) is a potential therapeutic strategy against rheumatoid arthritis (RA). CTGF consists of four distinct modules, including the insulin-like growth factor binding protein (IGFBP). In serum, insulin-like growth factors (IGFs) bind IGFBPs, interact with the IGF-1 receptor (IGF-1 R), and regulate anabolic effects and bone metabolism. We investigated the correlation between IGF-1 and the pathogenesis of RA, and the inhibitory effect on osteoclastogenesis and angiogenesis of the small molecular weight kinase inhibitor of the IGF-1 R, NVP-AEW541, against pathogenesis of RA in vitro. Cell proliferation was evaluated by cell count and immunoblotting. The expression of IGF-1 and IGF-1 R was evaluated by RT-PCR. Osteoclastogenesis was evaluated using tartrate-resistant acid phosphatase staining, a bone resorption assay, and osteoclast-specific enzyme production. Angiogenesis was evaluated by a tube formation assay using human umbilical vein endothelial cells (HUVECs). The proliferation of MH7A cells was found to be inhibited in the presence of NVP-AEW541, and the phosphorylation of extracellular signal-regulated kinase (ERK) and Akt was downregulated in MH7A cells. IGF-1 and IGF-1 R mRNA expression levels were upregulated during formation of M-colony stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL)-mediated osteoclast formation. Moreover, osteoclastogenesis was suppressed in the presence of NVP-AEW541. The formation of the tubular network was enhanced by IGF-1, and this effect was neutralized by NVP-ARE541. Our findings suggest that NVP-AEW541 may be utilized as a potential therapeutic agent in the treatment of RA.

Recent Progress in Functional Micellar Carriers with Intrinsic Therapeutic Activities for Anticancer Drug Delivery.

Science.gov (United States)

Qu, Ying; Chu, BingYang; Shi, Kun; Peng, JinRong; Qian, ZhiYong

2017-12-01

Polymeric micelles have presented superior delivery properties for poorly water-soluble chemotherapeutic agents. However, it remains discouraging that there may be some additional short or long-term toxicities caused by the metabolites of high quantities of carriers. If carriers had simultaneous therapeutic effects with the drug, these issues would not be a concern. For this, carriers not only simply act as drug carriers, but also exert an intrinsic therapeutic effect as a therapeutic agent. The functional micellar carriers would be beneficial to maximize the anticancer effect, overcome the drug resistance and reduce the systemic toxicity. In this review, we aim to summarize the recent progress on the development of functional micellar carriers with intrinsic anticancer activities for the delivery of anticancer drugs. This review focuses on the design strategies, properties of carriers and the drug loading behavior. In addition, the combinational therapeutic effects between carriers and chemotherapeutic agents are also discussed.

Evaluation of gloves as a water bag coupling agent for therapeutic ultrasound

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Lúcio Salustiano de Lima

2017-03-01

Full Text Available Abstract Introduction Therapeutic ultrasound (TUS is a widespread modality in physiotherapy, and the water bag technique is a coupling method employed in the presence of anatomical irregularities in the treatment area. The aim of the present study is to evaluate the acoustic attenuation of the water bag and its effectiveness as a TUS coupling agent. Methods The rated output powers (ROPs of the TUS equipment were evaluated based on IEC 61689. Then, a radiation force balance was used to measure ROP with and without a water bag (latex and nitrile gloves filled with deionized water between a TUS transducer and the cone-shaped target of the balance. Each experiment was performed five times for each nominal power (0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, and 7.0 W and in the following configurations: without the water bag (A, with nitrile gloves and with (B and without (C a height controller, and latex gloves with (D and without (E height controller. ROPs obtained in different media were compared. Results The highest relative error of ROP was 16.72% for 0.5 W. Although the power values of the equipment were within the range recommended by IEC, there was a significant difference between the ROP values measured with A and with B, C and D. Conclusion As intensity differences below 0.5 W/cm2 are considered clinically not relevant, conditions A, B, C, D, or E can be used interchangeably.

Impacts of the Human Gut Microbiome on Therapeutics.

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Vázquez-Baeza, Yoshiki; Callewaert, Chris; Debelius, Justine; Hyde, Embriette; Marotz, Clarisse; Morton, James T; Swafford, Austin; Vrbanac, Alison; Dorrestein, Pieter C; Knight, Rob

2018-01-06

The human microbiome contains a vast source of genetic and biochemical variation, and its impacts on therapeutic responses are just beginning to be understood. This expanded understanding is especially important because the human microbiome differs far more among different people than does the human genome, and it is also dramatically easier to change. Here, we describe some of the major factors driving differences in the human microbiome among individuals and populations. We then describe some of the many ways in which gut microbes modify the action of specific chemotherapeutic agents, including nonsteroidal anti-inflammatory drugs and cardiac glycosides, and outline the potential of fecal microbiota transplant as a therapeutic. Intriguingly, microbes also alter how hosts respond to therapeutic agents through various pathways acting at distal sites. Finally, we discuss some of the computational and practical issues surrounding use of the microbiome to stratify individuals for drug response, and we envision a future where the microbiome will be modified to increase everyone's potential to benefit from therapy.

Argan Oil as an Effective Nutri-Therapeutic Agent in Metabolic Syndrome: A Preclinical Study

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Adil El Midaoui

2017-11-01

Full Text Available The present study aims at examining the effects of argan oil on the three main cardiovascular risk factors associated with metabolic syndrome (hypertension, insulin resistance and obesity and on one of its main complications, neuropathic pain. Male Sprague-Dawley rats had free access to a drinking solution containing 10% d-glucose or tap water for 12 weeks. The effect of argan oil was compared to that of corn oil given daily by gavage during 12 weeks in glucose-fed rats. Glucose-fed rats showed increases in systolic blood pressure, epididymal fat, plasma levels of triglycerides, leptin, glucose and insulin, insulin resistance, tactile and cold allodynia in association with a rise in superoxide anion production and NADPH oxidase activity in the thoracic aorta, epididymal fat and gastrocnemius muscle. Glucose-fed rats also showed rises in B1 receptor protein expression in aorta and gastrocnemius muscle. Argan oil prevented or significantly reduced all those anomalies with an induction in plasma adiponectin levels. In contrast, the same treatment with corn oil had a positive impact only on triglycerides, leptin, adiponectin and insulin resistance. These data are the first to suggest that argan oil is an effective nutri-therapeutic agent to prevent the cardiovascular risk factors and complications associated with metabolic syndrome.

Dendrimers as Potential Therapeutic Tools in HIV Inhibition

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Xiangbo Li

2013-07-01

Full Text Available The present treatments for HIV transfection include chemical agents and gene therapies. Although many chemical drugs, peptides and genes have been developed for HIV inhibition, a variety of non-ignorable drawbacks limited the efficiency of these materials. In this review, we discuss the application of dendrimers as both therapeutic agents and non-viral vectors of chemical agents and genes for HIV treatment. On the one hand, dendrimers with functional end groups combine with the gp120 of HIV and CD4 molecule of host cell to suppress the attachment of HIV to the host cell. Some of the dendrimers are capable of intruding into the cell and interfere with the later stages of HIV replication as well. On the other hand, dendrimers are also able to transfer chemical drugs and genes into the host cells, which conspicuously increase the anti-HIV activity of these materials. Dendrimers as therapeutic tools provide a potential treatment for HIV infection.

Predicting Social Anxiety Treatment Outcome based on Therapeutic Email Conversations

NARCIS (Netherlands)

Hoogendoorn, M.; Berger, Thomas; Schulz, Ava; Stolz, Timo; Szolovits, Peter

2016-01-01

Predicting therapeutic outcome in the mental health domain is of utmost importance to enable therapists to provide the most effective treatment to a patient. Using information from the writings of a patient can potentially be a valuable source of information, especially now that more and more

Progranulin as a biomarker and potential therapeutic agent.

Science.gov (United States)

Abella, Vanessa; Pino, Jesús; Scotece, Morena; Conde, Javier; Lago, Francisca; Gonzalez-Gay, Miguel Angel; Mera, Antonio; Gómez, Rodolfo; Mobasheri, Ali; Gualillo, Oreste

2017-10-01

Progranulin is a cysteine-rich secreted protein with diverse pleiotropic actions and participates in several processes, such as inflammation or tumorigenesis. Progranulin was first identified as a growth factor and, recently, it was characterised as an adipokine implicated in obesity, insulin resistance and rheumatic disease. At a central level, progranulin acts as a neurotropic and neuroprotective factor and protects from neural degeneration. In this review, we summarise the most recent research advances concerning the potential role of progranulin as a therapeutic target and biomarker in cancer, neurodegenerative and inflammatory diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemotherapeutic agent and tracer composition and use thereof

International Nuclear Information System (INIS)

Babb, A. L.

1985-01-01

A therapeutic composition suitable for extracorporeal treatment of whole blood comprises a dialyzable chemotherapeutic agent and a dialyzable fluorescable tracer means. The removal rate of the fluorescable tracer compound from treated blood during hemodialysis is a function of the removal rate of unreacted chemotherapeutic agent present. The residual chemotherapeutic agent concentration after hemodialysis is ascertained by measuring the concentration of the fluorescable tracer compound in a dialysate using fluorometric techniques

{sup 166} Ho-HA Evaluation as therapeutic agent for rheumatoid arthritis treatment; Evaluacion de {sup 166}Ho-Ha como agente terapeutico en el tratamiento de la artritis reumatoidea

Energy Technology Data Exchange (ETDEWEB)

Chandia, M; Errazu, X [Comision Chilena de Energia Nuclear, Santiago (Chile); Mendoza, P [Departamento de Medicina Nuclear, Hospital Militar, Santiago (Chile); Troncoso, F [Comision Chilena de Energia Nuclear, Santiago (Chile); Jofre, J; Sierralta, P [Departamento de Medicina Nuclear, Hospital Militar, Santiago (Chile)

2003-01-01

Aim: Rheumatoid arthritis is a limiting disease having, among its pathological features, the inflammation of synovial tissue with progressive and later destruction of the articulation. This lead to joint deformation and loss of its function, generating pain and reducing the mobility of the affected articulation. The aim was to evaluate {sup 166}Ho-Hydroxyapatite ({sup 166} Ho-HA) as potential radiopharmaceutical for the syntomatic treatment of chronic and acute arthritis Materials and Methods: {sup 166}Holmiun was produced by irradiation of Ho{sub 2}O{sub 3} at La Reina Research Reactor, Nuclear Chilean Energy Commission. Hydroxyapatite was in-house synthetized. Its labelling and quality controls follows the internationally accepted procedures. An antigen arthritis was induced to eight New Zealand rabbits with the {sup 166}Ho-HA radiochemical being administred thereafter in two dosage modalities (single and double). The compound therapeutic efficiency was evaluated based upon clinical improvement and images from the inflamated articulation using {sup 67}Ga citrate before and after {sup 166} Ho-HA injection. Results: The radiochemical purity of the innoculated compound was greater than 98% as measured under sterility conditions. Clinically, an inflamation reduction (2 cm), appetite improvement and general well being was observed. The {sup 166} Ho-HA distribution and localization was monitored using gamma camera images taken at 4 and 24 h. There was no evidence of extraarticular leakage. From the {sup 67}Ga citrate imaging, the acute group shows an overall improvement of well being corresponding to a lesser uptake at the inflamated articulation, regarding to the chronic group. The {sup 166}Ho-HA double dosis, compared to the single dosis, suggest a reduced uptake of {sup 67}Ga citrate at the inflamated tissue, meaning an increased therapeutic effect. Conclusions: {sup 166} Ho-HA is usefull as therapeutic agent for the syntomatic treatment of rheumatoideal arthritis

Supramolecular Nanoparticles for Molecular Diagnostics and Therapeutics

Science.gov (United States)

Chen, Kuan-Ju

Over the past decades, significant efforts have been devoted to explore the use of various nanoparticle-based systems in the field of nanomedicine, including molecular imaging and therapy. Supramolecular synthetic approaches have attracted lots of attention due to their flexibility, convenience, and modularity for producing nanoparticles. In this dissertation, the developmental story of our size-controllable supramolecular nanoparticles (SNPs) will be discussed, as well as their use in specific biomedical applications. To achieve the self-assembly of SNPs, the well-characterized molecular recognition system (i.e., cyclodextrin/adamantane recognition) was employed. The resulting SNPs, which were assembled from three molecular building blocks, possess incredible stability in various physiological conditions, reversible size-controllability and dynamic disassembly that were exploited for various in vitro and in vivo applications. An advantage of using the supramolecular approach is that it enables the convenient incorporation of functional ligands onto SNP surface that confers functionality ( e.g., targeting, cell penetration) to SNPs. We utilized SNPs for molecular imaging such as magnetic resonance imaging (MRI) and positron emission tomography (PET) by introducing reporter systems (i.e., radio-isotopes, MR contrast agents, and fluorophores) into SNPs. On the other hand, the incorporation of various payloads, including drugs, genes and proteins, into SNPs showed improved delivery performance and enhanced therapeutic efficacy for these therapeutic agents. Leveraging the powers of (i) a combinatorial synthetic approach based on supramolecular assembly and (ii) a digital microreactor, a rapid developmental pathway was developed that is capable of screening SNP candidates for the ideal structural and functional properties that deliver optimal performance. Moreover, SNP-based theranostic delivery systems that combine reporter systems and therapeutic payloads into a

Development of a Multifaceted Ovarian Cancer Therapeutic and Imaging Agent

National Research Council Canada - National Science Library

Markland, Francis S

2008-01-01

...%. This project outlines the development of a recombinant version of a member of a class of proteins known as disintegrins as an innovative imaging and diagnostic agent for ovarian cancer (OC). Vicrostatin (VN...

Evolution of and perspectives on therapeutic approaches to nerve agent poisoning.

Science.gov (United States)

Masson, Patrick

2011-09-25

After more than 70 years of considerable efforts, research on medical defense against nerve agents has come to a standstill. Major progress in medical countermeasures was achieved between the 50s and 70s with the development of anticholinergic drugs and carbamate-based pretreatment, the introduction of pyridinium oximes as antidotes, and benzodiazepines in emergency treatments. These drugs ensure good protection of the peripheral nervous system and mitigate the acute effects of exposure to lethal doses of nerve agents. However, pyridostigmine and cholinesterase reactivators currently used in the armed forces do not protect/reactivate central acetylcholinesterases. Moreover, other drugs used are not sufficiently effective in protecting the central nervous system against seizures, irreversible brain damages and long-term sequelae of nerve agent poisoning.New developments of medical counter-measures focus on: (a) detoxification of organophosphorus molecules before they react with acetylcholinesterase and other physiological targets by administration of stoichiometric or catalytic scavengers; (b) protection and reactivation of central acetylcholinesterases, and (c) improvement of neuroprotection following delayed therapy.Future developments will aim at treatment of acute and long-term effects of low level exposure to nerve agents, research on alternative routes for optimizing drug delivery, and therapies. Though gene therapy for in situ generation of bioscavengers, and cell therapy based on neural progenitor engraftment for neuronal regeneration have been successfully explored, more studies are needed before practical medical applications can be made of these new approaches. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Emergent Macroeconomics An Agent-Based Approach to Business Fluctuations

CERN Document Server

Delli Gatti, Domenico; Gallegati, Mauro; Giulioni, Gianfranco; Palestrini, Antonio

2008-01-01

This book contributes substantively to the current state-of-the-art of macroeconomics by providing a method for building models in which business cycles and economic growth emerge from the interactions of a large number of heterogeneous agents. Drawing from recent advances in agent-based computational modeling, the authors show how insights from dispersed fields like the microeconomics of capital market imperfections, industrial dynamics and the theory of stochastic processes can be fruitfully combined to improve our understanding of macroeconomic dynamics. This book should be a valuable resource for all researchers interested in analyzing macroeconomic issues without recurring to a fictitious representative agent.

Vulnerability of particularly valuable areas. Summary

Energy Technology Data Exchange (ETDEWEB)

NONE

2012-07-01

This report is part of the scientific basis for the management plan for the North Sea and Skagerrak. The report focuses on the vulnerability of particularly valuable areas to petroleum activities, maritime transport, fisheries, land-based and coastal activities and long-range transboundary pollution. A working group with representatives from many different government agencies, headed by the Institute of Marine Research and the Directorate for Nature Management, has been responsible for drawing up the present report on behalf of the Expert Group for the North Sea and Skagerrak. The present report considers the 12 areas that were identified as particularly valuable during an earlier stage of the management plan process on the environment, natural resources and pollution. There are nine areas along the coast and three open sea areas in the North Sea that were identified according to the same predefined criteria as used for the management plans for the Barents Sea: Lofoten area and the Norwegian Sea. The most important criteria for particularly valuable areas are importance for biological production and importance for biodiversity.(Author)

Vulnerability of particularly valuable areas. Summary

International Nuclear Information System (INIS)

2012-01-01

This report is part of the scientific basis for the management plan for the North Sea and Skagerrak. The report focuses on the vulnerability of particularly valuable areas to petroleum activities, maritime transport, fisheries, land-based and coastal activities and long-range transboundary pollution. A working group with representatives from many different government agencies, headed by the Institute of Marine Research and the Directorate for Nature Management, has been responsible for drawing up the present report on behalf of the Expert Group for the North Sea and Skagerrak. The present report considers the 12 areas that were identified as particularly valuable during an earlier stage of the management plan process on the environment, natural resources and pollution. There are nine areas along the coast and three open sea areas in the North Sea that were identified according to the same predefined criteria as used for the management plans for the Barents Sea: Lofoten area and the Norwegian Sea. The most important criteria for particularly valuable areas are importance for biological production and importance for biodiversity.(Author)

A Sustainable and Selective Roasting and Water-Leaching Process to Simultaneously Extract Valuable Metals from Low-Grade Ni-Cu Matte

Science.gov (United States)

Cui, Fuhui; Mu, Wenning; Wang, Shuai; Xin, Haixia; Xu, Qian; Zhai, Yuchun

2018-03-01

Due to stringent environmental requirements and the complex occurrence of valuable metals, traditional pyrometallurgical methods are unsuitable for treating low-grade nickel-copper matte. A clean and sustainable two-stage sulfating roasting and water-leaching process was used to simultaneously extract valuable metals from low-grade nickel-copper matte. Ammonium and sodium sulfate were used as sulfating agents. The first roasting temperature, mass ratio of ammonium sulfate to matte, roasting time, dosage of sodium sulfate, second roasting temperature and leaching temperature were studied. Under optimal conditions, 98.89% of Ni, 97.48% of Cu and 95.82% of Co, but only 1.34% of Fe, were extracted. X-ray diffraction (XRD) and scanning electron microscopy (SEM) were used to reveal the sulfating mechanism during the roasting process.

A comparative study on the cost of new antibiotics and drugs of other therapeutic categories.

Science.gov (United States)

Falagas, Matthew E; Fragoulis, Konstantinos N; Karydis, Ioannis

2006-12-20

Drug treatment is becoming more expensive due to the increased cost for the introduction of new drugs, and there seems to be an uneven distribution of medication cost for different therapeutic categories. We hypothesized that the cost of new antimicrobial agents may differ from that of other therapeutic categories and this may play a role in the stagnation of development of new antibiotics. We performed a pharmaco-economical comparative analysis of the drug cost of treatment for new agents introduced in the United States drug market in various therapeutic categories. We calculated the drug cost (in US dollars) of a ten-day treatment of all new drugs approved by the FDA during the period between January 1997 and July 2003, according to the 2004 Red Book Pharmacy's Fundamental Reference. New anti-neoplastic agents were found to be the most expensive drugs in comparison to all other therapeutic categories, with a median ten-day drug-treatment cost of US$848 compared to the median ten-day drug-treatment costs of all other categories ranging from US$29 to US$301. On the other hand, new antimicrobial drugs were found to be much less expensive, with a median ten-day drug-treatment cost of US$137 and $US85 for all anti-microbial agents and for anti-microbial agents excluding anti-HIV medications, respectively. The drug-treatment cost of new medications varies considerably by different therapeutic categories. This fact may influence industry decisions regarding the development of new drugs and may play a role in the shortage of new antimicrobial agents in the fight against the serious problem of antimicrobial resistance.

Microbial glycolipoprotein-capped silver nanoparticles as emerging antibacterial agents against cholera.

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Gahlawat, Geeta; Shikha, Sristy; Chaddha, Baldev Singh; Chaudhuri, Saumya Ray; Mayilraj, Shanmugam; Choudhury, Anirban Roy

2016-02-01

With the increased number of cholera outbreaks and emergence of multidrug resistance in Vibrio cholerae strains it has become necessary for the scientific community to devise and develop novel therapeutic approaches against cholera. Recent studies have indicated plausibility of therapeutic application of metal nano-materials. Among these, silver nanoparticles (AgNPs) have emerged as a potential antimicrobial agent to combat infectious diseases. At present nanoparticles are mostly produced using physical or chemical techniques which are toxic and hazardous. Thus exploitation of microbial systems could be a green eco-friendly approach for the synthesis of nanoparticles having similar or even better antimicrobial activity and biocompatibility. Hence, it would be worth to explore the possibility of utilization of microbial silver nanoparticles and their conjugates as potential novel therapeutic agent against infectious diseases like cholera. The present study attempted utilization of Ochrobactrum rhizosphaerae for the production of AgNPs and focused on investigating their role as antimicrobial agents against cholera. Later the exopolymer, purified from the culture supernatant, was used for the synthesis of spherical shaped AgNPs of around 10 nm size. Further the exopolymer was characterized as glycolipoprotein (GLP). Antibacterial activity of the novel GLP-AgNPs conjugate was evaluated by minimum inhibitory concentration, XTT reduction assay, scanning electron microscopy (SEM) and growth curve analysis. SEM studies revealed that AgNPs treatment resulted in intracellular contents leakage and cell lysis. The potential of microbially synthesized nanoparticles, as novel therapeutic agents, is still relatively less explored. In fact, the present study first time demonstrated that a glycolipoprotein secreted by the O. rhizosphaerae strain can be exploited for production of AgNPs which can further be employed to treat infectious diseases. Although this type of polymer has

Molecular Therapeutic Approaches for Pediatric Acute Myeloid Leukemia

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Sarah K Tasian

2014-03-01

Full Text Available Approximately two thirds of children with acute myeloid leukemia (AML are cured with intensive multi-agent chemotherapy. However, primary chemorefractory and relapsed AML remains a significant source of childhood cancer mortality, highlighting the need for new therapies. Further therapy intensification with traditional cytotoxic agents is not feasible given the potential for significant toxicity to normal tissues with conventional chemotherapy and the risk for long-term end-organ dysfunction. Significant emphasis has been placed upon the development of molecularly targeted therapeutic approaches for adults and children with high-risk subtypes of AML with the goal of improving remission induction and minimizing relapse. Several promising agents are currently in clinical testing or late preclinical development for AML, including monoclonal antibodies against leukemia cell surface proteins, kinase inhibitors, proteasome inhibitors, epigenetic agents, and chimeric antigen receptor engineered T cell immunotherapies. Many of these therapies have been specifically tested in children with relapsed/refractory AML via phase 1 and 2 trials with a smaller number of new agents under phase 3 evaluation for children with de novo AML. Although successful identification and implementation of new drugs for children with AML remains a formidable challenge, enthusiasm for novel molecular therapeutic approaches is great given the potential for significant clinical benefit for children who will otherwise fail standard therapy.

Peptides as Therapeutic Agents for Dengue Virus.

Science.gov (United States)

Chew, Miaw-Fang; Poh, Keat-Seong; Poh, Chit-Laa

2017-01-01

Dengue is an important global threat caused by dengue virus (DENV) that records an estimated 390 million infections annually. Despite the availability of CYD-TDV as a commercial vaccine, its long-term efficacy against all four dengue virus serotypes remains unsatisfactory. There is therefore an urgent need for the development of antiviral drugs for the treatment of dengue. Peptide was once a neglected choice of medical treatment but it has lately regained interest from the pharmaceutical industry following pioneering advancements in technology. In this review, the design of peptide drugs, antiviral activities and mechanisms of peptides and peptidomimetics (modified peptides) action against dengue virus are discussed. The development of peptides as inhibitors for viral entry, replication and translation is also described, with a focus on the three main targets, namely, the host cell receptors, viral structural proteins and viral non-structural proteins. The antiviral peptides designed based on these approaches may lead to the discovery of novel anti-DENV therapeutics that can treat dengue patients.

Real Estate Agent Commission Disputes

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Anida Duarte

2015-06-01

Full Text Available The purpose of this study was to examine the relationship among Procuring Cause Law, real estate agent years of experience, and real estate commission disputes. A pilot survey was conducted in the southwestern United States among real estate agents, realtor(s, and brokers. After testing the hypothesis, the decision was made to fail to reject the hypothesis and conclude that real estate agent experience and not Procuring Cause Law produced favorable outcomes in disputes. As a result, the following recommendations were made: (a Agency seller and buyer’s agreements should be used in each transaction to avoid disputes, (b proper expectations and guidelines should be reviewed prior to starting any real estate transaction, (c a checklist may assist in the assurance that all valuable information is reviewed, (d agents could benefit from fully understanding Procuring Cause Law and sharing this information with their clients, (e state and national regulatory requirements of the law could be modified for easier understanding and use, and (f consumers who willfully violate the law could be subject to monetary penalties.

The future of antibody therapeutics: ADCs bi-specifics and RIT

International Nuclear Information System (INIS)

Reichert, J.

2015-01-01

Full text of publication follows. Antibodies are widely accepted as remarkably versatile therapeutic agents. As evidence of this, the ∼ 30 antibody products marketed worldwide had total global sales of more than 50 billion dollars in 2012, and the commercial clinical pipeline currently comprises over 350 antibody-based product candidates. In a testament to scientific ingenuity, the investigational molecules (clinical and preclinical) are notably diverse in their composition of matter and include antibodies conjugated to a variety of agents (drugs, radioisotopes), bi-specific antibodies, and fragments or domains of antibodies. The concepts that form the basis of these agents were established decades ago, but advances in technology are now allowing new opportunities for their development. In this presentation, future directions in antibody therapeutics development will be discussed, with a focus on antibody-drug conjugates, bi-specific antibodies and radioimmunotherapy. (author)

Oncolytic Viruses: Therapeutics With an Identity Crisis

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Caroline J. Breitbach

2016-07-01

Full Text Available Oncolytic viruses (OV are replicating viral therapeutics for the treatment of cancer and have been in laboratory development for about twenty years. Recently, the FDA approved Imlygic, a herpes virus based therapeutic for the treatment of melanoma and thus OVs have entered a new era where they are a weapon in the armament of the oncologist. OVs are unique therapeutics with multiple mechanisms of therapeutic activity. The exact path for their development and eventual uptake by pharmaceutical companies is somewhat clouded by an uncertain identity. Are they vaccines, tumour lysing therapeutics, inducers of innate immunity, gene therapy vectors, anti-vascular agents or all of the above? Should they be developed as stand-alone loco-regional therapeutics, systemically delivered tumour hunters or immune modulators best tested as combination therapeutics? We summarize data here supporting the idea, depending upon the virus, that OVs can be any or all of these things. Pursuing a “one-size fits all” approach is counter-productive to their clinical development and instead as a field we should build on the strengths of individual virus platforms.

Evaluation of oral abdominal contrast agent containing ferric ammonium citrate

International Nuclear Information System (INIS)

Shiga, Toshiko; Kawamura, Yasutaka; Iwasaki, Toshiko

1991-01-01

We evaluated the effectiveness of oral MRI contrast agent containing ferric ammonium citrate. Twenty patients were arbitrarily divided into 2 groups according to the given dose of 100 and 200 mg Fe of oral MRI contrast agent. MRI was performed before and immediately after ingesting 300 ml solution of oral MRI contrast agent using a 1.5 T superconducting system (GE: Signa). Each dose of 100 and 200 mg Fe of oral MRI contrast agent produced sufficient enhancement of gastrointestinal tract, enough to make clear the pancreatic contour and porta hepatis. There was no significant change in blood and urine analysis observed after taking oral MRI contrast agent. The use of ferric ammonium citrate as an oral MRI contrast agent seems to add valuable information in performing upper abdominal MRI imaging. (author)

Diagnostic and therapeutic peroral cholangioscopy

Directory of Open Access Journals (Sweden)

Jong Ho Moon

2012-01-01

Full Text Available Peroral cholangioscopy (POC provides direct visualization of the bile duct and facilitates diagnostic or therapeutic intervention. The currently available single-operator POC systems are "Mother-baby" scope system, SpyGlass direct visualization system, and direct POC using a regular ultra-slim upper endoscope. Direct POC using an ultra-slim upper endoscope having a larger 2-mm working channel can provide a valuable and economic solution for evaluating bile-duct lesions. Main diagnostic procedures under direct POC are visual characterization and optically guided target biopsy for the indeterminate bile duct lesion. Image-enhanced endoscopy such as narrow-band imaging has shown promise for more detailed evaluation of mucosal abnormality and can be performed under direct POC. Intracorporeal lithotripsy such as electrohydraulic lithotripsy or laser lithotripsy is a main therapeutic intervention of direct POC for patients with bile duct stones that are resistant to conventional endoscopic stone-removal procedures. Besides, tumor ablation therapy, such as photodynamic therapy and argon plasma coagulation may be also performed using direct POC. Further developments of the endoscope and specialized accessories or devices are expected to facilitate diagnostic and therapeutic role of this cholangioscopic procedure.

[Antiangiogenic agents in ARMD treatment].

Science.gov (United States)

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

2012-01-01

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

Aptamer therapeutics: A review of current practice

International Nuclear Information System (INIS)

Perkins, A.C.; Missailidis, S.

2007-01-01

Full text: The development of nuclease resistant oligonucleotide agents known as aptamers, offers an alternative to antibodies as targeting, diagnostic and delivery agents. The production technique of specific receptor binding molecules based on defined nucleic acid sequences is known as systematic evolution of ligands by exponential enrichment (SELEX). Using this technique, aptamers can be produced rapidly and with high homogeneity. Furthermore, they are stable over long term storage at ambient room temperatures. A monomeric aptamer is small in size, with a molecular weight as low as 5 to 10 kDa. However, the aptamer molecule may be used as a building block for custom designed targeting agents, offering several advantages. Aptamers have been found to bind their targets with high specificity and with dissociation constants in the subnanomolar or picomolar range. The first pharmaceutical aptamer formulation, Macugen (pegaptanib sodium injection) was approved in the United States in December of 2004. This is an anti-VEGF aptamer formulation used for the treatment of Neovascular agerelated macular degeneration. Other possibilities in cardiovascular, neurodegenerative and tropical medicine are apparent. As tumour targeting agents, aptamers penetrate tissues readily, reach peak levels quickly and clear from the body rapidly, thus having properties of low toxicity and immunoreactivity. Work with radiolabelled aptamers is limited to pre-clinical studies, but the body of evidence is steadily growing and aptamers are emerging as valuable clinical products for diagnostic imaging and therapy. Peptide coupling reactions between amino and carboxylic groups offer the possibility of labelling the aptamers with a number of chelators that, coupled with appropriate radionuclides, would generate novel targeted radiopharmaceuticals for the diagnosis and therapy of disease. The unparalleled combinatorial chemical diversity, small size and modification ability of aptamers is expected to

Characterization of a Francisella tularensis-Caenorhabditis elegans Pathosystem for the Evaluation of Therapeutic Compounds

OpenAIRE

Jayamani, Elamparithi; Tharmalingam, Nagendran; Rajamuthiah, Rajmohan; Coleman, Jeffrey J.; Kim, Wooseong; Okoli, Ikechukwu; Hernandez, Ana M.; Lee, Kiho; Nau, Gerard J.; Ausubel, Frederick M.; Mylonakis, Eleftherios

2017-01-01

Francisella tularensis is a highly infectious Gram-negative intracellular pathogen that causes tularemia. Because of its potential as a bioterrorism agent, there is a need for new therapeutic agents. We therefore developed a whole-animal Caenorhabditis elegans-F. tularensis pathosystem for high-throughput screening to identify and characterize potential therapeutic compounds. We found that the C. elegans p38 mitogen-activate protein (MAP) kinase cascade is involved in the immune response to F...

Therapeutic Effect of Novel Single-Stranded RNAi Agent Targeting Periostin in Eyes with Retinal Neovascularization

Directory of Open Access Journals (Sweden)

Takahito Nakama

2017-03-01

Full Text Available Retinal neovascularization (NV due to retinal ischemia remains one of the principal causes of vision impairment in patients with ischemic retinal diseases. We recently reported that periostin (POSTN may play a role in the development of preretinal fibrovascular membranes, but its role in retinal NV has not been determined. The purpose of this study was to examine the expression of POSTN in the ischemic retinas of a mouse model of oxygen-induced retinal NV. We also studied the function of POSTN on retinal NV using Postn KO mice and human retinal endothelial cells (HRECs in culture. In addition, we used a novel RNAi agent, NK0144, which targets POSTN to determine its effect on the development of retinal NV. Our results showed that the expression of POSTN was increased in the vascular endothelial cells, pericytes, and M2 macrophages in ischemic retinas. POSTN promoted the ischemia-induced retinal NV by Akt phosphorylation through integrin αvβ3. NK0144 had a greater inhibitory effect than canonical double-stranded siRNA on preretinal pathological NV in vivo and in vitro. These findings suggest a causal relationship between POSTN and retinal NV, and indicate a potential therapeutic role of intravitreal injection of NK0144 for retinal neovascular diseases.

Multiwalled carbon nanotube hybrids as MRI contrast agents

Directory of Open Access Journals (Sweden)

Nikodem Kuźnik

2016-07-01

Full Text Available Magnetic resonance imaging (MRI is one of the most commonly used tomography techniques in medical diagnosis due to the non-invasive character, the high spatial resolution and the possibility of soft tissue imaging. Contrast agents, such as gadolinium complexes and superparamagnetic iron oxides, are administered to spotlight certain organs and their pathologies. Many new models have been proposed that reduce side effects and required doses of these already clinically approved contrast agents. These new candidates often possess additional functionalities, e.g., the possibility of bioactivation upon action of particular stimuli, thus serving as smart molecular probes, or the coupling with therapeutic agents and therefore combining both a diagnostic and therapeutic role. Nanomaterials have been found to be an excellent scaffold for contrast agents, among which carbon nanotubes offer vast possibilities. The morphology of multiwalled carbon nanotubes (MWCNTs, their magnetic and electronic properties, the possibility of different functionalization and the potential to penetrate cell membranes result in a unique and very attractive candidate for a new MRI contrast agent. In this review we describe the different issues connected with MWCNT hybrids designed for MRI contrast agents, i.e., their synthesis and magnetic and dispersion properties, as well as both in vitro and in vivo behavior, which is important for diagnostic purposes. An introduction to MRI contrast agent theory is elaborated here in order to point to the specific expectations regarding nanomaterials. Finally, we propose a promising, general model of MWCNTs as MRI contrast agent candidates based on the studies presented here and supported by appropriate theories.

Ivacaftor: A Novel Gene-Based Therapeutic Approach for Cystic Fibrosis

OpenAIRE

Condren, Michelle E.; Bradshaw, Marquita D.

2013-01-01

Ivacaftor is a new therapeutic agent that acts at the cystic fibrosis transmembrane conductance regulator (CFTR) channel to alter activity. It is approved for use in patients 6 years and older with cystic fibrosis who have at least 1 G551D mutation in the CFTR gene. It is unlike any other current pharmacologic agent for cystic fibrosis in that it specifically targets the gene defect associated with cystic fibrosis as opposed to treating resulting symptomology. Mucoactive agents, antibiotics, ...

Evaluation of real-time data obtained from gravimetric preparation of antineoplastic agents shows medication errors with possible critical therapeutic impact: Results of a large-scale, multicentre, multinational, retrospective study.

Science.gov (United States)

Terkola, R; Czejka, M; Bérubé, J

2017-08-01

Medication errors are a significant cause of morbidity and mortality especially with antineoplastic drugs, owing to their narrow therapeutic index. Gravimetric workflow software systems have the potential to reduce volumetric errors during intravenous antineoplastic drug preparation which may occur when verification is reliant on visual inspection. Our aim was to detect medication errors with possible critical therapeutic impact as determined by the rate of prevented medication errors in chemotherapy compounding after implementation of gravimetric measurement. A large-scale, retrospective analysis of data was carried out, related to medication errors identified during preparation of antineoplastic drugs in 10 pharmacy services ("centres") in five European countries following the introduction of an intravenous workflow software gravimetric system. Errors were defined as errors in dose volumes outside tolerance levels, identified during weighing stages of preparation of chemotherapy solutions which would not otherwise have been detected by conventional visual inspection. The gravimetric system detected that 7.89% of the 759 060 doses of antineoplastic drugs prepared at participating centres between July 2011 and October 2015 had error levels outside the accepted tolerance range set by individual centres, and prevented these doses from reaching patients. The proportion of antineoplastic preparations with deviations >10% ranged from 0.49% to 5.04% across sites, with a mean of 2.25%. The proportion of preparations with deviations >20% ranged from 0.21% to 1.27% across sites, with a mean of 0.71%. There was considerable variation in error levels for different antineoplastic agents. Introduction of a gravimetric preparation system for antineoplastic agents detected and prevented dosing errors which would not have been recognized with traditional methods and could have resulted in toxicity or suboptimal therapeutic outcomes for patients undergoing anticancer treatment. �

New therapeutic agent for radiation synovectomy - preparation of {sup 166}Ho-EDTMP-HA particle

Energy Technology Data Exchange (ETDEWEB)

Bai, H.; Jin, X.; Du, J.; Wang, F.; Chen, D.; Fan, H.; Cheng, Z.; Zhang, J. [China Institute of Atomic Energy, Beijing (Switzerland). Isotope Department

1997-10-01

In order to prepare new therapeutical agent for radiation synovectomy, Hydroxyapatite (HA) was labelled with {sup 166}Ho by EDTMP that had high affinity to HA particles. Radiolabelling of HA particles was divided into two steps, {sup 166}Ho-EDTMP was prepared first; then mixed with HA particles completely and vibrated for 15 minutes on the micromixer at room temperature, washed 3 times with deionized water. Radiolabelling particle was separated from free {sup 166}Ho via centrifugation to determine its radiolabelling efficiency. {sup 166}Ho-EDTMP-HA and {sup 166}Ho-EDTMP were injected into knee joint of normal rabbits respectively, every group was killed at different time postinjection, took out major organ and collected urine and blood, then weighted and determined their radio counts. HA particles, as a natural component of bone was known to have good compatibility with soft tissue and biodegrade into calcium and phosphate in vivo. It was readily prepared from common chemical and formed into particles of desired size range in a controlled process, it had high stability in vitro and vivo. Radiolabelling of HA particle with {sup 166}Ho by EDTMP was simple to perform and provides an excellent labelling yield that was more than 95% under the optimal labelling condition. The optimal labelling condition at room temperature was pH 6.0-8.0 and vibration time 15 minutes. The absorbed capacity of HA particle was 5 mg Ho/g HA particle and size of radiolabelling particle was at range of 2-5,{mu}m that is suitable for therapy of radiation synovectomy. {sup 166}Ho-EDTMP-HA particle demonstrated high in vitro stability in either normal saline or 1% BSA solution, but instability under extremely acidic condition (pH 1-2). The control studies performed with {sup 166}Ho-EDTMP not bound to HA particle provided information on the distribution of radioactivity that would occur upon leakage of the radiochemical compound from joint. Its short half-life, its extremely low leakage from the

Recovering valuable shale oils, etc

Energy Technology Data Exchange (ETDEWEB)

Engler, C

1922-09-26

A process is described for the recovery of valuable shale oils or tars, characterized in that the oil shale is heated to about 300/sup 0/C or a temperature not exceeding this essentially and then is treated with a solvent with utilization of this heat.

Resveratrol as a Therapeutic Agent for Alzheimer's Disease

Science.gov (United States)

Ma, Teng; Tan, Meng-Shan; Yu, Jin-Tai; Tan, Lan

2014-01-01

Alzheimer's disease (AD) is the most common cause of dementia, but there is no effective therapy till now. The pathogenic mechanisms of AD are considerably complex, including Aβ accumulation, tau protein phosphorylation, oxidative stress, and inflammation. Exactly, resveratrol, a polyphenol in red wine and many plants, is indicated to show the neuroprotective effect on mechanisms mostly above. Recent years, there are numerous researches about resveratrol acting on AD in many models, both in vitro and in vivo. However, the effects of resveratrol are limited by its pool bioavailability; therefore researchers have been trying a variety of methods to improve the efficiency. This review summarizes the recent studies in cell cultures and animal models, mainly discusses the molecular mechanisms of the neuroprotective effects of resveratrol, and thus investigates the therapeutic potential in AD. PMID:25525597

Use of contrast agents for liver MRI

International Nuclear Information System (INIS)

Ward, Janice

2007-01-01

Contrast-enhanced MRI is recognised as one of the most accurate imaging methods for investigating diseases of the liver. Uniquely several different types of contrast agents are available for liver MRI. They can be divided into non-specific extracellular fluid space (ECF), hepatocyte specific and reticulo-endothelial system (RES) specific agents. They are used to improve the detection of focal liver lesions by increasing normal-abnormal tissue contrast and to assist in lesion characterisation by demonstrating tissue perfusion and cellular function. ECF-gadolinium (Gd) chelates have been widely used in abdominal MRI for many years. They provide valuable information regarding the vascularisation and perfusion characteristics of lesions and assist in lesion detection, particularly of hypervascular lesions. The hepatocyte and RES-specific agents further improve lesion detection, provide important functional information and allow the distinction between hepatocellular and non-hepatocellular tumours. This article describes the different MR contrast agents and discusses their current status for diagnosing focal liver lesions. The importance of optimised technique and appropriate selection of contrast agent is emphasised

Empirical agent-based modelling challenges and solutions

CERN Document Server

Barreteau, Olivier

2014-01-01

This instructional book showcases techniques to parameterise human agents in empirical agent-based models (ABM). In doing so, it provides a timely overview of key ABM methodologies and the most innovative approaches through a variety of empirical applications.  It features cutting-edge research from leading academics and practitioners, and will provide a guide for characterising and parameterising human agents in empirical ABM.  In order to facilitate learning, this text shares the valuable experiences of other modellers in particular modelling situations. Very little has been published in the area of empirical ABM, and this contributed volume will appeal to graduate-level students and researchers studying simulation modeling in economics, sociology, ecology, and trans-disciplinary studies, such as topics related to sustainability. In a similar vein to the instruction found in a cookbook, this text provides the empirical modeller with a set of 'recipes'  ready to be implemented. Agent-based modeling (AB...

Tumor angiogenesis--a new therapeutic target in gliomas

DEFF Research Database (Denmark)

Lund, E L; Spang-Thomsen, M; Skovgaard-Poulsen, H

1998-01-01

significant angiogenic activity primarily by the expression of the angiogenic factor VEGF Anti-angiogenic therapy represents a new promising therapeutic modality in solid tumors. Several agents are currently under evaluation in clinical trials. The present review describes the principal inducers...

Imaging findings and therapeutic alternatives for peripheral vascular malformations

International Nuclear Information System (INIS)

Monsignore, Lucas Moretti; Nakiri, Guilherme Seizem; Santos, Daniela dos; Abud, Thiago Giansante; Abud, Daniel Giansante

2010-01-01

Peripheral vascular malformations represent a spectrum of lesions that appear through the lifetime and can be found in the whole body. Such lesions are uncommon and are frequently confounded with infantile hemangioma, a common benign neoplastic lesion. In the presence of such lesions, the correlation between the clinical and radiological findings is extremely important to achieve a correct diagnosis, which will guide the best therapeutic approach. The most recent classifications for peripheral vascular malformations are based on the blood flow (low or high) and on the main vascular components (arterial, capillary, lymphatic or venous). Peripheral vascular malformations represent a diagnostic and therapeutic challenge, and complementary methods such as computed tomography, Doppler ultrasonography and magnetic resonance imaging, in association with clinical findings can provide information regarding blood flow characteristics and lesions extent. Arteriography and venography confirm the diagnosis, evaluate the lesions extent and guide the therapeutic decision making. Generally, low flow vascular malformations are percutaneously treated with sclerosing agents injection, while in high flow lesions the approach is endovascular, with permanent liquid or solid embolization agents. (author)

Melatonin and Nitrones As Potential Therapeutic Agents for Stroke

Directory of Open Access Journals (Sweden)

Alejandro Romero

2016-11-01

Full Text Available Stroke is a disease of aging affecting millions of people worldwide, and recombinant tissue-type plasminogen activator (r-tPA is the only treatment approved. However, r-tPA has a low therapeutic window and secondary effects which limit its beneficial outcome, urging thus the search for new more efficient therapies. Among them, neuroprotection based on melatonin or nitrones, as free radical traps, have arisen as drug candidates due to their strong antioxidant power. In this Perspective article, an update on the specific results of the melatonin and several new nitrones are presented.

Exploring complex dynamics in multi agent-based intelligent systems: Theoretical and experimental approaches using the Multi Agent-based Behavioral Economic Landscape (MABEL) model

Science.gov (United States)

Alexandridis, Konstantinos T.

This dissertation adopts a holistic and detailed approach to modeling spatially explicit agent-based artificial intelligent systems, using the Multi Agent-based Behavioral Economic Landscape (MABEL) model. The research questions that addresses stem from the need to understand and analyze the real-world patterns and dynamics of land use change from a coupled human-environmental systems perspective. Describes the systemic, mathematical, statistical, socio-economic and spatial dynamics of the MABEL modeling framework, and provides a wide array of cross-disciplinary modeling applications within the research, decision-making and policy domains. Establishes the symbolic properties of the MABEL model as a Markov decision process, analyzes the decision-theoretic utility and optimization attributes of agents towards comprising statistically and spatially optimal policies and actions, and explores the probabilogic character of the agents' decision-making and inference mechanisms via the use of Bayesian belief and decision networks. Develops and describes a Monte Carlo methodology for experimental replications of agent's decisions regarding complex spatial parcel acquisition and learning. Recognizes the gap on spatially-explicit accuracy assessment techniques for complex spatial models, and proposes an ensemble of statistical tools designed to address this problem. Advanced information assessment techniques such as the Receiver-Operator Characteristic curve, the impurity entropy and Gini functions, and the Bayesian classification functions are proposed. The theoretical foundation for modular Bayesian inference in spatially-explicit multi-agent artificial intelligent systems, and the ensembles of cognitive and scenario assessment modular tools build for the MABEL model are provided. Emphasizes the modularity and robustness as valuable qualitative modeling attributes, and examines the role of robust intelligent modeling as a tool for improving policy-decisions related to land

Recovery of valuable metals from waste cathode materials of spent lithium-ion batteries using mild phosphoric acid

Energy Technology Data Exchange (ETDEWEB)

Chen, Xiangping, E-mail: chenxiangping101@163.com [School of Environmental Science and Engineering, Shaanxi University of Science & Technology, Xi’an 710021 (China); College of Chemistry and Chemical Engineering, Central South University, Changsha 410083 (China); Ma, Hongrui, E-mail: mahr@sust.edu.cn [School of Environmental Science and Engineering, Shaanxi University of Science & Technology, Xi’an 710021 (China); Luo, Chuanbao; Zhou, Tao [College of Chemistry and Chemical Engineering, Central South University, Changsha 410083 (China)

2017-03-15

Graphical abstract: Cobalt can be directly recovered as Co{sub 3}(PO{sub 4}){sub 2} from waste LiCoO{sub 2} using H{sub 3}PO{sub 4} as leaching and precipitating agent. - Highlights: • Phosphoric acid was innovatively used as leaching and precipitating agent. • Over 99% Co and Li can be separated and recovered in a single leaching step. • Co and Li can be separated under mild conditions of 40 °C and 0.7 M H{sub 3}PO{sub 4}. • Activation energy values for Co and Li are 7.3 and 10.168 kJ/mol. • Cobalt phosphate (97.1% in purity) can be obtained as the leaching product. - Abstract: Sustainable recycling of valuable metals from spent lithium-ion batteries (LIBs) may be necessary to alleviate the depletion of strategic metal resources and potential risk of environmental pollution. Herein a hydrometallurgical process was proposed to explore the possibility for the recovery of valuable metals from the cathode materials (LiCoO{sub 2}) of spent LIBs using phosphoric acid as both leaching and precipitating agent under mild leaching conditions. According to the leaching results, over 99% Co can be separated and recovered as Co{sub 3}(PO{sub 4}){sub 2} in a short-cut process involved merely with leaching and filtrating, under the optimized leaching conditions of 40 °C (T), 60 min (t), 4 vol.% H{sub 2}O{sub 2}, 20 mL g{sup −1} (L/S) and 0.7 mol/L H{sub 3}PO{sub 4}. Then leaching kinetics was investigated based on the logarithmic rate kinetics model and the obtained results indicate that the leaching of Co and Li fits well with this model and the activation energies (Ea) for Co and Li are 7.3 and 10.2 kJ/mol, respectively. Finally, it can be discovered from characterization results that the obtained product is 97.1% pure cobalt phosphate (Co{sub 3}(PO{sub 4}){sub 2}).

Limited-Sampling Strategies for Therapeutic Drug Monitoring of Moxifloxacin in Patients With Tuberculosis

NARCIS (Netherlands)

Pranger, Arianna D.; Kosterink, Jos G. W.; van Altena, Richard; Aarnoutse, Rob E.; van der Werf, Tjip S.; Uges, Donald R. A.; Alffenaar, Jan-Willem C.

Background: Moxifloxacin (MFX) is a potent drug for multidrug resistant tuberculosis(TB) treatment and is also useful if first-line agents are not tolerated. Therapeutic drug monitoring may help to prevent treatment failure. Obtaining a full concentration-time curve of MFX for therapeutic drug

Limited-sampling strategies for therapeutic drug monitoring of moxifloxacin in patients with tuberculosis

NARCIS (Netherlands)

Pranger, A.D.; Kosterink, J.G.W.; Altena, R. van; Aarnoutse, R.E.; Werf, T.S. van der; Uges, D.R.A.; Alffenaar, J.W.C.

2011-01-01

BACKGROUND: Moxifloxacin (MFX) is a potent drug for multidrug resistant tuberculosis(TB) treatment and is also useful if first-line agents are not tolerated. Therapeutic drug monitoring may help to prevent treatment failure. Obtaining a full concentration-time curve of MFX for therapeutic drug

The influence of AT1002 on the nasal absorption of molecular weight markers and therapeutic agents when co-administered with bioadhesive polymers and an AT1002 antagonist, AT1001.

Science.gov (United States)

Song, Keon-Hyoung; Eddington, Natalie D

2012-01-01

The purpose of this study was to demonstrate the effects of the tight junction permeation enhancer, AT1002, on the nasal absorption of molecular weight markers and low bioavailable therapeutic agents co-administered with bioadhesive polymers or zonulin antagonist. The bioadhesive polymers, carrageenan and Na-CMC, were prepared with AT1002 to examine the permeation-enhancing effect of AT1002 on the nasal absorption of inulin, calcitonin and saquinavir after nasal administration to Sprague-Dawley rats. Blood samples were collected over a 6-hour period from a jugular cannula. In addition, we determined whether AT1002 exerts a permeation-enhancing effect via activation of PAR-2 specific binding to a putative receptor of zonulin. To examine this zonulin antagonist, AT1001, was administered 30 min prior to dosing with an AT1002/inulin solution and blood samples were collected over a 6-hour period. The bioadhesive polymers did not directly increase the absorption of inulin, calcitonin and saquinavir, but promoted the permeation-enhancing effect of AT1002 when delivered nasally, thereby significantly increasing the absorption of each drug. Pre-treatment with AT1001 antagonized the zonulin receptor and significantly minimized the permeation-enhancing effect of AT1002. These findings will assist in understanding the permeation-enhancing capability of and the receptor binding of AT1002. Further, combining AT1002 with carrageenan supports the development of the mucosal delivery of therapeutic agents that have low bioavailability even with bioadhesive agents. © 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.

Multi-agents Based Modelling for Distribution Network Operation with Electric Vehicle Integration

DEFF Research Database (Denmark)

Hu, Junjie; Morais, Hugo; Zong, Yi

2014-01-01

Electric vehicles (EV) can become integral part of a smart grid because instead of just consuming power they are capable of providing valuable services to power systems. To integrate EVs smoothly into the power systems, a multi-agents system (MAS) with hierarchical organization structure...... and its role is to manage the distribution network safely by avoiding grid congestions and using congestion prices to coordinate the energy schedule of VPPs. VPP agents belong to the middle level and their roles are to manage the charge periods of the EVs. EV agents sit in the bottom level...

Meeting Report: High-Throughput Technologies for In Vivo Imaging Agents

Directory of Open Access Journals (Sweden)

Robert J. Gillies

2005-04-01

Full Text Available Combinatorial chemistry and high-throughput screening have become standard tools for discovering new drug candidates with suitable pharmacological properties. Now, those same technologies are starting to be applied to the problem of discovering novel in vivo imaging agents. Important differences in the biological and pharmacological properties needed for imaging agents, compared to those for a therapeutic agent, require new screening methods that emphasize those characteristics, such as optimized residence time and tissue specificity, that make for a good imaging agent candidate.

Multi-targeting Andrographolide and its Natural Analogs as Potential Therapeutic Agents.

Science.gov (United States)

Kishore, V; Yarla, Nagendra Sastry; Bishayee, Anupam; Putta, Swathi; Malla, Ramarao; Neelapu, Nageswara Rao Reddy; Challa, Surekha; Das, Subhasish; Shiralgi, Yallappa; Hegde, Gurumurthy; Dhananjaya, Bhadrapura Lakkappa

2017-01-01

Andrographis paniculata (A. paniculata) is a medicinal plant used in the Indian and Chinese traditional medicinal systems for its various beneficial properties of therapeutics. This is due to the presence of a diterpene lactone called 'andrographolide'. Several biological activities like antiinflammatory, antitumour, anti-hyperglycaemic, anti-fertility, antiviral, cardio protective and hepatoprotective properties are attributed to andrographolide and its natural analogs. The studies have shown that not only this diterpene lactone (andrographolide), but also other related terpenoid analogs from A. paniculata could be exploited for disease prevention due to their structural similarity with diverse pharmacological activities. Several scientific groups are trying to unveil the underlying mechanisms involved in these biological actions brough aout by andrographolide and its analogs. This review aims at giving an overview on the therapeutical and/or pharmacological activities of andrographolide and its derivatives and also exemplify the underlying mechanisms involved. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Immunological effects of hypomethylating agents.

Science.gov (United States)

Lindblad, Katherine E; Goswami, Meghali; Hourigan, Christopher S; Oetjen, Karolyn A

2017-08-01

Epigenetic changes resulting from aberrant methylation patterns are a recurrent observation in hematologic malignancies. Hypomethylating agents have a well-established role in the management of patients with high-risk myelodysplastic syndrome or acute myeloid leukemia. In addition to the direct effects of hypomethylating agents on cancer cells, there are several lines of evidence indicating a role for immune-mediated anti-tumor benefits from hypomethylating therapy. Areas covered: We reviewed the clinical and basic science literature for the effects of hypomethylating agents, including the most commonly utilized therapeutics azacitidine and decitabine, on immune cell subsets. We summarized the effects of hypomethylating agents on the frequency and function of natural killer cells, T cells, and dendritic cells. In particular, we highlight the effects of hypomethylating agents on expression of immune checkpoint inhibitors, leukemia-associated antigens, and endogenous retroviral elements. Expert commentary: In vitro and ex vivo studies indicate mixed effects on the function of natural killer, dendritic cells and T cells following treatment with hypomethylating agents. Clinical correlates of immune function have suggested that hypomethylating agents have immunomodulatory functions with the potential to synergize with immune checkpoint therapy for the treatment of hematologic malignancy, and has become an active area of clinical research.

Contrast Agent in Magnetic Resonance Imaging

DEFF Research Database (Denmark)

Vu-Quang, Hieu

2015-01-01

Nanoparticles have been employed as contrast agent in magnetic resonance imaging (MRI) in order to improve sensitivity and accuracy in diagnosis. In addition, these contrast agents are potentially combined with other therapeutic compounds or near infrared bio-imaging (NIR) fluorophores to obtain...... theranostic or dual imaging purposes, respectively. There were two main types of MRI contrast agent that were synthesized during this PhD project including fluorine containing nanoparticles and magnetic nanoparticles. In regard of fluorine containing nanoparticles, there were two types contrast agent...... cancer cells for cancer diagnosis in MRI. F127-Folate coated SPION were stable in various types of suspension medium for over six months. They could specifically target folate receptor of cancer cells in vitro and in vivo thus enhancing the contrast in MRI T2/T2* weighted images. These are preliminary...

Semantic Document Image Classification Based on Valuable Text Pattern

Directory of Open Access Journals (Sweden)

Hossein Pourghassem

2011-01-01

Full Text Available Knowledge extraction from detected document image is a complex problem in the field of information technology. This problem becomes more intricate when we know, a negligible percentage of the detected document images are valuable. In this paper, a segmentation-based classification algorithm is used to analysis the document image. In this algorithm, using a two-stage segmentation approach, regions of the image are detected, and then classified to document and non-document (pure region regions in the hierarchical classification. In this paper, a novel valuable definition is proposed to classify document image in to valuable or invaluable categories. The proposed algorithm is evaluated on a database consisting of the document and non-document image that provide from Internet. Experimental results show the efficiency of the proposed algorithm in the semantic document image classification. The proposed algorithm provides accuracy rate of 98.8% for valuable and invaluable document image classification problem.

Radioprotective Agents

Directory of Open Access Journals (Sweden)

Ilker Kelle

2008-01-01

Full Text Available Since1949, a great deal of research has been carried out on the radioprotective activity of various chemical substances. Thiol compounds, compounds which contain –SH radical, different classes of pharmacological agents and other compounds such as vitamine C and WR-2721 have been shown to reduce mortality when administered prior to exposure to a lethal dose of radiation. Recently, honey bee venom as well as that of its components melittin and histamine have shown to be valuable in reduction of radiation-induced damage and also provide prophylactic alternative treatment for serious side effects related with radiotherapy. It has been suggested that the radioprotective activity of bee venom components is related with the stimulation of the hematopoetic system.

Valuable Internet Advertising and Customer Satisfaction Cycle(VIACSC)

OpenAIRE

Muhammad Awais; Tanzila Samin; Muhammad Bilal

2012-01-01

Now-a-days it is very important for the business persons to attract their target customers towards their products through valuable mode of promotion and communication. Increasing use of World Wide Web has completely changed the scenario of business sector. Customized products and services, customers preferences, @ and dot com craze have elevated the importance of internet advertising. This research paper investigates valuable internet advertising which will help to enhance the value of intern...

Tofacitinib Suppresses Antibody Responses to Protein Therapeutics in Murine Hosts1

Science.gov (United States)

Onda, Masanori; Ghoreschi, Kamran; Steward-Tharp, Scott; Thomas, Craig; O’Shea, John J.; Pastan, Ira H.; FitzGerald, David J.

2014-01-01

Immunogenicity remains the ‘Achilles’ heel’ of protein-based therapeutics. Anti-drug antibodies produced in response to protein therapeutics can severely limit both the safety and efficacy of this expanding class of agent. Here we report that monotherapy of mice with tofacitinib (the Janus kinase inhibitor) quells antibody responses to an immunotoxin derived from the bacterial protein, Pseudomonas exotoxin A, as well as to the model antigen, keyhole limpet hemocyanin. Thousandfold reductions in IgG1 titers to both antigens were observed 21 days post-immunization. In fact, suppression was evident for all IgG isotypes and IgM. A reduction in IgG3 production was also noted with a thymus-independent type II antigen. Mechanistic investigations revealed that tofacitinib treatment led to reduced numbers of CD127+ pro-B cells. Furthermore, we observed fewer germinal center B cells and the impaired formation of germinal centers of mice treated with tofacitinib. Since normal immunoglobulin levels were still present during the tofacitinib treatment, this agent specifically reduced anti-drug antibodies, thus preserving the potential efficacy of biological therapeutics, including those that are used as cancer therapeutics. PMID:24890727

Targeted Therapeutic Nanoparticles: An Immense Promise to Fight against Cancer

Directory of Open Access Journals (Sweden)

Sheikh Tasnim Jahan

2017-01-01

Full Text Available In nanomedicine, targeted therapeutic nanoparticle (NP is a virtual outcome of nanotechnology taking the advantage of cancer propagation pattern. Tying up all elements such as therapeutic or imaging agent, targeting ligand, and cross-linking agent with the NPs is the key concept to deliver the payload selectively where it intends to reach. The microenvironment of tumor tissues in lymphatic vessels can also help targeted NPs to achieve their anticipated accumulation depending on the formulation objectives. This review accumulates the application of poly(lactic-co-glycolic acid (PLGA and polyethylene glycol (PEG based NP systems, with a specific perspective in cancer. Nowadays, PLGA, PEG, or their combinations are the mostly used polymers to serve the purpose of targeted therapeutic NPs. Their unique physicochemical properties along with their biological activities are also discussed. Depending on the biological effects from parameters associated with existing NPs, several advantages and limitations have been explored in teaming up all the essential facts to give birth to targeted therapeutic NPs. Therefore, the current article will provide a comprehensive review of various approaches to fabricate a targeted system to achieve appropriate physicochemical properties. Based on such findings, researchers can realize the benefits and challenges for the next generation of delivery systems.

Development of Novel Therapeutic Agents by Inhibition of Oncogenic MicroRNAs

Directory of Open Access Journals (Sweden)

Dinh-Duc Nguyen

2017-12-01

Full Text Available MicroRNAs (miRs, miRNAs are regulatory small noncoding RNAs, with their roles already confirmed to be important for post-transcriptional regulation of gene expression affecting cell physiology and disease development. Upregulation of a cancer-causing miRNA, known as oncogenic miRNA, has been found in many types of cancers and, therefore, represents a potential new class of targets for therapeutic inhibition. Several strategies have been developed in recent years to inhibit oncogenic miRNAs. Among them is a direct approach that targets mature oncogenic miRNA with an antisense sequence known as antimiR, which could be an oligonucleotide or miRNA sponge. In contrast, an indirect approach is to block the biogenesis of miRNA by genome editing using the CRISPR/Cas9 system or a small molecule inhibitor. The development of these inhibitors is straightforward but involves significant scientific and therapeutic challenges that need to be resolved. In this review, we summarize recent relevant studies on the development of miRNA inhibitors against cancer.

Co-culturing of Fungal Strains Against Botrytis cinerea as a Model for the Induction of Chemical Diversity and Therapeutic Agents

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Olga Genilloud

2017-04-01

Full Text Available New fungal SMs (SMs have been successfully described to be produced by means of in vitro-simulated microbial community interactions. Co-culturing of fungi has proved to be an efficient way to induce cell–cell interactions that can promote the activation of cryptic pathways, frequently silent when the strains are grown in laboratory conditions. Filamentous fungi represent one of the most diverse microbial groups known to produce bioactive natural products. Triggering the production of novel antifungal compounds in fungi could respond to the current needs to fight health compromising pathogens and provide new therapeutic solutions. In this study, we have selected the fungus Botrytis cinerea as a model to establish microbial interactions with a large set of fungal strains related to ecosystems where they can coexist with this phytopathogen, and to generate a collection of extracts, obtained from their antagonic microbial interactions and potentially containing new bioactive compounds. The antifungal specificity of the extracts containing compounds induced after B. cinerea interaction was determined against two human fungal pathogens (Candida albicans and Aspergillus fumigatus and three phytopathogens (Colletotrichum acutatum, Fusarium proliferatum, and Magnaporthe grisea. In addition, their cytotoxicity was also evaluated against the human hepatocellular carcinoma cell line (HepG2. We have identified by LC-MS the production of a wide variety of known compounds induced from these fungal interactions, as well as novel molecules that support the potential of this approach to generate new chemical diversity and possible new therapeutic agents.

Localized sequence-specific release of a chemopreventive agent and an anticancer drug in a time-controllable manner to enhance therapeutic efficacy.

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Pan, Wen-Yu; Lin, Kun-Ju; Huang, Chieh-Cheng; Chiang, Wei-Lun; Lin, Yu-Jung; Lin, Wei-Chih; Chuang, Er-Yuan; Chang, Yen; Sung, Hsing-Wen

2016-09-01

Combination chemotherapy with multiple drugs commonly requires several injections on various schedules, and the probability that the drug molecules reach the diseased tissues at the proper time and effective therapeutic concentrations is very low. This work elucidates an injectable co-delivery system that is based on cationic liposomes that are adsorbed on anionic hollow microspheres (Lipos-HMs) via electrostatic interaction, from which the localized sequence-specific release of a chemopreventive agent (1,25(OH)2D3) and an anticancer drug (doxorubicin; DOX) can be thermally driven in a time-controllable manner by an externally applied high-frequency magnetic field (HFMF). Lipos-HMs can greatly promote the accumulation of reactive oxygen species (ROS) in tumor cells by reducing their cytoplasmic expression of an antioxidant enzyme (superoxide dismutase) by 1,25(OH)2D3, increasing the susceptibility of cancer cells to the cytotoxic action of DOX. In nude mice that bear xenograft tumors, treatment with Lipos-HMs under exposure to HFMF effectively inhibits tumor growth and is the most effective therapeutic intervention among all the investigated. These empirical results demonstrate that the synergistic anticancer effects of sequential release of 1,25(OH)2D3 and DOX from the Lipos-HMs may have potential for maximizing DOX cytotoxicity, supporting more effective cancer treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Possíveis etapas na patogênese da cefaléia tensional e indicações de tratamento Tension headache: possible pathogenic stages and its relations with therapeutic agents

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Ceme Ferreira Jordy

1995-09-01

Full Text Available Análise de resultados obtidos no estudo de uma série de 100 pacientes com diagnóstico de cefaléia tensional permitem sugerir 5 etapas de um processo fisiopatogênico implicado. Com base nesta sugestão, a indicação para o tratamento e respectiva eficácia, dependerão da etapa patogênica sobre a qual se pretenda fazer incidir a ação terapêutica.Five steps in the pathogenic process involved in the tension headache pathogenesis are suggested from a 100 patients clinical study. Therapeutic efficacy in the treatment of the tension headache is considered to be linked to the relation between the therapeutic agent and the stage in which it has focused its effect, in the pathogenic process.

Punica granatum and its therapeutic implications on breast carcinogenesis: A review.

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Vini, Ravindran; Sreeja, Sreeharshan

2015-01-01

Punica granatum has a recorded history of pharmacological properties which can be attributed to its rich reservoir of phytochemicals. Investigations in recent years have established its tremendous potential as an antitumorogenic agent against various cancers including breast cancer, which is the second leading cause of cancer-related deaths in women. The plausible role of Punica as a therapeutic agent, as an adjuvant in chemotherapy, and its dietary implications as chemopreventive agent in breast cancer have been explored. Mechanistic studies have revealed that Punica extracts and its components, individually or in combination, can modulate and target key proteins and genes involved in breast cancer. Our earlier finding also demonstrated the role of methanolic extract of pomegranate pericarp in reducing proliferation in breast cancer by binding to estrogen receptor at the same time not affecting uterine weight unlike estradiol or tamoxifen. This review analyses other plausible mechanisms of Punica in preventing the progression of breast cancer and how it can possibly be a therapeutic agent by acting at various steps of carcinogenesis including proliferation, invasion, migration, metastasis, angiogenesis, and inflammation via various molecular mechanisms. © 2015 International Union of Biochemistry and Molecular Biology.

Bee Pollen: Chemical Composition and Therapeutic Application

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Katarzyna Komosinska-Vassev

2015-01-01

Full Text Available Bee pollen is a valuable apitherapeutic product greatly appreciated by the natural medicine because of its potential medical and nutritional applications. It demonstrates a series of actions such as antifungal, antimicrobial, antiviral, anti-inflammatory, hepatoprotective, anticancer immunostimulating, and local analgesic. Its radical scavenging potential has also been reported. Beneficial properties of bee pollen and the validity for their therapeutic use in various pathological condition have been discussed in this study and with the currently known mechanisms, by which bee pollen modulates burn wound healing process.

Antimicrobial Peptides: An Emerging Category of Therapeutic Agents.

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Mahlapuu, Margit; Håkansson, Joakim; Ringstad, Lovisa; Björn, Camilla

2016-01-01

Antimicrobial peptides (AMPs), also known as host defense peptides, are short and generally positively charged peptides found in a wide variety of life forms from microorganisms to humans. Most AMPs have the ability to kill microbial pathogens directly, whereas others act indirectly by modulating the host defense systems. Against a background of rapidly increasing resistance development to conventional antibiotics all over the world, efforts to bring AMPs into clinical use are accelerating. Several AMPs are currently being evaluated in clinical trials as novel anti-infectives, but also as new pharmacological agents to modulate the immune response, promote wound healing, and prevent post-surgical adhesions. In this review, we provide an overview of the biological role, classification, and mode of action of AMPs, discuss the opportunities and challenges to develop these peptides for clinical applications, and review the innovative formulation strategies for application of AMPs.

[Therapeutic use of cannabis derivatives].

Science.gov (United States)

Benyamina, Amine; Reynaud, Michel

2014-02-01

The therapeutic use of cannabis has generated a lot of interest in the past years, leading to a better understanding of its mechanisms of action. Countries like the United States and Canada have modified their laws in order to make cannabinoid use legal in the medical context. It's also the case in France now, where a recent decree was issued, authorizing the prescription of medication containing "therapeutic cannabis" (decree no. 2013-473, June 5, 2013). Cannabinoids such as dronabinol, Sativex and nabilone have been tested for the treatment of acute and chronic pain. These agents are most promising to relieve chronic pain associated with cancer, with human immunodeficiency virus infection and with multiple sclerosis. However, longer-term studies are required to determine potential long-term adverse effects and risks of misuse and addiction.

Oral available agents in the treatment of RRMS

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Aupérin T

2013-10-01

Full Text Available Thierry Aupérin Medical Communications, Global MS Medical Affairs, Genzyme Corporation, Cambridge, MA, USAWe read with interest the article by Drs Thöne and Ellrichmann entitled "Oral available agents in the treatment of relapsing remitting multiple sclerosis: an overview of merits and culprits" recently published in Drug, Healthcare and Patient Safety.1 The review provides a valuable overview of a number of new therapeutic options for multiple sclerosis (MS, with a focus on proposed mechanisms of action and efficacy and safety profiles of the respective agents.In reading the article, however, we did note a number of errors pertaining to teriflunomide, a once-daily oral immunomodulator approved in several countries for the treatment of relapsing forms of MS (RMS and relapsing-remitting MS (RRMS. The most significant error pertains to a statement made within the safety section, which states: "Serious adverse effects (AEs included pathological liver function, neutropenia, and trigeminal neuralgia as well as one case of progressive multifocal leukoencephalopathy (PML in a patient with systemic lupus erythematosus." We would like to draw the authors’ attention to the fact that this case of PML pertains to the use of the related drug, leflunomide, and not teriflunomide as suggested. It is important to note that leflunomide is licensed to treat active rheumatoid arthritis in adults, and has not been evaluated or approved for the treatment of MS; as such it is inappropriate to extrapolate this observation to the use of teriflunomide. Furthermore, the case of PML cited in the article is complicated by the fact that the patient received prior multiple immunosuppressant therapies before leflunomide (ie, prednisone, azathioprine, chloroquine, danazol, cyclosporin A and methotrexate, which may have contributed to the development of PML.View original paper by Thöne and Ellrichmann.

Photoactivatable Lipid-based Nanoparticles as a Vehicle for Dual Agent Delivery | NCI Technology Transfer Center | TTC

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Researchers at the National Cancer Institute (NCI) RNA Biology Laboratory have developed nanoparticles that can deliver an agent (i.e., therapeutic or imaging) and release the agent upon targeted photoactivation allowing for controlled temporal and localized release of the agent.

Avian Diagnostic and Therapeutic Antibodies

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Bradley, David Sherman [UND SMHS

2012-12-31

A number of infectious agents have the potential of causing significant clinical symptomology and even death, but dispite this, the number of incidence remain below the level that supports producing a vaccine. Therapeutic antibodies provide a viable treatment option for many of these diseases. We proposed that antibodies derived from West Nile Virus (WNV) immunized geese would be able to treat WNV infection in mammals and potential humans. We demonstrated that WNV specific goose antibodies are indeed successful in treating WNV infection both prophylactically and therapeutically in a golden hamster model. We demonstrated that the goose derived antibodies are non-reactogenic, i.e. do not cause an inflammatory response with multiple exposures in mammals. We also developed both a specific pathogen free facility to house the geese during the antibody production phase and a patent-pending purification process to purify the antibodies to greater than 99% purity. Therefore, the success of these study will allow a cost effective rapidly producible therapeutic toward clinical testing with the necessary infrastructure and processes developed and in place.

Anti-herpesvirus agents: a patent and literature review (2003 to present).

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Skoreński, Marcin; Sieńczyk, Marcin

2014-08-01

The standard therapy used to treat herpesvirus infections is based on the application of DNA polymerase inhibitors such as ganciclovir or aciclovir. Unfortunately, all of these compounds exhibit relatively high toxicity and the mutation of herpesviruses results in the appearance of new drug-resistant strains. Consequently, there is a great need for the development of new, effective and safe anti-herpesvirus agents that employ different patterns of therapeutic action at various stages of the virus life cycle. Patents and patent applications concerning the development of anti-herpesvirus agents displaying different mechanisms of action that have been published since 2003 are reviewed. In addition, major discoveries in this field that have been published in academic papers have also been included. Among all the anti-herpesvirus agents described in this article, the inhibitors of viral serine protease seem to present one of the most effective/promising therapeutics. Unfortunately, the practical application of these antiviral agents has not yet been proven in any clinical trials. Nevertheless, the dynamic and extensive work on this subject gives hope that a new class of anti-herpesvirus agents aimed at the enzymatic activity of herpesvirus serine protease may be developed.

Reactor-produced therapeutic radioisotopes

International Nuclear Information System (INIS)

Knapp, F.F. Jr.

2002-01-01

The significant worldwide increase in therapeutic radioisotope applications in nuclear medicine, oncology and interventional cardiology requires the dependable production of sufficient levels of radioisotopes for these applications (Reba, 2000; J. Nucl. Med., 1998; Nuclear News, 1999; Adelstein and Manning, 1994). The issues associated with both accelerator- and reactor-production of therapeutic radioisotopes is important. Clinical applications of therapeutic radioisotopes include the use of both sealed sources and unsealed radiopharmaceutical sources. Targeted radiopharmaceutical agents include those for cancer therapy and palliation of bone pain from metastatic disease, ablation of bone marrow prior to stem cell transplantation, treatment modalities for mono and oligo- and polyarthritis, for cancer therapy (including brachytherapy) and for the inhibition of the hyperplastic response following coronary angioplasty and other interventional procedures (For example, see Volkert and Hoffman, 1999). Sealed sources involve the use of radiolabeled devices for cancer therapy (brachytherapy) and also for the inhibition of the hyperplasia which is often encountered after angioplasty, especially with the exponential increase in the use of coronary stents and stents for the peripheral vasculature and other anatomical applications. Since neutron-rich radioisotopes often decay by beta decay or decay to beta-emitting daughter radioisotopes which serve as the basis for radionuclide generator systems, reactors are expected to play an increasingly important role for the production of a large variety of therapeutic radioisotopes required for these and other developing therapeutic applications. Because of the importance of the availability of reactor-produced radioisotopes for these applications, an understanding of the contribution of neutron spectra for radioisotope production and determination of those cross sections which have not yet been established is important. This

Development of a Multifaceted Ovarian Cancer Therapeutic and Imaging Agent

Science.gov (United States)

2011-04-01

by 1-ethyl-3- [3-(dimethylamino) propyl ]carbodiimide (EDC) and N-hydroxysulfonosuccinimide (SNHS) at pH 5.5 for 30 min with a molar ratio of...particle-coated migratory substrate that can act as a permanent record of cellular movement. The gold chloride solution was prepared using 0.342 g... Synthesis and clinical Evaluation. Anticancer Agents Med. Chem. McLane, M.A., Joerger, T., Mahmoud, A., 2008. Disintegrins in health and disease. Front

Potential of Icariin Metabolites from Epimedium koreanum Nakai as Antidiabetic Therapeutic Agents

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Da Hye Kim

2017-06-01

Full Text Available The therapeutic properties of Epimedium koreanum are presumed to be due to the flavonoid component icariin, which has been reported to have broad pharmacological potential and has demonstrated anti-diabetic, anti-Alzheimer’s disease, anti-tumor, and hepatoprotective activities. Considering these therapeutic properties of icariin, its deglycosylated icaritin and glycosylated flavonoids (icaeriside II, epimedin A, epimedin B, and epimedin C were evaluated for their ability to inhibit protein tyrosine phosphatase 1B (PTP1B and α-glucosidase. The results show that icaritin and icariside II exhibit potent inhibitory activities, with 50% inhibition concentration (IC50 values of 11.59 ± 1.39 μM and 9.94 ± 0.15 μM against PTP1B and 74.42 ± 0.01 and 106.59 ± 0.44 μM against α-glucosidase, respectively. With the exceptions of icaritin and icariside II, glycosylated flavonoids did not exhibit any inhibitory effects in the two assays. Enzyme kinetics analyses revealed that icaritin and icariside II demonstrated noncompetitive-type inhibition against PTP1B, with inhibition constant (Ki values of 11.41 and 11.66 μM, respectively. Moreover, molecular docking analysis confirmed that icaritin and icariside II both occupy the same site as allosteric ligand. Thus, the molecular docking simulation results were in close agreement with the experimental data with respect to inhibition activity. In conclusion, deglycosylated metabolites of icariin from E. koreanum might offer therapeutic potential for the treatment of type 2 diabetes mellitus.

Chromosome analyses of nurses handling cytostatic agents

International Nuclear Information System (INIS)

Waksvik, H.; Klepp, O.; Brogger, A.

1981-01-01

A cytogenetic study of ten nurses handling cytostatic agents (average exposure, 2150 hours) and ten female hospital clerks revealed an increased frequency of chromosome gaps and a slight increase in sister chromatid exchange frequency among the nurses. The increase may be due to exposure to cytostatic drugs and points to these agents as a possible occupational health hazard. A second group of 11 nurses handling cytostatic agents for a shorter period of time (average exposure, 1078 hours), and three other groups (eight nurses engaged in therapeutic and diagnostic radiology, nine nurses engaged in anesthesiology, and seven nurses in postoperative ward) did not differ from the office personnel, except for an increased frequency of chromosome gaps in the radiology group

Recovering valuable liquid hydrocarbons

Energy Technology Data Exchange (ETDEWEB)

Pier, M

1931-06-11

A process for recovering valuable liquid hydrocarbons from coking coal, mineral coal, or oil shale through treatment with hydrogen under pressure at elevated temperature is described. Catalysts and grinding oil may be used in the process if necessary. The process provides for deashing the coal prior to hydrogenation and for preventing the coking and swelling of the deashed material. During the treatment with hydrogen, the coal is either mixed with coal low in bituminous material, such as lean coal or active coal, as a diluent or the bituminous constituents which cause the coking and swelling are removed by extraction with solvents. (BLM)

Ravens reconcile after aggressive conflicts with valuable partners.

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Fraser, Orlaith N; Bugnyar, Thomas

2011-03-25

Reconciliation, a post-conflict affiliative interaction between former opponents, is an important mechanism for reducing the costs of aggressive conflict in primates and some other mammals as it may repair the opponents' relationship and reduce post-conflict distress. Opponents who share a valuable relationship are expected to be more likely to reconcile as for such partners the benefits of relationship repair should outweigh the risk of renewed aggression. In birds, however, post-conflict behavior has thus far been marked by an apparent absence of reconciliation, suggested to result either from differing avian and mammalian strategies or because birds may not share valuable relationships with partners with whom they engage in aggressive conflict. Here, we demonstrate the occurrence of reconciliation in a group of captive subadult ravens (Corvus corax) and show that it is more likely to occur after conflicts between partners who share a valuable relationship. Furthermore, former opponents were less likely to engage in renewed aggression following reconciliation, suggesting that reconciliation repairs damage caused to their relationship by the preceding conflict. Our findings suggest not only that primate-like valuable relationships exist outside the pair bond in birds, but that such partners may employ the same mechanisms in birds as in primates to ensure that the benefits afforded by their relationships are maintained even when conflicts of interest escalate into aggression. These results provide further support for a convergent evolution of social strategies in avian and mammalian species.

Multimodal nanoparticle imaging agents: design and applications

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Burke, Benjamin P.; Cawthorne, Christopher; Archibald, Stephen J.

2017-10-01

Molecular imaging, where the location of molecules or nanoscale constructs can be tracked in the body to report on disease or biochemical processes, is rapidly expanding to include combined modality or multimodal imaging. No single imaging technique can offer the optimum combination of properties (e.g. resolution, sensitivity, cost, availability). The rapid technological advances in hardware to scan patients, and software to process and fuse images, are pushing the boundaries of novel medical imaging approaches, and hand-in-hand with this is the requirement for advanced and specific multimodal imaging agents. These agents can be detected using a selection from radioisotope, magnetic resonance and optical imaging, among others. Nanoparticles offer great scope in this area as they lend themselves, via facile modification procedures, to act as multifunctional constructs. They have relevance as therapeutics and drug delivery agents that can be tracked by molecular imaging techniques with the particular development of applications in optically guided surgery and as radiosensitizers. There has been a huge amount of research work to produce nanoconstructs for imaging, and the parameters for successful clinical translation and validation of therapeutic applications are now becoming much better understood. It is an exciting time of progress for these agents as their potential is closer to being realized with translation into the clinic. The coming 5-10 years will be critical, as we will see if the predicted improvement in clinical outcomes becomes a reality. Some of the latest advances in combination modality agents are selected and the progression pathway to clinical trials analysed. This article is part of the themed issue 'Challenges for chemistry in molecular imaging'.

Dendrimer-based Macromolecular MRI Contrast Agents: Characteristics and Application

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Hisataka Kobayashi

2003-01-01

Full Text Available Numerous macromolecular MRI contrast agents prepared employing relatively simple chemistry may be readily available that can provide sufficient enhancement for multiple applications. These agents operate using a ~100-fold lower concentration of gadolinium ions in comparison to the necessary concentration of iodine employed in CT imaging. Herein, we describe some of the general potential directions of macromolecular MRI contrast agents using our recently reported families of dendrimer-based agents as examples. Changes in molecular size altered the route of excretion. Smaller-sized contrast agents less than 60 kDa molecular weight were excreted through the kidney resulting in these agents being potentially suitable as functional renal contrast agents. Hydrophilic and larger-sized contrast agents were found better suited for use as blood pool contrast agents. Hydrophobic variants formed with polypropylenimine diaminobutane dendrimer cores created liver contrast agents. Larger hydrophilic agents are useful for lymphatic imaging. Finally, contrast agents conjugated with either monoclonal antibodies or with avidin are able to function as tumor-specific contrast agents, which also might be employed as therapeutic drugs for either gadolinium neutron capture therapy or in conjunction with radioimmunotherapy.

Preponderant agent, what is that?

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Clara Luz Álvarez

2015-05-01

Full Text Available Purpose – Preponderant agent is a new instrument for preventing and reverting adverse impact in competition due to highly concentrated markets. Therefore, this paper's objective is to present and analyze the preponderant agent concept in Mexico with emphasis on the broadcast sector, the telecommunication regulator decisions and the courts' interpretation. Methodology/approach/design – The objectives were achieved by researching and analyzing the main legal documents, the Congress reports and debates, the regulator's decisions and other relevant regulator's documents, as well as final decisions by the courts in connection with broadcast sector. Findings – Among the findings are that certain topics were not duly addressed by the Mexican regulator, or by the Congress, whereas the courts were more willing to hold decisions in favor of public interest based on constitutional intent and deference to the regulator's decision. Originality/value – This paper will be valuable for persons interested in telecommunications, broadcast and antitrust. Although the preponderant agent concept created in Mexico is not necessarily a “best practice”, it does provide an alternative instrument in antitrust. Moreover, the courts decisions also provide criteria regarding regulatory deference for the regulator.

MCM-41 mesoporous silica nanoparticles functionalized with aptamer and radiolabelled with {sup 90}Y and {sup 159}Gd as a potential therapeutic agent against colorectal cancer; Nanoparticulas de silica mesoporosa MCM-41 funcionalizadas com aptamero e radiomarcadas com {sup 90}Y e {sup 159}Gd como um potencial agente terapeutico contra cancer colorretal

Energy Technology Data Exchange (ETDEWEB)

Ferreira, Carolina de Aguiar

2014-06-01

Colorectal cancer (CRC) is a malignancy that affects large intestine and rectum, and it is the most common malignancy of the gastrointestinal tract, the third most commonly diagnosed type of cancer in the world and the second leading cause of cancer-related death in the United States. Nowadays, available therapeutic procedures for this type of cancer are limited and ineffective. Conventional radiotherapy is not an often used approach in the treatment of CRC due to the fact that peristaltic movements hamper the targeting of ionizing radiation and this type of treatment is used as adjuvant and palliative to control symptoms. Therefore, surgical intervention is the primary therapeutic choice against this disease. Researches based on the combination of radioisotopes and nanostructured carriers systems have demonstrated significant results in improving the selectivity action as well as reducing the radiation dose into healthy tissues. MCM-41 mesoporous silica nanoparticles have unique characteristics such as high surface area and well-defined pore diameters making these nanoparticles an ideal candidate of therapeutic agent carrier. Thus, the objective of this work is to synthesize and characterize MCM-41 mesoporous silica nanoparticles conjugated with yttrium-90 and gadolinium-159 and evaluate this system as a potential therapeutic agent. The nanoparticles were synthesized via sol-gel method. The sample was characterized using FTIR, SAXS, PCS, Zeta Potential analysis, Thermal analysis, CHN elemental analysis, nitrogen adsorption, scanning and transmission electron microscopy. The ability to incorporate Y{sup +3} and Gd{sup +3} ion was determined in vitro using different ratios (1:1, 1:3, 1:5 v/v) of YCL{sub 3} and Gd{sub 2}O{sub 3} and silica nanoparticles dispersed in saline, pH 7.4. The non-incorporated Y{sup +3} and Gd{sup +3} ions were removed by ultracentrifugation procedure and the concentration of ions in the supernatant was determined by ICP-AES. Cell viability

Bifunctional chelating agent for the design and development of site specific radiopharmaceuticals and biomolecule conjugation strategy

Science.gov (United States)

Katti, Kattesh V.; Prabhu, Kandikere R.; Gali, Hariprasad; Pillarsetty, Nagavara Kishore; Volkert, Wynn A.

2003-10-21

There is provided a method of labeling a biomolecule with a transition metal or radiometal in a site specific manner to produce a diagnostic or therapeutic pharmaceutical compound by synthesizing a P.sub.2 N.sub.2 -bifunctional chelating agent intermediate, complexing the intermediate with a radio metal or a transition metal, and covalently linking the resulting metal-complexed bifunctional chelating agent with a biomolecule in a site specific manner. Also provided is a method of synthesizing the --PR.sub.2 containing biomolecules by synthesizing a P.sub.2 N.sub.2 -bifunctional chelating agent intermediate, complexing the intermediate with a radiometal or a transition metal, and covalently linking the resulting radio metal-complexed bifunctional chelating agent with a biomolecule in a site specific manner. There is provided a therapeutic or diagnostic agent comprising a --PR.sub.2 containing biomolecule.

MicroRNAs in cancer therapeutics: "from the bench to the bedside".

Science.gov (United States)

Monroig-Bosque, Paloma del C; Rivera, Carlos A; Calin, George A

2015-01-01

MicroRNAs (miRNAs) are non-coding RNA transcripts that regulate physiological processes by targeting proteins directly. Their involvement in research has been robust, and evidence of their regulative functions has granted them the title: master regulators of the human genome. In cancer, they are considered important therapeutic agents, due to the fact that their aberrant expression contributes to disease development, progression, metastasis, therapeutic response and patient overall survival. This has endeavored fields of biomedical sciences to invest in developing and exploiting miRNA-based therapeutics thoroughly. Herein we highlight relevant ongoing/open clinical trials involving miRNAs and cancer.

EphB4 as a therapeutic target in mesothelioma

International Nuclear Information System (INIS)

Liu, Ren; Ferguson, Benjamin D; Zhou, Yue; Naga, Kranthi; Salgia, Ravi; Gill, Parkash S; Krasnoperov, Valery

2013-01-01

Malignant pleural mesothelioma (MPM) often develops decades following exposure to asbestos. Current best therapy produces a response in only half of patients, and the median survival with this therapy remains under a year. A search for novel targets and therapeutics is underway, and recently identified targets include VEGF, Notch, and EphB4-Ephrin-B2. Each of these targets has dual activity, promoting tumor cell growth as well as tumor angiogenesis. We investigated EphB4 expression in 39 human mesothelioma tissues by immunohistochemistry. Xenograft tumors established with human mesothelioma cells were treated with an EphB4 inhibitor (monomeric soluble EphB4 fused to human serum albumin, or sEphB4-HSA). The combinatorial effect of sEphB4-HSA and biologic agent was also studied. EphB4 was overexpressed in 72% of mesothelioma tissues evaluated, with 85% of epithelioid and 38% of sarcomatoid subtypes demonstrating overexpression. The EphB4 inhibitor sEphB4-HSA was highly active as a single agent to inhibit tumor growth, accompanied by tumor cell apoptosis and inhibition of PI3K and Src signaling. Combination of sEphB4-HSA and the anti-VEGF antibody (Bevacizumab) was superior to each agent alone and led to complete tumor regression. EphB4 is a potential therapeutic target in mesothelioma. Clinical investigation of sEphB4-HSA as a single agent and in combination with VEGF inhibitors is warranted

The Promise of Neuroprotective Agents in Parkinson’s Disease

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Judith ePotashkin

2011-11-01

Full Text Available Parkinson’s Disease is characterized by loss of dopamine neurons in the substantia nigra of the brain. Since there are limited treatment options for PD, neuroprotective agents are currently being tested as a means to slow disease progression. Agents targeting oxidative stress, mitochondrial dysfunction and inflammation are prime candidates for neuroprotection. This review identifies Rasagiline, Minocycline and creatine, as the most promising neuroprotective agents for PD, and they are all currently in phase III trials. Other agents possessing protective characteristics in delaying PD include stimulants, vitamins, supplements, and other drugs. Additionally, combination therapies also show benefits in slowing PD progression. The identification of neuroprotective agents for PD provides us with therapeutic opportunities for modifying the course of disease progression and, perhaps, reducing the risk of onset when preclinical biomarkers become available.

Botanical polysaccharides: macrophage immunomodulation and therapeutic potential.

Science.gov (United States)

Schepetkin, Igor A; Quinn, Mark T

2006-03-01

Botanical polysaccharides exhibit a number of beneficial therapeutic properties, and it is thought that the mechanisms involved in these effects are due to the modulation of innate immunity and, more specifically, macrophage function. In this review, we summarize our current state of understanding of the macrophage modulatory effects of botanical polysaccharides isolated from a wide array of different species of flora, including higher plants, mushrooms, lichens and algae. Overall, the primary effect of botanical polysaccharides is to enhance and/or activate macrophage immune responses, leading to immunomodulation, anti-tumor activity, wound-healing and other therapeutic effects. Furthermore, botanical and microbial polysaccharides bind to common surface receptors and induce similar immunomodulatory responses in macrophages, suggesting that evolutionarily conserved polysaccharide structural features are shared between these organisms. Thus, the evaluation of botanical polysaccharides provides a unique opportunity for the discovery of novel therapeutic agents and adjuvants that exhibit beneficial immunomodulatory properties.

Systemic use of tumor necrosis factor alpha as an anticancer agent

Science.gov (United States)

Roberts, Nicholas J.; Zhou, Shibin; Diaz, Luis A.; Holdhoff, Matthias

2011-01-01

Tumor necrosis factor-α (TNF-α) has been discussed as a potential anticancer agent for many years, however initial enthusiasm about its clinical use as a systemic agent was curbed due to significant toxicities and lack of efficacy. Combination of TNF-α with chemotherapy in the setting of hyperthermic isolated limb perfusion (ILP), has provided new insights into a potential therapeutic role of this agent. The therapeutic benefit from TNF-α in ILP is thought to be not only due to its direct anti-proliferative effect, but also due to its ability to increase penetration of the chemotherapeutic agents into the tumor tissue. New concepts for the use of TNF-α as a facilitator rather than as a direct actor are currently being explored with the goal to exploit the ability of this agent to increase drug delivery and to simultaneously reduce systemic toxicity. This review article provides a comprehensive overview on the published previous experience with systemic TNF-α. Data from 18 phase I and 10 phase II single agent as well as 18 combination therapy studies illustrate previously used treatment and dose schedules, response data as well as the most prominently observed adverse effects. Also discussed, based on recent preclinical data, is a potential future role of systemic TNF-α in combination with liposomal chemotherapy to facilitate increased drug uptake into tumors. PMID:22036896

Preparation of 125IUdR and its evaluation in animal tumour model as a potential therapeutic agent

International Nuclear Information System (INIS)

Korde, A.; Venkatesh, M.; Banerjee, S.; Pillai, M.R.A.; Sarma, H.D.

1998-01-01

5-Iodo-2'-deoxyuridine or iodoxyuridine (IUdR), an analogue of thymidine, is taken up by the proliferating cells during DNA synthesis. Radioiodinated IUdR is a potential therapeutic agent since radiohalogenated thymidine analogues are used for in-vivo tumour targeting and Auger electrons from radionuclides such as 123 I and 125 I are very effective in cell destruction when internalised. 125 IUdR was prepared and studied for its suitability as an in-vivo tumour therapy agent. 125 IUdR was prepared both by direct iodination of 2'-deoxyuridine and iododemercuration of 5-chloromercury-2'-deoxyuridine. Radioiodination yields were between 60-80% at pH 7. Iododemercuration was preferred since with direct iodination poor yields were observed when high specific activity product was desired and also the purification procedure was lengthier. The identity of 125 IUdR was established by comparison of TLC and HPLC patterns with those of authentic IUdR. The purified 125 IUdR had radiochemical purity >95% and was stable for 20 days at 4 deg. C and for a week at 23 deg. C and 37 deg. C. Bio-uptake of 125 IUdR was studied by injecting the tracer in tumour bearing mice (Sarcoma S-180). The uptake in tumour cells was 4.28 +- 2.7% per gram at 3 h and 1.48 +- 0.19% at 24 h post injection. In-vivo deiodination of the product was observed as seen by the uptake of the activity in the thyroid. About 40% the activity from all other organs was excreted in 70 h. The optimum time for injection of the tracer for therapy was studied by observing the delay in tumour growth and survival rate in mice injected at 0,3,9 and 12 days after tumour induction. Injection of the tracer on the third day was found to be the most beneficial for retardation of tumour growth, while injection of the activity on the zeroth and ninth day had no effect. (author)

Therapeutic advancement of chronic lymphocytic leukemia

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Lu Kang

2012-09-01

Full Text Available Abstract Despite the combinations of chemotherapy with monoclonal antibodies have further improved response rates, chronic lymphocytic leukemia (CLL remains an incurable disease with an extremely variable course. This article reviews the ongoing clinical advances in the treatment of CLL in both previously untreated and relapsed disease and focuses on the benefit of different therapeutic strategies, the most effective therapy combinations and the potential activity of novel agents. Novel agents and combination therapies have been investigated by several studies in both the upfront and relapsed setting, particularly for patients with 17p deletion, TP53 mutation and fludarabine-refractory CLL. While these agents and combination therapies have improved initial response rates, ongoing studies are continued to determine and improve the efficacy and safety. Despite advancements in the treatment of CLL have led to high response rates, allogeneic hematopoietic stem cell transplantation (allo-HSCT remains the only curative option and reduced-intensity conditioning (RIC allo-HSCT must be strongly considered whenever feasible. As such, ongoing studies of these agents and other novel approaches in clinical development are needed to expand and improve treatment options for CLL patients.

Engineered Polymer-Based Nanomaterials for Diagnostic, Therapeutic and Theranostic Applications.

Science.gov (United States)

Parisi, Ortensia Ilaria; Scrivano, Luca; Sinicropi, Maria Stefania; Picci, Nevio; Puoci, Francesco

2016-01-01

Nanomedicine can be defined as the medical application of molecular nanotechnology and it plays a key role and pharmaceutical research and development, especially related to cancer prevention, monitoring, diagnosis and treatment. In this context, nanomaterials are attracting significant research interest due to their abilities to stay in the blood for long time, accumulate in pathological sites including tumors or inflammatory areas via the enhanced permeability and retention (EPR) effect, and facilitate targeted delivery of specific therapeutic agents. In the last decades, considerable attention was attracted by the development of nano-sized carriers, based on natural or synthetic polymers, able to provide the controlled release of anticancer drugs in the aim to overcome the drawbacks associated to the conventional chemotherapy. Furthermore, when loaded with imaging agents, this kind of systems offers the opportunity to exploit optical or magnetic resonance imaging (MRI) in cancer diagnosis. Polymeric materials are characterized by several functionalities where both therapeutic and imaging components, and also targeting moieties, can be attached for simultaneous targeted therapy and imaging providing innovative platforms defined as theranostic agents with a great potential in monitoring and treatment of cancer.

Resveratrol as a Therapeutic Agent for Alzheimer’s Disease

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Teng Ma

2014-01-01

Full Text Available Alzheimer’s disease (AD is the most common cause of dementia, but there is no effective therapy till now. The pathogenic mechanisms of AD are considerably complex, including Aβ accumulation, tau protein phosphorylation, oxidative stress, and inflammation. Exactly, resveratrol, a polyphenol in red wine and many plants, is indicated to show the neuroprotective effect on mechanisms mostly above. Recent years, there are numerous researches about resveratrol acting on AD in many models, both in vitro and in vivo. However, the effects of resveratrol are limited by its pool bioavailability; therefore researchers have been trying a variety of methods to improve the efficiency. This review summarizes the recent studies in cell cultures and animal models, mainly discusses the molecular mechanisms of the neuroprotective effects of resveratrol, and thus investigates the therapeutic potential in AD.

Immunotherapeutics in Pediatric Autoimmune Central Nervous System Disease: Agents and Mechanisms.

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Nosadini, Margherita; Sartori, Stefano; Sharma, Suvasini; Dale, Russell C

2017-08-01

Beyond the major advances produced by careful clinical-radiological phenotyping and biomarker development in autoimmune central nervous system disorders, a comprehensive knowledge of the range of available immune therapies and a deeper understanding of their action should benefit therapeutic decision-making. This review discusses the agents used in neuroimmunology and their mechanisms of action. First-line treatments typically include corticosteroids, intravenous immunoglobulin, and plasmapheresis, while for severe disease second-line "induction" agents such as rituximab or cyclophosphamide are used. Steroid-sparing agents such as mycophenolate, azathioprine, or methotrexate are often used in potentially relapsing or corticosteroid-dependent diseases. Lessons from adult neuroimmunology and rheumatology could be translated into pediatric autoimmune central nervous system disease in the future, including the potential utility of monoclonal antibodies targeting lymphocytes, adhesion molecules for lymphocytic migration, cytokines or their receptors, or complement. Finally, many agents used in other fields have multiple mechanisms of action, including immunomodulation, with potential usefulness in neuroimmunology, such as antibiotics, psychotropic drugs, probiotics, gut health, and ketogenic diet. All currently accepted and future potential agents have adverse effects, which can be severe; therefore, a "risk-versus-benefit" determination should guide therapeutic decision-making. Copyright © 2017 Elsevier Inc. All rights reserved.

Superparamagnetic Bifunctional Bisphosphonates Nanoparticles: A Potential MRI Contrast Agent for Osteoporosis Therapy and Diagnostic

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Y. Lalatonne

2010-01-01

Full Text Available A bone targeting nanosystem is reported here which combined magnetic contrast agent for Magnetic Resonance Imaging (MRI and a therapeutic agent (bisphosphonates into one drug delivery system. This new targeting nanoplatform consists of superparamagnetic γFe2O3 nanoparticles conjugated to 1,5-dihydroxy-1,5,5-tris-phosphono-pentyl-phosphonic acid (di-HMBPs molecules with a bisphosphonate function at the outer of the nanoparticle surface for bone targeting. The as-synthesized nanoparticles were evaluated as a specific MRI contrast agent by adsorption study onto hydroxyapatite and MRI measurment. The strong adsorption of the bisphosphonates nanoparticles to hydroxyapatite and their use as MRI T2∗ contrast agent were demonstrated. Cellular tests performed on human osteosarcoma cells (MG63 show that γFe2O3@di-HMBP hybrid nanomaterial has no citoxity effect in cell viability and may act as a diagnostic and therapeutic system.

Therapeutic strategies in the treatment of periodontitis

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Liljana Bogdanovska

2012-04-01

Full Text Available Periodontitis is a chronic inflammatory process which affects the tooth - supporting structures of the teeth. The disease is initiated by subgingival periopathogenic bacteria in susceptible periodontal sites. The host immune response towards periodontal pathogens helps to sustain periodontal disease and eventual alveolar bone loss. Although scaling and root planing is the standard treatment modality for periodontitis, it suffers from several drawbacks such as the inability to reach the base of deep pockets and doesn’t arrest migration of periodontal pathogens from other sites in the oral cavity. In order to overcome the limitations of scaling and root planning, adjunctive chemotherapeutics and host modulatory agents to the treatment are used. These therapeutic agents show substantial beneficial effects when compared to scaling and root planning alone. This review will cover an update on chemotherapeutic and past and future host immune modulatory agents used adjunctively to treat and manage periodontal diseases.

Therapeutic Vaccination for HPV Induced Cervical Cancers

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Joeli A. Brinkman

2007-01-01

Full Text Available Cervical Cancer is the second leading cause of cancer–related deaths in women worldwide and is associated with Human Papillomavirus (HPV infection, creating a unique opportunity to treat cervical cancer through anti-viral vaccination. Although a prophylactic vaccine may be available within a year, millions of women, already infected, will continue to suffer from HPV-related disease, emphasizing the need to develop therapeutic vaccination strategies. A majority of clinical trials examining therapeutic vaccination have shown limited efficacy due to examining patients with more advanced-stage cancer who tend to have decreased immune function. Current trends in clinical trials with therapeutic agents examine patients with pre-invasive lesions in order to prevent invasive cervical cancer. However, longer follow-up is necessary to correlate immune responses to lesion regression. Meanwhile, preclinical studies in this field include further exploration of peptide or protein vaccination, and the delivery of HPV antigens in DNA-based vaccines or in viral vectors. As long as pre-clinical studies continue to advance, the prospect of therapeutic vaccination to treat existing lesions seem good in the near future. Positive consequences of therapeutic vaccination would include less disfiguring treatment options and fewer instances of recurrent or progressive lesions leading to a reduction in cervical cancer incidence.

Therapeutic peptides for cancer therapy. Part I - peptide inhibitors of signal transduction cascades.

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Bidwell, Gene L; Raucher, Drazen

2009-10-01

Therapeutic peptides have great potential as anticancer agents owing to their ease of rational design and target specificity. However, their utility in vivo is limited by low stability and poor tumor penetration. The authors review the development of peptide inhibitors with potential for cancer therapy. Peptides that inhibit signal transduction cascades are discussed. The authors searched Medline for articles concerning the development of therapeutic peptides and their delivery. Given our current knowledge of protein sequences, structures and interaction interfaces, therapeutic peptides that inhibit interactions of interest are easily designed. These peptides are advantageous because they are highly specific for the interaction of interest, and they are much more easily developed than small molecule inhibitors of the same interactions. The main hurdle to application of peptides for cancer therapy is their poor pharmacokinetic and biodistribution parameters. Therefore, successful development of peptide delivery vectors could potentially make possible the use of this new and very promising class of anticancer agents.

Valuable Nutrients and Functional Bioactives in Different Parts of Olive (Olea europaea L.)—A Review

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Ghanbari, Rahele; Anwar, Farooq; Alkharfy, Khalid M.; Gilani, Anwarul-Hassan; Saari, Nazamid

2012-01-01

The Olive tree (Olea europaea L.), a native of the Mediterranean basin and parts of Asia, is now widely cultivated in many other parts of the world for production of olive oil and table olives. Olive is a rich source of valuable nutrients and bioactives of medicinal and therapeutic interest. Olive fruit contains appreciable concentration, 1–3% of fresh pulp weight, of hydrophilic (phenolic acids, phenolic alchohols, flavonoids and secoiridoids) and lipophilic (cresols) phenolic compounds that are known to possess multiple biological activities such as antioxidant, anticarcinogenic, antiinflammatory, antimicrobial, antihypertensive, antidyslipidemic, cardiotonic, laxative, and antiplatelet. Other important compounds present in olive fruit are pectin, organic acids, and pigments. Virgin olive oil (VOO), extracted mechanically from the fruit, is also very popular for its nutritive and health-promoting potential, especially against cardiovascular disorders due to the presence of high levels of monounsaturates and other valuable minor components such as phenolics, phytosterols, tocopherols, carotenoids, chlorophyll and squalene. The cultivar, area of production, harvest time, and the processing techniques employed are some of the factors shown to influence the composition of olive fruit and olive oil. This review focuses comprehensively on the nutrients and high-value bioactives profile as well as medicinal and functional aspects of different parts of olives and its byproducts. Various factors affecting the composition of this food commodity of medicinal value are also discussed. PMID:22489153

Acoustically active lipospheres containing paclitaxel: a new therapeutic ultrasound contrast agent.

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Unger, E C; McCreery, T P; Sweitzer, R H; Caldwell, V E; Wu, Y

1998-12-01

Paclitaxel-carrying lipospheres (MRX-552) were developed and evaluated as a new ultrasound contrast agent for chemotherapeutic drug delivery. Paclitaxel was suspended in soybean oil and added to an aqueous suspension of phospholipids in vials. The headspace of the vials was replaced with perfluorobutane gas; the vials were sealed, and they were agitated at 4200 rpm on a shaking device. The resulting lipospheres containing paclitaxel were studied for concentration, size, acute toxicity in mice, and acoustic activity and drug release with ultrasound. Lipospheres containing sudan black dye were produced to demonstrate the acoustically active liposphere (AAL)-ultrasound release concept. Acoustically active lipospheres containing paclitaxel had a mean particle count of approximately 1 x 10(9) particles per mL and a mean size of 2.9 microns. Acute toxicity studies in mice showed a 10-fold reduction in toxicity for paclitaxel in AALs compared with free paclitaxel. The AALs reflected ultrasound as a contrast agent. Increasing amounts of ultrasound energy selectively ruptured the AALs and released the paclitaxel. Acoustically active lipospheres represent a new class of acoustically active drug delivery vehicles. Future studies will assess efficacy of AALs for ultrasound-mediated drug delivery.

Sphingosine 1-phosphate (S1P) signalling: Role in bone biology and potential therapeutic target for bone repair.

Science.gov (United States)

Sartawi, Ziad; Schipani, Ernestina; Ryan, Katie B; Waeber, Christian

2017-11-01

The lipid mediator sphingosine 1-phosphate (S1P) affects cellular functions in most systems. Interest in its therapeutic potential has increased following the discovery of its G protein-coupled receptors and the recent availability of agents that can be safely administered in humans. Although the role of S1P in bone biology has been the focus of much less research than its role in the nervous, cardiovascular and immune systems, it is becoming clear that this lipid influences many of the functions, pathways and cell types that play a key role in bone maintenance and repair. Indeed, S1P is implicated in many osteogenesis-related processes including stem cell recruitment and subsequent differentiation, differentiation and survival of osteoblasts, and coupling of the latter cell type with osteoclasts. In addition, S1P's role in promoting angiogenesis is well-established. The pleiotropic effects of S1P on bone and blood vessels have significant potential therapeutic implications, as current therapeutic approaches for critical bone defects show significant limitations. Because of the complex effects of S1P on bone, the pharmacology of S1P-like agents and their physico-chemical properties, it is likely that therapeutic delivery of S1P agents will offer significant advantages compared to larger molecular weight factors. Hence, it is important to explore novel methods of utilizing S1P agents therapeutically, and improve our understanding of how S1P and its receptors modulate bone physiology and repair. Copyright © 2017 Elsevier Ltd. All rights reserved.

Star-Shaped Polypeptides: Synthesis and Opportunities for Delivery of Therapeutics.

Science.gov (United States)

Byrne, Mark; Murphy, Robert; Kapetanakis, Antonios; Ramsey, Joanne; Cryan, Sally-Ann; Heise, Andreas

2015-09-17

Significant advances in the synthesis of polypeptides by N-carboxyanhydride (NCA) polymerisation over the last decade have enabled the design of advanced polypeptide architectures such as star-shaped polypeptides. These materials combine the functionality offered by amino acids with the flexibility of creating stable nanoparticles with adjustable cargo space for therapeutic delivery. This review highlights recent advances in the synthesis of star polypeptides by NCA polymerisation followed by a critical review of the applications of this class of polymer in the delivery of therapeutic agents. This includes examples of traditional small-molecule drugs as well as the emerging class of biologics such as genetic therapeutics (gene delivery). © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Specificity enhancement by electrospray ionization multistage mass spectrometry--a valuable tool for differentiation and identification of 'V'-type chemical warfare agents.

Science.gov (United States)

Weissberg, Avi; Tzanani, Nitzan; Dagan, Shai

2013-12-01

The use of chemical warfare agents has become an issue of emerging concern. One of the challenges in analytical monitoring of the extremely toxic 'V'-type chemical weapons [O-alkyl S-(2-dialkylamino)ethyl alkylphosphonothiolates] is to distinguish and identify compounds of similar structure. MS analysis of these compounds reveals mostly fragment/product ions representing the amine-containing residue. Hence, isomers or derivatives with the same amine residue exhibit similar mass spectral patterns in both classical EI/MS and electrospray ionization-MS, leading to unavoidable ambiguity in the identification of the phosphonate moiety. A set of five 'V'-type agents, including O-ethyl S-(2-diisopropylamino)ethyl methylphosphonothiolate (VX), O-isobutyl S-(2-diethylamino)ethyl methylphosphonothiolate (RVX) and O-ethyl S-(2-diethylamino)ethyl methylphosphonothiolate (VM) were studied by liquid chromatography/electrospray ionization/MS, utilizing a QTRAP mass detector. MS/MS enhanced product ion scans and multistage MS(3) experiments were carried out. Based on the results, possible fragmentation pathways were proposed, and a method for the differentiation and identification of structural isomers and derivatives of 'V'-type chemical warfare agents was obtained. MS/MS enhanced product ion scans at various collision energies provided information-rich spectra, although many of the product ions obtained were at low abundance. Employing MS(3) experiments enhanced the selectivity for those low abundance product ions and provided spectra indicative of the different phosphonate groups. Study of the fragmentation pathways, revealing some less expected structures, was carried out and allowed the formulation of mechanistic rules and the determination of sets of ions typical of specific groups, for example, methylphosphonothiolates versus ethylphosphonothiolates. The new group-specific ions elucidated in this work are also useful for screening unknown 'V'-type agents and related

Novel compounds for the treatment of Duchenne muscular dystrophy: emerging therapeutic agents

Directory of Open Access Journals (Sweden)

Steve D Wilton

2011-03-01

Full Text Available Steve D Wilton, Sue FletcherCentre for Neuromuscular and Neurological Disorders, University of Western Australia, Crawley, Perth, WA, AustraliaAbstract: The identification of dystrophin and the causative role of mutations in this gene in Duchenne and Becker muscular dystrophies (D/BMD was expected to lead to timely development of effective therapies. Despite over 20 years of research, corticosteroids remain the only available pharmacological treatment for DMD, although significant benefits and extended life have resulted from advances in the clinical care and management of DMD individuals. Effective treatment of DMD will require dystrophin restitution in skeletal, cardiac, and smooth muscles and nonmuscle tissues; however, modulation of muscle loss and regeneration has the potential to play an important role in altering the natural history of DMD, particularly in combination with other treatments. Emerging biological, molecular, and small molecule therapeutics are showing promise in ameliorating this devastating disease, and it is anticipated that regulatory environments will need to display some flexibility in order to accommodate the new treatment paradigms.Keywords: Duchenne muscular dystrophy, molecular therapeutics, small molecules

Developing Inhibitors of Translesion DNA Synthesis as Therapeutic Agents Against Lung Cancer

Science.gov (United States)

2014-10-01

pol eta when replicating damaged DNA. 1S. SUBJECT TERMS: Mutagenesis, DNA polymerases, nucleoside analogs, chemotherapeutic agents 16. SECURITY ...such as polymerase eta, iota , and kappa that are involved in replicating damaged DNA. Our kinetic data obtained under Task 1B indicates that pol eta

Imaging enabled platforms for development of therapeutics

Science.gov (United States)

Celli, Jonathan; Rizvi, Imran; Blanden, Adam R.; Evans, Conor L.; Abu-Yousif, Adnan O.; Spring, Bryan Q.; Muzikansky, Alona; Pogue, Brian W.; Finkelstein, Dianne M.; Hasan, Tayyaba

2011-03-01

Advances in imaging and spectroscopic technologies have enabled the optimization of many therapeutic modalities in cancer and noncancer pathologies either by earlier disease detection or by allowing therapy monitoring. Amongst the therapeutic options benefiting from developments in imaging technologies, photodynamic therapy (PDT) is exceptional. PDT is a photochemistry-based therapeutic approach where a light-sensitive molecule (photosensitizer) is activated with light of appropriate energy (wavelength) to produce reactive molecular species such as free radicals and singlet oxygen. These molecular entities then react with biological targets such as DNA, membranes and other cellular components to impair their function and lead to eventual cell and tissue death. Development of PDT-based imaging also provides a platform for rapid screening of new therapeutics in novel in vitro models prior to expensive and labor-intensive animal studies. In this study we demonstrate how an imaging platform can be used for strategizing a novel combination treatment strategy for multifocal ovarian cancer. Using an in vitro 3D model for micrometastatic ovarian cancer in conjunction with quantitative imaging we examine dose and scheduling strategies for PDT in combination with carboplatin, a chemotherapeutic agent presently in clinical use for management of this deadly form of cancer.

Irrigation System through Intelligent Agents Implemented with Arduino Technology

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Rodolfo SALAZAR

2013-11-01

Full Text Available The water has become in recent years a valuable and increasingly scarce. Its proper use in agriculture has demanded incorporate new technologies, mainly in the area of ICT. In this paper we present a smart irrigation system based on multi-agent architecture using fuzzy logic. The architecture incorporates different types of intelligent agents that an autonomous way monitor and are responsible for deciding if required enable / disable the irrigation system. This project proposes a real and innovative solution to the problem of inadequate water use with current irrigation systems employed in agricultural projects. This article presents the different technologies used, their adaptation to the solution of the problem and briefly discusses the first results obtained.

Speciation in Metal Toxicity and Metal-Based Therapeutics

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Douglas M. Templeton

2015-04-01

Full Text Available Metallic elements, ions and compounds produce varying degrees of toxicity in organisms with which they come into contact. Metal speciation is critical to understanding these adverse effects; the adjectives “heavy” and “toxic” are not helpful in describing the biological properties of individual elements, but detailed chemical structures are. As a broad generalization, the metallic form of an element is inert, and the ionic salts are the species that show more significant bioavailability. Yet the salts and other chelates of a metal ion can give rise to quite different toxicities, as exemplified by a range of carcinogenic potential for various nickel species. Another important distinction comes when a metallic element is organified, increasing its lipophilicity and hence its ability to penetrate the blood brain barrier, as is seen, for example, with organic mercury and tin species. Some metallic elements, such as gold and platinum, are themselves useful therapeutic agents in some forms, while other species of the same element can be toxic, thus focusing attention on species interconversions in evaluating metal-based drugs. The therapeutic use of metal-chelating agents introduces new species of the target metal in vivo, and this can affect not only its desired detoxification, but also introduce a potential for further mechanisms of toxicity. Examples of therapeutic iron chelator species are discussed in this context, as well as the more recent aspects of development of chelation therapy for uranium exposure.

Near Infrared Fluorescence Imaging in Nano-Therapeutics and Photo-Thermal Evaluation

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Vats, Mukti; Mishra, Sumit Kumar; Baghini, Mahdieh Shojaei; Chauhan, Deepak S.; Srivastava, Rohit; De, Abhijit

2017-01-01

The unresolved and paramount challenge in bio-imaging and targeted therapy is to clearly define and demarcate the physical margins of tumor tissue. The ability to outline the healthy vital tissues to be carefully navigated with transection while an intraoperative surgery procedure is performed sets up a necessary and under-researched goal. To achieve the aforementioned objectives, there is a need to optimize design considerations in order to not only obtain an effective imaging agent but to also achieve attributes like favorable water solubility, biocompatibility, high molecular brightness, and a tissue specific targeting approach. The emergence of near infra-red fluorescence (NIRF) light for tissue scale imaging owes to the provision of highly specific images of the target organ. The special characteristics of near infra-red window such as minimal auto-fluorescence, low light scattering, and absorption of biomolecules in tissue converge to form an attractive modality for cancer imaging. Imparting molecular fluorescence as an exogenous contrast agent is the most beneficial attribute of NIRF light as a clinical imaging technology. Additionally, many such agents also display therapeutic potentials as photo-thermal agents, thus meeting the dual purpose of imaging and therapy. Here, we primarily discuss molecular imaging and therapeutic potentials of two such classes of materials, i.e., inorganic NIR dyes and metallic gold nanoparticle based materials. PMID:28452928

Ab Interno Trabeculectomy With the Trabectome as a Valuable Therapeutic Option for Failed Filtering Blebs.

Science.gov (United States)

Wecker, Thomas; Neuburger, Matthias; Bryniok, Laura; Bruder, Kathrin; Luebke, Jan; Anton, Alexandra; Jordan, Jens F

2016-09-01

. The number of necessary IOP lowering medication drops at first, but seems to reach preoperative values after 20 months of follow-up. Trabectome surgery should be considered as a valuable escape procedure for patients with failed filtering blebs and uncontrolled IOP.

Synthetic Curcumin Analogs as Inhibitors of β -Amyloid Peptide Aggregation: Potential Therapeutic and Diagnostic Agents for Alzheimer's Disease.

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Bukhari, Syed Nasir Abbas; Jantan, Ibrahim

2015-01-01

There is a crucial need to develop new effective drugs for Alzheimer's disease (AD) as the currently available AD treatments provide only momentary and incomplete symptomatic relief. Amongst natural products, curcumin, a major constituent of turmeric, has been intensively investigated for its neuroprotective effect against β-amyloid (Aβ)-induced toxicity in cultured neuronal cells. The ability of curcumin to attach to Aβ peptide and prevent its accumulation is attributed to its three structural characteristics such as the presence of two aromatic end groups and their co-planarity, the length and rigidity of the linker region and the substitution conformation of these aromatics. However, curcumin failed to reach adequate brain levels after oral absorption in AD clinical trials due to its low water solubility and poor oral bioavailability. A number of new curcumin analogs that mimic the active site of the compound along with analogs that mimic the curcumin anti-amyloid effect combined with anticholinesterase effect have been developed to enhance the bioavailability, pharmacokinetics, water solubility, stability at physiological conditions and delivery of curcumin. In this article, we have summarized all reported synthetic analogs of curcumin showing effects on β-amyloid and discussed their potential as therapeutic and diagnostic agents for AD.

Development of new therapeutic methods of lung cancer through team approach study

International Nuclear Information System (INIS)

Park, Jong Ho; Zo, Jae Ill; Baek, Hee Jong; Jung, Jin Haeng; Lee, Jae Cheol; Ryoo, Baek Yeol; Kim, Mi Sook; Choi, Du Hwan; Park, Sun Young; Lee, Hae Young

2000-12-01

The aims of this study were to make the lung cancer clinics in Korea Cancer Center Hospital, and to establish new therapeutic methods of lung cancer for increasing the cure rate and survival rate of patients. Also another purpose of this study was to establish a common treatment method in our hospital. All patients who were operated in Korea Cancer Center Hospital from 1987 due to lung cancer were followed up and evaluated. And we have been studied the effect of postoperative adjuvant therapy in stage I, II, IIIA non-small cell lung cancer patients from 1989 with the phase three study form. Follow-up examinations were scheduled in these patients and interim analysis was made. Also we have been studied the effect of chemo-therapeutic agents in small cell lung cancer patients from 1997 with the phase two study form. We evaluated the results of this study. Some important results of this study were as follows. 1. The new therapeutic method (surgery + MVP chemotherapy) was superior to the standard therapeutic one in stage I Non-small cell lung cancer patients. So, we have to change the standard method of treatment in stage I NSCLC. 2. Also, this new therapeutic method made a good result in stage II NSCLC patients. And this result was reported in The Annals of Thoracic Surgery. 3. However, this new therapeutic method was not superior to the standard treatment method (surgery only) in stage IIIA NSCLC patients. So, we must develop new chemo-therapeutic agents in the future for advanced NSCLC patients. 4. In the results of the randomized phase II studies about small cell lung cancer, there was no difference in survival between Etoposide + Carboplatin + Ifosfamide + Cisplatin group and Etoposide + Carboplatin + Ifosfamide + Cisplatin + Tamoxifen group in both the limited and extended types of small cell lung cancer patients

An update on anti-TNF agents in ulcerative colitis

NARCIS (Netherlands)

Samaan, Mark A.; Bagi, Preet; Vande Casteele, Niels; D'Haens, Geert R.; Levesque, Barrett G.

2014-01-01

Anti-tumor necrosis factor-α agents are key therapeutic options for the treatment of ulcerative colitis. Their efficacy and safety have been shown in large randomized controlled trials. The key evidence gained from these trials of infliximab, adalimumab, and golimumab is reviewed along with their

The therapeutic journey of benzimidazoles: a review.

Science.gov (United States)

Bansal, Yogita; Silakari, Om

2012-11-01

Presence of benzimidazole nucleus in numerous categories of therapeutic agents such as antimicrobials, antivirals, antiparasites, anticancer, anti-inflammatory, antioxidants, proton pump inhibitors, antihypertensives, anticoagulants, immunomodulators, hormone modulators, CNS stimulants as well as depressants, lipid level modulators, antidiabetics, etc. has made it an indispensable anchor for development of new therapeutic agents. Varied substitutents around the benzimidazole nucleus have provided a wide spectrum of biological activities. Importance of this nucleus in some activities like, Angiotensin I (AT(1)) receptor antagonism and proton-pump inhibition is reviewed separately in literature. Even some very short reviews on biological importance of this nucleus are also known in literature. However, owing to fast development of new drugs possessing benzimidazole nucleus many research reports are generated in short span of time. So, there is a need to couple the latest information with the earlier information to understand the current status of benzimidazole nucleus in medicinal chemistry research. In the present review, various derivatives of benzimidazole with different pharmacological activities are described on the basis of substitution pattern around the nucleus with an aim to help medicinal chemists for developing an SAR on benzimidazole derived compounds for each activity. This discussion will further help in the development of novel benzimidazole compounds. Copyright © 2012 Elsevier Ltd. All rights reserved.

Trends in GPCR drug discovery: new agents, targets and indications

DEFF Research Database (Denmark)

Hauser, Alexander Sebastian; Gloriam, David E.; Attwood, Misty M.

2017-01-01

current trends across molecule types, drug targets and therapeutic indications, including showing that 475 drugs (~34% of all drugs approved by the US Food and Drug Administration (FDA)) act at 108 unique GPCRs. Approximately 321 agents are currently in clinical trials, of which ~20% target 66 potentially...... are also highly represented. The 224 (56%) non-olfactory GPCRs that have not yet been explored in clinical trials have broad untapped therapeutic potential, particularly in genetic and immune system disorders. Finally, we provide an interactive online resource to analyse and infer trends in GPCR drug......G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, mostly due to their substantial involvement in human pathophysiology and their pharmacological tractability. Here, we report an up-to-date analysis of all GPCR drugs and agents in clinical trials, which reveals...

Therapeutic applications of histone deacetylase inhibitors in sarcoma.

Science.gov (United States)

Tang, Fan; Choy, Edwin; Tu, Chongqi; Hornicek, Francis; Duan, Zhenfeng

2017-09-01

Sarcomas are a rare group of malignant tumors originating from mesenchymal stem cells. Surgery, radiation and chemotherapy are currently the only standard treatments for sarcoma. However, their response rates to chemotherapy are quite low. Toxic side effects and multi-drug chemoresistance make treatment even more challenging. Therefore, better drugs to treat sarcomas are needed. Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are epigenetic modifying agents that can inhibit sarcoma growth in vitro and in vivo through a variety of pathways, including inducing tumor cell apoptosis, causing cell cycle arrest, impairing tumor invasion and preventing metastasis. Importantly, preclinical studies have revealed that HDIs can not only sensitize sarcomas to chemotherapy and radiotherapy, but also increase treatment responses when combined with other chemotherapeutic drugs. Several phase I and II clinical trials have been conducted to assess the efficacy of HDIs either as monotherapy or in combination with standard chemotherapeutic agents or targeted therapeutic drugs for sarcomas. Combination regimen for sarcomas appear to be more promising than monotherapy when using HDIs. This review summarizes our current understanding and therapeutic applications of HDIs in sarcomas. Copyright © 2017 Elsevier Ltd. All rights reserved.

Peroxisome Proliferator-Activated Receptor Ligands and Their Role in Chronic Myeloid Leukemia: Therapeutic Strategies.

Science.gov (United States)

Yousefi, Bahman; Samadi, Nasser; Baradaran, Behzad; Shafiei-Irannejad, Vahid; Zarghami, Nosratollah

2016-07-01

Imatinib therapy remains the gold standard for treatment of chronic myeloid leukemia; however, the acquired resistance to this therapeutic agent in patients has urged the scientists to devise modalities for overcoming this chemoresistance. For this purpose, initially therapeutic agents with higher tyrosine kinase activity were introduced, which had the potential for inhibiting even mutant forms of Bcr-Abl. Furthermore, coupling imatinib with peroxisome proliferator-activated receptor ligands also showed beneficial effects in chronic myeloid leukemia cell proliferation. These combination protocols inhibited cell growth and induced apoptosis as well as differentiation in chronic myeloid leukemia cell lines. In addition, peroxisome proliferator-activated receptors ligands increased imatinib uptake by upregulating the expression of human organic cation transporter 1. Taken together, peroxisome proliferator-activated receptors ligands are currently being considered as novel promising therapeutic candidates for chronic myeloid leukemia treatment, because they can synergistically enhance the efficacy of imatinib. In this article, we reviewed the potential of peroxisome proliferator-activated receptors ligands for use in chronic myeloid leukemia treatment. The mechanism of action of these therapeutics modalities are also presented in detail. © 2016 John Wiley & Sons A/S.

Curcumin as a potential therapeutic candidate for Helicobacter pylori associated diseases

Science.gov (United States)

Sarkar, Avijit; De, Ronita; Mukhopadhyay, Asish K

2016-01-01

Curcumin, a yellow pigment and principal polyphenolic Curcuminoid obtained from the turmeric rhizome Curcuma longa, is commonly used as a food-coloring agent. Studies suggest that curcumin has a wide range of beneficial properties e.g., anti-inflammatory, anti-oxidant, anti-cancer, anti-proliferative, anti-fungal and anti-microbial. These pleiotropic activities prompted several research groups to elucidate the role of curcumin in Helicobacter pylori (H. pylori) infection. This is the first review with this heading where we discussed regarding the role of curcumin as an anti-H. pylori agent along with its potential in other gastrointestinal diseases. Based on several in vitro, early cell culture, animal research and few pre-clinical trials, curcumin projected as a potential therapeutic candidate against H. pylori mediated gastric pathogenesis. This review sheds light on the anti-H. pylori effects of curcumin in different models with meticulous emphasis on its anti-oxidant, anti-inflammatory and anti-carcinogenic effects as well as some critical signaling and effecter molecules. Remarkably, non-toxic molecule curcumin fulfills the characteristics for an ideal chemopreventive agent against H. pylori mediated gastric carcinogenesis but the foremost challenge is to obtain the optimum therapeutic levels of curcumin, due to its low solubility and poor bioavailability. Further, we have discussed about the possibilities for improving its efficacy and bioavailability. Lastly, we concluded with the anticipation that in near future curcumin may be used to develop a therapeutic drug against H. pylori mediated gastric ailments through improved formulation or delivery systems, facilitating its enhanced absorption and cellular uptake. PMID:26973412

Switchgrass a valuable biomass crop for energy

CERN Document Server

2012-01-01

The demand of renewable energies is growing steadily both from policy and from industry which seeks environmentally friendly feed stocks. The recent policies enacted by the EU, USA and other industrialized countries foresee an increased interest in the cultivation of energy crops; there is clear evidence that switchgrass is one of the most promising biomass crop for energy production and bio-based economy and compounds. Switchgrass: A Valuable Biomass Crop for Energy provides a comprehensive guide to  switchgrass in terms of agricultural practices, potential use and markets, and environmental and social benefits. Considering this potential energy source from its biology, breed and crop physiology to its growth and management to the economical, social and environmental impacts, Switchgrass: A Valuable Biomass Crop for Energy brings together chapters from a range of experts in the field, including a foreword from Kenneth P. Vogel, to collect and present the environmental benefits and characteristics of this a ...

Technological advancements for the detection of and protection against biological and chemical warfare agents.

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Eubanks, Lisa M; Dickerson, Tobin J; Janda, Kim D

2007-03-01

There is a growing need for technological advancements to combat agents of chemical and biological warfare, particularly in the context of the deliberate use of a chemical and/or biological warfare agent by a terrorist organization. In this tutorial review, we describe methods that have been developed both for the specific detection of biological and chemical warfare agents in a field setting, as well as potential therapeutic approaches for treating exposure to these toxic species. In particular, nerve agents are described as a typical chemical warfare agent, and the two potent biothreat agents, anthrax and botulinum neurotoxin, are used as illustrative examples of potent weapons for which countermeasures are urgently needed.

Acinetobacter pneumonia: Is the outcome different from the pneumonias caused by other agents

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Edis Ebru

2010-01-01

Full Text Available Background : The principal aim of the present study was to determine whether Acinetobacter spp. pneumonia differs from hospital-acquired pneumonias (HAPs caused by other agents with respect to therapeutic success and survival rate. METHODS : This study includes 140 adult patients diagnosed with HAPs caused by identified etiologic agents between March 2005 and February 2006. These patients were divided into two groups according to the agent responsible for their infection (Acinetobacter spp. [n = 63] or non-Acinetobacter spp. [n = 77]. The groups were compared in terms of risk factors, therapeutic success and six-week survival rates. Results : Previous antibiotic use and the risk of aspiration were independent factors responsible for the development of Acinetobacter spp. pneumonia. Hypoalbuminemia, steroid use and the use of a mechanical ventilator were determined to be mortality-associated independent risk factors for Acinetobacter spp. pneumonia. The clinical success rate at the end of therapy was 41.6% and, at the sixth week, the survival rate was 35% among patients in whom Acinetobacter spp. was the causative agent. Conversely, in the control group, these values were 43 and 32%, respectively ( P > 0.05. We found that the use of the appropriate antibiotics for the treatment of Acinetobacter spp. pneumonia was an important factor in survival ( P < 0.001. Conclusion : The outcomes of Acinetobacter spp. pneumonia do not differ from HAPs associated with non-Acinetobacter spp. in terms of therapeutic success and survival rates.

Valuable human capital: the aging health care worker.

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Collins, Sandra K; Collins, Kevin S

2006-01-01

With the workforce growing older and the supply of younger workers diminishing, it is critical for health care managers to understand the factors necessary to capitalize on their vintage employees. Retaining this segment of the workforce has a multitude of benefits including the preservation of valuable intellectual capital, which is necessary to ensure that health care organizations maintain their competitive advantage in the consumer-driven market. Retaining the aging employee is possible if health care managers learn the motivators and training differences associated with this category of the workforce. These employees should be considered a valuable resource of human capital because without their extensive expertise, intense loyalty and work ethic, and superior customer service skills, health care organizations could suffer severe economic repercussions in the near future.

Emerging protein targets for metal-based pharmaceutical agents : An update

NARCIS (Netherlands)

de Almeida, Andreia; Oliveira, Bruno L.; Correia, Joao D. G.; Soveral, Graca; Casini, Angela

2013-01-01

The peculiar chemical properties of metal-based drugs impart innovative pharmacological profiles to this class of therapeutic and diagnostic agents, most likely in relation to novel molecular mechanisms still poorly understood. However, inorganic drugs have been scarcely considered for medicinal

Future prospects of therapeutic clinical trials in acute myeloid leukemia

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Khan, Maliha; Mansoor, Armaghan-e-Rehman; Kadia, Tapan M

2017-01-01

Acute myeloid leukemia (AML) is a markedly heterogeneous hematological malignancy that is most commonly seen in elderly adults. The response to current therapies to AML is quite variable, and very few new drugs have been recently approved for use in AML. This review aims to discuss the issues with current trial design for AML therapies, including trial end points, patient enrollment, cost of drug discovery and patient heterogeneity. We also discuss the future directions in AML therapeutics, including intensification of conventional therapy and new drug delivery mechanisms; targeted agents, including epigenetic therapies, cell cycle regulators, hypomethylating agents and chimeric antigen receptor T-cell therapy; and detail of the possible agents that may be incorporated into the treatment of AML in the future. PMID:27771959

Engineering large-scale agent-based systems with consensus

Science.gov (United States)

Bokma, A.; Slade, A.; Kerridge, S.; Johnson, K.

1994-01-01

The paper presents the consensus method for the development of large-scale agent-based systems. Systems can be developed as networks of knowledge based agents (KBA) which engage in a collaborative problem solving effort. The method provides a comprehensive and integrated approach to the development of this type of system. This includes a systematic analysis of user requirements as well as a structured approach to generating a system design which exhibits the desired functionality. There is a direct correspondence between system requirements and design components. The benefits of this approach are that requirements are traceable into design components and code thus facilitating verification. The use of the consensus method with two major test applications showed it to be successful and also provided valuable insight into problems typically associated with the development of large systems.

Heterocyclic N-Oxides – An Emerging Class of Therapeutic Agents

Science.gov (United States)

Mfuh, Adelphe M.; Larionov, Oleg V.

2016-01-01

Heterocyclic N-oxides have emerged as potent compounds with anticancer, antibacterial, antihypertensive, antiparasitic, anti-HIV, anti-inflammatory, herbicidal, neuroprotective, and procognitive activities. The N-oxide motif has been successfully employed in a number of recent drug development projects. This review surveys the emergence of this scaffold in the mainstream medicinal chemistry with a focus on the discovery of the heterocyclic N-oxide drugs, N-oxide-specific mechanisms of action, drug-receptor interactions and synthetic avenues to these compounds. As the first review on this subject that covers the developments since 1950s to date, it is expected that it will inspire wider implementation of the heterocyclic N-oxide motif in the rational design of new medicinal agents. PMID:26087764

Energy threat to valuable land

International Nuclear Information System (INIS)

Caufield, C.

1982-01-01

Having considered the varying estimates of future UK energy requirements which have been made, the impact on the environment arising from the use of valuable sites for energy production is examined. It is shown that energy installations of all kinds clash with areas of natural beauty or ecological importance. As an example, a recent investigation of potential sites for nuclear power stations found that most of them were on or next to sites of special scientific interest, and other areas officially designated to be regarded as special or to be protected in some way. (U.K.)

Let the sun shine in: mechanisms and potential for therapeutics in skin photodamage.

Science.gov (United States)

Wondrak, Georg T

2007-05-01

Photoaging and photocarcinogenesis are the two Janus faces of skin photodamage. Reactivity-based design of prototype agents that antagonize, modulate and reverse the chemistry of skin photodamage holds promise in delivering unprecedented therapeutic benefit. In contrast to structure-based approaches that use selective ligands to target macromolecules, reactivity-based drug discovery uses chemical reagents as therapeutics to target reactive chemical species as key mediators of skin photo-oxidative stress. The following classes of reactivity-based agents for skin photoprotection can be distinguished based on their mechanism of action: direct antagonists of photo-oxidative stress (sunscreens, quenchers of photo-excited states, antioxidants, redox modulators and glycation inhibitors) and skin photo-adaptation inducers (nuclear factor erythroid 2-related factor 2 [Nrf2] activators, heat-shock response inducers and metallothionein inducers).

Challenges in the development of magnetic particles for therapeutic applications.

Science.gov (United States)

Barry, Stephen E

2008-09-01

Certain iron-based particle formulations have useful magnetic properties that, when combined with low toxicity and desirable pharmacokinetics, encourage their development for therapeutic applications. This mini-review begins with background information on magnetic particle use as MRI contrast agents and the influence of material size on pharmacokinetics and tissue penetration. Therapeutic investigations, including (1) the loading of bioactive materials, (2) the use of stationary, high-gradient (HG) magnetic fields to concentrate magnetic particles in tissues or to separate material bound to the particles from the body, and (3) the application of high power alternating magnetic fields (AMF) to generate heat in magnetic particles for hyperthermic therapeutic applications are then surveyed. Attention is directed mainly to cancer treatment, as selective distribution to tumors is well-suited to particulate approaches and has been a focus of most development efforts. While magnetic particles have been explored for several decades, their use in therapeutic products remains minimal; a discussion of future directions and potential ways to better leverage magnetic properties and to integrate their use into therapeutic regimens is discussed.

BET inhibitors in metastatic prostate cancer: therapeutic implications and rational drug combinations.

Science.gov (United States)

Markowski, Mark C; De Marzo, Angelo M; Antonarakis, Emmanuel S

2017-12-01

The bromodomain and extra-terminal (BET) family of proteins are epigenetic readers of acetylated histones regulating a vast network of protein expression across many different cancers. Therapeutic targeting of BET is an attractive area of clinical development for metastatic castration-resistant prostate cancer (mCRPC), particularly due to its putative effect on c-MYC expression and its interaction with the androgen receptor (AR). Areas covered: We speculate that a combination approach using inhibitors of BET proteins (BETi) with other targeted therapies may be required to improve the therapeutic index of BET inhibition in the management of prostate cancer. Preclinical data has identified several molecular targets that may enhance the effect of BET inhibition in the clinic. This review will summarize the known preclinical data implicating BET as an important therapeutic target in advanced prostate cancer, highlight the ongoing clinical trials targeting this protein family, and speculate on rationale combination strategies using BETi together with other agents in prostate cancer. A literature search using Pubmed was performed for this review. Expert opinion: Use of BETi in the treatment of mCRPC patients may require the addition of a second novel agent.

Preparation, Surface Properties, and Therapeutic Applications of Gold Nanoparticles in Biomedicine.

Science.gov (United States)

Panahi, Yunes; Mohammadhosseini, Majid; Nejati-Koshki, Kazem; Abadi, Azam Jafari Najaf; Moafi, Hadi Fallah; Akbarzadeh, Abolfazl; Farshbaf, Masoud

2017-02-01

Gold nanoparticles (AuNPs) due to their unique properties and manifold surface functionalities have been applied in bio-nanotechnology. The application of GNPs in recent medical and biological research is very extensive. Especially it involves applications such as detection and photothermalysis of microorganisms and cancer stem cells, biosensors; optical bio-imaging and observing of cells and these nanostructures also serve as practical platforms for therapeutic agents. In this review we studied all therapeutic applications of gold nanoparticles in biomedicine, synthesis methods, and surface properties. © Georg Thieme Verlag KG Stuttgart · New York.

Molecular Targets in Alzheimer’s Disease: From Pathogenesis to Therapeutics

Directory of Open Access Journals (Sweden)

Xuan Cheng

2015-01-01

Full Text Available Alzheimer’s disease (AD is characterized by progressive cognitive decline usually beginning with impairment in the ability to form recent memories. Nonavailability of definitive therapeutic strategy urges developing pharmacological targets based on cell signaling pathways. A great revival of interest in nutraceuticals and adjuvant therapy has been put forward. Tea polyphenols for their multiple health benefits have also attracted the attention of researchers. Tea catechins showed enough potentiality to be used in future as therapeutic targets to provide neuroprotection against AD. This review attempts to present a concise map of different receptor signaling pathways associated with AD with an insight into drug designing based on the proposed signaling pathways, molecular mechanistic details of AD pathogenesis, and a scientific rationale for using tea polyphenols as proposed therapeutic agents in AD.

Fecal Microbiota-based Therapeutics for Recurrent Clostridium difficile Infection, Ulcerative Colitis and Obesity

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Christian Carlucci

2016-11-01

Full Text Available The human gut microbiome is a complex ecosystem of fundamental importance to human health. Our increased understanding of gut microbial composition and functional interactions in health and disease states has spurred research efforts examining the gut microbiome as a valuable target for therapeutic intervention. This review provides updated insight into the state of the gut microbiome in recurrent Clostridium difficile infection (CDI, ulcerative colitis (UC, and obesity while addressing the rationale for the modulation of the gut microbiome using fecal microbiota transplant (FMT-based therapies. Current microbiome-based therapeutics in pre-clinical or clinical development are discussed. We end by putting this within the context of the current regulatory framework surrounding FMT and related therapies.

Decorporation of metal ions by chelating agents

International Nuclear Information System (INIS)

Koenig, T.

1978-01-01

Simple model designs to simulate the effect of therapeutical chelating agents on the behaviour of metals in mammal organisms with and without excretion have been derived and analytical solutions given for the corresponding differential equations. The possibilities of these models in the short-term description of plasma kinetics of various metals, the competition of the therapeutical ligands with proteins for the metal and of the metabolism of chelating agents were tested and the properties applying extreme conceivable parameters were analyzed. The simple models were successsively expanded in logical sequence, so that it was possible to qualitatively well describe over a long period of time, the metallic kinetics in plasma, organs and urine, the retention of the ligands and their effect on the metal excretion. Two suggestions were given to describe the so-called after-effect, an increased excretion of the metal at times when the ligand is almost completely excreted and their different behaviour after injecting the metal chelate is given. Calculations on the therapy with several ligand data as well as on dose fractionation are described resting on the ratios in the plutonium-239 chosen model parameters and the determining mechanisms analyzed. (orig./MG) [de

Molecular Characterization of Gastric Carcinoma: Therapeutic Implications for Biomarkers and Targets

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Lionel Kankeu Fonkoua

2018-03-01

Full Text Available Palliative chemotherapy is the mainstay of treatment of advanced gastric carcinoma (GC. Monoclonal antibodies including trastuzumab, ramucirumab, and pembrolizumab have been shown to provide additional benefits. However, the clinical outcomes are often unpredictable and they can vary widely among patients. Currently, no biomarker is available for predicting treatment response in the individual patient except human epidermal growth factor receptor 2 (HER2 amplification and programmed death-ligand 1 (PD-L1 expression for effectiveness of trastuzumab and pembrolizumab, respectively. Multi-platform molecular analysis of cancer, including GC, may help identify predictive biomarkers to guide selection of therapeutic agents. Molecular classification of GC by The Cancer Genome Atlas Research Network and the Asian Cancer Research Group is expected to identify therapeutic targets and predictive biomarkers. Complementary to molecular characterization of GC is molecular profiling by expression analysis and genomic sequencing of tumor DNA. Initial analysis of patients with gastroesophageal carcinoma demonstrates that the ratio of progression-free survival (PFS on molecular profile (MP-based treatment to PFS on treatment prior to molecular profiling exceeds 1.3, suggesting the potential value of MP in guiding selection of individualized therapy. Future strategies aiming to integrate molecular classification and profiling of tumors with therapeutic agents for achieving the goal of personalized treatment of GC are indicated.

Molecular Characterization of Gastric Carcinoma: Therapeutic Implications for Biomarkers and Targets.

Science.gov (United States)

Kankeu Fonkoua, Lionel; Yee, Nelson S

2018-03-09

Palliative chemotherapy is the mainstay of treatment of advanced gastric carcinoma (GC). Monoclonal antibodies including trastuzumab, ramucirumab, and pembrolizumab have been shown to provide additional benefits. However, the clinical outcomes are often unpredictable and they can vary widely among patients. Currently, no biomarker is available for predicting treatment response in the individual patient except human epidermal growth factor receptor 2 (HER2) amplification and programmed death-ligand 1 (PD-L1) expression for effectiveness of trastuzumab and pembrolizumab, respectively. Multi-platform molecular analysis of cancer, including GC, may help identify predictive biomarkers to guide selection of therapeutic agents. Molecular classification of GC by The Cancer Genome Atlas Research Network and the Asian Cancer Research Group is expected to identify therapeutic targets and predictive biomarkers. Complementary to molecular characterization of GC is molecular profiling by expression analysis and genomic sequencing of tumor DNA. Initial analysis of patients with gastroesophageal carcinoma demonstrates that the ratio of progression-free survival (PFS) on molecular profile (MP)-based treatment to PFS on treatment prior to molecular profiling exceeds 1.3, suggesting the potential value of MP in guiding selection of individualized therapy. Future strategies aiming to integrate molecular classification and profiling of tumors with therapeutic agents for achieving the goal of personalized treatment of GC are indicated.

Curcumin as potential therapeutic natural product: a nanobiotechnological perspective.

Science.gov (United States)

Shome, Soumitra; Talukdar, Anupam Das; Choudhury, Manabendra Dutta; Bhattacharya, Mrinal Kanti; Upadhyaya, Hrishikesh

2016-12-01

Nanotechnology-based drug delivery systems can resolve the poor bioavailability issue allied with curcumin. The therapeutic potential of curcumin can be enhanced by making nanocomposite preparation of curcumin with metal oxide nanoparticles, poly lactic-co-glycolic acid (PLGA) nanoparticles and solid lipid nanoparticles that increases its bioavailability in the tissue. Curcumin has manifold therapeutic effects which include antidiabetic, antihypertensive, anticancer, anti-inflammatory and antimicrobial properties. Curcumin can inhibit diabetes, heavy metal and stress-induced hypertension with its antioxidant, chelating and inhibitory effects on the pathways that lead to hypertension. Curcumin is an anticancer agent that can prevent abnormal cell proliferation. Nanocurcumin is an improved form of curcumin with enhanced therapeutic properties due to improved delivery to the diseased tissue, better internalization and reduced systemic elimination. Curcumin has multiple pharmacologic effects, but its poor bioavailability reduces its therapeutic effects. By conjugating curcumin to metal oxide nanoparticles or encapsulation in lipid nanoparticles, dendrimers, nanogels and polymeric nanoparticles, the water solubility and bioavailability of curcumin can be improved and thus increase its pharmacological effectiveness. © 2016 Royal Pharmaceutical Society.

Injectable agents affecting subcutaneous fats.

Science.gov (United States)

Chen, David Lk; Cohen, Joel L; Green, Jeremy B

2015-09-01

Mesotherapy is an intradermal or subcutaneous injection of therapeutic agents to induce local effects, and was pioneered in Europe during the 1950s. For the past 2 decades, there has been significant interest in the use of mesotherapy for minimally invasive local fat contouring. Based on the theorized lipolytic effects of the agent phosphatidylcholine, initial attempts involved its injection into subcutaneous tissue. With further studies, however, it became apparent that the activity attributed to phosphatidylcholine mesotherapy was due to the adipolytic effects of deoxycholate, a detergent used to solubilize phosphatidylcholine. Since then, clinical trials have surfaced that demonstrate the efficacy of a proprietary formulation of deoxycholate for local fat contouring. Current trials on mesotherapy with salmeterol, a b-adrenergic agonist and lipolysis stimulator, are underway-with promising preliminary results as well. ©2015 Frontline Medical Communications.

Development of radiolanthanide labeled porphyrin complexes as possible therapeutic agents in beast carcinoma xenografts

Energy Technology Data Exchange (ETDEWEB)

Vahidfar, Nasim; Aghanejad, Ayuob; Beiki, Davood; Khalaj, Ali [Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of). Faculty of Pharmacy; Jalilian, Amir R.; Fazaeli, Yousef; Bahrami-Samani, Ali; Alirezapour, Behrooz; Erfani, Mostafa [Nuclear Science and Technology Research Institute, Tehran (Iran, Islamic Republic of). Radiopharmacy Research Group

2014-10-01

Radiolabeled porphyrins are potential tumor avid radiopharmaceuticals because of their behaviour in the human body, ability to complex various radionuclides, water solubility, low toxicity etc., in this work radio ytterbium/samarium porphyrin complexes have been developed. {sup 175}Yb and {sup 153}Sm labeled 5,10,15,20-tetrakis(3,4-dimethoxyphenyl) porphyrins ([{sup 175}Yb]-TDMPP/[{sup 153}Sm]-TDMPP) were prepared using 5,10,15,20-tetrakis(3,4-dimethoxyphenyl) porphyrin (H{sub 2}TDMPP) and [{sup 175}Yb]YbCl{sub 3} or [{sup 153}Sm]SmCl{sub 3} in 12-24 h at 60 C. Stability of the complexes were checked in final formulation and human serum for 24 h, followed by partition coefficient determination and biodistribution studies in wild type and breast carcinoma-bearing mice. The radiocomplexes were obtained with acceptable radiochemical purity (> 95% (paper chromatography) and > 96% (HPLC) for [{sup 175}Yb]-TDMPP and > 97% (paper chromatography) and > 98% (HPLC) for [{sup 153}Sm]-TDMPP) with specific activities of 12-15 GBq/mmol and 278 GBq/mmol at the end of bombardment for [{sup 175}Yb]-TDMPP and [{sup 153}Sm]-TDMPP respectively. The partition coefficients were determined for [{sup 175}Yb]-TDMPP and [{sup 153}Sm]-TDMPP (log P = 0.63 and log P = 0.96 respectively). The [{sup 175}Yb]-TDMPP complex is mostly washed out from the circulation through kidneys. Liver and spleen also demonstrated significant activity uptake in 72 h post injection. Also [{sup 153}Sm]-TDMPP, is mostly washed out from the circulation through kidneys, however lungs are the major accumulation sites. The [{sup 153}Sm]-TDMPP complex demonstrated significant targeted uptake in breast carcinoma xenografts with tumor: blood ratios of 10.67, 10.47 and 19.01 in 24, 48 and 72 h respectively. Also interesting tumor: kidney/liver ratios were obtained. {sup 153}Sm-TDMPP properties suggest an efficient tumor targeting agent with high tumor-avidity. Further investigation on the therapeutic properties must be

Prevalence of acid-reducing agents (ARA) in cancer populations and ARA drug-drug interaction potential for molecular targeted agents in clinical development.

Science.gov (United States)

Smelick, Gillian S; Heffron, Timothy P; Chu, Laura; Dean, Brian; West, David A; Duvall, Scott L; Lum, Bert L; Budha, Nageshwar; Holden, Scott N; Benet, Leslie Z; Frymoyer, Adam; Dresser, Mark J; Ware, Joseph A

2013-11-04

Acid-reducing agents (ARAs) are the most commonly prescribed medications in North America and Western Europe. There are currently no data describing the prevalence of their use among cancer patients. However, this is a paramount question due to the potential for significant drug-drug interactions (DDIs) between ARAs, most commonly proton pump inhibitors (PPIs), and orally administered cancer therapeutics that display pH-dependent solubility, which may lead to decreased drug absorption and decreased therapeutic benefit. Of recently approved orally administered cancer therapeutics, >50% are characterized as having pH-dependent solubility, but there are currently no data describing the potential for this ARA-DDI liability among targeted agents currently in clinical development. The objectives of this study were to (1) determine the prevalence of ARA use among different cancer populations and (2) investigate the prevalence of orally administered cancer therapeutics currently in development that may be liable for an ARA-DDI. To address the question of ARA use among cancer patients, a retrospective cross-sectional analysis was performed using two large healthcare databases: Thomson Reuters MarketScan (N = 1,776,443) and the U.S. Department of Veterans Affairs (VA, N = 1,171,833). Among all cancer patients, the total prevalence proportion of ARA use (no. of cancer patients receiving an ARA/total no. of cancer patients) was 20% and 33% for the MarketScan and VA databases, respectively. PPIs were the most commonly prescribed agent, comprising 79% and 65% of all cancer patients receiving a prescription for an ARA (no. of cancer patients receiving a PPI /no. of cancer patients receiving an ARA) for the MarketScan and VA databases, respectively. To estimate the ARA-DDI liability of orally administered molecular targeted cancer therapeutics currently in development, two publicly available databases, (1) Kinase SARfari and (2) canSAR, were examined. For those orally administered

Contrast-enhanced peripheral MRA. Technique and contrast agents

International Nuclear Information System (INIS)

Nielsen, Yousef W.; Thomsen, Henrik S.

2012-01-01

In the last decade contrast-enhanced magnetic resonance angiography (CE-MRA) has gained wide acceptance as a valuable tool in the diagnostic work-up of patients with peripheral arterial disease. This review presents current concepts in peripheral CE-MRA with emphasis on MRI technique and contrast agents. Peripheral CE-MRA is defined as an MR angiogram of the arteries from the aortic bifurcation to the feet. Advantages of CE-MRA include minimal invasiveness and lack of ionizing radiation. The basic technique employed for peripheral CE-MRA is the bolus-chase method. With this method a paramagnetic MRI contrast agent is injected intravenously and T1-weighted images are acquired in the subsequent arterial first-pass phase. In order to achieve high quality MR angiograms without interfering venous contamination or artifacts, a number of factors need to be taken into account. This includes magnetic field strength of the MRI system, receiver coil configuration, use of parallel imaging, contrast bolus timing technique, and k-space filling strategies. Furthermore, it is possible to optimize peripheral CE-MRA using venous compression techniques, hybrid scan protocols, time-resolved imaging, and steady-state MRA. Gadolinium(Gd)-based contrast agents are used for CE-MRA of the peripheral arteries. Extracellular Gd agents have a pharmacokinetic profile similar to iodinated contrast media. Accordingly, these agents are employed for first-pass MRA. Blood-pool Gd-based agents are characterized by prolonged intravascular stay, due to macromolecular structure or protein binding. These agents can be used for first-pass, as well as steady-state MRA. Some Gd-based contrast agents with low thermodynamic stability have been linked to development of nephrogenic systemic fibrosis in patients with severe renal insufficiency. Using optimized technique and a stable MRI contrast agent, peripheral CE-MRA is a safe procedure with diagnostic accuracy close to that of conventional catheter X

Preparing valuable hydrocarbons by hydrogenation

Energy Technology Data Exchange (ETDEWEB)

Pier, M

1930-08-22

A process is described for the preparation of valuable hydrocarbons by treatment of carbonaceous materials, like coal, tars, minerals oils, and their distillation and conversion products, and for refining of liquid hydrocarbon mixture obtained at raised temperature and under pressure, preferably in the presence of catalysts, by the use of hydrogen-containing gases, purified and obtained by distilling solid combustibles, characterized by the purification of the hydrogen-containing gases being accomplished for the purpose of practically complete removal of the oxygen by heating at ordinary or higher pressure in the presence of a catalyst containing silver and oxides of metals of group VI of the periodic system.

Discriminating between absorption and scattering coefficients in optical characterisation measurements on gold nanoparticle based photoacoustic contrast agents

NARCIS (Netherlands)

Ungureanu, C.; Manohar, Srirang; van Leeuwen, Ton; Amelink, A.; Sterenborg, Henricus J.C.M.; Oraevsky, Alexander A.; Wang, Lihong V.

2009-01-01

Plasmon resonant nanoparticles such as gold nanoshells and gold nanorods can be tuned to possess sharp interaction peaks in the near-infrared wavelength regions. These have great importance as contrast agents in photoacoustic imaging and as photothermal agents for therapeutic applications due to

Usefulness of radiatively obtained acrylamide polymers for production of drug forms with controlled release of the therapeutic component

International Nuclear Information System (INIS)

Mosiniak, T.; Switek, W.

1988-01-01

Using 60 Co gamma radiation as a factor initiating polymerization and cross-linking of polymers, polyacrylamide matrices were formed with the following therapeutic agents: aspirin, amidopyrin, sodium salicylate. Gamma radiation doses ranged from 3.5 to 22.5 kGy, dose rate was 0.138 Gy x s -1 . Kinetics of the therapeutic agent release from the matrix polymers was determined by measurement of per cent of the drug release in the course of time and calculations of release rate constants. The preparations containing slowly released drugs were obtained. 12 figs., 2 tabs., 11 refs. (author)

New therapeutic targets in idiopathic pulmonary fibrosis. Aiming to rein in runaway wound-healing responses.

Science.gov (United States)

Ahluwalia, Neil; Shea, Barry S; Tager, Andrew M

2014-10-15

Idiopathic pulmonary fibrosis (IPF) is a devastating disease, with a median survival as short as 3 years from the time of diagnosis and no pharmacological therapies yet approved by the U.S. Food and Drug Administration. To address the great unmet need for effective IPF therapy, a number of new drugs have recently been, or are now being, evaluated in clinical trials. The rationales for most of these therapeutic candidates are based on the current paradigm of IPF pathogenesis, in which recurrent injury to the alveolar epithelium is believed to drive aberrant wound healing responses, resulting in fibrosis rather than repair. Here we discuss drugs in recently completed or currently ongoing phase II and III IPF clinical trials in the context of their putative mechanisms of action and the aberrant repair processes they are believed to target: innate immune activation and polarization, fibroblast accumulation and myofibroblast differentiation, or extracellular matrix deposition and stiffening. Placed in this context, the positive results of recently completed trials of pirfenidone and nintedanib, and results that will come from ongoing trials of other agents, should provide valuable insights into the still-enigmatic pathogenesis of this disease, in addition to providing benefits to patients with IPF.

New Therapeutic Targets in Idiopathic Pulmonary Fibrosis. Aiming to Rein in Runaway Wound-Healing Responses

Science.gov (United States)

Ahluwalia, Neil; Shea, Barry S.

2014-01-01

Idiopathic pulmonary fibrosis (IPF) is a devastating disease, with a median survival as short as 3 years from the time of diagnosis and no pharmacological therapies yet approved by the U.S. Food and Drug Administration. To address the great unmet need for effective IPF therapy, a number of new drugs have recently been, or are now being, evaluated in clinical trials. The rationales for most of these therapeutic candidates are based on the current paradigm of IPF pathogenesis, in which recurrent injury to the alveolar epithelium is believed to drive aberrant wound healing responses, resulting in fibrosis rather than repair. Here we discuss drugs in recently completed or currently ongoing phase II and III IPF clinical trials in the context of their putative mechanisms of action and the aberrant repair processes they are believed to target: innate immune activation and polarization, fibroblast accumulation and myofibroblast differentiation, or extracellular matrix deposition and stiffening. Placed in this context, the positive results of recently completed trials of pirfenidone and nintedanib, and results that will come from ongoing trials of other agents, should provide valuable insights into the still-enigmatic pathogenesis of this disease, in addition to providing benefits to patients with IPF. PMID:25090037

Antibody-Based Agents in the Management of Antibiotic-Resistant Staphylococcus aureus Diseases

Science.gov (United States)

Speziale, Pietro; Rindi, Simonetta

2018-01-01

Staphylococcus aureus is a human pathogen that can cause a wide spectrum of diseases, including sepsis, pneumonia, arthritis, and endocarditis. Ineffective treatment of a number of staphylococcal infections with antibiotics is due to the development and spread of antibiotic-resistant strains following decades of antibiotic usage. This has generated renewed interest within the scientific community in alternative therapeutic agents, such as anti-S. aureus antibodies. Although the role of antibodies in the management of S. aureus diseases is controversial, the success of this pathogen in neutralizing humoral immunity clearly indicates that antibodies offer the host extensive protection. In this review, we report an update on efforts to develop antibody-based agents, particularly monoclonal antibodies, and their therapeutic potential in the passive immunization approach to the treatment and prevention of S. aureus infections. PMID:29533985

3D culture of Her2+ breast cancer cells promotes AKT to MAPK switching and a loss of therapeutic response.

Science.gov (United States)

Gangadhara, Sharath; Smith, Chris; Barrett-Lee, Peter; Hiscox, Stephen

2016-06-01

The Her2 receptor is overexpressed in up to 25 % of breast cancers and is associated with a poor prognosis. Around half of Her2+ breast cancers also express the estrogen receptor and treatment for such tumours can involve both endocrine and Her2-targeted therapies. However, despite preclinical data supporting the effectiveness of these agents, responses can vary widely in the clinical setting. In light of the increasing evidence pointing to the interplay between the tumour and its extracellular microenvironment as a significant determinant of therapeutic sensitivity and response here we investigated the impact of 3D matrix culture of breast cancer cells on their therapeutic sensitivity. A 3D Matrigel-based culture system was established and optimized for the growth of ER+/Her2+ breast cancer cell models. Growth of cells in response to trastuzumab and endocrine agents in 3D culture versus routine monolayer culture were assessed using cell counting and Ki67 staining. Endogenous and trastuzumab-modulated signalling pathway activity in 2D and 3D cultures were assessed using Western blotting. Breast cancer cells in 3D culture displayed an attenuated response to both endocrine agents and trastuzumab compared with cells cultured in traditional 2D monolayers. Underlying this phenomenon was an apparent matrix-induced shift from AKT to MAPK signalling; consequently, suppression of MAPK in 3D cultures restores therapeutic response. These data suggest that breast cancer cells in 3D culture display a reduced sensitivity to therapeutic agents which may be mediated by internal MAPK-mediated signalling. Targeting of adaptive pathways that maintain growth in 3D culture may represent an effective strategy to improve therapeutic response clinically.

Engineering a predatory bacterium as a proficient killer agent for intracellular bio-products recovery

DEFF Research Database (Denmark)

Martinez, Virginia; Herencias, Cristina; Jurkevitch, Edouard

2016-01-01

This work examines the potential of the predatory bacterium Bdellovibrio bacteriovorus HD100, an obligate predator of other Gram-negative bacteria, as an external cell-lytic agent for recovering valuable intracellular bio-products produced by prey cultures. The bio-product targets to be recovered......% of that accumulated by the prey bacteria, even at high biomass concentrations. This innovative downstream process highlights how B. bacteriovorus can be used as a novel, biological lytic agent for the inexpensive, industrial scale recovery of intracellular products from different Gram-negative prey cultures....

Old and new challenges in Parkinson's disease therapeutics.

Science.gov (United States)

Pires, Ana O; Teixeira, F G; Mendes-Pinheiro, B; Serra, Sofia C; Sousa, Nuno; Salgado, António J

2017-09-01

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons and/or loss od neuronal projections, in several dopaminergic networks. Current treatments for idiopathic PD rely mainly on the use of pharmacologic agents to improve motor symptomatology of PD patients. Nevertheless, so far PD remains an incurable disease. Therefore, it is of utmost importance to establish new therapeutic strategies for PD treatment. Over the last 20 years, several molecular, gene and cell/stem-cell therapeutic approaches have been developed with the aim of counteracting or retarding PD progression. The scope of this review is to provide an overview of PD related therapies and major breakthroughs achieved within this field. In order to do so, this review will start by focusing on PD characterization and current treatment options covering thereafter molecular, gene and cell/stem cell-based therapies that are currently being studied in animal models of PD or have recently been tested in clinical trials. Among stem cell-based therapies, those using MSCs as possible disease modifying agents for PD therapy and, specifically, the MSCs secretome contribution to meet the clinical challenge of counteracting or retarding PD progression, will be more deeply explored. Copyright © 2017 Elsevier Ltd. All rights reserved.

Interactions of radiation with novel chemotherapeutic agents: Taxanes and nucleoside analogs

International Nuclear Information System (INIS)

Milas, Luka

1997-01-01

The combination of chemotherapeutic agents and radiotherapy is an appealing approach to improving the results of cancer treatment. By their independent action or interactive action chemotherapeutic drugs reduce cell burden in tumors undergoing radiotherapy, thereby increasing the chances of tumor control. In addition, the drugs may spatially cooperate with radiotherapy through their systemic action on metastatic disease. Recently, a number of new chemotherapeutic agents have been introduced for cancer treatment, which in addition have high potential to increase therapeutic ratio of radiotherapy. These agents include taxanes (paclitaxel and docetaxel) and the nucleoside analogs fludarabine and gemcitabine. Paclitaxel is a natural product isolated from the bark of Taxus brevifolia and taxotere is a semisynthetic analogue of paclitaxel prepared from needle extracts of Taxus baccata. By binding to cellular tubulin structures, taxanes interfere with tubulin polymerization and promote microtubule assembly, resulting in accumulation of cells in the radiosensitive G2 and M phases of the cell cycle. In vivo studies have demonstrated two major mechanisms of tumor radioenhancement by taxanes: mitotic arrest and tumor reoxygenation. Fludarabine and gemcitabine inhibit DNA synthesis and the repair of radiation-induced chromosome breaks. The mechanism of their radioenhancing activity include inhibition of repair of radiation induced damage, apoptosis induction and cell cycle synchronization. Because both classes of these agents affect radioresponse of normal dose-limiting tissues much less than that of tumors, they can greatly increase therapeutic ratio of radiotherapy. The objective of this course is to overview the rationale for using these drugs as radioenhancing agents, the experimental findings in preclinical studies, the mechanisms of their interaction, and the clinical application of these agents

Report on the Technical Meeting on Therapeutic Radiopharmaceuticals

International Nuclear Information System (INIS)

2009-01-01

The purpose of the TM was to provide an experts' platform to facilitate exploring the current status and future directions on therapeutic radiopharmaceuticals. The invited talks and presentations in the TM were in the following topics: - Radionuclide Production; - Production and availability of alpha emitters and their radiopharmaceuticals; - Therapeutic radiopharmaceutical chemistry; - Targets and biological evaluation; - Medical physics and dosimetry; - Clinical applications including radioimmunotherapy and clinical needs; - Peptide receptor mediated therapy Panel discussions: - Radionuclide therapy using alpha emitters; - Regulatory challenges with therapeutic radiopharmaceuticals; - International activities in radionuclide therapy. he technical meeting generated a large interest among scientists and physicians working in the field of targeted therapy using radiopharmaceuticals. Participants from both developed and developing MS reported on recent developments on the research work and clinical studies going on in the field and provided their views on the future developments in this field. The unexpected high number of participants and the high number of presentations with exceptional quality underlines the great interest of scientists and professionals in therapeutic applications using radiolabelled drugs / biomolecules. The intensive discussions including panels specified the challenges in the future on developing novel agents and to finally use them for the benefit of patients. The IAEA can play as vital role in streamlining developments and to provide tools to overcome scientific, professional and regulatory challenges in the field of therapeutic radiopharmaceuticals

Report on the Technical Meeting on Therapeutic Radiopharmaceuticals

Energy Technology Data Exchange (ETDEWEB)

NONE

2009-07-01

The purpose of the TM was to provide an experts' platform to facilitate exploring the current status and future directions on therapeutic radiopharmaceuticals. The invited talks and presentations in the TM were in the following topics: - Radionuclide Production; - Production and availability of alpha emitters and their radiopharmaceuticals; - Therapeutic radiopharmaceutical chemistry; - Targets and biological evaluation; - Medical physics and dosimetry; - Clinical applications including radioimmunotherapy and clinical needs; - Peptide receptor mediated therapy Panel discussions: - Radionuclide therapy using alpha emitters; - Regulatory challenges with therapeutic radiopharmaceuticals; - International activities in radionuclide therapy. he technical meeting generated a large interest among scientists and physicians working in the field of targeted therapy using radiopharmaceuticals. Participants from both developed and developing MS reported on recent developments on the research work and clinical studies going on in the field and provided their views on the future developments in this field. The unexpected high number of participants and the high number of presentations with exceptional quality underlines the great interest of scientists and professionals in therapeutic applications using radiolabelled drugs / biomolecules. The intensive discussions including panels specified the challenges in the future on developing novel agents and to finally use them for the benefit of patients. The IAEA can play as vital role in streamlining developments and to provide tools to overcome scientific, professional and regulatory challenges in the field of therapeutic radiopharmaceuticals

Biomedicines—Moving Biologic Agents into Approved Treatment Options

Directory of Open Access Journals (Sweden)

Kenneth Cornetta

2013-03-01

Full Text Available The development of biologic agents for therapeutic purposes, or biomedicines, has seen an active area of research both at the bench and in clinical trials. There is mounting evidence that biologic products can provide effective therapy for diseases that have been unresponsive to traditional pharmacologic approaches. Monoclonal antibody therapy for cancer and rheumatologic diseases has become a well accepted part of disease treatment plans. Gene therapy products have been approved in China and Europe. Bioengineering of new agents capitalizing on microRNA biology, nanoparticle technology, stem cell biology, and an increasing understanding of immunology predict a rich future for product development. [...

Quercetin in Cancer Treatment, Alone or in Combination with Conventional Therapeutics?

Science.gov (United States)

Brito, Ana Filipa; Ribeiro, Marina; Abrantes, Ana Margarida; Pires, Ana Salomé; Teixo, Ricardo Jorge; Tralhão, José Guilherme; Botelho, Maria Filomena

2015-01-01

Cancer is a problem of global importance, since the incidence is increasing worldwide and therapeutic options are generally limited. Thus, it becomes imperative to find new therapeutic targets as well as new molecules with therapeutic potential for tumors. Flavonoids are polyphenolic compounds that may be potential therapeutic agents. Several studies have shown that these compounds have a higher anticancer potential. Among the flavonoids in the human diet, quercetin is one of the most important. In the last decades, several anticancer properties of quercetin have been described, such as cell signaling, pro-apoptotic, anti-proliferative and anti-oxidant effects, growth suppression. In fact, it is now well known that quercetin has diverse biological effects, inhibiting multiple enzymes involved in cell proliferation, as well as, in signal transduction pathways. On the other hand, there are also studies reporting potential synergistic effects when combined quercetin with chemotherapeutic agents or radiotherapy. In fact, several studies which aim to explore the anticancer potential of these combined treatments have already been published, the majority with promising results. Actually it is well known that quercetin can act on the chemosensitization and radiosensitization but also as chemoprotective and radioprotective, protecting normal cells of the side effects that results from chemotherapy and radiotherapy, which obviously provides notable advantages in their use in anticancer treatment. Thus, all these data indicate that quercetin may have a key role in anticancer treatment. In this context, this review is focused on the relationship between flavonoids and cancer, with special emphasis on the role of quercetin.

Degradation product characterization of therapeutic oligonucleotides using liquid chromatography mass spectrometry.

Science.gov (United States)

Elzahar, N M; Magdy, N; El-Kosasy, Amira M; Bartlett, Michael G

2018-05-01

Synthetic antisense phosphorothioate oligonucleotides (PS) have undergone rapid development as novel therapeutic agents. The increasing significance of this class of drugs requires significant investment in the development of quality control methods. The determination of the many degradation pathways of such complex molecules presents a significant challenge. However, an understanding of the potential impurities that may arise is necessary to continue to advance these powerful new therapeutics. In this study, four different antisense oligonucleotides representing several generations of oligonucleotide therapeutic agents were evaluated under various stress conditions (pH, thermal, and oxidative stress) using ion-pairing reversed-phase liquid chromatography tandem mass spectrometry (IP-RPLC-MS/MS) to provide in-depth characterization and identification of the degradation products. The oligonucleotide samples were stressed under different pH values at 45 and 90 °C. The main degradation products were observed to be losses of nucleotide moieties from the 3'- and 5'-terminus, depurination, formation of terminal phosphorothioates, and production of ribose, ribophosphorothioates (Rp), and phosphoribophosphorothioates (pRp). Moreover, the effects of different concentrations of hydrogen peroxide were studied resulting in primarily extensive desulfurization and subsequent oxidation of the phosphorothioate linkage to produce the corresponding phosphodiester. The reaction kinetics for the degradation of the oligonucleotides under the different stress conditions were studied and were found to follow pseudo-first-order kinetics. Differences in rates exist even for oligonucleotides of similar length but consisting of different sequences. Graphical abstract Identification of degradation products across several generations of oligonucleotide therapeutics using LC-MS.

Will biofilm disassembly agents make it to market?

Science.gov (United States)

Romero, Diego; Kolter, Roberto

2011-07-01

Nearly 12 years after promising results suggested that antibiofilm agents might be developed into novel therapeutics, there are no such products on the market. In our opinion, the reasons for this have been predominantly economic. Recent developments, however, suggest that there could still be emerging opportunities for the developments of such products. Copyright © 2011 Elsevier Ltd. All rights reserved.

Life on the line: the therapeutic potentials of computer-mediated conversation.

Science.gov (United States)

Miller, J K; Gergen, K J

1998-04-01

In what ways are computer networking practices comparable to face-to-face therapy? With the exponential increase in computer-mediated communication and the increasing numbers of people joining topically based computer networks, the potential for grass-roots therapeutic (or antitherapeutic) interchange is greatly augmented. Here we report the results of research into exchanges on an electronic bulletin board devoted to the topic of suicide. Over an 11-month period participants offered each other valuable resources in terms of validation of experience, sympathy, acceptance, and encouragement. They also asked provocative questions and furnished broad-ranging advice. Hostile entries were rare. However, there were few communiques that parallel the change-inducing practices more frequent within many therapeutic settings. In effect, on-line dialogues seemed more sustaining than transforming. Further limits and potentials of on-line communication are explored.

Glyoxylate as a reducing agent for manganese(III) in salen scaffold ...

Indian Academy of Sciences (India)

being the monohydrate gem-diol forms) followed by the slow electron transfer ... stress and implicated as possible therapeutic agents .... excess HGl at different pHs (1.8–2.5) were set aside ...... sion (UGC), New Delhi in terms of a Teacher Fel-.

Therapeutic Symptomatic Strategies in the Parasomnias.

Science.gov (United States)

Manni, Raffaele; Toscano, Gianpaolo; Terzaghi, Michele

2018-06-05

The purpose of this review was to discuss the currently available pharmacologic and non-pharmacologic treatment options for parasomnias. Recent pathophysiological findings about sleep structure in parasomnias helped understanding several drug mechanisms of action. Serotoninergic theory accounts for the effect of serotoninergic drugs. Study about spectral analysis of sleep showed the effect of clonazepam on spectral bands. Cannabinoids proved to be effective in some of parasomnias, as in many other neurological disorders. A series of therapeutic strategies were analyzed and compared. Benzodiazepines, antidepressant drugs, and L-5-hydroxytryptophan may be beneficial in DOA. SSRI and topiramate are effective in SRED. RBD responds to clonazepam, melatonin, and to a lesser extent to dopaminergic and anticholinergic agents. Prazosin and cannabinoids are effective in nightmare disorder. Sleep paralysis may respond to antidepressant agents. Tricyclic antidepressant may be effective in sleep-related hallucinations and exploding head syndrome. Sleep enuresis may be successfully treated with desmopressin, anticholinergic drugs, and imipramine.

Challenges to oligonucleotides-based therapeutics for Duchenne muscular dystrophy

Directory of Open Access Journals (Sweden)

Goyenvalle Aurélie

2011-02-01

Full Text Available Abstract Antisense oligonucleotides are short nucleic acids designed to bind to specific messenger RNAs in order to modulate splicing patterns or inhibit protein translation. As such, they represent promising therapeutic tools for many disorders and have been actively developed for more than 20 years as a form of molecular medicine. Although significant progress has been made in developing these agents as drugs, they are yet not recognized as effective therapeutics and several hurdles remain to be overcome. Within the last few years, however, the prospect of successful oligonucleotides-based therapies has moved a step closer, in particular for Duchenne muscular dystrophy. Clinical trials have recently been conducted for this myopathy, where exon skipping is being used to achieve therapeutic outcomes. In this review, the recent developments and clinical trials using antisense oligonucleotides for Duchenne muscular dystrophy are discussed, with emphasis on the challenges ahead for this type of therapy, especially with regards to delivery and regulatory issues.

[Diagnostic and therapeutic use of human anti-D (Rho) monoclonal antibodies. Evaluation and perspectives].

Science.gov (United States)

Rouger, P; Goossens, D; Champomier, F; Tsikas, G; Liberge, G; Leblanc, J; Richard, C; Bailleul, C; Salmon, C

1985-12-01

Human monoclonal antibodies will be essential in medicine. They are valuable tools for biological diagnosis and therapeutics. Our model, human monoclonal antibodies directed against the Rhesus D antigen can be used for the determination of the Rhesus D phenotype and for the suppression of Rh(D) immunisation in women. These new products require new procedures of preparation, new regulations for the quality controls, which will be discussed in this paper.

Etanercept Inhibits Pro-inflammatory Cytokines Expression in ...

African Journals Online (AJOL)

Tropical Journal of Pharmaceutical Research June 2015; 14 (6): 983-987 ... valuable as a therapeutic agent for the treatment of prosthetic loosening in humans. ... loosening and rheumatoid arthritis, we proposed ..... follow-up. Scand J Rheumatol 2013; 42: 437-444. 12. Papp KA, Tyring S, Lahfa M, Prinz J, Griffiths CE,.

Gelatin sponge particle used as an embolic agent in transcatheter arterial chemoembolization treatment for primary hepatocellular carcinoma: its current situation in research

International Nuclear Information System (INIS)

Ao Jin; Zhang Yuewei; Xu Ke

2011-01-01

Transcatheter arterial chemoembolization (TACE) is one of the most commonly used therapeutic procedures for primary hepatocellular carcinoma (HCC). As an important and easily-available embolic agent, gelatin sponge (Gelfoam) particles have been constantly and widely employed in clinical practice. Various types of embolic agents have been continuously developed and effectively used in TACE for liver cancers. For recent years, great progress has been made in the clinical use of gelatin sponge particles, as the most traditional embolic agent, in the interventional therapeutic field for HCC. This article aims to make a comprehensive review about gelatin sponge. (authors)

Terapia com agentes biológicos na criança e no adolescente Treatment with biologic agents in child and adolescent

Directory of Open Access Journals (Sweden)

Ricardo Maisse Suehiro

2010-06-01

Full Text Available OBJETIVO: Revisar os mecanismos fisiopatológicos e novos alvos terapêuticos, os agentes biológicos disponíveis, principais indicações e a evidência científica atual para o uso de terapias biológicas na população pediátrica. FONTES DE DADOS: Pesquisa na base de dados Medline e SciELO, nas línguas inglesa e portuguesa, entre 2000 e 2009. As palavras-chave usadas foram "agentes biológicos", "crianças" e "adolescentes". SÍNTESE DOS DADOS: Os agentes biológicos são uma importante opção terapêutica para tratar as doenças autoimunes refratárias às terapias convencionais na infância e na adolescência. Com exceção da artrite idiopática juvenil, a maioria dos estudos em outras doenças autoimunes não é controlada. CONCLUSÕES: Os agentes biológicos têm demonstrado eficácia no tratamento de doenças autoimunes pediátricas como artrite idiopática juvenil, miopatias idiopáticas inflamatórias, lúpus eritematoso juvenil, vasculites, uveítes crônicas, doenças inflamatórias intestinais e púrpura trombocitopênica imune crônica, assim como no linfoma não-Hodgkin. Considerando-se o custo elevado e os potenciais eventos adversos, o uso desses agentes deve ser individualizado e acompanhado por especialista.OBJECTIVE: To review the physiopathology and new therapeutical targets, the available biologic agents, the main indications and the current scientific evidence for the use of biological therapies in the pediatric population. DATA SOURCES: A bibliographical search was obtained from Medline and SciELO databases in English and Portuguese from 2000 to 2009. The key-words included were "biologic agent", "children" and "adolescent". DATA SYNTHESIS: Biologic agents are important therapeutic options to treat refractory autoimmune diseases to conventional therapies in childhood and adolescence. Excluding juvenile idiopathic arthritis, the majority of studies in other autoimmune diseases are uncontrolled trials. CONCLUSIONS

Mechanisms of chemoresistance to alkylating agents in malignant glioma.

Science.gov (United States)

Sarkaria, Jann N; Kitange, Gaspar J; James, C David; Plummer, Ruth; Calvert, Hilary; Weller, Michael; Wick, Wolfgang

2008-05-15

Intrinsic or acquired chemoresistance to alkylating agents is a major cause of treatment failure in patients with malignant brain tumors. Alkylating agents, the mainstay of treatment for brain tumors, damage the DNA and induce apoptosis, but the cytotoxic activity of these agents is dependent on DNA repair pathways. For example, O6-methylguanine DNA adducts can cause double-strand breaks, but this is dependent on a functional mismatch repair pathway. Thus, tumor cell lines deficient in mismatch repair are resistant to alkylating agents. Perhaps the most important mechanism of resistance to alkylating agents is the DNA repair enzyme O6-methylguanine methyltransferase, which can eliminate the cytotoxic O6-methylguanine DNA adduct before it causes harm. Another mechanism of resistance to alkylating agents is the base excision repair (BER) pathway. Consequently, efforts are ongoing to develop effective inhibitors of BER. Poly(ADP-ribose)polymerase plays a pivotal role in BER and is an important therapeutic target. Developing effective strategies to overcome chemoresistance requires the identification of reliable preclinical models that recapitulate human disease and which can be used to facilitate drug development. This article describes the diverse mechanisms of chemoresistance operating in malignant glioma and efforts to develop reliable preclinical models and novel pharmacologic approaches to overcome resistance to alkylating agents.

Anticonvulsants for Nerve Agent-Induced Seizures: The Influence of the Therapeutic Dose of Atropine

National Research Council Canada - National Science Library

Shih, Tsung-Ming; Rowland, Tami C; McDonough, John H

2007-01-01

Two guinea pig models were used to study the anticonvulsant potency of diazepam, midazolam, and scopolamine against seizures induced by the nerve agents tabun, sarin, soman, cyclosarin, O-ethyl S-(2-(diisopropylamino)ethyl...

Hepatitis B core protein as a therapeutic target.

Science.gov (United States)

Mak, Lung-Yi; Wong, Danny Ka-Ho; Seto, Wai-Kay; Lai, Ching-Lung; Yuen, Man Fung

2017-12-01

Chronic hepatitis B virus (HBV) infection is difficult to cure, due to the presence of covalently-closed-circular DNA and virus-mediated blunting of host immune response. Existing therapies with nucleos(t)ide analogue or pegylated-interferon are not sufficient to achieve a high rate of HBV surface antigen seroclearance, a more desirable treatment outcome. Novel therapeutic agents targeting alternative viral replication steps are being developed. In this review, we will discuss the hepatitis B core antigen (HBcAg) as a therapeutic target. Areas covered: The basic structure and fundamental functions of HBcAg including nucleocapsid assembly, pre-genomic RNA encapsidation, reverse transcription, virion formation, cccDNA amplification, immune response regulation, and HBx protein interaction will be reviewed. Most of these are identified as therapeutic targets and tested in in vitro and in vivo studies, although clinical trials are scanty. Among the different components, the core protein allosteric modulators (CpAM) have been most widely investigated and appear promising in clinical trials. Expert opinion: The multiple and essential functions of HBcAg for HBV life cycle are important and attractive targets for HBV therapeutic interventions. Controlled trials involving CpAM are awaited. Apart from CpAM, drugs directed against different functions of HBcAg may be further explored to maximize the chance of cure.

Efficacy of antidotes (midazolam, atropine and HI-6) on nerve agent induced molecular and neuropathological changes

OpenAIRE

RamaRao, Golime; Afley, Prachiti; Acharya, Jyothiranjan; Bhattacharya, Bijoy Krishna

2014-01-01

Background Recent alleged attacks with nerve agent sarin on civilians in Syria indicate their potential threat to both civilian and military population. Acute nerve agent exposure can cause rapid death or leads to multiple and long term neurological effects. The biochemical changes that occur following nerve agent exposure needs to be elucidated to understand the mechanisms behind their long term neurological effects and to design better therapeutic drugs to block their multiple neurotoxic ef...

Production of Fatty Acid-Derived Valuable Chemicals in Synthetic Microbes

International Nuclear Information System (INIS)

Yu, Ai-Qun; Pratomo Juwono, Nina Kurniasih; Leong, Susanna Su Jan; Chang, Matthew Wook

2014-01-01

Fatty acid derivatives, such as hydroxy fatty acids, fatty alcohols, fatty acid methyl/ethyl esters, and fatty alka(e)nes, have a wide range of industrial applications including plastics, lubricants, and fuels. Currently, these chemicals are obtained mainly through chemical synthesis, which is complex and costly, and their availability from natural biological sources is extremely limited. Metabolic engineering of microorganisms has provided a platform for effective production of these valuable biochemicals. Notably, synthetic biology-based metabolic engineering strategies have been extensively applied to refactor microorganisms for improved biochemical production. Here, we reviewed: (i) the current status of metabolic engineering of microbes that produce fatty acid-derived valuable chemicals, and (ii) the recent progress of synthetic biology approaches that assist metabolic engineering, such as mRNA secondary structure engineering, sensor-regulator system, regulatable expression system, ultrasensitive input/output control system, and computer science-based design of complex gene circuits. Furthermore, key challenges and strategies were discussed. Finally, we concluded that synthetic biology provides useful metabolic engineering strategies for economically viable production of fatty acid-derived valuable chemicals in engineered microbes.

Production of Fatty Acid-Derived Valuable Chemicals in Synthetic Microbes

Energy Technology Data Exchange (ETDEWEB)

Yu, Ai-Qun; Pratomo Juwono, Nina Kurniasih [Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (Singapore); Synthetic Biology Research Program, National University of Singapore, Singapore (Singapore); Leong, Susanna Su Jan [Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (Singapore); Synthetic Biology Research Program, National University of Singapore, Singapore (Singapore); Singapore Institute of Technology, Singapore (Singapore); Chang, Matthew Wook, E-mail: bchcmw@nus.edu.sg [Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (Singapore); Synthetic Biology Research Program, National University of Singapore, Singapore (Singapore)

2014-12-23

Fatty acid derivatives, such as hydroxy fatty acids, fatty alcohols, fatty acid methyl/ethyl esters, and fatty alka(e)nes, have a wide range of industrial applications including plastics, lubricants, and fuels. Currently, these chemicals are obtained mainly through chemical synthesis, which is complex and costly, and their availability from natural biological sources is extremely limited. Metabolic engineering of microorganisms has provided a platform for effective production of these valuable biochemicals. Notably, synthetic biology-based metabolic engineering strategies have been extensively applied to refactor microorganisms for improved biochemical production. Here, we reviewed: (i) the current status of metabolic engineering of microbes that produce fatty acid-derived valuable chemicals, and (ii) the recent progress of synthetic biology approaches that assist metabolic engineering, such as mRNA secondary structure engineering, sensor-regulator system, regulatable expression system, ultrasensitive input/output control system, and computer science-based design of complex gene circuits. Furthermore, key challenges and strategies were discussed. Finally, we concluded that synthetic biology provides useful metabolic engineering strategies for economically viable production of fatty acid-derived valuable chemicals in engineered microbes.

Antimicrobials and therapeutic decision making: an historical perspective.

Science.gov (United States)

Quintiliani, R; Nightingale, C H

1991-01-01

In an effort to remedy inappropriate and excessive use of antimicrobials and to control costs, most hospitals have developed some type of antimicrobial management program. At Hartford Hospital, our most effective approaches have been those that reduce the chances for physician error, decrease the burden on ancillary services, and encourage short hospital stays. These include automatic correction of dose and dosing intervals of antimicrobials and, if possible, their conversion by pharmacy to cost-effective alternative agents; daily review of patients who are taking the drugs by an antimicrobial team; and replacement of parenteral with oral agents as soon as possible. Physician acceptance of these approaches will require significant changes in traditional prescribing styles and willingness to allow pharmacists to implement the recommendations of therapeutic and medical staff committees.

Development of (F-18)-Labeled Amyloid Imaging Agents for PET

International Nuclear Information System (INIS)

Mathis, C.A.

2007-01-01

The applicant proposes to design and synthesize a series of fluorine-18-labeled radiopharmaceuticals to be used as amyloid imaging agents for positron emission tomography (PET). The investigators will conduct comprehensive iterative in vitro and in vivo studies based upon well defined acceptance criteria in order to identify lead agents suitable for human studies. The long term goals are to apply the selected radiotracers as potential diagnostic agents of Alzheimer's disease (AD), as surrogate markers of amyloid in the brain to determine the efficacy of anti-amyloid therapeutic drugs, and as tools to help address basic scientific questions regarding the progression of the neuropathology of AD, such as testing the 'amyloid cascade hypothesis' which holds that amyloid accumulation is the primary cause of AD.

An Overview on Citrus aurantium L.: Its Functions as Food Ingredient and Therapeutic Agent

Directory of Open Access Journals (Sweden)

Ipek Suntar

2018-01-01

Full Text Available Citrus aurantium L. (Rutaceae, commonly known as bitter orange, possesses multiple therapeutic potentials. These biological credentials include anticancer, antianxiety, antiobesity, antibacterial, antioxidant, pesticidal, and antidiabetic activities. The essential oil of C. aurantium was reported to display marked pharmacological effects and great variation in chemical composition depending on growing locations but mostly contained limonene, linalool, and β-myrcene. Phytochemically, C. aurantium is rich in p-synephrine, an alkaloid, and many health-giving secondary metabolites such as flavonoids. Animal studies have demonstrated a low affinity of p-synephrine for adrenergic receptors and an even lower affinity in human models. The present review focuses on the different biological activities of the C. aurantium in animal and human models in the form of extract and its pure secondary metabolites. Finally, it is concluded that both the extract and isolated compounds have no unwanted effects in human at therapeutic doses and, therefore, can confidently be used in various dietary formulations.

Therapeutic Approaches Using Riboflavin in Mitochondrial Energy Metabolism Disorders.

Science.gov (United States)

Henriques, Bárbara J; Lucas, Tânia G; Gomes, Cláudio M

2016-01-01

Riboflavin, or vitamin B2, plays an important role in the cell as biological precursor of FAD and FMN, two important flavin cofactors which are essential for the structure and function of flavoproteins. Riboflavin has been used in therapeutic approaches of various inborn errors of metabolism, notably in metabolic disorders resulting either from defects in proteins involved in riboflavin metabolism and transport or from defects in flavoenzymes. The scope of this review is to provide an updated perspective of clinical cases in which riboflavin was used as a potential therapeutic agent in disorders affecting mitochondrial energy metabolism. In particular, we discuss available mechanistic insights on the role of riboflavin as a pharmacological chaperone for the recovery of misfolded metabolic flavoenzymes.

[Utilization of polymeric micelle magnetic resonance imaging (MRI) contrast agent for theranostic system].

Science.gov (United States)

Shiraishi, Kouichi

2013-01-01

We applied a polymeric micelle carrier system for the targeting of a magnetic resonance imaging (MRI) contrast agent. Prepared polymeric micelle MRI contrast agent exhibited a long circulation characteristic in blood, and considerable amount of the contrast agent was found to accumulate in colon 26 solid tumor by the EPR effect. The signal intensities of tumor area showed 2-folds increase in T1-weighted images at 24 h after i.v. injection. To observe enhancement of the EPR effect by Cderiv pretreatment on tumor targeting, we used the contrast agent for the evaluation by means of MRI. Cderiv pretreatment significantly enhanced tumor accumulation of the contrast agent. Interestingly, very high signal intensity in tumor region was found at 24 h after the contrast agent injection in Cderiv pretreated mice. The contrast agent visualized a microenvironmental change in tumor. These results indicate that the contrast agent exhibits potential use for tumor diagnostic agent. To combine with a polymeric micelle carrier system for therapeutic agent, the usage of the combination makes a new concept of "theranostic" for a better cancer treatment.

The development prospection of HDAC inhibitors as a potential therapeutic direction in Alzheimer?s disease

OpenAIRE

Yang, Shuang-shuang; Zhang, Rui; Wang, Gang; Zhang, Yong-fang

2017-01-01

Alzheimer?s disease (AD) is a chronic neurodegenerative disease, which is associated with learning and memory impairment in the elderly. Recent studies have found that treating AD in the way of chromatin remodeling via histone acetylation is a promising therapeutic regimen. In a number of recent studies, inhibitors of histone deacetylase (HDACs) have been found to be a novel promising therapeutic?agents for neurological disorders, particularly for AD and other neurodegenerative diseases. Alth...

Therapeutic Potential of Mesenchymal Stem Cell-Derived Exosomes in the Treatment of Eye Diseases.

Science.gov (United States)

Harrell, C Randall; Simovic Markovic, Bojana; Fellabaum, Crissy; Arsenijevic, Aleksandar; Djonov, Valentin; Arsenijevic, Nebojsa; Volarevic, Vladislav

2018-05-18

Mesenchymal stem cells (MSCs) were, due to their immunomodulatory and pro-angiogenic characteristics, extensively explored as new therapeutic agents in cell-based therapy of uveitis, glaucoma, retinal and ocular surface diseases.Since it was recently revealed that exosomes play an important role in biological functions of MSCs, herewith we summarized current knowledge about the morphology, structure, phenotype and functional characteristics of MSC-derived exosomes emphasizing their therapeutic potential in the treatment of eye diseases.MSC-derived exosomes were as efficient as transplanted MSCs in limiting the extent of eye injury and inflammation. Immediately after intravitreal injection, MSC-derived exosomes, due to nano-dimension, diffused rapidly throughout the retina and significantly attenuated retinal damage and inflammation. MSC-derived exosomes successfully delivered trophic and immunomodulatory factors to the inner retina and efficiently promoted survival and neuritogenesis of injured retinal ganglion cells. MSC-derived exosomes efficiently suppressed migration of inflammatory cells, attenuated detrimental Th1 and Th17 cell-driven immune response and ameliorated experimental autoimmune uveitis. MSC-derived exosomes were able to fuse with the lysosomes within corneal cells, enabling delivering of MSC-derived active β-glucuronidase and consequent catabolism of accumulated glycosaminoglycans, indicating their therapeutic potential in the treatment of Mucopolysaccharidosis VII (Sly Syndrome). Importantly, beneficent effects were noticed only in animals that received MSC-derived exosomes and were not seen after therapy with fibroblasts-derived exosomes confirming specific therapeutic potential of MSCs and their products in the treatment of eye diseases.In conclusion, MSC-derived exosomes represent potentially new therapeutic agents in the therapy of degenerative and inflammatory ocular diseases.

Scaling adult doses of antifungal and antibacterial agents to children.

Science.gov (United States)

Dawson, Thomas H

2012-06-01

My general pharmacokinetic scaling theory is discussed for the important matter of determining pediatric dosing for existing and new therapeutic drugs when optimal, or near-optimal, dosing for adults is known. The basis for the scaling is the requirement of a time-scaled likeness of the free-drug concentration time histories of children and adults. Broad categories of single and periodic dosing are considered. The former involves the scaling of dosage, and the latter involves both the dosage and schedule. The validity of the scaling relations is demonstrated by using measurements from previously reported clinical trials with adults and children (with ages generally 1 year or older) for the relatively new antifungal agent caspofungin and for the relatively new antibacterial agent linezolid. Standard pharmacodynamic effectiveness criteria are shown to be satisfied for the scaled dosage and schedule for children to the same extent that they are for the referenced adult. Consideration of scaling from adults to children is discussed for the case of new agents where no pediatric data are available and needed parameters are determined from in vitro measurements and preclinical animal data. A connection is also made between the allometric representation of clearance data and the dosing formulas. Limitations of the scaling results for infants because of growth and maturational matters are discussed. The general conclusion from this work is that the scaling theory does indeed have application to pediatric dosing for children, for both confirmation and refinement of present practice and guidance in pediatric treatment with new therapeutic agents.

Prediction of a Therapeutic Dose for Buagafuran, a Potent Anxiolytic Agent by Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling Starting from Pharmacokinetics in Rats and Human

Directory of Open Access Journals (Sweden)

Fen Yang

2017-10-01

Full Text Available Physiologically based pharmacokinetic (PBPK/pharmacodynamic (PD models can contribute to animal-to-human extrapolation and therapeutic dose predictions. Buagafuran is a novel anxiolytic agent and phase I clinical trials of buagafuran have been completed. In this paper, a potentially effective dose for buagafuran of 30 mg t.i.d. in human was estimated based on the human brain concentration predicted by a PBPK/PD modeling. The software GastroPlusTM was used to build the PBPK/PD model for buagafuran in rat which related the brain tissue concentrations of buagafuran and the times of animals entering the open arms in the pharmacological model of elevated plus-maze. Buagafuran concentrations in human plasma were fitted and brain tissue concentrations were predicted by using a human PBPK model in which the predicted plasma profiles were in good agreement with observations. The results provided supportive data for the rational use of buagafuran in clinic.

New Therapies Offer Valuable Options for Patients with Melanoma

Science.gov (United States)

Two phase III clinical trials of new therapies for patients with metastatic melanoma presented in June at the 2011 ASCO conference confirmed that vemurafenib and ipilimumab (Yervoy™) offer valuable new options for the disease.

Nitric oxide: cancer target or anticancer agent?

Science.gov (United States)

Mocellin, Simone

2009-03-01

Despite the improved understanding of nitric oxide (NO) biology and the large amount of preclinical experiments testing its role in cancer development and progression, it is still debated whether NO should be considered a potential anticancer agent or instead a carcinogen. The complexity of NO effects within a cell and the variability of the final biological outcome depending upon NO levels makes it highly challenging to determine the therapeutic value of interfering with the activity of this intriguing gaseous messenger. This uncertainty has so far halted the clinical implementation of NO-based therapeutics in the field of oncology. Accordingly, only an in depth knowledge of the mechanisms leading to experimental tumor regression or progression in response to NO will allow us to exploit this molecule to fight cancer.

A case report on inVALUABLE: insect value chain in a circular bioeconomy

DEFF Research Database (Denmark)

Heckmann, L.-H.; Andersen, J.L.; Eilenberg, J.

2018-01-01

partners span the entire value chain and include entrepreneurs, experts in biology, biotechnology, automation, processing and food tech and safety. This paper provides an overview of the goal, activities and some preliminary results obtained during the first year of the project.......The vision of inVALUABLE is to create a sustainable resource-efficient industry for animal production based on insects. inVALUABLE has focus on the R&D demand for scaling up production of insects in Denmark and assessing the application potential of particularly mealworms. The inVALUABLE consortium...

Promising biocidal activity of thymol loaded chitosan silver nanoparticles (T-C@AgNPs) as anti-infective agents against perilous pathogens.

Science.gov (United States)

Manukumar, H M; Umesha, S; Kumar, H N Naveen

2017-09-01

The advent of biodegradable polymer-encapsulated drug nanoparticles has made an exciting area of drug delivery research. The present study investigated novel and simple route for synthesis of thymol loaded chitosan silver nanoparticles (T-C@AgNPs) using chitosan and thymol as reducing, capping agent respectively to understand the therapeutic efficacy. The UV-vis spectroscopy, DLS, FT-IR, SEM, EDS, XRD used for characterization and radical scavenging activity, anti-microbial and biocompatibility was taken to ascertain an efficacy of novel T-C@AgNPs. The T-C@AgNPs intense peak at 490nm indicates the formation of nanoparticles and had average particle size of 28.94nm with spherical shape, monodisperse state in water, also exhibited excellent biocompatibility of cubic shaped pure silver element containing T-C@AgNPs. The antibacterial activity was studied for gram positive and gram negative food-borne pathogens and effective inhibition at 100μgmL -1 to S. aureus, S. epidermidis, S. haemolyticus (10.08, 10.00, 11.23mm) and S. typhimurium, P. aeruginosa and S. flexneri (9.28, 9.33, 12.03mm) compared to antibiotic Streptomycin. This study revealed the efficacy against multiple food-borne pathogens and therapeutic efficacy of T-C@AgNPs offers a valuable contribution in the area of nanotechnology. This proved to be a first-class novel antimicrobial material for the first time in this study. Copyright © 2017 Elsevier B.V. All rights reserved.

Manufacturing of Human Extracellular Vesicle-Based Therapeutics for Clinical Use

Directory of Open Access Journals (Sweden)

Mario Gimona

2017-06-01

Full Text Available Extracellular vesicles (EVs derived from stem and progenitor cells may have therapeutic effects comparable to their parental cells and are considered promising agents for the treatment of a variety of diseases. To this end, strategies must be designed to successfully translate EV research and to develop safe and efficacious therapies, whilst taking into account the applicable regulations. Here, we discuss the requirements for manufacturing, safety, and efficacy testing of EVs along their path from the laboratory to the patient. Development of EV-therapeutics is influenced by the source cell types and the target diseases. In this article, we express our view based on our experience in manufacturing biological therapeutics for routine use or clinical testing, and focus on strategies for advancing mesenchymal stromal cell (MSC-derived EV-based therapies. We also discuss the rationale for testing MSC-EVs in selected diseases with an unmet clinical need such as critical size bone defects, epidermolysis bullosa and spinal cord injury. While the scientific community, pharmaceutical companies and clinicians are at the point of entering into clinical trials for testing the therapeutic potential of various EV-based products, the identification of the mode of action underlying the suggested potency in each therapeutic approach remains a major challenge to the translational path.

Transforming stand-alone expert system into a community of cooperating agents

CERN Document Server

Jennings, N R; Aarnts, R P; Fuchs, J; Skarek, Paul

1993-01-01

Distributed Artificial Intelligence (DAI) systems in which multiple problem solving agents cooperate to achieve a common objective is a rapidly emerging and promising technology. However, as yet, there have been relatively few reported cases of such systems being employed to tackle real-world problems in realistic domains. One of the reasons for this is that DAI researchers have given virtually no consideration to the process of incorporating pre-existing systems into a community of cooperating agents. Yet reuse is a primary consideration for any organisation with a large software base. To redress the balance, this paper reports on an experiment undertaken at the CERN laboratories, in which two pre-existing and standalone expert systems for diagnosing faults in a particle accelerator were transformed into a community of cooperating agents. The experiences and insights gained during this process provide a valuable first step towards satisfying the needs of potential users of DAI technology - identifying the ty...

Recent advances in (therapeutic protein drug development [version 1; referees: 2 approved

Directory of Open Access Journals (Sweden)

H.A. Daniel Lagassé

2017-02-01

Full Text Available Therapeutic protein drugs are an important class of medicines serving patients most in need of novel therapies. Recently approved recombinant protein therapeutics have been developed to treat a wide variety of clinical indications, including cancers, autoimmunity/inflammation, exposure to infectious agents, and genetic disorders. The latest advances in protein-engineering technologies have allowed drug developers and manufacturers to fine-tune and exploit desirable functional characteristics of proteins of interest while maintaining (and in some cases enhancing product safety or efficacy or both. In this review, we highlight the emerging trends and approaches in protein drug development by using examples of therapeutic proteins approved by the U.S. Food and Drug Administration over the previous five years (2011–2016, namely January 1, 2011, through August 31, 2016.

Angiogenesis and Its Therapeutic Opportunities

Directory of Open Access Journals (Sweden)

So Young Yoo

2013-01-01

Full Text Available Angiogenesis plays critical roles in human physiology that range from reproduction and fetal growth to wound healing and tissue repair. The sophisticated multistep process is tightly regulated in a spatial and temporal manner by “on-off switch signals” between angiogenic factors, extracellular matrix components, and endothelial cells. Uncontrolled angiogenesis may lead to several angiogenic disorders, including vascular insufficiency (myocardial or critical limb ischemia and vascular overgrowth (hemangiomas, vascularized tumors, and retinopathies. Thus, numerous therapeutic opportunities can be envisaged through the successful understanding and subsequent manipulation of angiogenesis. Here, we review the clinical implications of angiogenesis and discuss pro- and antiangiogenic agents that offer potential therapy for cancer and other angiogenic diseases.

Trends in GPCR drug discovery: new agents, targets and indications.

Science.gov (United States)

Hauser, Alexander S; Attwood, Misty M; Rask-Andersen, Mathias; Schiöth, Helgi B; Gloriam, David E

2017-12-01

G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, mostly due to their substantial involvement in human pathophysiology and their pharmacological tractability. Here, we report an up-to-date analysis of all GPCR drugs and agents in clinical trials, which reveals current trends across molecule types, drug targets and therapeutic indications, including showing that 475 drugs (~34% of all drugs approved by the US Food and Drug Administration (FDA)) act at 108 unique GPCRs. Approximately 321 agents are currently in clinical trials, of which ~20% target 66 potentially novel GPCR targets without an approved drug, and the number of biological drugs, allosteric modulators and biased agonists has increased. The major disease indications for GPCR modulators show a shift towards diabetes, obesity and Alzheimer disease, although several central nervous system disorders are also highly represented. The 224 (56%) non-olfactory GPCRs that have not yet been explored in clinical trials have broad untapped therapeutic potential, particularly in genetic and immune system disorders. Finally, we provide an interactive online resource to analyse and infer trends in GPCR drug discovery.

Therapeutic options to treat sulfur mustard poisoning--the road ahead.

Science.gov (United States)

Smith, William J

2009-09-01

For the past 15 years the international research community has conducted a basic and applied research program aimed at identifying a medical countermeasure against chemical threat vesicant, or blistering, agents. The primary emphasis of this program has been the development of therapeutic protection against sulfur mustard and its cutaneous pathology-blister formation. In addition to the work on a medical countermeasures, significant research has been conducted on the development of topical skin protectants and medical strategies for wound healing. This review will focus on the pharmacological strategies investigated, novel therapeutic targets currently under investigation and therapeutic approaches being considered for transition to advanced development. Additionally, we will review the expansion of our understanding of the pathophysiological mechanisms of mustard injury that has come from this research. While great strides have been made through these investigations, the complexity of the mustard insult demands that further studies extend the inroads made and point the way toward better understanding of cellular and tissue disruptions caused by sulfur mustard.

Human Health Consequences of Use of Antimicrobial Agents in Aquaculture

DEFF Research Database (Denmark)

Heuer, Ole Eske; Kruse, H.; Grave, K.

2009-01-01

industry in many regions of the world and the widespread, intensive, and often unregulated use of antimicrobial agents in this area of animal production, efforts are needed to prevent development and spread of antimicrobial resistance in aquaculture to reduce the risk to human health....... in aquaculture, several are classified by the World Health Organisation as critically important for use in humans. Occurrence of resistance to these antimicrobial agents in human pathogens severely limits the therapeutic options in human infections. Considering the rapid growth and importance of aquaculture...... gene transfer and reach human pathogens, or drug-resistant pathogens from the aquatic environment may reach humans directly. Horizontal gene transfer may occur in the aquaculture environment, in the food chain, or in the human intestinal tract. Among the antimicrobial agents commonly used...

Therapeutic Strategies to Enhance the Anticancer Efficacy of Histone Deacetylase Inhibitors

Directory of Open Access Journals (Sweden)

Claudia P. Miller

2011-01-01

Full Text Available Histone acetylation is a posttranslational modification that plays a role in regulating gene expression. More recently, other nonhistone proteins have been identified to be acetylated which can regulate their function, stability, localization, or interaction with other molecules. Modulating acetylation with histone deacetylase inhibitors (HDACi has been validated to have anticancer effects in preclinical and clinical cancer models. This has led to development and approval of the first HDACi, vorinostat, for the treatment of cutaneous T cell lymphoma. However, to date, targeting acetylation with HDACi as a monotherapy has shown modest activity against other cancers. To improve their efficacy, HDACi have been paired with other antitumor agents. Here, we discuss several combination therapies, highlighting various epigenetic drugs, ROS-generating agents, proteasome inhibitors, and DNA-damaging compounds that together may provide a therapeutic advantage over single-agent strategies.

Therapeutic and diagnostic nanomaterials

CERN Document Server

Devasena T

2017-01-01

This brief highlights nanoparticles used in the diagnosis and treatment of prominent diseases and toxic conditions. Ecofriendly methods which are ideal for the synthesis of medicinally valued nanoparticles are explained and the characteristic features of these particles projected. The role of these particles in the therapeutic field, and the induced biological changes in some diseases are discussed. The main focus is on inflammation, oxidative stress and cellular membrane integrity alterations. The effect of nanoparticles on these changes produced by various agents are highlighted using in vitro and in vivo models. The mechanism of nanoparticles in ameliorating the biological changes is supported by relevant images and data. Finally, the brief demonstrates recent developments on the use of nanoparticles in diagnosis or sensing of some biological materials and biologically hazardous environmental materials.

The Prognostic, Diagnostic, and Therapeutic Potential of Tumor Antigens

DEFF Research Database (Denmark)

Olsen, Lars Rønn

or abundance in cancer cells is often unique and their roles and functions in tumorigenesis are, in many cases, studied extensively. They, therefore, have the potential to be highly specific biomarkers as well as therapeutic targets, but complex analysis combining basic science, high-throughput methods...... of genomics and proteomics, and clinical studies need to be combined. These analyses produce large amounts of data that require advanced bioinformatics methods for collection, management, integration and interpretation. In this thesis, I have explored the potential of tumor antigens as biomarkers...... and therapeutic agents, by developing and implementing several computational tools and databases for immunotherapy target discovery, and have analyzed the potential of tumor antigens as proteogenomic biomarkers in invasive ductal carcinomas. In this analysis I have shown that the combination of proteomics...

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

Science.gov (United States)

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

2014-11-01

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

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

International Nuclear Information System (INIS)

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

2014-01-01

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

Plants as sources of antiviral agents | Abonyi | African Journal of ...

African Journals Online (AJOL)

Antivirals are substances other than a virus or virus containing vaccine or specific antibody which can produce either a protective or therapeutic effect to the clear detectable advantage of the virus infected host. The search for antiviral agents began in earnest in the 1950s but this was directed mainly by chance, with little or ...

Cancer chemopreventive and therapeutic effects of diosgenin, a food saponin.

Science.gov (United States)

Raju, Jayadev; Mehta, Rekha

2009-01-01

Cancer chemoprevention is a strategy taken to retard, regress, or resist the multistep process of carcinogenesis, including the blockage of its vital morphogenetic milestones viz. normal-preneoplasia-neoplasia-metastasis. For several reasons, including safety, minimal (or no) toxicity and side-effects, and better availability, alternatives such as naturally occurring phytochemicals that are found in foods are becoming increasingly popular over synthetic drugs. Food saponins have been used in complimentary and traditional medicine against a variety of diseases including several cancers. Diosgenin, a naturally occurring steroid saponin found abundantly in legumes and yams, is a well-known precursor of various synthetic steroidal drugs that are extensively used in the pharmaceutical industry. Over the past decade, a series of preclinical and mechanistic studies have been conducted to understand the role of diosgenin as a chemopreventive/therapeutic agent against several cancers. This review highlights the biological activity of diosgenin that contributes to cancer chemoprevention and control. The anticancer mode of action of diosgenin has been demonstrated via modulation of multiple cell signaling events involving critical molecular candidates associated with growth, differentiation, apoptosis, and oncogenesis. Altogether, these preclinical and mechanistic findings strongly implicate the use of diosgenin as a novel, multitarget-based chemopreventive or therapeutic agent against several cancer types. Future research in this field will help to establish not only whether diosgenin is safe and efficacious as a chemopreventive agent against several human cancers, but also to develop and evaluate standards of evidence for health claims for diosgenin-containing foods as they become increasingly popular and enter the marketplace labeled as functional foods and nutraceuticals.

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Science.gov (United States)

Gross, Christina; Berry-Kravis, Elizabeth M; Bassell, Gary J

2012-01-01

Fragile X syndrome (FXS) is an inherited neurodevelopmental disease caused by loss of function of the fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group 1 metabotropic glutamate receptors is elevated and insensitive to stimulation, which may underlie many of the neurological and neuropsychiatric features of FXS. Treatment of FXS animal models with negative allosteric modulators of these receptors and preliminary clinical trials in human patients support the hypothesis that metabotropic glutamate receptor signaling is a valuable therapeutic target in FXS. However, recent research has also shown that FMRP may regulate diverse aspects of neuronal signaling downstream of several cell surface receptors, suggesting a possible new route to more direct disease-targeted therapies. Here, we summarize promising recent advances in basic research identifying and testing novel therapeutic strategies in FXS models, and evaluate their potential therapeutic benefits. We provide an overview of recent and ongoing clinical trials motivated by some of these findings, and discuss the challenges for both basic science and clinical applications in the continued development of effective disease mechanism-targeted therapies for FXS. PMID:21796106

Nucleotide excision repair is a potential therapeutic target in multiple myeloma

Science.gov (United States)

Szalat, R; Samur, M K; Fulciniti, M; Lopez, M; Nanjappa, P; Cleynen, A; Wen, K; Kumar, S; Perini, T; Calkins, A S; Reznichenko, E; Chauhan, D; Tai, Y-T; Shammas, M A; Anderson, K C; Fermand, J-P; Arnulf, B; Avet-Loiseau, H; Lazaro, J-B; Munshi, N C

2018-01-01

Despite the development of novel drugs, alkylating agents remain an important component of therapy in multiple myeloma (MM). DNA repair processes contribute towards sensitivity to alkylating agents and therefore we here evaluate the role of nucleotide excision repair (NER), which is involved in the removal of bulky adducts and DNA crosslinks in MM. We first evaluated NER activity using a novel functional assay and observed a heterogeneous NER efficiency in MM cell lines and patient samples. Using next-generation sequencing data, we identified that expression of the canonical NER gene, excision repair cross-complementation group 3 (ERCC3), significantly impacted the outcome in newly diagnosed MM patients treated with alkylating agents. Next, using small RNA interference, stable knockdown and overexpression, and small-molecule inhibitors targeting xeroderma pigmentosum complementation group B (XPB), the DNA helicase encoded by ERCC3, we demonstrate that NER inhibition significantly increases sensitivity and overcomes resistance to alkylating agents in MM. Moreover, inhibiting XPB leads to the dual inhibition of NER and transcription and is particularly efficient in myeloma cells. Altogether, we show that NER impacts alkylating agents sensitivity in myeloma cells and identify ERCC3 as a potential therapeutic target in MM. PMID:28588253

Myocardial Energetics and Heart Failure: a Review of Recent Therapeutic Trials.

Science.gov (United States)

Bhatt, Kunal N; Butler, Javed

2018-06-01

Several novel therapeutics being tested in patients with heart failure are based on myocardial energetics. This review will provide a summary of the recent trials in this area, including therapeutic options targeting various aspects of cellular and mitochondrial metabolism. Agents that improve the energetic balance in myocardial cells have the potential to improve clinical heart failure status. The most promising therapies currently under investigation in this arena include (1) elamipretide, a cardiolipin stabilizer; (2) repletion of iron deficiency with intravenous ferrous carboxymaltose; (3) coenzyme Q10; and (4) the partial adenosine receptor antagonists capadenoson and neladenosone. Myocardial energetics-based therapeutics are groundbreaking in that they utilize novel mechanisms of action to improve heart failure symptoms, without causing the adverse neurohormonal side effects associated with current guideline-based therapies. The drugs appear likely to be added to the heart failure therapy armamentarium as adjuncts to current regimens in the near future.

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

International Nuclear Information System (INIS)

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

2011-01-01

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

Hypoxia-Inducible Factors: Mediators of Cancer Progression; Prognostic and Therapeutic Targets in Soft Tissue Sarcomas

International Nuclear Information System (INIS)

Sadri, Navid; Zhang, Paul J.

2013-01-01

Soft-tissue sarcomas remain aggressive tumors that result in death in greater than a third of patients due to either loco-regional recurrence or distant metastasis. Surgical resection remains the main choice of treatment for soft tissue sarcomas with pre- and/or post-operational radiation and neoadjuvant chemotherapy employed in more advanced stage disease. However, in recent decades, there has been little progress in the average five-year survival for the majority of patients with high-grade soft tissue sarcomas, highlighting the need for improved targeted therapeutic agents. Clinical and preclinical studies demonstrate that tumor hypoxia and up-regulation of hypoxia-inducible factors (HIFs) is associated with decreased survival, increased metastasis, and resistance to therapy in soft tissue sarcomas. HIF-mediated gene expression regulates many critical aspects of tumor biology, including cell survival, metabolic programming, angiogenesis, metastasis, and therapy resistance. In this review, we discuss HIFs and HIF-mediated genes as potential prognostic markers and therapeutic targets in sarcomas. Many pharmacological agents targeting hypoxia-related pathways are in development that may hold therapeutic potential for treating both primary and metastatic sarcomas that demonstrate increased HIF expression

Biologic agents in rheumatology: unmet issues after 200 trials and $200 billion sales.

Science.gov (United States)

Ioannidis, John P A; Karassa, Fotini B; Druyts, Eric; Thorlund, Kristian; Mills, Edward J

2013-11-01

Anti-TNF agents and other biologic therapies are widely prescribed for a variety of indications, with total sales that exceed $200 billion to date. In rheumatic diseases, biologic agents have now been studied in more than 200 randomized clinical trials and over 100 subsequent meta-analyses; however, the information obtained does not always meet the needs of patients and clinicians. In this Review, we discuss the current issues concerning the evidence derived from such studies: potential biases favouring positive results; a paucity of head-to-head comparisons between biologically active agents; overwhelming involvement of manufacturer sponsors in trials and in the synthesis of the evidence; the preference for trials with limited follow-up; and the potential for spurious findings on adverse events, leading to endless debates about malignancy risk. We debate the responsibilities of regulatory authorities, the pharmaceutical industry and academia in attempting to solve these shortcomings and challenges. We propose that improvements in the evidence regarding biologic treatments that are continually being added to the therapeutic armamentarium for rheumatic diseases might require revisiting the design and conduct of studies. For example, trials with long-term follow-up that are independent of the pharmaceutical industry, head-to-head comparisons of therapeutic agents and the use of rigorous clinical outcomes should be considered, and public availability of raw data endorsed.

Augmentation of therapeutic potential of curcumin using nanotechnology: current perspectives.

Science.gov (United States)

Sivasami, Pulavendran; Hemalatha, Thiagarajan

2018-02-28

Curcumin, an active principle of Curcuma longa, is extracted from the rhizome. Its therapeutic efficiency has been proved using various in vitro and in vivo models. Inflammatory, neoplastic and preneoplastic diseases are the major targets using curcumin as therapeutic agent. Feasible clinical formulations could not be obtained because of its lack of solubility, stability and higher degradation rate. Recently, many techniques have been evolved to improve the physicochemical properties of pharmacological compounds, thereby increasing their biological activity. Curcumin has been developed using various techniques, particularly micro and nanotechnology to improve its stability and bioavailability. This review focuses on the studies pertaining to the delivery of curcumin in the form of micro and nanosize formulations for the treatment of a variety of diseases.

Helping Oxytocin Deliver: Considerations in the Development of Oxytocin-Based Therapeutics for Brain Disorders.

Directory of Open Access Journals (Sweden)

Kai eMacdonald

2013-03-01

Full Text Available Concerns regarding a drought in psychopharmacology have risen from many quarters. From one perspective, the wellspring of bedrock medications for anxiety disorders, depression, and schizophrenia was serendipitously discovered over thirty year ago, the swell of pharmaceutical investment in drug discovery has receded, and the pipeline’s flow of medications with unique mechanisms of action (i.e. glutamatergic agents, CRF antagonists has slowed to a trickle. Might oxytocin (OT-based therapeutics be an oasis? Though a large basic science literature and a slowly increasing number of studies in human diseases support this hope, the bulk of extant OT studies in humans are single-dose studies on normals, and do not directly relate to improvements in human brain-based diseases. Instead, these studies have left us with a field pregnant with therapeutic possibilities, but barren of definitive treatments. In this clinically-oriented review, we discuss the extant OT literature with an eye toward helping OT deliver on its promise as a therapeutic agent. To this end, we identify ten key questions that we believe future OT research should address. From this overview, several conclusions are clear: 1 the OT system represents an extremely promising target for novel CNS drug development; 2 there is a pressing need for rigorous, randomized controlled clinical trials targeting actual patients; and 3 in order to inform the design and execution of these vital trials, we need further translational studies addressing the questions posed in this review. Looking forward, we extend a cautious hope that the next decade of OT research will birth oxytocin-targetted therapeutics that can truly deliver on this system’s therapeutic potential.

Sustainable production of valuable compound 3-succinoyl-pyridine by genetically engineering Pseudomonas putida using the tobacco waste.

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Wang, Weiwei; Xu, Ping; Tang, Hongzhi

2015-11-17

Treatment of solid and liquid tobacco wastes with high nicotine content remains a longstanding challenge. Here, we explored an environmentally friendly approach to replace tobacco waste disposal with resource recovery by genetically engineering Pseudomonas putida. The biosynthesis of 3-succinoyl-pyridine (SP), a precursor in the production of hypotensive agents, from the tobacco waste was developed using whole cells of the engineered Pseudomonas strain, S16dspm. Under optimal conditions in fed-batch biotransformation, the final concentrations of product SP reached 9.8 g/L and 8.9 g/L from aqueous nicotine solution and crude suspension of the tobacco waste, respectively. In addition, the crystal compound SP produced from aqueous nicotine of the tobacco waste in batch biotransformation was of high purity and its isolation yield on nicotine was 54.2%. This study shows a promising route for processing environmental wastes as raw materials in order to produce valuable compounds.

Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma

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Adrian Biddle

2016-02-01

Full Text Available Cancer stem cells (CSCs drive tumour spread and therapeutic resistance, and can undergo epithelial-to-mesenchymal transition (EMT and mesenchymal-to-epithelial transition (MET to switch between epithelial and post-EMT sub-populations. Examining oral squamous cell carcinoma (OSCC, we now show that increased phenotypic plasticity, the ability to undergo EMT/MET, underlies increased CSC therapeutic resistance within both the epithelial and post-EMT sub-populations. The post-EMT CSCs that possess plasticity exhibit particularly enhanced therapeutic resistance and are defined by a CD44highEpCAMlow/−CD24+ cell surface marker profile. Treatment with TGFβ and retinoic acid (RA enabled enrichment of this sub-population for therapeutic testing, through which the endoplasmic reticulum (ER stressor and autophagy inhibitor Thapsigargin was shown to selectively target these cells. Demonstration of the link between phenotypic plasticity and therapeutic resistance, and development of an in vitro method for enrichment of a highly resistant CSC sub-population, provides an opportunity for the development of improved chemotherapeutic agents that can eliminate CSCs.

Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma.

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Biddle, Adrian; Gammon, Luke; Liang, Xiao; Costea, Daniela Elena; Mackenzie, Ian C

2016-02-01

Cancer stem cells (CSCs) drive tumour spread and therapeutic resistance, and can undergo epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) to switch between epithelial and post-EMT sub-populations. Examining oral squamous cell carcinoma (OSCC), we now show that increased phenotypic plasticity, the ability to undergo EMT/MET, underlies increased CSC therapeutic resistance within both the epithelial and post-EMT sub-populations. The post-EMT CSCs that possess plasticity exhibit particularly enhanced therapeutic resistance and are defined by a CD44(high)EpCAM(low/-) CD24(+) cell surface marker profile. Treatment with TGFβ and retinoic acid (RA) enabled enrichment of this sub-population for therapeutic testing, through which the endoplasmic reticulum (ER) stressor and autophagy inhibitor Thapsigargin was shown to selectively target these cells. Demonstration of the link between phenotypic plasticity and therapeutic resistance, and development of an in vitro method for enrichment of a highly resistant CSC sub-population, provides an opportunity for the development of improved chemotherapeutic agents that can eliminate CSCs.

Widening and Elaboration of Consecutive Research into Therapeutic Antioxidant Enzyme Derivatives

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Alexander V. Maksimenko

2016-01-01

Full Text Available Undiminishing actuality of enzyme modification for therapeutic purposes has been confirmed by application of modified enzymes in clinical practice and numerous research data on them. Intravenous injection of the superoxide dismutase-chondroitin sulfate-catalase (SOD-CHS-CAT conjugate in preventive and medicative regimes in rats with endotoxin shock induced with a lipopolysaccharide bolus has demonstrated that antioxidant agents not only effectively prevent damage caused by oxidative stress (as believed previously but also can be used for antioxidative stress therapy. The results obtained emphasize the importance of investigation into the pathogenesis of vascular damage and the role of oxidative stress in it. The effects of intravenous medicative injection of SOD-CHS-CAT in a rat model of endotoxin shock have demonstrated a variety in the activity of this conjugate in addition to prevention of NO conversion in peroxynitrite upon interaction with O2∙- superoxide radical. Together with the literature data, these findings offer a prospect for the study of NO-independent therapeutic effects of SOD-CHS-CAT, implying the importance of a better insight into the mechanisms of the conjugate activity in modeled cardiovascular damage involving vasoactive agents other than NO.

Biomedicines?Moving Biologic Agents into Approved Treatment Options

OpenAIRE

Cornetta, Kenneth

2013-01-01

The development of biologic agents for therapeutic purposes, or biomedicines, has seen an active area of research both at the bench and in clinical trials. There is mounting evidence that biologic products can provide effective therapy for diseases that have been unresponsive to traditional pharmacologic approaches. Monoclonal antibody therapy for cancer and rheumatologic diseases has become a well accepted part of disease treatment plans. Gene therapy products have been approved in China and...

A readily applicable strategy to convert peptides to peptoid-based therapeutics.

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Minyoung Park

Full Text Available Incorporation of unnatural amino acids and peptidomimetic residues into therapeutic peptides is highly efficacious and commonly employed, but generally requires laborious trial-and-error approaches. Previously, we demonstrated that C20 peptide has the potential to be a potential antiviral agent. Herein we report our attempt to improve the biological properties of this peptide by introducing peptidomimetics. Through combined alanine, proline, and sarcosine scans coupled with a competitive fluorescence polarization assay developed for identifying antiviral peptides, we enabled to pinpoint peptoid-tolerant peptide residues within C20 peptide. The synergistic benefits of combining these (and other commonly employed methods could lead to a easily applicable strategy for designing and refining therapeutically-attractive peptidomimetics.

Rituximab: An emerging therapeutic agent for kidney transplantation

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Joseph Kahwaji

2009-10-01

Full Text Available Joseph Kahwaji, Chris Tong, Stanley C Jordan, Ashley A VoComprehensive Transplant Center, Transplant immunology Laboratory, HLA Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA, USAAbstract: Rituximab (anti-CD20, anti-B-cell is now emerging as an important drug for modification of B-cell and antibody responses in solid-organ transplant recipients. Its uses are varied and range from facilitating desensitization and ABO blood group-incompatible transplantation to the treatment of antibody-mediated rejection (AMR, post-transplant lymphoproliferative disorder (PTLD, and recurrent glomerular diseases in the renal allograft. Despite these uses, prospective randomized trials are lacking. Only case reports exist in regards to its use in de novo and recurrent diseases in the renal allograft. Recent reports suggests that the addition of rituximab to intravenous immunoglobulin (IVIG may have significant benefits for desensitization and treatment of AMR and chronic rejection. Current dosing recommendations are based on data from United States Food and Drug Administration-approved indications for treatment of B-cell lymphomas and rheumatoid arthritis. From the initial reported experience in solid organ transplant recipients, the drug is well tolerated and not associated with increased infectious risks. However, close monitoring for viral infections is recommended with rituximab use. The occurrence of progressive multifocal leukoencephalopathy (PML has been reported with rituximab use. However, this is rare and not reported in the renal transplant population. Here we will review current information regarding the effectiveness of rituximab as an agent for desensitization of highly human leukocyte antigen-sensitized and ABO-incompatible transplant recipients and its use in treatment of AMR. In addition, the post-transplant use of rituximab for treatment of PTLD and for recurrent and de novo glomerulonephritis in the allograft will be discussed. In

Evolutionary autonomous agents and the nature of apraxia

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Jin Frank

2005-01-01

Full Text Available Abstract Background Evolutionary autonomous agents are robots or robot simulations whose controller is a dynamical neural network and whose evolution occurs autonomously under the guidance of a fitness function without the detailed or explicit direction of an external programmer. They are embodied agents with a simple neural network controller and as such they provide the optimal forum by which sensorimotor interactions in a specified environment can be studied without the computational assumptions inherent in standard neuroscience. Methods Evolutionary autonomous agents were evolved that were able to perform identical movements under two different contexts, one which represented an automatic movement and one which had a symbolic context. In an attempt to model the automatic-voluntary dissociation frequently seen in ideomotor apraxia, lesions were introduced into the neural network controllers resulting in a behavioral dissociation with loss of the ability to perform the movement which had a symbolic context and preservation of the simpler, automatic movement. Results Analysis of the changes in the hierarchical organization of the networks in the apractic EAAs demonstrated consistent changes in the network dynamics across all agents with loss of longer duration time scales in the network dynamics. Conclusion The concepts of determinate motor programs and perceptual representations that are implicit in the present day understanding of ideomotor apraxia are assumptions inherent in the computational understanding of brain function. The strength of the present study using EAAs to model one aspect of ideomotor apraxia is the absence of these assumptions and a grounding of all sensorimotor interactions in an embodied, autonomous agent. The consistency of the hierarchical changes in the network dynamics across all apractic agents demonstrates that this technique is tenable and will be a valuable adjunct to a computational formalism in the understanding

Solid lipid nanoparticles as attractive drug vehicles: Composition, properties and therapeutic strategies.

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Geszke-Moritz, Małgorzata; Moritz, Michał

2016-11-01

This work briefly reviews up-to-date developments in solid lipid nanoparticles (SLNs) as effective nanocolloidal system for drug delivery. It summarizes SLNs in terms of their preparation, surface modification and properties. The application of SLNs as a carrier system enables to improve the therapeutic efficacy of drugs from various therapeutic groups. Present uses of SLNs include cancer therapy, dermatology, bacterial infections, brain targeting and eye disorders among others. The usage of SLNs provides enhanced pharmacokinetic properties and modulated release of drugs. SLN ubiquitous application results from their specific features such as possibility of surface modification, increased permeation through biological barriers, resistance to chemical degradation, possibility of co-delivery of various therapeutic agents or stimuli-responsiveness. This paper will be useful to the scientists working in the domain of SLN-based drug delivery systems. Copyright © 2016 Elsevier B.V. All rights reserved.

Therapeutic Targeting of CPT-11 Induced Diarrhea: A Case for Prophylaxis

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Swami, Umang; Goel, Sanjay; Mani, Sridhar

2014-01-01

CPT-11 (irinotecan), a DNA topoisomerase I inhibitor is one of the main treatments for colorectal cancer. The main dose limiting toxicities are neutropenia and late onset diarrhea. Though neutropenia is manageable, CPT-11 induced diarrhea is frequently severe, resulting in hospitalizations, dose reductions or omissions leading to ineffective treatment administration. Many potential agents have been tested in preclinical and clinical studies to prevent or ameliorate CPT-11 induced late onset diarrhea. It is predicted that prophylaxis of CPT-11 induced diarrhea will reduce sub-therapeutic dosing as well as hospitalizations and will eventually lead to dose escalations resulting in better response rates. This article reviews various experimental agents and strategies employed to prevent this debilitating toxicity. Covered topics include schedule/dose modification, intestinal alkalization, structural/chemical modification, genetic testing, anti-diarrheal therapies, transporter (ABCB1, ABCC2, BCRP2) inhibitors, enzyme (β-glucuronidase, UGT1A1, CYP3A4, carboxylesterase, COX-2) inducers and inhibitors, probiotics, antibiotics, adsorbing agents, cytokine and growth factor activators and inhibitors and other miscellaneous agents. PMID:23597015

Design and Application of an Intelligent Agent for Web Information Discovery

Institute of Scientific and Technical Information of China (English)

闵君; 冯珊; 唐超; 许立达

2003-01-01

With the propagation of applications on the internet, the internet has become a great information source which supplies users with valuable information. But it is hard for users to quickly acquire the right information on the web. This paper an intelligent agent for internet applications to retrieve and extract web information under user's guidance. The intelligent agent is made up of a retrieval script to identify web sources, an extraction script based on the document object model to express extraction process, a data translator to export the extracted information into knowledge bases with frame structures, and a data reasoning to reply users' questions. A GUI tool named Script Writer helps to generate the extraction script visually, and knowledge rule databases help to extract wanted information and to generate the answer to questions.

Therapeutic potential of the SARMs: revisiting the androgen receptor for drug discovery.

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Segal, Scott; Narayanan, Ramesh; Dalton, James T

2006-04-01

Selective androgen receptor modulators (SARMS) bind to the androgen receptor and demonstrate anabolic activity in a variety of tissues; however, unlike testosterone and other anabolic steroids, these nonsteroidal agents are able to induce bone and muscle growth, as well as shrinking the prostate. The potential of SARMS is to maximise the positive attributes of steroidal androgens as well as minimising negative effects, thus providing therapeutic opportunities in a variety of diseases, including muscle wasting associated with burns, cancer, end-stage renal disease, osteoporosis, frailty and hypogonadism. This review summarises androgen physiology, the current status of the R&D of SARMS and potential therapeutic indications for this emerging class of drugs.

Novel extractants with high selectivity for valuable metals in seawater. Calixarene derivatives

International Nuclear Information System (INIS)

Kakoi, Takahiko; Goto, Masahiro

1997-01-01

Seawater contains various valuable metals such as uranium and lithium. Therefore, attempts are being made to develop highly selective extractants which recognize target metal ions in reclaimed seawater. In this review, we have focused our study on the application of novel cyclic compound calixarene based extractants. A novel host compound calixarene, which is a cyclic compound connecting some phenol rings, is capable of forming several different extractant ring sizes and introducing various kinds of functional groups towards targeting of metal ions in seawater. Therefore, calixarene derivatives are capable of extracting valuable metals such as uranium, alkaline metals, heavy metals, rare earth metals and noble metals selectively by varying structural ring size and functional groups. The novel host compound calixarene has given promising results which line it up as a potential extractant for the separation of valuable metal ions in seawater. (author)

CATS-based Air Traffic Controller Agents

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Callantine, Todd J.

2002-01-01

This report describes intelligent agents that function as air traffic controllers. Each agent controls traffic in a single sector in real time; agents controlling traffic in adjoining sectors can coordinate to manage an arrival flow across a given meter fix. The purpose of this research is threefold. First, it seeks to study the design of agents for controlling complex systems. In particular, it investigates agent planning and reactive control functionality in a dynamic environment in which a variety perceptual and decision making skills play a central role. It examines how heuristic rules can be applied to model planning and decision making skills, rather than attempting to apply optimization methods. Thus, the research attempts to develop intelligent agents that provide an approximation of human air traffic controller behavior that, while not based on an explicit cognitive model, does produce task performance consistent with the way human air traffic controllers operate. Second, this research sought to extend previous research on using the Crew Activity Tracking System (CATS) as the basis for intelligent agents. The agents use a high-level model of air traffic controller activities to structure the control task. To execute an activity in the CATS model, according to the current task context, the agents reference a 'skill library' and 'control rules' that in turn execute the pattern recognition, planning, and decision-making required to perform the activity. Applying the skills enables the agents to modify their representation of the current control situation (i.e., the 'flick' or 'picture'). The updated representation supports the next activity in a cycle of action that, taken as a whole, simulates air traffic controller behavior. A third, practical motivation for this research is to use intelligent agents to support evaluation of new air traffic control (ATC) methods to support new Air Traffic Management (ATM) concepts. Current approaches that use large, human

Renal candidiasis in newborn: the ultrasonography as diagnostic and therapeutic method

International Nuclear Information System (INIS)

Lopez Pino, M.A.; Serrano Hernandez, C.; Alba Romero, C.; Aransay Bramtot, A.; Paul Diaz, L.

1995-01-01

We present a case of systemic candidiasis in a low-weight newborn. Renal involvement presented as unilateral hydronephrosis secondary to the fungal construction. Ultrasound served not only as a diagnostic tool, but as a guide for the performance of performance of percutaneous nephrostomy which was included in the therapeutic approach to decompress the excretory pathway and allow local installation of anti fungal agents. (Author) 16 refs

Neurosteroids in Schizophrenia: Pathogenic and Therapeutic Implications

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HuaLin Cai

2018-03-01

Full Text Available Neurosteroids are a group of important endogenous molecules affecting many neural functions in the brain. Increasing evidence suggests a possible role of these neurosteroids in the pathology and symptomatology of schizophrenia (SZ and other mental disorders. The aim of this review is to summarize the current knowledge about the neural functions of neurosteroids in the brain, and to evaluate the role of the key neurosteroids as candidate modulators in the etiology and therapeutics of SZ. The present paper provides a brief introduction of neurosteroid metabolism and distribution, followed by a discussion of the mechanisms underlying neurosteroid actions in the brain. The content regarding the modulation of the GABAA receptor is elaborated, given the considerable knowledge of its interactions with other neurotransmitter and neuroprotective systems, as well as its ameliorating effects on stress that may play a role in the SZ pathophysiology. In addition, several preclinical and clinical studies suggested a therapeutic benefit of neurosteroids in SZ patients, even though the presence of altered neurosteroid pathways in the circulating blood and/or brain remains debatable. Following treatment of antipsychotic drugs in SZ, therapeutic benefits have also been linked to the regulation of neurosteroid signaling. Specifically, the neurosteroids such as pregnenolone and dehydroepiandrosterone affect a broad spectrum of behavioral functions through their unique molecular characteristics and may represent innovative therapeutic targets for SZ. Future investigations in larger cohorts with long-term follow-ups will be required to ascertain the neuropsychopharmacological role of this yet unexploited class of neurosteroid agents.

Advances in Molecular Imaging of Locally Delivered Targeted Therapeutics for Central Nervous System Tumors

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Umberto Tosi

2017-02-01

Full Text Available Thanks to the recent advances in the development of chemotherapeutics, the morbidity and mortality of many cancers has decreased significantly. However, compared to oncology in general, the field of neuro-oncology has lagged behind. While new molecularly targeted chemotherapeutics have emerged, the impermeability of the blood–brain barrier (BBB renders systemic delivery of these clinical agents suboptimal. To circumvent the BBB, novel routes of administration are being applied in the clinic, ranging from intra-arterial infusion and direct infusion into the target tissue (convection enhanced delivery (CED to the use of focused ultrasound to temporarily disrupt the BBB. However, the current system depends on a “wait-and-see” approach, whereby drug delivery is deemed successful only when a specific clinical outcome is observed. The shortcomings of this approach are evident, as a failed delivery that needs immediate refinement cannot be observed and corrected. In response to this problem, new theranostic agents, compounds with both imaging and therapeutic potential, are being developed, paving the way for improved and monitored delivery to central nervous system (CNS malignancies. In this review, we focus on the advances and the challenges to improve early cancer detection, selection of targeted therapy, and evaluation of therapeutic efficacy, brought forth by the development of these new agents.

Advances in Molecular Imaging of Locally Delivered Targeted Therapeutics for Central Nervous System Tumors

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Tosi, Umberto; Marnell, Christopher S.; Chang, Raymond; Cho, William C.; Ting, Richard; Maachani, Uday B.; Souweidane, Mark M.

2017-01-01

Thanks to the recent advances in the development of chemotherapeutics, the morbidity and mortality of many cancers has decreased significantly. However, compared to oncology in general, the field of neuro-oncology has lagged behind. While new molecularly targeted chemotherapeutics have emerged, the impermeability of the blood–brain barrier (BBB) renders systemic delivery of these clinical agents suboptimal. To circumvent the BBB, novel routes of administration are being applied in the clinic, ranging from intra-arterial infusion and direct infusion into the target tissue (convection enhanced delivery (CED)) to the use of focused ultrasound to temporarily disrupt the BBB. However, the current system depends on a “wait-and-see” approach, whereby drug delivery is deemed successful only when a specific clinical outcome is observed. The shortcomings of this approach are evident, as a failed delivery that needs immediate refinement cannot be observed and corrected. In response to this problem, new theranostic agents, compounds with both imaging and therapeutic potential, are being developed, paving the way for improved and monitored delivery to central nervous system (CNS) malignancies. In this review, we focus on the advances and the challenges to improve early cancer detection, selection of targeted therapy, and evaluation of therapeutic efficacy, brought forth by the development of these new agents. PMID:28208698

The antioxidant paradox: what are antioxidants and how should they be used in a therapeutic context for cancer.

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Bonner, Michael Y; Arbiser, Jack L

2014-01-01

So-called antioxidants have yet to make a clinical impact on the treatment of human cancer. The reasons for this failure are several. First, many agents that are called antioxidants are truly antioxidants at a given dose, but this dose may not have been given in clinical trials. Second, many agents are not antioxidants at all. Third, not all tumors use reactive oxygen as a signaling mechanism. Finally, reactive oxygen inhibition is often insufficient to kill or regress a tumor cell by itself, but requires sequential introduction of a therapeutic agent for maximal effect. We hope to provide a framework for the logical use of these agents in cancer.

A Prokinetic Agent with a Dual Effect – Itopride – In the Treatment of Dysmotility

OpenAIRE

Petr Dite; Martin Rydlo; Milan Dockal; Arnost Martinek

2014-01-01

A wide range of dyspeptic symptoms in clinical practice reflect the high prevalence of functional disorders of the gastrointestinal (GI) tract. Prokinetic agents are the current mainstay in the therapy of functional dyspepsia. One of these drugs is itopride. We evaluated therapeutic efficacy of itopride according to the literature review. The therapeutic potential of itopride is connected with a dual effect: influencing of enzyme acetylcholinesterase activity and blocking dopamine D2 receptor...

Social Workers' Reflections on the Therapeutic Encounter With Elder Abuse and Neglect.

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Goldblatt, Hadass; Band-Winterstein, Tova; Alon, Sara

2016-02-24

The aim of this qualitative study was to explore social workers' reflections on their experience of the therapeutic encounter with victims and perpetrators of elder abuse and neglect. The research questions were as follows: How do social workers tune themselves toward the therapeutic encounter with elder abuse? How do they position themselves vis-à-vis the clients? How do social workers describe the meaning of the intervention both for the clients and for themselves? What is the added value of the therapeutic encounter in this field for the social workers? Participants were 17 experienced women social workers, who worked with abusers and with abused and neglected older adults in Israel. Data were collected via in-depth semi-structured interviews, which were later transcribed and content analyzed. Two main themes emerged from the findings, emphasizing two key aspects of the social workers' reflective process experienced during the therapeutic encounter: (a) focus on the client: "This is the journey of their lives"-reflection on the therapeutic "journey"; (b) focus on the social worker's inner and professional world: "'There is nothing to be done' is no longer in my vocabulary"-a personal and professional maturation process. The social workers expressed a positive attitude toward their elder clients. A unique dialogue developed in the therapeutic encounter, whereby the social workers considered any change as valuable if it allowed the elders a sense of control and self-worth, whereas the social workers were enriched by the elders' life experience, and matured both personally and professionally. Thus, both sides benefited from this reciprocal relationship. Implications for further research and practice are discussed. © The Author(s) 2016.

Oral (Systemic) Botanical Agents for the Treatment of Psoriasis: A Review.

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Farahnik, Benjamin; Sharma, Divya; Alban, Joseph; Sivamani, Raja

2017-06-01

Patients with psoriasis often use botanical therapies as part of their treatment. It is important for clinicians to be aware of the current evidence regarding these agents as they treat patients. A systematic literature search was conducted using the PubMed, MEDLINE, and EMBASE database for randomized clinical trials assessing the use of botanical therapeutics for psoriasis. The search included the following keywords: "psoriasis" and "plant" or "herbal" or "botanical." Citations within articles were also reviewed to identify relevant sources. The results were then further refined by route of administration, and the oral (systemic) botanical agents are reviewed herein. A total of 12 controlled and uncontrolled clinical trials addressing the use of oral, systemic botanical agents for psoriasis were assessed in this review. While overall evidence is limited in quantity and quality, HESA-A, curcumin, neem extract, and, to a lesser degree, Traditional Chinese Medicine seem to be the most efficacious agents. The literature addresses a large amount of studies in regards to botanicals for the treatment of psoriasis. While most agents appear to be safe, further research is necessary for evidence-based recommendation of oral botanical agents to psoriasis patients.

Acquired hemophilia A: a review of recent data and new therapeutic options.

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Franchini, Massimo; Vaglio, Stefania; Marano, Giuseppe; Mengoli, Carlo; Gentili, Sara; Pupella, Simonetta; Liumbruno, Giancarlo Maria

2017-10-01

Acquired hemophilia A (AHA) is a rare, but potentially life-threatening, bleeding disorder caused by an autoantibody against factor VIII that interferes with its coagulant function. We performed a narrative review focusing on the diagnostic aspects of AHA and on the current treatment strategies with particular regard to new data and therapeutic developments. The management of this severe hemorrhagic disorder is based on the control of bleeding with the use of bypassing agents and on the utilization of a variety of immunosuppressant agents with the goal of eliminating the autoantibody permanently. The optimal management of AHA should be multidisciplinary and requires a close collaboration between physicians from various specialties.

Gynecologic cancer treatment: risk factors for therapeutically induced neoplasia

International Nuclear Information System (INIS)

Messerschmidt, G.L.; Hoover, R.; Young, R.C.

1980-01-01

Therapeutic intervention in a course of illness, while producing the desired result, also may have some adverse long-term effects on the patient. Second malignancies are one of the known complications of therapy. The treatments of gynecologic cancers by surgery, irradiation and chemotherapy have been associated with subsequent neoplasms. The use of normal skin from the thigh to fabricate an artificial vagina has resulted in more squamous cell carcinomas than expected. Alkylating agents used in the treatment of ovarian cancer and other diseases have been shown to lead to an increased risk of leukemia. The incidence of lymphoma and uterine, urinary bladder and colon carcinomas has been associated with prior irradiation for gynecologic disease. The literature regarding the therapeutically induced risk factors in gynecologic therapy is reviewed and areas of our knowledge that require more investigation are identified

Is staged external fixation a valuable strategy for war injuries to the limbs?

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Lerner, Alexander; Fodor, Lucian; Soudry, Michael

2006-07-01

High-energy weapons or blast injuries usually result in substantial tissue damage and are serious medical and public health problems. We report our experience with staged external fixation for war injuries to the extremities. Forty-seven patients with 64 high-energy limb fractures caused by war weapons were retrospectively reviewed. The fractures were associated with severe soft tissue damage. There were 14 Gustilo-Anderson Type IIIA fractures, 40 Type IIIB fractures, and 10 Type IIIC fractures. Soft tissue débridement followed by axial realignment of the fractured bones with immediate skeletal stabilization using the AO/ASIF unilateral tubular external fixator was performed on the day of admission. The primary tubular fixators were exchanged 5 to 7 days later for Ilizarov frames. Delayed primary closure, skin grafts, or flaps were used for soft tissue coverage. The mean followup was 40 months, and the Ilizarov/hybrid external fixator was the definitive treatment in all patients. Bone union was achieved at an average of 8 months in 58 (90.6%) fractures. Three patients had nonunions and one patient required an amputation. Two patients were lost to followup. Staged external fixation is a valuable strategy for treatment of war injuries to the extremities. Therapeutic study, Level IV. See the Guidelines for Authors for a complete description of levels of evidence.

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

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Vera ePaefgen

2015-09-01

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

Investigation of Stilbenoids as Potential Therapeutic Agents for Rotavirus Gastroenteritis

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Judith M. Ball

2015-01-01

Full Text Available Rotavirus (RV infections cause severe diarrhea in infants and young children worldwide. Vaccines are available but cost prohibitive for many countries and only reduce severe symptoms. Vaccinated infants continue to shed infectious particles, and studies show decreased efficacy of the RV vaccines in tropical and subtropical countries where they are needed most. Continuing surveillance for new RV strains, assessment of vaccine efficacy, and development of cost effective antiviral drugs remain an important aspect of RV studies. This study was to determine the efficacy of antioxidant and anti-inflammatory stilbenoids to inhibit RV replication. Peanut (A. hypogaea hairy root cultures were induced to produce stilbenoids, which were purified by high performance countercurrent chromatography (HPCCC and analyzed by HPLC. HT29.f8 cells were infected with RV in the presence stilbenoids. Cell viability counts showed no cytotoxic effects on HT29.f8 cells. Viral infectivity titers were calculated and comparatively assessed to determine the effects of stilbenoid treatments. Two stilbenoids, trans-arachidin-1 and trans-arachidin-3, show a significant decrease in RV infectivity titers. Western blot analyses performed on the infected cell lysates complemented the infectivity titrations and indicated a significant decrease in viral replication. These studies show the therapeutic potential of the stilbenoids against RV replication.

Singing as a Therapeutic Agent, inThe Etude, 1891-1949.

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Hunter

1999-01-01

The Etude music magazine, founded by Theodore Presser, was one of a number of popular music magazines published in the years prior to the establishment of the music therapy profession in 1950. During its publication run from 1883 to 1957, over 100 music therapy related articles appeared, including 13 on the health benefits of singing published between 1891 and 1949. Written by authors with diverse backgrounds, such as the famous Battle Creek, Michigan physician John Harvey Kellogg and Boston music critic Louis C. Elson, the articles contained consistent and adamant support regarding the health benefits of singing. The advantages described were both physical and psychological, and were recommended prophylactically for well persons and therapeutically for ill persons. Although the articles varied in perspective, from philosophical to theoretical to pedagogical, there is a consistent holistic medicine theme that appeared almost ahead of its time and no doubt linked to the push for vocal music education in that era. The importance of The Etude in promulgating ideas that helped shape the early practice of music therapy should not be underestimated. For much of its publication run The Etude was the largest music periodical in print, reaching its peak circulation of 250,000 copies per month in 1924.

IMPACT web portal: oncology database integrating molecular profiles with actionable therapeutics.

Science.gov (United States)

Hintzsche, Jennifer D; Yoo, Minjae; Kim, Jihye; Amato, Carol M; Robinson, William A; Tan, Aik Choon

2018-04-20

With the advancement of next generation sequencing technology, researchers are now able to identify important variants and structural changes in DNA and RNA in cancer patient samples. With this information, we can now correlate specific variants and/or structural changes with actionable therapeutics known to inhibit these variants. We introduce the creation of the IMPACT Web Portal, a new online resource that connects molecular profiles of tumors to approved drugs, investigational therapeutics and pharmacogenetics associated drugs. IMPACT Web Portal contains a total of 776 drugs connected to 1326 target genes and 435 target variants, fusion, and copy number alterations. The online IMPACT Web Portal allows users to search for various genetic alterations and connects them to three levels of actionable therapeutics. The results are categorized into 3 levels: Level 1 contains approved drugs separated into two groups; Level 1A contains approved drugs with variant specific information while Level 1B contains approved drugs with gene level information. Level 2 contains drugs currently in oncology clinical trials. Level 3 provides pharmacogenetic associations between approved drugs and genes. IMPACT Web Portal allows for sequencing data to be linked to actionable therapeutics for translational and drug repurposing research. The IMPACT Web Portal online resource allows users to query genes and variants to approved and investigational drugs. We envision that this resource will be a valuable database for personalized medicine and drug repurposing. IMPACT Web Portal is freely available for non-commercial use at http://tanlab.ucdenver.edu/IMPACT .

Acquired thrombotic thrombocytopenic purpura: new therapeutic options and their optimal use.

Science.gov (United States)

Cataland, S R; Wu, H M

2015-06-01

Advances in our understanding of the pathophysiology of both congenital and acquired thrombotic thrombocytopenic purpura (TTP) have led to both an increased understanding of the disease and novel approaches to therapy. The efficacy of rituximab in acquired TTP has led to consideration of rituximab as a prophylactic therapy to prevent relapse of TTP. Novel therapies that target the A1 domain of von Willebrand factor (VWF) to block the formation of microthrombotic disease have also entered clinical study and have demonstrated promise as potential therapeutic options. Additionally, a recombinant ADAMTS13 protease has been developed which may be an important therapeutic option for both congenital and acquired TTP. The development of these new therapeutic options for patients diagnosed with TTP has increased the importance of conducting prospective, randomized studies with these agents to both confirm their efficacy and more importantly understand their most appropriate role in the treatment of patients with TTP. © 2015 International Society on Thrombosis and Haemostasis.

Alpha-1 antitrypsin: a potent anti-inflammatory and potential novel therapeutic agent.

LENUS (Irish Health Repository)

Bergin, David A

2012-04-01

Alpha-1 antitrypsin (AAT) has long been thought of as an important anti-protease in the lung where it is known to decrease the destructive effects of major proteases such as neutrophil elastase. In recent years, the perception of this protein in this simple one dimensional capacity as an anti-protease has evolved and it is now recognised that AAT has significant anti-inflammatory properties affecting a wide range of inflammatory cells, leading to its potential therapeutic use in a number of important diseases. This present review aims to discuss the described anti-inflammatory actions of AAT in modulating key immune cell functions, delineate known signalling pathways and specifically to identify the models of disease in which AAT has been shown to be effective as a therapy.

Therapeutic effects of saffron (Crocus sativus L. in digestive disorders: a review

Directory of Open Access Journals (Sweden)

Alireza Rezaee Khorasany

2016-05-01

Full Text Available Saffron, the dried red-orange stigmas of Crocus sativus L, has been known as a flavoring agent, food coloring and traditional herbal medicine. Pharmacological effects of saffron are mainly attributed to crocin, crocetin, picrocrocin and safranal. These components especially crocin, have significant effects including antidepressant and anticonvulsant, analgesic, anti-cancer and other therapeutic effects on different parts of our body namely cardiovascular, immune, respiratory, genital-urinary and central nervous system. According to the reports and findings, saffron plays a key role to cure different digestive system disorders via chemopreventive, inhibition of cell proliferation, induction of apoptosis, antioxidant effects and radical scavenging, genoprotective property, prevention of lipid peroxidation and anti-inflammatory processes. The outcome of the above mentioned mechanisms shows potential therapeutic properties of saffron against liver cancer, hepatotoxicity, fatty liver, hyperlipidemia, stomach cancer, peptic ulcer, colon cancer, ulcerative colitis, diabetes and pancreas cancer and ileum contractions. According to global statistics, the susceptibility to intestinal diseases is considered as a significant matter and can be important in health planning in any community. Several strategies for treatment and prevention of the digestive system diseases have provided that the use of herbal remedies seems effective and useful. Considering the available findings, the present study aims to introduce saffron as a prophylactic and therapeutic agent against gastrointestinal tract disorders. However, further clinical studies seem necessary in various aspects of saffron effects in different parts of body to verify these findings.

Recent developments in antiviral agents against enterovirus 71 infection.

Science.gov (United States)

Tan, Chee Wah; Lai, Jeffrey Kam Fatt; Sam, I-Ching; Chan, Yoke Fun

2014-02-12

Enterovirus 71 (EV-71) is the main etiological agent of hand, foot and mouth disease (HFMD). Recent EV-71 outbreaks in Asia-Pacific were not limited to mild HFMD, but were associated with severe neurological complications such as aseptic meningitis and brainstem encephalitis, which may lead to cardiopulmonary failure and death. The absence of licensed therapeutics for clinical use has intensified research into anti-EV-71 development. This review highlights the potential antiviral agents targeting EV-71 attachment, entry, uncoating, translation, polyprotein processing, virus-induced formation of membranous RNA replication complexes, and RNA-dependent RNA polymerase. The strategies for antiviral development include target-based synthetic compounds, anti-rhinovirus and poliovirus libraries screening, and natural compound libraries screening. Growing knowledge of the EV-71 life cycle will lead to successful development of antivirals. The continued effort to develop antiviral agents for treatment is crucial in the absence of a vaccine. The coupling of antivirals with an effective vaccine will accelerate eradication of the disease.

A Multi-Agent Control Architecture for a Robotic Wheelchair

Directory of Open Access Journals (Sweden)

C. Galindo

2006-01-01

Full Text Available Assistant robots like robotic wheelchairs can perform an effective and valuable work in our daily lives. However, they eventually may need external help from humans in the robot environment (particularly, the driver in the case of a wheelchair to accomplish safely and efficiently some tricky tasks for the current technology, i.e. opening a locked door, traversing a crowded area, etc. This article proposes a control architecture for assistant robots designed under a multi-agent perspective that facilitates the participation of humans into the robotic system and improves the overall performance of the robot as well as its dependability. Within our design, agents have their own intentions and beliefs, have different abilities (that include algorithmic behaviours and human skills and also learn autonomously the most convenient method to carry out their actions through reinforcement learning. The proposed architecture is illustrated with a real assistant robot: a robotic wheelchair that provides mobility to impaired or elderly people.

Possible role of common spices as a preventive and therapeutic agent for Alzheimer′s disease

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Omid Mirmosayyeb

2017-01-01

Full Text Available For centuries, spices have been consumed as food additives or medicinal agents. However, there is increasing evidence indicating the plant-based foods in regular diet may lower the risk of neurodegenerative diseases including Alzheimer disease. Spices, as one of the most commonly used plant-based food additives may provide more than just flavors, but as agents that may prevent or even halt neurodegenerative processes associated with aging. In this article, we review the role and application of five commonly used dietary spices including saffron turmeric, pepper family, zingiber, and cinnamon. Besides suppressing inflammatory pathways, these spices may act as antioxidant and inhibit acetyl cholinesterase and amyloid β aggregation. We summarized how spice-derived nutraceuticals mediate such different effects and what their molecular targets might be. Finally, some directions for future research are briefly discussed.

Aptámeros: agentes diagnósticos y terapéuticos = Aptamers: diagnostic and therapeutic agents

Directory of Open Access Journals (Sweden)

Frank J Hernandez

2012-04-01

Full Text Available Los aptámeros son ácidos nucleicos de cadena sencilla, ADN o ARN, que reconocen una gran variedad de moléculas. Cada aptámero posee una estructura tridimensional particular que le permite unirse con afinidad y especificidad altas a la molécula diana. Los aptámeros tienen propiedades de reconocimiento equiparables a las de los anticuerpos; sin embargo, por la naturaleza de su composición tienen ventajas significativas en cuanto a su tamaño, producción y modificación. Estas características los hacen excelentes candidatos para el desarrollo de nuevas plataformas biotecnológicas. Se han identificado aptámeros con propiedades terapéuticas que han sido evaluados exitosamente en modelos animales; entre ellos, algunos se encuentran en fase clínica y uno ya fue aprobado para tratamiento por la FDA (Food and Drug Administration. Todos estos avances ocurridos durante las dos últimas décadas permiten anticipar el protagonismo que tendrán los aptámeros como agentes diagnósticos y terapéuticos en un futuro cercano.

Nanocomposite scaffolds with tunable mechanical and degradation capabilities: co-delivery of bioactive agents for bone tissue engineering.

Science.gov (United States)

Cattalini, Juan P; Roether, Judith; Hoppe, Alexander; Pishbin, Fatemeh; Haro Durand, Luis; Gorustovich, Alejandro; Boccaccini, Aldo R; Lucangioli, Silvia; Mouriño, Viviana

2016-10-21

Novel multifunctional nanocomposite scaffolds made of nanobioactive glass and alginate crosslinked with therapeutic ions such as calcium and copper were developed for delivering therapeutic agents, in a highly controlled and sustainable manner, for bone tissue engineering. Alendronate, a well-known antiresorptive agent, was formulated into microspheres under optimized conditions and effectively loaded within the novel multifunctional scaffolds with a high encapsulation percentage. The size of the cation used for the alginate crosslinking impacted directly on porosity and viscoelastic properties, and thus, on the degradation rate and the release profile of copper, calcium and alendronate. According to this, even though highly porous structures were created with suitable pore sizes for cell ingrowth and vascularization in both cases, copper-crosslinked scaffolds showed higher values of porosity, elastic modulus, degradation rate and the amount of copper and alendronate released, when compared with calcium-crosslinked scaffolds. In addition, in all cases, the scaffolds showed bioactivity and mechanical properties close to the endogenous trabecular bone tissue in terms of viscoelasticity. Furthermore, the scaffolds showed osteogenic and angiogenic properties on bone and endothelial cells, respectively, and the extracts of the biomaterials used promoted the formation of blood vessels in an ex vivo model. These new bioactive nanocomposite scaffolds represent an exciting new class of therapeutic cell delivery carrier with tunable mechanical and degradation properties; potentially useful in the controlled and sustainable delivery of therapeutic agents with active roles in bone formation and angiogenesis, as well as in the support of cell proliferation and osteogenesis for bone tissue engineering.

Power in the hypnotic relationship: therapeutic or abusive?

Science.gov (United States)

Walling, D P; Levine, R E

1997-01-01

The unique relationship between hypnotist and subject has been theorized as one explanation for the effectiveness of hypnosis. This relationship carries a power differential, present in most therapeutic relationships, but accentuated by hypnosis. The power differential is sometimes perceived as the ability of the hypnotist to control the subject. Perceptions of hypnosis offered by stage hypnotists, the popular media, and some clinicians perpetuate the notion that the hypnotist has the ability to exert undue influence upon the client. The present article examines the relationship between hypnotist and subject focusing on issues of power and control. The authors examine the unique dynamics accompanying the use of hypnosis and their impact on the therapeutic dyad. Evidence is offered demonstrating the power differential, and how this differential can serve as either a positive or negative agent of change. Therapists should be aware of the dynamics created by using hypnosis. Implications for training therapists in the use of hypnosis are suggested.

Current and Emerging Topical Antibacterials and Antiseptics: Agents, Action, and Resistance Patterns.

Science.gov (United States)

Williamson, Deborah A; Carter, Glen P; Howden, Benjamin P

2017-07-01

Bacterial skin infections represent some of the most common infectious diseases globally. Prevention and treatment of skin infections can involve application of a topical antimicrobial, which may be an antibiotic (such as mupirocin or fusidic acid) or an antiseptic (such as chlorhexidine or alcohol). However, there is limited evidence to support the widespread prophylactic or therapeutic use of topical agents. Challenges involved in the use of topical antimicrobials include increasing rates of bacterial resistance, local hypersensitivity reactions (particularly to older agents, such as bacitracin), and concerns about the indiscriminate use of antiseptics potentially coselecting for antibiotic resistance. We review the evidence for the major clinical uses of topical antibiotics and antiseptics. In addition, we review the mechanisms of action of common topical agents and define the clinical and molecular epidemiology of antimicrobial resistance in these agents. Moreover, we review the potential use of newer and emerging agents, such as retapamulin and ebselen, and discuss the role of antiseptic agents in preventing bacterial skin infections. A comprehensive understanding of the clinical efficacy and drivers of resistance to topical agents will inform the optimal use of these agents to preserve their activity in the future. Copyright © 2017 American Society for Microbiology.

Screening of Anti-Obesity Agent from Herbal Mixtures

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Sung-Kee Jo

2012-03-01

Full Text Available Globally, one in three of the World’s adults are overweight and one in 10 is obese. By 2015, World Health Organization (WHO estimates the number of chubby adults will balloon to 2.3 billion—Equal to the combined populations of China, Europe and the United States. The discovery of bioactive compounds from herbs is one possible way to control obesity and to prevent or reduce the risks of developing various obesity-related diseases. In this study, we screened anti-obesity agents such as methyl gallate from the herbal composition known as HemoHIM that actively inhibits lipid formation as evidenced by Oil Red O staining and triglyceride (TG contents in 3T3-L1 adipocytes, suggesting their use as an anti-obesity agent. Furthermore, the amount of glycerol released from cells into the medium had increased by treatment of methyl gallate in a concentration-dependent manner. The present study suggests that a promising anti-obesity agent like methyl gallate might be of therapeutic interest for the treatment of obesity.

Screening of anti-obesity agent from herbal mixtures.

Science.gov (United States)

Roh, Changhyun; Jung, Uhee; Jo, Sung-Kee

2012-03-23

Globally, one in three of the World's adults are overweight and one in 10 is obese. By 2015, World Health Organization (WHO) estimates the number of chubby adults will balloon to 2.3 billion--Equal to the combined populations of China, Europe and the United States. The discovery of bioactive compounds from herbs is one possible way to control obesity and to prevent or reduce the risks of developing various obesity-related diseases. In this study, we screened anti-obesity agents such as methyl gallate from the herbal composition known as HemoHIM that actively inhibits lipid formation as evidenced by Oil Red O staining and triglyceride (TG) contents in 3T3-L1 adipocytes, suggesting their use as an anti-obesity agent. Furthermore, the amount of glycerol released from cells into the medium had increased by treatment of methyl gallate in a concentration-dependent manner. The present study suggests that a promising anti-obesity agent like methyl gallate might be of therapeutic interest for the treatment of obesity.

Towards new therapeutic approaches for malignant melanoma.

Science.gov (United States)

Pacheco, Ivan; Buzea, Cristina; Tron, Victor

2011-11-01

Recent progress in understanding the molecular mechanisms of the initiation and progression of melanoma has created new opportunities for developing novel therapeutic modalities to manage this potentially lethal disease. Although at first glance, melanoma carcinogenesis appears to be a chaotic system, it is indeed, arguably, a deterministic multistep process involving sequential alterations of proto-oncogenes, tumour suppressors and miRNA genes. The scope of this article is to discuss the most recent and significant advances in melanoma molecular therapeutics. It is apparent that using single agents targeting solely individual melanoma pathways might be insufficient for long-term survival. However, the outstanding results on melanoma survival observed with novel selective inhibitors of B-RAF, such as PLX4032 give hope that melanoma can be cured. The fact that melanoma develops acquired resistance to PLX4032 emphasises the importance of simultaneously targeting several pathways. Because the most striking feature of melanoma is its unsurpassed ability to metastasise, it is important to implement newer systems for drug delivery adapted from research on stem cells and nanotechnology.

Dried blood spot analysis for therapeutic drug monitoring of linezolid in patients with multidrug-resistant tuberculosis

NARCIS (Netherlands)

Vu, D H; Bolhuis, M S; Koster, R A; Greijdanus, B; de Lange, W C M; van Altena, R; Brouwers, J R B J; Uges, D R A; Alffenaar, J W C

2012-01-01

Linezolid is a promising antimicrobial agent for the treatment of multidrug-resistant tuberculosis (MDR-TB), but its use is limited by toxicity. Therapeutic drug monitoring (TDM) may help to minimize toxicity while adequate drug exposure is maintained. Conventional plasma sampling and monitoring

Therapeutic embolization in pulmonary hemorrhage

International Nuclear Information System (INIS)

Gasparini, D.

1989-01-01

The author's purpose was to evaluate the efficacy of therapeutic embolization in pulmonary hemorrage performed with fibrin foam (Spongostan) suspended in sclerosing agents (hidroxy-poliethoxy-dodecano 3%, or natrium morruate 5%), and electrocoagulation (Bitrol, spa) as an alternative to surgery. Twenty patients were embolized: 17 with fibrin foam and sclerosing agents only, 2 with the addition of electrocoagulation and a Gianturco coil respectively, and 1 with electrocoagulation alone. The follow-up ranges from 3 to 42 months (average 22). A patient affected by aspergilloma died a few days after hemoptysis. The patient treated by electrocoagulation alone suffers from periodical hematic expectoration (spitting). The remaining 18 patients have not shown any pathological findings. In 2 cases the arterial occlusion was confirmed by angiography, while in 1 case partial arterial recanalization was observed. Such a finding was due to the vessel dimensions and to hyperflux values. In similar cases, obstruction must be completed different techniques (e.g. Gianturco coils, electrocoagulation, detachable balloons, etc.). The absence of flux resulting from embolization improves electrocoagulation efficiency, which should be considered as the technique of choice. Even though additional trials are needed, the techniques have proven quite reliable and suitable to replace surgery in low-aggression lesions

Therapeutic Options for the Management of the Cardiorenal Syndrome

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Katerina Koniari

2011-01-01

Full Text Available Patients with heart failure often present with impaired renal function, which is a predictor of poor outcome. The cardiorenal syndrome is the worsening of renal function, which is accelerated by worsening of heart failure or acute decompensated heart failure. Although it is a frequent clinical entity due to the improved survival of heart failure patients, still its pathophysiology is not well understood, and thus its therapeutic approach remains controversial and sometimes ineffective. Established therapeutic strategies, such as diuretics and inotropes, are often associated with resistance and limited clinical success. That leads to an increasing concern about novel options, such as the use of vasopressin antagonists, adenosine A1 receptor antagonists, and renal-protective dopamine. Initial clinical trials have shown quite encouraging results in some heart failure subpopulations but have failed to demonstrate a clear beneficial role of these agents. On the other hand, ultrafiltration appears to be a more promising therapeutic procedure that will improve volume regulation, while preserving renal and cardiac function. Further clinical studies are required in order to determine their net effect on renal function and potential cardiovascular outcomes. Until then, management of the cardiorenal syndrome remains quite empirical.

Field Trips as Valuable Learning Experiences in Geography Courses

Science.gov (United States)

Krakowka, Amy Richmond

2012-01-01

Field trips have been acknowledged as valuable learning experiences in geography. This article uses Kolb's (1984) experiential learning model to discuss how students learn and how field trips can help enhance learning. Using Kolb's experiential learning theory as a guide in the design of field trips helps ensure that field trips contribute to…

Molecular hydrogen in sports medicine: new therapeutic perspectives.

Science.gov (United States)

Ostojic, S M

2015-04-01

In the past 2 decades, molecular hydrogen emerged as a novel therapeutic agent, with antioxidant, anti-inflammatory and anti-apoptotic effects demonstrated in plethora of animal disease models and human studies. Beneficial effects of molecular hydrogen in clinical environment are observed especially in oxidative stress-mediated diseases, such as diabetes mellitus, brain stem infarction, rheumatoid arthritis, or neurodegenerative diseases. A number of more recent studies have reported that molecular hydrogen affects cell signal transduction and acts as an alkalizing agent, with these newly identified mechanisms of action having the potential to widen its application in clinical medicine even further. In particular, hydrogen therapy may be an effective and specific innovative treatment for exercise-induced oxidative stress and sports injury, with potential for the improvement of exercise performance. This review will summarize recent research findings regarding the clinical aspects of molecular hydrogen use, emphasizing its application in the field of sports medicine. © Georg Thieme Verlag KG Stuttgart · New York.

Therapeutic Effect of Caffeine Treatment Immediately Following Neonatal Hypoxic-Ischemic Injury on Spatial Memory in Male Rats

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R. Holly Fitch

2013-03-01

Full Text Available Hypoxia Ischemia (HI refers to the disruption of blood and/or oxygen delivery to the brain. Term infants suffering perinatal complications that result in decreased blood flow and/or oxygen delivery to the brain are at risk for HI. Among a variety of developmental delays in this population, HI injured infants demonstrate subsequent memory deficits. The Rice-Vannucci rodent HI model can be used to explore behavioral deficits following early HI events, as well as possible therapeutic agents to help reduce deleterious outcomes. Caffeine is an adenosine receptor antagonist that has recently shown promising results as a therapeutic agent following HI injury. The current study sought to investigate the therapeutic benefit of caffeine following early HI injury in male rats. On post-natal day (P 7, HI injury was induced (cauterization of the right common carotid artery, followed by two hours of 8% oxygen. Male sham animals received only a midline incision with no manipulation of the artery followed by room air exposure for two hours. Subsets of HI and sham animals then received either an intraperitoneal (i.p. injection of caffeine (10 mg/kg, or vehicle (sterile saline immediately following hypoxia. All animals later underwent testing on the Morris Water Maze (MWM from P90 to P95. Results show that HI injured animals (with no caffeine treatment displayed significant deficits on the MWM task relative to shams. These deficits were attenuated by caffeine treatment when given immediately following the induction of HI. We also found a reduction in right cortical volume (ipsilateral to injury in HI saline animals as compared to shams, while right cortical volume in the HI caffeine treated animals was intermediate. These findings suggest that caffeine is a potential therapeutic agent that could be used in HI injured infants to reduce brain injury and preserve subsequent cognitive function.

Monoclonal Antibody Fragments for Targeting Therapeutics to Growth Plate Cartilage | NCI Technology Transfer Center | TTC

Science.gov (United States)

Researchers at The Eunice Kennedy Shriver National Institute on Child Health and Human Development (NICHD) have discovered monoclonal antibodies that bind to matrilin-3, a protein specifically expressed in cartilage tissue, that could be used for treating or inhibiting growth plate disorders, such as a skeletal dysplasia or short stature. The monoclonal antibodies can also be used to target therapeutic agents, such as anti-arthritis agents, to cartilage tissue. NICHD seeks statements of capability or interest from parties interested in collaborative research to co-develop, evaluate, or commercialize treatment of skeletal disorders using targeting antibodies.

Designer exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson's disease treatment.

Science.gov (United States)

Kojima, Ryosuke; Bojar, Daniel; Rizzi, Giorgio; Hamri, Ghislaine Charpin-El; El-Baba, Marie Daoud; Saxena, Pratik; Ausländer, Simon; Tan, Kelly R; Fussenegger, Martin

2018-04-03

Exosomes are cell-derived nanovesicles (50-150 nm), which mediate intercellular communication, and are candidate therapeutic agents. However, inefficiency of exosomal message transfer, such as mRNA, and lack of methods to create designer exosomes have hampered their development into therapeutic interventions. Here, we report a set of EXOsomal transfer into cells (EXOtic) devices that enable efficient, customizable production of designer exosomes in engineered mammalian cells. These genetically encoded devices in exosome producer cells enhance exosome production, specific mRNA packaging, and delivery of the mRNA into the cytosol of target cells, enabling efficient cell-to-cell communication without the need to concentrate exosomes. Further, engineered producer cells implanted in living mice could consistently deliver cargo mRNA to the brain. Therapeutic catalase mRNA delivery by designer exosomes attenuated neurotoxicity and neuroinflammation in in vitro and in vivo models of Parkinson's disease, indicating the potential usefulness of the EXOtic devices for RNA delivery-based therapeutic applications.

Copper-64 Dichloride as Theranostic Agent for Glioblastoma Multiforme: A Preclinical Study

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Cristina Ferrari

2015-01-01

Full Text Available Glioblastoma multiforme (GBM is the most common primary malignant brain tumor in adults with a median survival time less than one year. To date, there are only a limited number of effective agents available for GBM therapy and this does not seem to add much survival advantage over the conventional approach based on surgery and radiotherapy. Therefore, the development of novel therapeutic approaches to GBM is essential and those based on radionuclide therapy could be of significant clinical impact. Experimental evidence has clearly demonstrated that cancer cells have a particularly high fractional content of copper inside the nucleus compared to normal cells. This behavior can be conveniently exploited both for diagnosis and for delivering therapeutic payloads (theranostic of the radionuclide copper-64 into the nucleus of cancerous cells by intravenous administration of its simplest chemical form as dichloride salt [64Cu]CuCl2. To evaluate the potential theranostic role of [64Cu]CuCl2 in GBM, the present work reports results from a preclinical study carried out in a xenografted GBM tumor mouse model. Biodistribution data of this new agent were collected using a small-animal PET tomograph. Subsequently, groups of tumor implanted nude mice were treated with [64Cu]CuCl2 to simulate single- and multiple-dose therapy protocols, and results were analyzed to estimate therapeutic efficacy.

Biological and therapeutic activities, and anticancer properties of curcumin.

Science.gov (United States)

Perrone, Donatella; Ardito, Fatima; Giannatempo, Giovanni; Dioguardi, Mario; Troiano, Giuseppe; Lo Russo, Lucio; DE Lillo, Alfredo; Laino, Luigi; Lo Muzio, Lorenzo

2015-11-01

Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant. Curcumin has been used extensively in Ayurvedic medicine, as it is nontoxic and exhibits a variety of therapeutic properties, including antioxidant, analgesic, anti-inflammatory and antiseptic activities. Recently, certain studies have indicated that curcumin may exert anticancer effects in a variety of biological pathways involved in mutagenesis, apoptosis, tumorigenesis, cell cycle regulation and metastasis. The present study reviewed previous studies in the literature, which support the therapeutic activity of curcumin in cancer. In addition, the present study elucidated a number of the challenges concerning the use of curcumin as an adjuvant chemotherapeutic agent. All the studies reviewed herein suggest that curcumin is able to exert anti-inflammatory, antiplatelet, antioxidative, hepatoprotective and antitumor activities, particularly against cancers of the liver, skin, pancreas, prostate, ovary, lung and head neck, as well as having a positive effect in the treatment of arthritis.

Promising novel therapeutic approaches in the management of gastrointestinal stromal tumors.

Science.gov (United States)

Szucs, Zoltan; Thway, Khin; Fisher, Cyril; Bulusu, Ramesh; Constantinidou, Anastasia; Benson, Charlotte; van der Graaf, Winette Ta; Jones, Robin L

2017-01-01

Primary and secondary resistance to currently available licensed tyrosine kinase inhibitors poses a real clinical challenge in the management of advanced gastrointestinal stromal tumors. Within the frame of early phase clinical trials novel systemic treatments are currently being evaluated to target both the well explored and novel emerging downstream effectors of KIT and PDGFRA signaling. Alternative therapeutic approaches also include exploring novel inhibitors of the KIT/PDGFRA receptors, immune checkpoint and cyclin-dependent kinase inhibitors. The final clinical trial outcome data for these agents are highly anticipated. Integration of new diagnostic techniques into routine clinical practice can potentially guide tailored delivery of agents in the treatment of a highly polyclonal, heterogeneous disease such as heavily pretreated advanced gastrointestinal stromal tumor.

Alkylating chemotherapeutic agents cyclophosphamide and melphalan cause functional injury to human bone marrow-derived mesenchymal stem cells.

Science.gov (United States)

Kemp, Kevin; Morse, Ruth; Sanders, Kelly; Hows, Jill; Donaldson, Craig

2011-07-01

The adverse effects of melphalan and cyclophosphamide on hematopoietic stem cells are well-known; however, the effects on the mesenchymal stem cells (MSCs) residing in the bone marrow are less well characterised. Examining the effects of chemotherapeutic agents on patient MSCs in vivo is difficult due to variability in patients and differences in the drug combinations used, both of which could have implications on MSC function. As drugs are not commonly used as single agents during high-dose chemotherapy (HDC) regimens, there is a lack of data comparing the short- or long-term effects these drugs have on patients post treatment. To help address these problems, the effects of the alkylating chemotherapeutic agents cyclophosphamide and melphalan on human bone marrow MSCs were evaluated in vitro. Within this study, the exposure of MSCs to the chemotherapeutic agents cyclophosphamide or melphalan had strong negative effects on MSC expansion and CD44 expression. In addition, changes were seen in the ability of MSCs to support hematopoietic cell migration and repopulation. These observations therefore highlight potential disadvantages in the use of autologous MSCs in chemotherapeutically pre-treated patients for future therapeutic strategies. Furthermore, this study suggests that if the damage caused by chemotherapeutic agents to marrow MSCs is substantial, it would be logical to use cultured allogeneic MSCs therapeutically to assist or repair the marrow microenvironment after HDC.

Nanoparticles as conjugated delivery agents for therapeutic applications

Science.gov (United States)

Muroski, Megan Elizabeth

This dissertation explores the use of nanoparticles as conjugated delivery agents. Chapter 1 is a general introduction. Chapter 2 discusses the delivery by a nanoparticle platform provides a method to manipulate gene activation, by taking advantage of the high surface area of a nanoparticle and the ability to selectively couple a desired biological moiety to the NP surface. The nanoparticle based transfection approach functions by controlled release of gene regulatory elements from a 6 nm AuNP (gold nanoparticle) surface. The endosomal release of the regulatory elements from the nanoparticle surface results in endogenous protein knockdown simultaneously with exogenous protein expression for the first 48 h. The use of fluorescent proteins as the endogenous and exogenous signals for protein expression enables the efficiency of co-delivery of siRNA (small interfering RNA) for GFP (green fluorescent protein) knockdown and a dsRed-express linearized plasmid for induction to be optically analyzed in CRL-2794, a human kidney cell line expressing an unstable green fluorescent protein. Delivery of the bimodal nanoparticle in cationic liposomes results in 20% GFP knockdown within 24 h of delivery and continues exhibiting knockdown for up to 48 h for the bimodal agent. Simultaneous dsRed expression is observed to initiate within the same time frame with expression levels reaching 34% after 25 days although cells have divided approximately 20 times, implying daughter cell transfection has occurred. Fluorescence cell sorting results in a stable colony, as demonstrated by Western blot analysis. The simultaneous delivery of siRNA and linearized plasmid DNA on the surface of a single nanocrystal provides a unique method for definitive genetic control within a single cell and leads to a very efficient cell transfection protocol. In Chapter 3, we wanted to understand the NP complex within the cell, and to look at the dynamics of release utilizing nanometal surface energy transfer as

Immunomodulators as Therapeutic Agents in Mitigating the Progression of Parkinson’s Disease

Directory of Open Access Journals (Sweden)

Bethany Grimmig

2016-09-01

Full Text Available Parkinson’s disease (PD is a common neurodegenerative disorder that primarily afflicts the elderly. It is characterized by motor dysfunction due to extensive neuron loss in the substantia nigra pars compacta. There are multiple biological processes that are negatively impacted during the pathogenesis of PD, and are implicated in the cell death in this region. Neuroinflammation is evidently involved in PD pathology and mitigating the inflammatory cascade has been a therapeutic strategy. Age is the number one risk factor for PD and thus needs to be considered in the context of disease pathology. Here, we discuss the role of neuroinflammation within the context of aging as it applies to the development of PD, and the potential for two representative compounds, fractalkine and astaxanthin, to attenuate the pathophysiology that modulates neurodegeneration that occurs in Parkinson’s disease.

Chalcones and their therapeutic targets for the management of diabetes: structural and pharmacological perspectives.

Science.gov (United States)

Mahapatra, Debarshi Kar; Asati, Vivek; Bharti, Sanjay Kumar

2015-03-06

Diabetes Mellitus (DM) is the fastest growing metabolic disorder affecting about 387 million people across the globe and is estimated to affect 592 million people by year 2030. The search for newer anti-diabetic agents is the foremost need to control the accelerating diabetic population. Several natural and (semi) synthetic chalcones deserve the credit of being potential candidates that act by modulating the therapeutic targets PPAR-γ, DPP-4, α-glucosidase, PTP1B, aldose reductase, and stimulate insulin secretion and tissue sensitivity. In this review, a comprehensive study (from January 1977 to October 2014) of anti-diabetic chalcones, their molecular targets, structure activity relationships (SARs), mechanism of actions (MOAs) and patents have been described. The compounds which showed promising activity and have a well-defined MOAs, SARs must be considered as prototype for the design and development of potential anti-diabetic agents. They should be evaluated critically at all clinical stages to ensure their therapeutic and toxicological profile to meet the demand of diabetics. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

MIDAS: a practical Bayesian design for platform trials with molecularly targeted agents.

Science.gov (United States)

Yuan, Ying; Guo, Beibei; Munsell, Mark; Lu, Karen; Jazaeri, Amir

2016-09-30

Recent success of immunotherapy and other targeted therapies in cancer treatment has led to an unprecedented surge in the number of novel therapeutic agents that need to be evaluated in clinical trials. Traditional phase II clinical trial designs were developed for evaluating one candidate treatment at a time and thus not efficient for this task. We propose a Bayesian phase II platform design, the multi-candidate iterative design with adaptive selection (MIDAS), which allows investigators to continuously screen a large number of candidate agents in an efficient and seamless fashion. MIDAS consists of one control arm, which contains a standard therapy as the control, and several experimental arms, which contain the experimental agents. Patients are adaptively randomized to the control and experimental agents based on their estimated efficacy. During the trial, we adaptively drop inefficacious or overly toxic agents and 'graduate' the promising agents from the trial to the next stage of development. Whenever an experimental agent graduates or is dropped, the corresponding arm opens immediately for testing the next available new agent. Simulation studies show that MIDAS substantially outperforms the conventional approach. The proposed design yields a significantly higher probability for identifying the promising agents and dropping the futile agents. In addition, MIDAS requires only one master protocol, which streamlines trial conduct and substantially decreases the overhead burden. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

The pharmacology and toxicology of three new biologic agents used in pulmonary medicine.

Science.gov (United States)

Albertson, T E; Walby, W F; Allen, R P; Tharratt, R S

1995-01-01

Biological agents have played an important role in the evolution of modern medical therapeutics. Recent advances in biologicals have in part been stimulated by the biotechnology revolution seen over the last several years. Toxicologists need to be aware of the proposed mechanisms and approved and experimental uses of these new biologic agents. Further, controversies about their use, efficacy, cost issues and potential toxicities should be known. Often these drugs are designed for small patient populations thus limiting the availability of human toxicological data bases. This paper reviews the pharmacology and toxicology of three new biologics (recombinant human DNase I, alpha 1-protease inhibitor, and nitric oxide). These agents appear to have important roles in treating specific diseases or disease states seen in pulmonary medicine.

Patients' experiences with technology during inpatient rehabilitation: opportunities to support independence and therapeutic engagement.

Science.gov (United States)

Fager, Susan Koch; Burnfield, Judith M

2014-03-01

To understand individuals' perceptions of technology use during inpatient rehabilitation. A qualitative phenomenological study using semi-structured interviews of 10 individuals with diverse underlying diagnoses and/or a close family member who participated in inpatient rehabilitation. Core themes focused on assistive technology usage (equipment set-up, reliability and fragility of equipment, expertise required to use assistive technology and use of mainstream technologies) and opportunities for using technology to increase therapeutic engagement (opportunities for practice outside of therapy, goals for therapeutic exercises and technology for therapeutic exercises: motivation and social interaction). Interviews revealed the need for durable, reliable and intuitive technology without requiring a high level of expertise to install and implement. A strong desire for the continued use of mainstream devices (e.g. cell phones, tablet computers) reinforces the need for a wider range of access options for those with limited physical function. Finally, opportunities to engage in therapeutically meaningful activities beyond the traditional treatment hours were identified as valuable for patients to not only improve function but to also promote social interaction. Assistive technology increases functional independence of severely disabled individuals. End-users (patients and families) identified a need for designs that are durable, reliable, intuitive, easy to consistently install and use. Technology use (adaptive or commercially available) provides a mechanism to extend therapeutic practice beyond the traditional therapy day. Adapting skeletal tracking technology used in gaming software could automate exercise tracking, documentation and feedback for patient motivation and clinical treatment planning and interventions.

[Therapeutic approaches to improve blood glucose control in a patient with type 2 diabetes on a metformin-sulfonylurea combination].

Science.gov (United States)

Scheen, A J; Paquot, N

2011-04-01

Beyond lifestyle changes, the management of type 2 diabetes comprises the administration of oral glucose-lowering agents, especially the classical metformin-sulfonylurea combination. If such a dual oral therapy could not (any more) obtain an adequate glucose control, intensified management becomes mandatory. Several therapeutic approaches may be proposed at this stage, with some advantages and disadvantages of each of them. The present clinical case aims at illustrating such difficult therapeutic choice. We will provide the pro-contra arguments concerning each therapeutic alternative and describe the practical modalities of an appropriate management according to the patient's characteristics.

Combination Therapy With Histone Deacetylase Inhibitors (HDACi for the Treatment of Cancer: Achieving the Full Therapeutic Potential of HDACi

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Amila Suraweera

2018-03-01

Full Text Available Genetic and epigenetic changes in DNA are involved in cancer development and tumor progression. Histone deacetylases (HDACs are key regulators of gene expression that act as transcriptional repressors by removing acetyl groups from histones. HDACs are dysregulated in many cancers, making them a therapeutic target for the treatment of cancer. Histone deacetylase inhibitors (HDACi, a novel class of small-molecular therapeutics, are now approved by the Food and Drug Administration as anticancer agents. While they have shown great promise, resistance to HDACi is often observed and furthermore, HDACi have shown limited success in treating solid tumors. The combination of HDACi with standard chemotherapeutic drugs has demonstrated promising anticancer effects in both preclinical and clinical studies. In this review, we summarize the research thus far on HDACi in combination therapy, with other anticancer agents and their translation into preclinical and clinical studies. We additionally highlight the side effects associated with HDACi in cancer therapy and discuss potential biomarkers to either select or predict a patient’s response to these agents, in order to limit the off-target toxicity associated with HDACi.

The Botulinum Toxin as a Therapeutic Agent: Molecular Structure and Mechanism of Action in Motor and Sensory Systems.

Science.gov (United States)

Kumar, Raj; Dhaliwal, Harkiran Preet; Kukreja, Roshan Vijay; Singh, Bal Ram

2016-02-01

Botulinum neurotoxin (BoNT) produced by Clostridium botulinum is the most potent molecule known to mankind. Higher potency of BoNT is attributed to several factors, including structural and functional uniqueness, target specificity, and longevity. Although BoNT is an extremely toxic molecule, it is now increasingly used for the treatment of disorders related to muscle hyperactivity and glandular hyperactivity. Weakening of muscles due to peripheral action of BoNT produces a therapeutic effect. Depending on the target tissue, BoNT can block the cholinergic neuromuscular or cholinergic autonomic innervation of exocrine glands and smooth muscles. In recent observations of the analgesic properties of BoNT, the toxin modifies the sensory feedback loop to the central nervous system. Differential effects of BoNT in excitatory and inhibitory neurons provide a unique therapeutic tool. In this review the authors briefly summarize the structure and mechanism of actions of BoNT on motor and sensory neurons to explain its therapeutic effects and future potential. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Change Agent – A Force Generating Resistance To Change Within An Organization?

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Mariana Prediscan

2012-12-01

Full Text Available The purpose of this research is to identify if the change agent represents or not a force generating resistance to change within an organization. The employees affected by a change process are usually the ones who oppose to new implementations. Their opposition is bigger or smaller, depending on the extent that they are affected and also by the direction, either positive or negative. However, employee’s opposition can be potentiated or reduced, depending on the manifestation of the following forces within an organization: communications, the type of organizational structure, management style and organizational culture, forces which refer to the organizational climate. To answer our question, we have researched the current literature and discovered that the change agent can represent a force generating resistance to change within an organization in those situations when he or she identifies with a middle or top manager from the organizational pyramid. This information is valuable to researchers and practitioners, as for a long time, employees were considered the only ones manifesting resistance, the possibility that the change agent can oppose new changes being ignored.

MVT a most valuable theorem

CERN Document Server

Smorynski, Craig

2017-01-01

This book is about the rise and supposed fall of the mean value theorem. It discusses the evolution of the theorem and the concepts behind it, how the theorem relates to other fundamental results in calculus, and modern re-evaluations of its role in the standard calculus course. The mean value theorem is one of the central results of calculus. It was called “the fundamental theorem of the differential calculus” because of its power to provide simple and rigorous proofs of basic results encountered in a first-year course in calculus. In mathematical terms, the book is a thorough treatment of this theorem and some related results in the field; in historical terms, it is not a history of calculus or mathematics, but a case study in both. MVT: A Most Valuable Theorem is aimed at those who teach calculus, especially those setting out to do so for the first time. It is also accessible to anyone who has finished the first semester of the standard course in the subject and will be of interest to undergraduate mat...

Elemental imaging of MRI contrast agents: benchmarking of LA-ICP-MS to MRI

Energy Technology Data Exchange (ETDEWEB)

Pugh, J.A.T. [University of Sheffield, Centre for Analytical Sciences, Sheffield (United Kingdom); University of Sheffield, Department of Chemical and Biological Engineering, Sheffield (United Kingdom); Cox, A.G.; McLeod, C.W. [University of Sheffield, Centre for Analytical Sciences, Sheffield (United Kingdom); Bunch, J. [University of Birmingham, School of Chemistry, Birmingham (United Kingdom); Writer, M.J.; Hart, S.L. [UCL Institute of Child Health, Wolfson Centre for Gene Therapy of Childhood Disease, London (United Kingdom); Bienemann, A.; White, E. [University of Bristol, School of Clinical Sciences, Southmead Hospital, Bristol (United Kingdom); Bell, J. [Hammersmith Hospital, Metabolic and Molecular Imaging Group, MRC Clinical Sciences Centre, Imperial College London, London (United Kingdom)

2012-06-15

Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) has been used to map the spatial distribution of magnetic resonance imaging (MRI) contrast agents (Gd-based) in histological sections in order to explore synergies with in vivo MRI. Images from respective techniques are presented for two separate studies namely (1) convection enhanced delivery of a Gd nanocomplex (developmental therapeutic) into rat brain and (2) convection enhanced delivery, with co-infusion of Magnevist (commercial Gd contrast agent) and Carboplatin (chemotherapy drug), into pig brain. The LA technique was shown to be a powerful compliment to MRI not only in offering improved sensitivity, spatial resolution and signal quantitation but also in giving added value regarding the fate of administered agents (Gd and Pt agents). Furthermore simultaneous measurement of Fe enabled assignment of an anomalous contrast enhancement region in rat brain to haemorrhage at the infusion site. (orig.)

Remote control of therapeutic T cells through a small molecule-gated chimeric receptor

Science.gov (United States)

Wu, Chia-Yung; Roybal, Kole T.; Puchner, Elias M.; Onuffer, James; Lim, Wendell A.

2016-01-01

There is growing promise in using engineered cells as therapeutic agents. For example, synthetic Chimeric Antigen Receptors (CARs) can redirect T cells to recognize and eliminate tumor cells expressing specific antigens. Despite promising clinical results, excessive activity and poor control over such engineered T cells can cause severe toxicities. We present the design of “ON-switch” CARs that enable small molecule-control over T cell therapeutic functions, while still retaining antigen specificity. In these split receptors, antigen binding and intracellular signaling components only assemble in the presence of a heterodimerizing small molecule. This titratable pharmacologic regulation could allow physicians to precisely control the timing, location, and dosage of T cell activity, thereby mitigating toxicity. This work illustrates the potential of combining cellular engineering with orthogonal chemical tools to yield safer therapeutic cells that tightly integrate both cell autonomous recognition and user control. PMID:26405231

Investigating Therapeutic Potential of Trigonella foenum-graecum L. as Our Defense Mechanism against Several Human Diseases

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Shivangi Goyal

2016-01-01

Full Text Available Current lifestyle, stress, and pollution have dramatically enhanced the progression of several diseases in human. Globally, scientists are looking for therapeutic agents that can either cure or delay the onset of diseases. Medicinal plants from time immemorial have been used frequently in therapeutics. Of many such plants, fenugreek is one of the oldest herbs which have been identified as an important medicinal plant by the researchers around the world. It is potentially beneficial in a number of diseases such as diabetes, hypercholesterolemia, and inflammation and probably in several kinds of cancers. It has industrial applications such as synthesis of steroidal hormones. Its medicinal properties and their role in clinical domain can be attributed to its chemical constituents. The 3 major chemical constituents which have been identified as responsible for principle health effects are galactomannan, 4-OH isoleucine, and steroidal saponin. Numerous experiments have been carried out in vivo and in vitro for beneficial effects of both the crude chemical and of its active constituent. Due to its role in health care, the functional food industry has referred to it as a potential nutraceutical. This paper is about various medicinal benefits of fenugreek and its potential application as therapeutic agent against several diseases.

78 FR 77471 - Prospective Grant of Exclusive License for: Convection Enhanced Delivery of a Therapeutic Agent...

Science.gov (United States)

2013-12-23

...; nationalized), U.S. Patent Application 7,371,225, European Patent Application 03756863.1, Australian Patent 2003299140, to Medicenna Therapeutics, Inc. having a principle place of business in 1075 West Georgia St... date of this published notice, NIH receives written evidence and argument that establishes that the...

A review on phytochemistry and therapeutic uses of Hibiscus sabdariffa L.

Science.gov (United States)

Riaz, Ghazala; Chopra, Rajni

2018-06-01

Hibiscus sabdariffa L. (roselle) belonging to the Malvaceae family is widely grown in many countries. This plant is often used in the traditional medicine being rich in phytochemicals like polyphenols especially anthocyanins, polysaccharides and organic acids thus having enormous prospective in modern therapeutic uses. The study aimed to review and document all the available evidence and information about the calyces of Hibiscus sabdariffa (roselle) with the special focus on their nutritional composition, bioactive constituents and therapeutic uses. The electronic database was searched up to 2017, using keywords Hibiscus sabdariffa, chemical constituents of roselle, therapeutic uses of roselle. Journals, books and conference proceedings were also searched. The review provides valuable information about the nutraceutical component of Hibiscus sabdariffa L. and their utilization for curing various degenerative diseases like hypertension, hyperlipidemia, cancer and other inflammatory diseases of liver and kidney. Their toxicological effects have also been discussed from a safety point of view. Most studies supported and provided the scientific basis for the statement that Hibiscus sabdariffa and their active constituents play an important role in the prevention of chronic and degenerative diseases that are associated with oxidative stress. Our study suggests, that good research is needed, to establish a potential strategy that can balance the pharmacological and toxic effects of roselle and standardized fingerprint of Hibiscus sabdariffa is required internationally for quality control. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Salt Lakes of the African Rift System: A Valuable Research ...

African Journals Online (AJOL)

Salt Lakes of the African Rift System: A Valuable Research Opportunity for Insight into Nature's Concenrtated Multi-Electrolyte Science. JYN Philip, DMS Mosha. Abstract. The Tanzanian rift system salt lakes present significant cultural, ecological, recreational and economical values. Beyond the wealth of minerals, resources ...

Gene therapy prospects--intranasal delivery of therapeutic genes.

Science.gov (United States)

Podolska, Karolina; Stachurska, Anna; Hajdukiewicz, Karolina; Małecki, Maciej

2012-01-01

Gene therapy is recognized to be a novel method for the treatment of various disorders. Gene therapy strategies involve gene manipulation on broad biological processes responsible for the spreading of diseases. Cancer, monogenic diseases, vascular and infectious diseases are the main targets of gene therapy. In order to obtain valuable experimental and clinical results, sufficient gene transfer methods are required. Therapeutic genes can be administered into target tissues via gene carriers commonly defined as vectors. The retroviral, adenoviral and adeno-associated virus based vectors are most frequently used in the clinic. So far, gene preparations may be administered directly into target organs or by intravenous, intramuscular, intratumor or intranasal injections. It is common knowledge that the number of gene therapy clinical trials has rapidly increased. However, some limitations such as transfection efficiency and stable and long-term gene expression are still not resolved. Consequently, great effort is focused on the evaluation of new strategies of gene delivery. There are many expectations associated with intranasal delivery of gene preparations for the treatment of diseases. Intranasal delivery of therapeutic genes is regarded as one of the most promising forms of pulmonary gene therapy research. Gene therapy based on inhalation of gene preparations offers an alternative way for the treatment of patients suffering from such lung diseases as cystic fibrosis, alpha-1-antitrypsin defect, or cancer. Experimental and first clinical trials based on plasmid vectors or recombinant viruses have revealed that gene preparations can effectively deliver therapeutic or marker genes to the cells of the respiratory tract. The noninvasive intranasal delivery of gene preparations or conventional drugs seems to be very encouraging, although basic scientific research still has to continue.

Acute pancreatitis related to therapeutic dosing with colchicine: a case report

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Ting Joseph

2007-08-01

Full Text Available Abstract Background Colchicine is used in the treatment and prophylaxis of gout. It possesses a narrow therapeutic window, frequently resulting in dose-limiting gastrointestinal side-effects such as diarrhoea and emesis. As colchicine is a cellular anti-mitotic agent, the most serious effects include myelosuppression, myoneuropathy and multiple organ failure. This occurs with intentional overdose or with therapeutic dosing in patients with reduced clearance of colchicine due to pre-existing renal or hepatic impairment. Acute pancreatitis has rarely been reported, and only in association with severe colchicine overdose accompanied by multi-organ failure. Case presentation We report a case of acute pancreatitis without other organ toxicity related to recent commencement of colchicine for acute gout, occurring in an elderly male with pre-existing renal impairment. Conclusion 1 Colchicine should be used with care in elderly patients or patients with impaired renal function. 2 Aside from myelosuppression, myoneuropathy and multiple organ failure, colchicine may now be associated with acute pancreatitis even with therapeutic dosing; this has not previously being reported.

Partial Reduction of Esters to Aldehydes Using a Novel Modified Red-Al Reducing Agent

Energy Technology Data Exchange (ETDEWEB)

Shin, Won Kyu; Kang, Daehoon; An, Duk Keun [Kangwon National Univ., Chunchon (Korea, Republic of)

2014-07-15

We have developed a convenient alternative method for the synthesis of aldehydes from both aromatic and aliphatic esters in very good to excellent yields in the absence of any additives using a modified Red-Al that was easily prepared by reacting commercially available Red-Al with cis-2,6-dimethyl morpholine. The advantages of the present methodology are as follows: simple preparation procedure of the reducing agent, improved product yields, convenient reaction temperature, and short reaction times. Therefore, the new reagent has great potential to be a useful alternative partial reducing agent for the synthesis of aldehydes from esters in organic synthesis. Aldehydes are valuable building blocks and reactive intermediates in organic synthesis. The general and classical syntheses of aldehydes from esters involve reduction-oxidation and partial reduction using efficient partial reducing agents. Obviously, one-step partial reduction methods are more useful than two-step reduction-oxidation methods owing to their simplicity, and generality in organic synthesis.

Therapeutic effects of hydrogen on chronic graft-versus-host disease.

Science.gov (United States)

Qian, Liren; Liu, Xiaopeng; Shen, Jianliang; Zhao, Defeng; Yin, Wenjie

2017-10-01

The incidence of chronic graft-versus-host disease (cGVHD) is rising recent years, which has been the leading cause of non-transplantation mortality post allogenetic hematopoietic stem cell transplantation (HSCT). Imbalance of inflammatory cytokines and fibrosis plays critical roles in the pathogenesis of cGVHD. Recent studies showed that molecular hydrogen has anti-inflammatory, antioxidant, anti-fibrosis effects. Therefore, we hypothesized that molecular hydrogen may have therapeutic effects on cGVHD. To determine whether hydrogen could protect mice from cGVHD in an MHC-incompatible murine bone marrow transplantation (BMT) model, survival rates of mice were calculated, and skin lesions were also evaluated after BMT. This article demonstrated that administration of hydrogen-rich saline increased survival rate of cGVHD mice. Administration of hydrogen-rich saline after transplantation also reduced skin lesions of cGVHD mice. Previously, we reported the therapeutic effects of hydrogen on acute GVHD. However, there was no report on the therapeutic effects of hydrogen on cGVHD mice. It is suggested that hydrogen has a potential as an effective and safe therapeutic agent on cGVHD. This study will provide new ideas on the treatment of cGVHD and has important theoretical values. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Marketed nonsteroidal anti-inflammatory agents, antihypertensives, and human immunodeficiency virus protease inhibitors: as-yet-unused weapons of the oncologists’ arsenal

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Papanagnou P

2015-05-01

Full Text Available Panagiota Papanagnou,1 Panagiotis Baltopoulos,2 Maria Tsironi1 1Department of Nursing, Faculty of Human Movement and Quality of Life Sciences, University of Peloponnese, Sparta, 2Department of Sports Medicine and Biology of Physical Activity, Faculty of Physical Education and Sport Science, National and Kapodistrian University of Athens, Athens, Greece Abstract: Experimental data indicate that several pharmacological agents that have long been used for the management of various diseases unrelated to cancer exhibit profound in vitro and in vivo anticancer activity. This is of major clinical importance, since it would possibly aid in reassessing the therapeutic use of currently used agents for which clinicians already have experience. Further, this would obviate the time-consuming process required for the development and the approval of novel antineoplastic drugs. Herein, both pre-clinical and clinical data concerning the antineoplastic function of distinct commercially available pharmacological agents that are not currently used in the field of oncology, ie, nonsteroidal anti-inflammatory drugs, antihypertensive agents, and anti-human immunodeficiency virus agents inhibiting viral protease, are reviewed. The aim is to provide integrated information regarding not only the molecular basis of the antitumor function of these agents but also the applicability of the reevaluation of their therapeutic range in the clinical setting. Keywords: repositioning, tumorigenesis, pleiotropy, exploitation

Synthesis and biological activity of imidazopyridine anticoccidial agents: part I.

Science.gov (United States)

Scribner, Andrew; Dennis, Richard; Hong, Jean; Lee, Shuliang; McIntyre, Donald; Perrey, David; Feng, Dennis; Fisher, Michael; Wyvratt, Matthew; Leavitt, Penny; Liberator, Paul; Gurnett, Anne; Brown, Chris; Mathew, John; Thompson, Donald; Schmatz, Dennis; Biftu, Tesfaye

2007-01-01

Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we present the synthesis and biological activity of imidazo[1,2-a]pyridine anticoccidial agents. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development.

Vitamin A-aldehyde adducts: AMD risk and targeted therapeutics.

Science.gov (United States)

Sparrow, Janet R

2016-04-26

Although currently available treatment options for age-related macular degeneration (AMD) are limited, particularly for atrophic AMD, the identification of predisposing genetic variations has informed clinical studies addressing therapeutic options such as complement inhibitors and anti-inflammatory agents. To lower risk of early AMD, recommended lifestyle interventions such as the avoidance of smoking and the intake of low glycemic antioxidant-rich diets have largely followed from the identification of nongenetic modifiable factors. On the other hand, the challenge of understanding the complex relationship between aging and cumulative damage leading to AMD has fueled investigations of the visual cycle adducts that accumulate in retinal pigment epithelial (RPE) cells and are a hallmark of aging retina. These studies have revealed properties of these compounds that provide insights into processes that may compromise RPE and could contribute to disease mechanisms in AMD. This work has also led to the design of targeted therapeutics that are currently under investigation.

Chicken cathelicidin-2-derived peptides with enhanced immunomodulatory and antibacterial activities against biological warfare agents

NARCIS (Netherlands)

Molhoek, E.M.; Dijk, A. van; Veldhuizen, E.J.A.; Dijk-Knijnenburg, H.; Mars-Groenendijk, R.H.; Boele, L.C.L.; Kaman-van Zanten, W.E.; Haagsman, H.P.; Bikker, F.J.

2010-01-01

Host defence peptides (HDPs) are considered to be excellent candidates for the development of novel therapeutic agents. Recently, it was demonstrated that the peptide C1-15, an N-terminal segment of chicken HDP cathelicidin-2, exhibits potent antibacterial activity while lacking cytotoxicity towards

Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib

DEFF Research Database (Denmark)

Nijhof, I. S.; Groen, R. W. J.; Noort, W. A.

2015-01-01

lenalidomide- and/or bortezomib-refractory patients. In these assays, lenalidomide but not bortezomib, synergistically enhanced daratumumab-mediated multiple myeloma lysis through activation of natural killer cells. Finally, in an in vivo xenograft model, only the combination of daratumumab with lenalidomide......Purpose: Novel therapeutic agents have significantly improved the survival of patients with multiple myeloma. Nonetheless, the prognosis of patients with multiple myeloma who become refractory to the novel agents lenalidomide and bortezomib is very poor, indicating the urgent need for new...... therapeutic options for these patients. The human CD38 monoclonal antibody daratumumab is being evaluated as a novel therapy for multiple myeloma. Prompted with the encouraging results of ongoing clinical phase I/II trials, we now addressed the potential value of daratumumab alone or in combination...

Effect of therapeutic interchange on medication reconciliation during hospitalization and upon discharge in a geriatric population.

Directory of Open Access Journals (Sweden)

Jessica S Wang

Full Text Available Therapeutic interchange of a same class medication for an outpatient medication is a widespread practice during hospitalization in response to limited hospital formularies. However, therapeutic interchange may increase risk of medication errors. The objective was to characterize the prevalence and safety of therapeutic interchange.Secondary analysis of a transitions of care study. We included patients over age 64 admitted to a tertiary care hospital between 2009-2010 with heart failure, pneumonia, or acute coronary syndrome who were taking a medication in any of six commonly-interchanged classes on admission: proton pump inhibitors (PPIs, histamine H2-receptor antagonists (H2 blockers, hydroxymethylglutaryl CoA reductase inhibitors (statins, angiotensin-converting enzyme (ACE inhibitors, angiotensin receptor blockers (ARBs, and inhaled corticosteroids (ICS. There was limited electronic medication reconciliation support available. Main measures were presence and accuracy of therapeutic interchange during hospitalization, and rate of medication reconciliation errors on discharge. We examined charts of 303 patients taking 555 medications at time of admission in the six medication classes of interest. A total of 244 (44.0% of medications were therapeutically interchanged to an approved formulary drug at admission, affecting 64% of the study patients. Among the therapeutically interchanged drugs, we identified 78 (32.0% suspected medication conversion errors. The discharge medication reconciliation error rate was 11.5% among the 244 therapeutically interchanged medications, compared with 4.2% among the 311 unchanged medications (relative risk [RR] 2.75, 95% confidence interval [CI] 1.45-5.19.Therapeutic interchange was prevalent among hospitalized patients in this study and elevates the risk for potential medication errors during and after hospitalization. Improved electronic systems for managing therapeutic interchange and medication reconciliation

Antimicrobial topical agents used in the vagina.

Science.gov (United States)

Frey Tirri, Brigitte

2011-01-01

Vaginally applied antimicrobial agents are widely used in the vagina in women with lower genital tract infections. An 'antimicrobial' is a general term that refers to a group of drugs that are effective against bacteria, fungi, viruses and protozoa. Topical treatments can be prescribed for a wide variety of vaginal infections. Many bacterial infections, such as bacterial vaginosis, desquamative inflammatory vaginitis or, as some European authors call it, aerobic vaginitis as well as infection with Staphylococcus aureus or group A streptococci, may be treated in this way. Candida vulvovaginitis is a fungal infection that is very amenable to topical treatment. The most common viral infections which can be treated with topical medications are condylomata acuminata and herpes simplex. The most often encountered protozoal vaginitis, which is caused by Trichomonas vaginalis, may be susceptible to topical medications, although this infection is treated systemically. This chapter covers the wide variety of commonly used topical antimicrobial agents for these diseases and focuses on the individual therapeutic agents and their clinical efficacy. In addition, potential difficulties that can occur in practice, as well as the usage of these medications in the special setting of pregnancy, are described in this chapter. Copyright © 2011 S. Karger AG, Basel.

Risk evaluation and monitoring in multiple sclerosis therapeutics.

Science.gov (United States)

Clanet, Michel C; Wolinsky, Jerry S; Ashton, Raymond J; Hartung, Hans-Peter; Reingold, Stephen C

2014-09-01

Risk for multiple sclerosis (MS) disease-modifying therapies (DMT) must be assessed on an ongoing basis. Early concerns regarding the first-approved DMTs for MS have been mitigated, but recently licensed therapies have been linked to possibly greater risks. The objective of this review is to discuss risk assessment in MS therapeutics based on an international workshop and comprehensive literature search and recommend strategies for risk assessment/monitoring. Assessment and perception of therapeutic risks vary between patients, doctors and regulators. Acceptability of risk depends on the magnitude of risk and the demonstrated clinical benefits of any agent. Safety signals must be distinguishable from chance occurrences in a clinical trial and in long-term use of medications. Post-marketing research is crucial for assessing longer-term safety in large patient cohorts. Reporting of adverse events is becoming more proactive, allowing more rapid identification of risks. Communication about therapeutic risks and their relationship to clinical benefit must involve patients in shared decision making. It is difficult to produce a general risk-assessment algorithm for all MS therapies. Specific algorithms are required for each DMT in every treated-patient population. New and evolving risks must be evaluated and communicated rapidly to allow patients and physicians to be well informed and able to share treatment decisions. © The Author(s) 2013.

Challenges in the development of therapeutics for narcolepsy.

Science.gov (United States)

Black, Sarah Wurts; Yamanaka, Akihiro; Kilduff, Thomas S

2017-05-01

Narcolepsy is a neurological disorder that afflicts 1 in 2000 individuals and is characterized by excessive daytime sleepiness and cataplexy-a sudden loss of muscle tone triggered by positive emotions. Features of narcolepsy include dysregulation of arousal state boundaries as well as autonomic and metabolic disturbances. Disruption of neurotransmission through the hypocretin/orexin (Hcrt) system, usually by degeneration of the HCRT-producing neurons in the posterior hypothalamus, results in narcolepsy. The cause of Hcrt neurodegeneration is unknown but thought to be related to autoimmune processes. Current treatments for narcolepsy are symptomatic, including wake-promoting therapeutics that increase presynaptic dopamine release and anticataplectic agents that activate monoaminergic neurotransmission. Sodium oxybate is the only medication approved by the US Food and Drug Administration that alleviates both sleep/wake disturbances and cataplexy. Development of therapeutics for narcolepsy has been challenged by historical misunderstanding of the disease, its many disparate symptoms and, until recently, its unknown etiology. Animal models have been essential to elucidating the neuropathology underlying narcolepsy. These models have also aided understanding the neurobiology of the Hcrt system, mechanisms of cataplexy, and the pharmacology of narcolepsy medications. Transgenic rodent models will be critical in the development of novel therapeutics for the treatment of narcolepsy, particularly efforts directed to overcome challenges in the development of hypocretin replacement therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Study of Interactions of an Anticancer Drug Neratinib With Bovine Serum Albumin: Spectroscopic and Molecular Docking Approach

OpenAIRE

Tanveer A. Wani; Ahmed H. Bakheit; Ahmed H. Bakheit; M. A. Abounassif; Seema Zargar

2018-01-01

Binding of therapeutic agents to plasma proteins, particularly to serum albumin, provides valuable information in the drug development. This study was designed to evaluate the binding interaction of neratinib with bovine serum albumin (BSA). Neratinib blocks HER2 signaling and is effective in trastuzumab-resistant breast cancer treatment. Spectrofluorometric, UV spectrophotometric, and fourier transform infrared (FT-IR) and molecular docking experiments were performed to study this interactio...

pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

Directory of Open Access Journals (Sweden)

Erum Malik

2016-11-01

Full Text Available Antimicrobial peptides (AMPs are potent antibiotics of the innate immune system that have been extensively investigated as a potential solution to the global problem of infectious diseases caused by pathogenic microbes. A group of AMPs that are increasingly being reported are those that utilise pH dependent antimicrobial mechanisms, and here we review research into this area. This review shows that these antimicrobial molecules are produced by a diverse spectrum of creatures, including vertebrates and invertebrates, and are primarily cationic, although a number of anionic examples are known. Some of these molecules exhibit high pH optima for their antimicrobial activity but in most cases, these AMPs show activity against microbes that present low pH optima, which reflects the acidic pH generally found at their sites of action, particularly the skin. The modes of action used by these molecules are based on a number of major structure/function relationships, which include metal ion binding, changes to net charge and conformational plasticity, and primarily involve the protonation of histidine, aspartic acid and glutamic acid residues at low pH. The pH dependent activity of pore forming antimicrobial proteins involves mechanisms that generally differ fundamentally to those used by pH dependent AMPs, which can be described by the carpet, toroidal pore and barrel-stave pore models of membrane interaction. A number of pH dependent AMPs and antimicrobial proteins have been developed for medical purposes and have successfully completed clinical trials, including kappacins, LL-37, histatins and lactoferrin, along with a number of their derivatives. Major examples of the therapeutic application of these antimicrobial molecules include wound healing as well as the treatment of multiple cancers and infections due to viruses, bacteria and fungi. In general, these applications involve topical administration, such as the use of mouth washes, cream formulations

Ondansetron. Therapeutic use as an antiemetic

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Milne, R.J.; Heel, R.C. (Adis Drug Information Services, Auckland (New Zealand))

1991-04-01

Ondansetron (GR 38032F) is a highly selective 5-HT3 receptor antagonist, one of a new class of compounds which may have several therapeutic applications. Animal and clinical studies show that ondansetron reduces the 24-hour incidence and severity of nausea and vomiting induced by cytotoxic drugs, including cisplatin, and by single exposure, high dose radiation. Ondansetron is more effective than high dose metoclopramide in the 24 hours following chemotherapy, and preliminary clinical evidence suggests that it is equally effective in the following 4 days. It is also more effective than the moderate doses of metoclopramide used to suppress emesis following radiotherapy. The antiemetic efficacy of ondansetron is enhanced by dexamethasone in cisplatin-treated patients. Importantly, extrapyramidal effects have not been reported with ondansetron. Further comparisons are required with standard combination antiemetic therapy to complement the data presently available. Thus, ondansetron is a promising new agent for prophylaxis against nausea and vomiting in chemotherapy and radiotherapy. It may be particularly useful in young and elderly patients who are more susceptible to extrapyramidal symptoms induced by high dose metoclopramide. With its improved tolerability and clinical response profiles, ondansetron represents an important advance in a difficult area of therapeutics. 101 refs.

Ondansetron. Therapeutic use as an antiemetic

International Nuclear Information System (INIS)

Milne, R.J.; Heel, R.C.

1991-01-01

Ondansetron (GR 38032F) is a highly selective 5-HT3 receptor antagonist, one of a new class of compounds which may have several therapeutic applications. Animal and clinical studies show that ondansetron reduces the 24-hour incidence and severity of nausea and vomiting induced by cytotoxic drugs, including cisplatin, and by single exposure, high dose radiation. Ondansetron is more effective than high dose metoclopramide in the 24 hours following chemotherapy, and preliminary clinical evidence suggests that it is equally effective in the following 4 days. It is also more effective than the moderate doses of metoclopramide used to suppress emesis following radiotherapy. The antiemetic efficacy of ondansetron is enhanced by dexamethasone in cisplatin-treated patients. Importantly, extrapyramidal effects have not been reported with ondansetron. Further comparisons are required with standard combination antiemetic therapy to complement the data presently available. Thus, ondansetron is a promising new agent for prophylaxis against nausea and vomiting in chemotherapy and radiotherapy. It may be particularly useful in young and elderly patients who are more susceptible to extrapyramidal symptoms induced by high dose metoclopramide. With its improved tolerability and clinical response profiles, ondansetron represents an important advance in a difficult area of therapeutics. 101 refs

Therapeutic Potential of Non-Psychotropic Cannabidiol in Ischemic Stroke

Directory of Open Access Journals (Sweden)

Michihiro Fujiwara

2010-07-01

Full Text Available Cannabis contains the psychoactive component delta9-tetrahydrocannabinol (delta9-THC, and the non-psychoactive components cannabidiol (CBD, cannabinol, and cannabigerol. It is well-known that delta9-THC and other cannabinoid CB1 receptor agonists are neuroprotective during global and focal ischemic injury. Additionally, delta9-THC also mediates psychological effects through the activation of the CB1 receptor in the central nervous system. In addition to the CB1 receptor agonists, cannabis also contains therapeutically active components which are CB1 receptor independent. Of the CB1 receptor-independent cannabis, the most important is CBD. In the past five years, an increasing number of publications have focused on the discovery of the anti-inflammatory, anti-oxidant, and neuroprotective effects of CBD. In particular, CBD exerts positive pharmacological effects in ischemic stroke and other chronic diseases, including Parkinson’s disease, Alzheimer’s disease, and rheumatoid arthritis. The cerebroprotective action of CBD is CB1 receptor-independent, long-lasting, and has potent anti-oxidant activity. Importantly, CBD use does not lead to tolerance. In this review, we will discuss the therapeutic possibility of CBD as a cerebroprotective agent, highlighting recent pharmacological advances, novel mechanisms, and therapeutic time window of CBD in ischemic stroke.

Introduction to metabolic genetic engineering for the production of valuable secondary metabolites in in vivo and in vitro plant systems.

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Benedito, Vagner A; Modolo, Luzia V

2014-01-01

Plants are capable of producing a myriad of chemical compounds. While these compounds serve specific functions in the plant, many have surprising effects on the human body, often with positive action against diseases. These compounds are often difficult to synthesize ex vivo and require the coordinated and compartmentalized action of enzymes in living organisms. However, the amounts produced in whole plants are often small and restricted to single tissues of the plant or even cellular organelles, making their extraction an expensive process. Since most natural products used in therapeutics are specialized, secondary plant metabolites, we provide here an overview of the classification of the main classes of these compounds, with its biochemical pathways and how this information can be used to create efficient in and ex planta production pipelines to generate highly valuable compounds. Metabolic genetic engineering is introduced in light of physiological and genetic methods to enhance production of high-value plant secondary metabolites.

Advances in sarcoma gene mutations and therapeutic targets.

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Gao, Peng; Seebacher, Nicole A; Hornicek, Francis; Guo, Zheng; Duan, Zhenfeng

2018-01-01

Sarcomas are rare and complex malignancies that have been associated with a poor prognostic outcome. Over the last few decades, traditional treatment with surgery and/or chemotherapy has not significantly improved outcomes for most types of sarcomas. In recent years, there have been significant advances in the understanding of specific gene mutations that are important in driving the pathogenesis and progression of sarcomas. Identification of these new gene mutations, using next-generation sequencing and advanced molecular techniques, has revealed a range of potential therapeutic targets. This, in turn, may lead to the development of novel agents targeted to different sarcoma subtypes. In this review, we highlight the advances made in identifying sarcoma gene mutations, including those of p53, RB, PI3K and IDH genes, as well as novel therapeutic strategies aimed at utilizing these mutant genes. In addition, we discuss a number of preclinical studies and ongoing early clinical trials in sarcoma targeting therapies, as well as gene editing technology, which may provide a better choice for sarcoma patient management. Published by Elsevier Ltd.

A Novel Therapeutic Agent for Type 2 Diabetes Mellitus: SGLT2 Inhibitor

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Chang Hee Jung

2014-08-01

Full Text Available Type 2 diabetes mellitus (T2DM is a complex endocrine and metabolic disorder, and a major public health problem that is rapidly increasing in prevalence. Although a wide range of pharmacotherapies for glycemic control is now available, management of T2DM remains complex and challenging. The kidneys contribute immensely to glucose homeostasis by reabsorbing glucose from the glomerular filtrate. Sodium-glucose cotransporter 2 (SGLT2 inhibitors, a new class of antidiabetic agents that inhibit glucose absorption from the kidney independent of insulin, offer a unique opportunity to improve the outcomes of patients with T2DM. In this review, we provide an overview of two globally-approved SGLT2 inhibitors, dapagliflozin and canagliflozin, and discuss their effects and safety. This information will help clinicians to decide whether these drugs will benefit their patients.

Bee Pollen Flavonoids as a Therapeutic Agent in Allergic and Immunological Disorders.

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Jannesar, Masoomeh; Sharif Shoushtari, Maryam; Majd, Ahmad; Pourpak, Zahra

2017-06-01

Bee pollen grains, as the male reproductive part of seed-bearing plants contain considerable concentrations of various phytochemicals and nutrients. Since antiquity, people throughout the world used pollens to cure colds, flu, ulcers, premature aging, anemia and colitis. It is now well-documented that some bee pollen secondary metabolites (e.g. flavonoid) may have positive health effects. In recent years, the flavonoids have attracted much interest because of their wide range of biological properties and their beneficial effects on human health. The current review, points out potential therapeutic effects of bee pollen flavonoids as one of the main bee pollen bioactive compounds in allergic and immunological diseases. Due to the fact that some types of flavonoid components in bee pollen have anti-allergic, anti-oxidant and anti-inflammatory properties, bee pollen flavonoids can be excellent candidates for future studies including phytotherapy, molecular pharmacology and substitutes for chemicals used in treating allergic and immunological disorders.

A school peer mediation program as a context for exploring therapeutic jurisprudence (TJ): Can a peer mediation program inform the law?

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McWilliam, Nicky

2010-01-01

This paper reports an exploratory study of a school peer mediation program implemented as an alternative way to manage bullying and other destructive conflict. The study explores the effects of the program on the well-being of members of the school community by examining perceptions of students, staff and a sample of parents and former students. Drawing on therapeutic jurisprudence (TJ) the study explores whether the component parts of the program, separately or together, promote intended or unintended therapeutic effects. The preliminary findings of the study emphasise the importance of peer mediation training and suggest that existing scholarship in the area of school conflict resolution and peer mediation, when viewed through a TJ lens, may provide valuable insights into how to optimally configure programs for development and adoption in schools and other community settings. The study highlights the lack of attention paid by the legal system to valuable scholarship in the area of school conflict resolution and peer mediation, which may have implications for the understanding and development of legal processes and the law in general. Copyright © 2010 Elsevier Ltd. All rights reserved.

Whole-Genome Sequence of Pseudomonas graminis Strain UASWS1507, a Potential Biological Control Agent and Biofertilizer Isolated in Switzerland.

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Crovadore, Julien; Calmin, Gautier; Chablais, Romain; Cochard, Bastien; Schulz, Torsten; Lefort, François

2016-10-06

We report here the whole-genome shotgun sequence of the strain UASWS1507 of the species Pseudomonas graminis, isolated in Switzerland from an apple tree. This is the first genome registered for this species, which is considered as a potential and valuable resource of biological control agents and biofertilizers for agriculture. Copyright © 2016 Crovadore et al.

Combined-modality treatment of solid tumors using radiotherapy and molecular targeted agents.

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Ma, Brigette B Y; Bristow, Robert G; Kim, John; Siu, Lillian L

2003-07-15

Molecular targeted agents have been combined with radiotherapy (RT) in recent clinical trials in an effort to optimize the therapeutic index of RT. The appeal of this strategy lies in their potential target specificity and clinically acceptable toxicity. This article integrates the salient, published research findings into the underlying molecular mechanisms, preclinical efficacy, and clinical applicability of combining RT with molecular targeted agents. These agents include inhibitors of intracellular signal transduction molecules, modulators of apoptosis, inhibitors of cell cycle checkpoints control, antiangiogenic agents, and cyclo-oxygenase-2 inhibitors. Molecular targeted agents can have direct effects on the cytoprotective and cytotoxic pathways implicated in the cellular response to ionizing radiation (IR). These pathways involve cellular proliferation, DNA repair, cell cycle progression, nuclear transcription, tumor angiogenesis, and prostanoid-associated inflammation. These pathways can also converge to alter RT-induced apoptosis, terminal growth arrest, and reproductive cell death. Pharmacologic modulation of these pathways may potentially enhance tumor response to RT though inhibition of tumor repopulation, improvement of tumor oxygenation, redistribution during the cell cycle, and alteration of intrinsic tumor radiosensitivity. Combining RT and molecular targeted agents is a rational approach in the treatment of solid tumors. Translation of this approach from promising preclinical data to clinical trials is actively underway.

Remote control of therapeutic T cells through a small molecule-gated chimeric receptor.

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Wu, Chia-Yung; Roybal, Kole T; Puchner, Elias M; Onuffer, James; Lim, Wendell A

2015-10-16

There is growing interest in using engineered cells as therapeutic agents. For example, synthetic chimeric antigen receptors (CARs) can redirect T cells to recognize and eliminate tumor cells expressing specific antigens. Despite promising clinical results, these engineered T cells can exhibit excessive activity that is difficult to control and can cause severe toxicity. We designed "ON-switch" CARs that enable small-molecule control over T cell therapeutic functions while still retaining antigen specificity. In these split receptors, antigen-binding and intracellular signaling components assemble only in the presence of a heterodimerizing small molecule. This titratable pharmacologic regulation could allow physicians to precisely control the timing, location, and dosage of T cell activity, thereby mitigating toxicity. This work illustrates the potential of combining cellular engineering with orthogonal chemical tools to yield safer therapeutic cells that tightly integrate cell-autonomous recognition and user control. Copyright © 2015, American Association for the Advancement of Science.

A theranostic dental pulp capping agent with improved MRI and CT contrast and biological properties.

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Mastrogiacomo, S; Güvener, N; Dou, W; Alghamdi, H S; Camargo, W A; Cremers, J G O; Borm, P J A; Heerschap, A; Oosterwijk, E; Jansen, J A; Walboomers, X F

2017-10-15

Different materials have been used for vital dental pulp treatment. Preferably a pulp capping agent should show appropriate biological performance, excellent handling properties, and a good imaging contrast. These features can be delivered into a single material through the combination of therapeutic and diagnostic agents (i.e. theranostic). Calcium phosphate based composites (CPCs) are potentially ideal candidate for pulp treatment, although poor imaging contrast and poor dentino-inductive properties are limiting their clinical use. In this study, a theranostic dental pulp capping agent was developed. First, imaging properties of the CPC were improved by using a core-shell structured dual contrast agent (csDCA) consisting of superparamagnetic iron oxide (SPIO) and colloidal gold, as MRI and CT contrast agent respectively. Second, biological properties were implemented by using a dentinogenic factor (i.e. bone morphogenetic protein 2, BMP-2). The obtained CPC/csDCA/BMP-2 composite was tested in vivo, as direct pulp capping agent, in a male Habsi goat incisor model. Our outcomes showed no relevant alteration of the handling and mechanical properties (e.g. setting time, injectability, and compressive strength) by the incorporation of csDCA particles. In vivo results proved MRI contrast enhancement up to 7weeks. Incisors treated with BMP-2 showed improved tertiary dentin deposition as well as faster cement degradation as measured by µCT assessment. In conclusion, the presented theranostic agent matches the imaging and regenerative requirements for pulp capping applications. In this study, we combined diagnostic and therapeutic agents in order to developed a theranostic pulp capping agent with enhanced MRI and CT contrast and improved dentin regeneration ability. In our study we cover all the steps from material preparation, mechanical and in vitro characterization, to in vivo study in a goat dental model. To the best of our knowledge, this is the first time that a

an assessment of timber trees producing valuable fruits and seeds ...

African Journals Online (AJOL)

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It is observed that most of the timber trees producing valuable fruits and seeds have low ... sector of the economy by providing major raw materials (saw logs, ... the trees also produce industrial raw materials like latex, ... villagers while avoiding some of the ecological costs of ..... enzymes of rats with carbon tetrachloride.

Neurotrophin receptor agonists and antagonists as therapeutic agents: An evolving paradigm.

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Josephy-Hernandez, Sylvia; Jmaeff, Sean; Pirvulescu, Iulia; Aboulkassim, Tahar; Saragovi, H Uri

2017-01-01

Neurodegenerative disorders are prevalent, complex and devastating conditions, with very limited treatment options currently available. While they manifest in many forms, there are commonalities that link them together. In this review, we will focus on neurotrophins - a family of related factors involved in neuronal development and maintenance. Neurodegenerative diseases often present with a neurotrophin imbalance, in which there may be decreases in trophic signaling through Trk receptors for example, and/or increases in pro-apoptotic activity through p75. Clinical trials with neurotrophins have continuously failed due to their poor pharmacological properties as well as the unavoidable activation of p75. Thus, there is a need for drugs without such setbacks. Small molecule neurotrophin mimetics are favorable options since they can selectively activate Trks or inactivate p75. In this review, we will initially present a brief outline of how these molecules are synthesized and their mechanisms of action; followed by an update in the current state of neurotrophins and small molecules in major neurodegenerative diseases. Although there has been significant progress in the development of potential therapeutics, more studies are needed to establish clear mechanisms of action and target specificity in order to transition from animal models to the assessment of safety and use in humans. Copyright © 2016. Published by Elsevier Inc.

AN OVERVIEW OF BIOLOGICS: SCIENCE BEHIND PROTEIN THERAPEUTICS

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Inderjeet Kaur

2012-12-01

Full Text Available Biosimilars or ‘follow-on biologics’ are new biopharmaceutical agents that are ‘similar’ but not identical to a reference biopharmaceutical product. Biosimilars are considered ‘comparable’ to the reference product, but this does not ensure therapeutic equivalence. Inherent differences between biosimilars may produce dissimilarities in clinical efficacy, safety, and immunogenicity. Therefore accurate measurement and characterization of these differences and absolute quantification of biosimilars is the significant requirement at present. Mass spectrometry coupled with high performance liquid chromatography offers the most sensitive and accurate solution for this. This review discusses the potential strategies for the absolute quantification of biosimilars using mass spectrometry.

BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia

International Nuclear Information System (INIS)

Da Costa, D; Agathanggelou, A; Perry, T; Weston, V; Petermann, E; Zlatanou, A; Oldreive, C; Wei, W; Stewart, G; Longman, J; Smith, E; Kearns, P; Knapp, S; Stankovic, T

2013-01-01

Paediatric B-precursor ALL is a highly curable disease, however, treatment resistance in some patients and the long-term toxic effects of current therapies pose the need for more targeted therapeutic approaches. We addressed the cytotoxic effect of JQ1, a highly selective inhibitor against the transcriptional regulators, bromodomain and extra-terminal (BET) family of proteins, in paediatric ALL. We showed a potent in vitro cytotoxic response of a panel of primary ALL to JQ1, independent of their prognostic features but dependent on high MYC expression and coupled with transcriptional downregulation of multiple pro-survival pathways. In agreement with earlier studies, JQ1 induced cell cycle arrest. Here we show that BET inhibition also reduced c-Myc protein stability and suppressed progression of DNA replication forks in ALL cells. Consistent with c-Myc depletion and downregulation of pro-survival pathways JQ1 sensitised primary ALL samples to the classic ALL therapeutic agent dexamethasone. Finally, we demonstrated that JQ1 reduces ALL growth in ALL xenograft models, both as a single agent and in combination with dexamethasone. We conclude that targeting BET proteins should be considered as a new therapeutic strategy for the treatment of paediatric ALL and particularly those cases that exhibit suboptimal responses to standard treatment

New Therapeutic Targets in Soft Tissue Sarcoma

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Demicco, Elizabeth G; Maki, Robert G; Lev, Dina C.; Lazar, Alexander J

2012-01-01

Soft tissue sarcomas are an uncommon and diverse group of more than 50 mesenchymal malignancies. The pathogenesis of many of these is poorly understood, but others have begun to reveal the secrets of their inner workings. With considerable effort over recent years, soft tissue sarcomas have increasingly been classified on the basis of underlying molecular alterations. In turn, this has allowed the development and application of targeted agents in several specific, molecularly defined, sarcoma subtypes. This review will focus the rationale for targeted therapy in sarcoma, with emphasis on the relevance of specific molecular factors and pathways in both translocation-associated sarcomas and in genetically complex tumors. In addition, we will address some of the early successes in sarcoma targeted therapy as well as a few challenges and disappointments in this field. Finally we will discuss several possible opportunities represented by poorly understood, but potentially promising new therapeutic targets, as well as several novel biologic agents currently in preclinical and early phase I/II trials. This will provide the reader with context for understanding the current state this field and a sense of where it may be headed in the coming years. PMID:22498582

The clinical application of ultrasonography-guided percutaneous transhepatic injection of iodized oil containing chemotherapeutic agent for the treatment of hilar lymphatic metastasis

International Nuclear Information System (INIS)

Zhao Guangsheng; Zhang Yuewei; Yang Xiaohong; Li Chuang; Zhao Mu; Wang Wenqing; Wang Ruoyu

2010-01-01

Objective: To discuss the technique and the clinical effect of ultrasonography-guided percutaneous transhepatic injection of iodized oil containing chemotherapeutic agent for the treatment of hepatic hilar lymphatic metastasis. Methods: Under ultrasonographic guidance,percutaneous transhepatic injection of iodized oil containing chemotherapeutic agent, so-called chemo-ablation, into the diseased lymph nodes was performed in thirteen patients with hepatic hilar lymphatic metastasis. The therapeutic results were evaluated based on the post-operative imaging examinations as well as the alleviation of the clinical symptoms. Results: Percutaneous transhepatic injection of iodized oil containing chemotherapeutic agent into the diseased lymph nodes was successfully carried out in all thirteen patients. After the procedure,the patients were followed up for a mean period of 13.5 months. The therapeutic effectiveness was 100%, while the regression rate of the lesions was 76.9%. No operation-related complications occurred. Conclusion: Percutaneous transhepatic injection of iodized oil containing chemotherapeutic agent into the diseased lymph nodes under ultrasonographic guidance is an effective and safe treatment for hepatic hilar lymphatic metastasis with reliable effectiveness. (authors)

Emerging medical informatics with case-based reasoning for aiding clinical decision in multi-agent system.

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Shen, Ying; Colloc, Joël; Jacquet-Andrieu, Armelle; Lei, Kai

2015-08-01

This research aims to depict the methodological steps and tools about the combined operation of case-based reasoning (CBR) and multi-agent system (MAS) to expose the ontological application in the field of clinical decision support. The multi-agent architecture works for the consideration of the whole cycle of clinical decision-making adaptable to many medical aspects such as the diagnosis, prognosis, treatment, therapeutic monitoring of gastric cancer. In the multi-agent architecture, the ontological agent type employs the domain knowledge to ease the extraction of similar clinical cases and provide treatment suggestions to patients and physicians. Ontological agent is used for the extension of domain hierarchy and the interpretation of input requests. Case-based reasoning memorizes and restores experience data for solving similar problems, with the help of matching approach and defined interfaces of ontologies. A typical case is developed to illustrate the implementation of the knowledge acquisition and restitution of medical experts. Copyright © 2015 Elsevier Inc. All rights reserved.

Neuroimaging: do we really need new contrast agents for MRI?

International Nuclear Information System (INIS)

Roberts, T.P.L.; Chuang, N.; Roberts, H.C.

2000-01-01

The use of exogenous contrast media in magnetic resonance imaging of the brain has brought dramatic improvement in the sensitivity of detection and delineation of pathological structures, such as primary and metastatic brain tumors, inflammation and ischemia. Disruption of the blood brain barrier leads to accumulation of the intravenously injected contrast material in the extravascular space, leading to signal enhancement. Magnetic resonance angiography benefits from T 1 -shortening effects of contrast agent, improving small vessel depiction and providing vascular visualization even in situations of slow flow. High speed dynamic MRI after bolus injection of contrast media allows tracer kinetic modeling of cerebral perfusion. Progressive enhancement over serial post-contrast imaging allows modeling of vascular permeability and thus quantitative estimation of the severity of blood brain barrier disruption. With such an array of capabilities and ever improving technical abilities, it seems that the role of contrast agents in MR neuroimaging is established and the development of new agents may be superfluous. However, new agents are being developed with prolonged intravascular residence times, and with in-vivo binding of ever-increasing specificity. Intravascular, or blood pool, agents are likely to benefit magnetic resonance angiography of the carotid and cerebral vessels; future agents may allow the visualization of therapeutic drug delivery, the monitoring of, for example, gene expression, and the imaging evaluation of treatment efficacy. So while there is a substantial body of work that can be performed with currently available contrast agents, especially in conjunction with optimized image acquisition strategies, post processing, and mathematical analysis, there are still unrealized opportunities for novel contrast agent introduction, particularly those exploiting biological specificity. This article reviews the current use of contrast media in magnetic resonance

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.

The therapeutic value of glycolic acid peels in dermatology

Directory of Open Access Journals (Sweden)

Grover C

2003-03-01

Full Text Available Chemical peeling or chemexfoliation has become increasingly popular in recent years for treatment of a number of cosmetic skin problems. Topical glycolic acid in the concentration of 10-30% for 3-5 minutes at fortnightly intervals was investigated as a therapeutic peeling agent in 41 patients having acne (39%, melasma (36.5%, post inflammatory hyperpigmentation (12% and superficial scarring of varied etiology (12%. A final evaluation done at 16 weeks revealed that this modality is useful especially in superficial scarring and melasma, moderately successful in acne patients with no response in dermal pigmentation. No significant untoward effects were seen.

Diagnostic and therapeutic value of laparoscopy for small bowel blunt injuries: A case report.

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Addeo, Pietro; Calabrese, Daniela Paola

2011-01-01

Small bowel injuries after blunt abdominal trauma represent both a diagnostic and a therapeutic challenge. Early diagnosis and prompt treatment are necessary in order to avoid a dangerous diagnostic delay. Laparoscopy can represent a diagnostic and therapeutic tool in patients with uncertain clinical symptoms. We report the case of a 25-year-old man, haemodynamically stable, admitted for acute abdominal pain a few hours after a physical assault. Giving the persistence of the abdominal pain and the presence of free fluids at the computed tomography examination, an exploratory laparoscopy was performed. At the laparoscopic exploration, an isolated small bowel perforation was found, 60 cm distal from the ligament of Treitz. The injury was repaired by laparoscopic suturing and the patient was discharged home at postoperative day 3 after an uneventful postoperative course. Laparoscopy represents a valuable tool for patients with small bowel blunt injuries allowing a timely diagnosis and a prompt treatment.

Therapeutic effects of ritual ayahuasca use in the treatment of substance dependence--qualitative results.

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Loizaga-Velder, Anja; Verres, Rolf

2014-01-01

This qualitative empirical study explores the ritual use of ayahuasca in the treatment of addictions. Ayahuasca is an Amazonian psychedelic plant compound created from an admixture of the vine Banisteriopsis caapi and the bush Psychotria viridis. The study included interviews with 13 therapists who apply ayahuasca professionally in the treatment of addictions (four indigenous healers and nine Western mental health professionals with university degrees), two expert researchers, and 14 individuals who had undergone ayahuasca-assisted therapy for addictions in diverse contexts in South America. The study provides empirically based hypotheses on therapeutic mechanisms of ayahuasca in substance dependence treatment. Findings indicate that ayahuasca can serve as a valuable therapeutic tool that, in carefully structured settings, can catalyze neurobiological and psychological processes that support recovery from substance dependencies and the prevention of relapse. Treatment outcomes, however, can be influenced by a number of variables that are explained in this study. In addition, issues related to ritual transfer and strategies for minimizing undesired side-effects are discussed.

Multifunctional quantum dots-based cancer diagnostics and stem cell therapeutics for regenerative medicine.

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Onoshima, Daisuke; Yukawa, Hiroshi; Baba, Yoshinobu

2015-12-01

A field of recent diagnostics and therapeutics has been advanced with quantum dots (QDs). QDs have developed into new formats of biomolecular sensing to push the limits of detection in biology and medicine. QDs can be also utilized as bio-probes or labels for biological imaging of living cells and tissues. More recently, QDs has been demonstrated to construct a multifunctional nanoplatform, where the QDs serve not only as an imaging agent, but also a nanoscaffold for diagnostic and therapeutic modalities. This review highlights the promising applications of multi-functionalized QDs as advanced nanosensors for diagnosing cancer and as innovative fluorescence probes for in vitro or in vivo stem cell imaging in regenerative medicine. Copyright © 2015 Elsevier B.V. All rights reserved.

Therapeutic Plasmapheresis in Kidney Transplantation

Directory of Open Access Journals (Sweden)

Zeynep Kendi Celebi

2013-02-01

Full Text Available In 1960's, with succesfully renal transplantations, acute rejection became to be a serious problem for graft survival. From 1965 to 2010, with the introduction of new immunosuppressant agents such as cyclosporine, mycophenolate mofetile and tacrolimus, the acute rejection rates declined from 80% to 10% . There is an ongoing gradual improvement in allograft survival. Use of Therapeutic plasma exchange (TPE is not evidence based treatment, but TPE is necessary for pre- and also post transplantation in patients with DSA. TPE is also a main treatment for antibody mediated rejection (AMR , but in clinical practice the duration and frequency of TPE and individual difference of antibody production is unclear. There is a requirement for more specific antibody elimination. Further randomised controlled studies are needed to elucidate TPE use before and after kidney transplantation. [Dis Mol Med 2013; 1(1.000: 8-10

Antiadhesion agents against Gram-positive pathogens.

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Cascioferro, Stella; Cusimano, Maria Grazia; Schillaci, Domenico

2014-01-01

A fundamental step of Gram-positive pathogenesis is the bacterial adhesion to the host tissue involving interaction between bacterial surface molecules and host ligands. This review is focused on antivirulence compounds that target Gram-positive adhesins and on their potential development as therapeutic agents alternative or complementary to conventional antibiotics in the contrast of pathogens. In particular, compounds that target the sortase A, wall theicoic acid inhibitors, carbohydrates able to bind bacterial proteins and proteins capable of influencing the bacterial adhesion, were described. We further discuss the advantages and disadvantages of this strategy in the development of novel antimicrobials and the future perspective of this research field still at its first steps.

Penicillin: the medicine with the greatest impact on therapeutic outcomes.

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Kardos, Nelson; Demain, Arnold L

2011-11-01

The principal point of this paper is that the discovery of penicillin and the development of the supporting technologies in microbiology and chemical engineering leading to its commercial scale production represent it as the medicine with the greatest impact on therapeutic outcomes. Our nomination of penicillin for the top therapeutic molecule rests on two lines of evidence concerning the impact of this event: (1) the magnitude of the therapeutic outcomes resulting from the clinical application of penicillin and the subsequent widespread use of antibiotics and (2) the technologies developed for production of penicillin, including both microbial strain selection and improvement plus chemical engineering methods responsible for successful submerged fermentation production. These became the basis for production of all subsequent antibiotics in use today. These same technologies became the model for the development and production of new types of bioproducts (i.e., anticancer agents, monoclonal antibodies, and industrial enzymes). The clinical impact of penicillin was large and immediate. By ushering in the widespread clinical use of antibiotics, penicillin was responsible for enabling the control of many infectious diseases that had previously burdened mankind, with subsequent impact on global population demographics. Moreover, the large cumulative public effect of the many new antibiotics and new bioproducts that were developed and commercialized on the basis of the science and technology after penicillin demonstrates that penicillin had the greatest therapeutic impact event of all times. © Springer-Verlag 2011

Depletion of mammalian O6-alkylguanine-DNA alkyltransferase activity by O6-benzylguanine provides a means to evaluate the role of this protein in protection against carcinogenic and therapeutic alkylating agents

International Nuclear Information System (INIS)

Dolan, M.E.; Pegg, A.E.; Moschel, R.

1990-01-01

O 6 -Alkylguanine-DNA alkyltransferase was rapidly and irreversibly inactivated by exposure to O 6 -benzylguanine or the p-chlorobenzyl and p-methylbenzyl analogues. This inactivation was much more rapid than with O 6 -methylguanine: incubation with 2.5 μM O 6 -benzylguanine led to more than a 90% loss of activity within 10 min, whereas 0.2 mM O 6 -methylguanine for 60 min was required for the same reduction. O 6 -Benzylguanine was highly effective in depleting the alkyltransferase activity of cultured human colon tumor (HT29) cells. Complete loss of activity was produced within 15 min after addition of O 6 -benzylguanine to the culture medium and a maximal effect was obtained with 5 μM. In contrast, at least 100 μM O 6 -methylguanine for 4 hr was needed to get a maximal effect, and this reduced the alkyltransferase by only 80%. Pretreatment of HT29 cells with 10 μM O 6 -benzylguanine for 2 hr led to a dramatic increase in the cytotoxicity produced by the chemotherapeutic agents 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) or 2-chloroethyl(methylsulfonyl)methanesulfonate (Clomesone). Administration of O 6 -benzylguanine to mice at a dose of 10 mg/kg reduced alkyltransferase levels by more than 95% in both liver and kidney. These results indicate that depletion of the alkyltransferase by O 6 -benzylguanine may be used to investigate the role of the DNA repair protein in carcinogenesis and mutagensis and that this treatment may be valuable to increase the chemotherapeutic effectiveness of chloroethylating agents

Therapeutic burst-suppression coma in pediatric febrile refractory status epilepticus.

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Lin, Jainn-Jim; Chou, Cheng-Che; Lan, Shih-Yun; Hsiao, Hsiang-Ju; Wang, Yu; Chan, Oi-Wa; Hsia, Shao-Hsuan; Wang, Huei-Shyong; Lin, Kuang-Lin

2017-09-01

Evidence for the beneficial effect of therapeutic burst-suppression coma in pediatric patients with febrile refractory status epilepticus is limited, and the clinical outcomes of this treatment strategy are largely unknown. Therefore, the aim of this study was to explore the outcomes of therapeutic burst-suppression coma in a series of children with febrile refractory status epilepticus. We retrospectively reviewed consecutive pediatric patients with febrile refractory status epilepticus admitted to our pediatric intensive care unit between January 2000 and December 2013. The clinical characteristics were analyzed. Thirty-five patients (23 boys; age range: 1-18years) were enrolled, of whom 28 (80%) developed super-refractory status epilepticus. All of the patients received the continuous administration of intravenous antiepileptic drugs for febrile refractory status epilepticus, and 26 (74.3%) achieved therapeutic burst-suppression coma. All of the patients received mechanical ventilatory support, and 26 (74.3%) received inotropic agents. Eight (22.9%) patients died within 1month. The neurologically functional outcomes at 6months were good in six (27.3%) of the 22 survivors, of whom two returned to clinical baseline. The patients with therapeutic burst-suppression coma were significantly associated with hemodynamic support than the patients with electrographic seizures control (p=0.03), and had a trend of higher 1-month mortality rate, worse 6months outcomes, and a longer duration of hospitalization. Our results suggest that therapeutic burst-suppression coma to treat febrile refractory status epilepticus may lead to an increased risk of hemodynamic instability and a trend of worse outcomes. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

DNA interstrand cross-link repair: understanding role of Fanconi anemia pathway and therapeutic implications.

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Shukla, Pallavi; Solanki, Avani; Ghosh, Kanjaksha; Vundinti, Babu Rao

2013-11-01

Interstrand cross-links (ICLs) are extremely toxic DNA lesions that prevent DNA double-helix separation due to the irreversible covalent linkage binding of some agents on DNA strands. Agents that induce these ICLs are thus widely used as chemotherapeutic drugs but may also lead to tumor growth. Fanconi anemia (FA) is a rare genetic disorder that leads to ICL sensitivity. This review provides update on current understanding of the role of FA proteins in repairing ICLs at various stages of cell cycle. We also discuss link between DNA cross-link genotoxicity caused by aldehydes in FA pathway. Besides this, we summarize various ICL agents that act as drugs to treat different types of tumors and highlight strategies for modulating ICL sensitivity for therapeutic interventions that may be helpful in controlling cancer and life-threatening disease, FA. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Nootropic agents enhance the recruitment of fast GABAA inhibition in rat neocortex.

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Ling, Douglas S F; Benardo, Larry S

2005-07-01

It is widely believed that nootropic (cognition-enhancing) agents produce their therapeutic effects by augmenting excitatory synaptic transmission in cortical circuits, primarily through positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors (AMPARs). However, GABA-mediated inhibition is also critical for cognition, and enhanced GABA function may be likewise therapeutic for cognitive disorders. Could nootropics act through such a mechanism as well? To address this question, we examined the effects of nootropic agents on excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) recorded from layer V pyramidal cells in acute slices of somatosensory cortex. Aniracetam, a positive modulator of AMPA/kainate receptors, increased the peak amplitude of evoked EPSCs and the amplitude and duration of polysynaptic fast IPSCs, manifested as a greater total charge carried by IPSCs. As a result, the EPSC/IPSC ratio of total charge was decreased, representing a shift in the excitation-inhibition balance that favors inhibition. Aniracetam did not affect the magnitude of either monosynaptic IPSCs (mono-IPSCs) recorded in the presence of excitatory amino acid receptor antagonists, or miniature IPSCs (mIPSCs) recorded in the presence of tetrodotoxin. However, the duration of both mono-IPSCs and mIPSCs was prolonged, suggesting that aniracetam also directly modulates GABAergic transmission. Cyclothiazide, a preferential modulator of AMPAR function, enhanced the magnitude and duration of polysynaptic IPSCs, similar to aniracetam, but did not affect mono-IPSCs. Concanavalin A, a kainate receptor modulator, had little effect on EPSCs or IPSCs, suggesting there was no contribution from kainate receptor activity. These findings indicate that AMPAR modulators strengthen inhibition in neocortical pyramidal cells, most likely by altering the kinetics of AMPARs on synaptically connected interneurons and possibly by modulating GABA(A) receptor responses

Therapeutic benefits of enhancing permeability barrier for atopic eczema

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George Man

2015-06-01

Full Text Available The regulatory role of epidermal permeability barrier function in cutaneous inflammation has been well appreciated. While barrier disruption induces cutaneous inflammation, improvement of permeability barrier function alleviates inflammation. Studies have demonstrated that improvement of epidermal permeability barrier function not only prevents the development of atopic eczema, but also delays the relapse of these diseases. Moreover, enhancing the epidermal permeability barrier also alleviates atopic eczema. Furthermore, co-applications of barrier enhancing products with glucocorticoids can increase the therapeutic efficacy and reduce the adverse effects of glucocorticoids in the treatment of atopic eczema. Therefore, utilization of permeability barrier enhancing products alone or in combination with glucocorticoids could be a valuable approach in the treatment of atopic eczema. In this review, we discuss the benefits of improving the epidermal permeability barrier in the management of atopic eczema.

An integrative assessment of the commercial air transportation system via adaptive agents

Science.gov (United States)

Lim, Choon Giap

The overarching research objective is to address the tightly-coupled interactions between the demand-side and supply-side components of the United States Commercial Air Transportation System (CATS) in a time-variant environment. A system-of-system perspective is adopted, where the scope is extended beyond the National Airspace System (NAS) level to the National Transportation System (NTS) level to capture the intermodal and multimodal relationships between the NTS stakeholders. The Agent-Based Modeling and Simulation technique is employed where the NTS/NAS is treated as an integrated Multi-Agent System comprising of consumer and service provider agents, representing the demand-side and supply-side components respectively. Successful calibration and validation of both model components against the observable real world data resulted in a CATS simulation tool where the aviation demand is estimated from socioeconomic and demographic properties of the population instead of merely based on enplanement growth multipliers. This valuable achievement enabled a 20-year outlook simulation study to investigate the implications of a global fuel price hike on the airline industry and the U.S. CATS at large. Simulation outcomes revealed insights into the airline competitive behaviors and the subsequent responses from transportation consumers.

Function and Therapeutic Potential of Mesenchymal Stem Cells in Atherosclerosis

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Feifei Li

2017-05-01

Full Text Available Atherosclerosis is a complicated disorder and largely attributable to dyslipidaemia and chronic inflammation. Despite therapeutic advances over past decades, atherosclerosis remains the leading cause of mortality worldwide. Due to their capability of immunomodulation and tissue regeneration, mesenchymal stem cells (MSCs have evolved as an attractive therapeutic agent in various diseases including atherosclerosis. Accumulating evidences support the protective role of MSCs in all stages of atherosclerosis. In this review, we highlight the current understanding of MSCs including their characteristics such as molecular markers, tissue distribution, migratory property, immune-modulatory competence, etc. We also summarize MSC functions in animal models of atherosclerosis. MSC transplantation is able to modulate cytokine and chemokine secretion, reduce endothelial dysfunction, promote regulatory T cell function, decrease dyslipidemia, and stabilize vulnerable plaques during atherosclerosis development. In addition, MSCs may migrate to lesions where they develop into functional cells during atherosclerosis formation. Finally, the perspectives of MSCs in clinical atherosclerosis therapy are discussed.

Curcumin: Reintroduced Therapeutic Agent from Traditional Medicine for Alcoholic Liver Disease

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Hamid Reza Rahimi

2015-03-01

Full Text Available Alcoholic liver disease (ALD is the main cause of chronic liver disease across the world and can lead to fibrosis and cirrhosis. The etiopathogenesis of ALD is related to ethanol-induced oxidative stress, glutathione reduction, abnormal methionine metabolism, malnutrition, and production of endotoxins that activate Kupffer cells. Curcumin is an active ingredient of the rhizome of turmeric. The substance is shown to have minor adverse effects. As the substance possess low bioavailability in free formulation, different strategies has been conducted to improve its bioavailability which resulted in production of nanomiscels and nanoparticles. Curcumin can provide protection for the liver against toxic effects of alcohol use. Several studies showed curcumin blocks endotoxin-mediated activation of NF-κB and suppresses the expression of cytokines, chemokines, COX-2, and iNOS in Kupffer cells. According to the molecular studies, curcumin inhibits NF-κB signaling pathway, regulates cytokines production and modulates immune response. It has been shown that curcumin can suppress gene expression, especially cytokines genes resulting in down-regulation of tumor necrosis factor-α (TNF-α, interleukin 1 (IL-1, IL-6, IL-8, adhesion molecules (ICAM, VCAM and C-reactive protein. Hence, curcumin can have therapeutic effects on the majority of chronic inflammatory diseases such as asthma, bronchitis, inflammatory bowel disease, rheumatoid arthritis, ALD, fatty liver, and allergy.

Antimicrobial peptides: Possible anti-infective agents.

Science.gov (United States)

Lakshmaiah Narayana, Jayaram; Chen, Jyh-Yih

2015-10-01

Multidrug-resistant bacterial, fungal, viral, and parasitic infections are major health threats. The Infectious Diseases Society of America has expressed concern on the decrease of pharmaceutical companies working on antibiotic research and development. However, small companies, along with academic research institutes, are stepping forward to develop novel therapeutic methods to overcome the present healthcare situation. Among the leading alternatives to current drugs are antimicrobial peptides (AMPs), which are abundantly distributed in nature. AMPs exhibit broad-spectrum activity against a wide variety of bacteria, fungi, viruses, and parasites, and even cancerous cells. They also show potential immunomodulatory properties, and are highly responsive to infectious agents and innate immuno-stimulatory molecules. In recent years, many AMPs have undergone or are undergoing clinical development, and a few are commercially available for topical and other applications. In this review, we outline selected anion and cationic AMPs which are at various stages of development, from preliminary analysis to clinical drug development. Moreover, we also consider current production methods and delivery tools for AMPs, which must be improved for the effective use of these agents. Copyright © 2015 Elsevier Inc. All rights reserved.

Combination therapy of potential gene to enhance oral cancer therapeutic effect

Science.gov (United States)

Yeh, Chia-Hsien; Hsu, Yih-Chih

2015-03-01

The epidermal growth factor receptor (EGFR) over-regulation related to uncontrolled cell division and promotes progression in tumor. Over-expression of human epidermal growth factor receptor (EGFR) has been detected in oral cancer cells. EGFR-targeting agents are potential therapeutic modalities for treating oral cancer based on our in vitro study. Liposome nanotechnology is used to encapsulate siRNA and were modified with target ligand to receptors on the surface of tumor cells. We used EGFR siRNA to treat oral cancer in vitro.

Trophallaxis-inspired model for distributed transport between randomly interacting agents

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Gräwer, Johannes; Ronellenfitsch, Henrik; Mazza, Marco G.; Katifori, Eleni

2017-08-01

Trophallaxis, the regurgitation and mouth to mouth transfer of liquid food between members of eusocial insect societies, is an important process that allows the fast and efficient dissemination of food in the colony. Trophallactic systems are typically treated as a network of agent interactions. This approach, though valuable, does not easily lend itself to analytic predictions. In this work we consider a simple trophallactic system of randomly interacting agents with finite carrying capacity, and calculate analytically and via a series of simulations the global food intake rate for the whole colony as well as observables describing how uniformly the food is distributed within the nest. Our model and predictions provide a useful benchmark to assess to what level the observed food uptake rates and efficiency in food distribution is due to stochastic effects or specific trophallactic strategies by the ant colony. Our work also serves as a stepping stone to describing the collective properties of more complex trophallactic systems, such as those including division of labor between foragers and workers.

Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury.

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Pachori, Alok S; Melo, Luis G; Hart, Melanie L; Noiseux, Nicholas; Zhang, Lunan; Morello, Fulvio; Solomon, Scott D; Stahl, Gregory L; Pratt, Richard E; Dzau, Victor J

2004-08-17

Ischemia and reperfusion represent major mechanisms of tissue injury and organ failure. The timing of administration and the duration of action limit current treatment approaches using pharmacological agents. In this study, we have successfully developed a preemptive strategy for tissue protection using an adenoassociated vector system containing erythropoietin hypoxia response elements for ischemia-regulated expression of the therapeutic gene human heme-oxygenase-1 (hHO-1). We demonstrate that a single administration of this vector several weeks in advance of ischemia/reperfusion injury to multiple tissues such as heart, liver, and skeletal muscle yields rapid and timely induction of hHO-1 during ischemia that resulted in dramatic reduction in tissue damage. In addition, overexpression of therapeutic transgene prevented long-term pathological tissue remodeling and normalized tissue function. Application of this regulatable system using an endogenous physiological stimulus for expression of a therapeutic gene may be a feasible strategy for protecting tissues at risk of ischemia/reperfusion injury.

Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury

Science.gov (United States)

Pachori, Alok S.; Melo, Luis G.; Hart, Melanie L.; Noiseux, Nicholas; Zhang, Lunan; Morello, Fulvio; Solomon, Scott D.; Stahl, Gregory L.; Pratt, Richard E.; Dzau, Victor J.

2004-08-01

Ischemia and reperfusion represent major mechanisms of tissue injury and organ failure. The timing of administration and the duration of action limit current treatment approaches using pharmacological agents. In this study, we have successfully developed a preemptive strategy for tissue protection using an adenoassociated vector system containing erythropoietin hypoxia response elements for ischemia-regulated expression of the therapeutic gene human heme-oxygenase-1 (hHO-1). We demonstrate that a single administration of this vector several weeks in advance of ischemia/reperfusion injury to multiple tissues such as heart, liver, and skeletal muscle yields rapid and timely induction of hHO-1 during ischemia that resulted in dramatic reduction in tissue damage. In addition, overexpression of therapeutic transgene prevented long-term pathological tissue remodeling and normalized tissue function. Application of this regulatable system using an endogenous physiological stimulus for expression of a therapeutic gene may be a feasible strategy for protecting tissues at risk of ischemia/reperfusion injury.

Antibody mimetics: promising complementary agents to animal-sourced antibodies.

Science.gov (United States)

Baloch, Abdul Rasheed; Baloch, Abdul Wahid; Sutton, Brian J; Zhang, Xiaoying

2016-01-01

Despite their wide use as therapeutic, diagnostic and detection agents, the limitations of polyclonal and monoclonal antibodies have inspired scientists to design the next generation biomedical agents, so-called antibody mimetics that offer many advantages over conventional antibodies. Antibody mimetics can be constructed by protein-directed evolution or fusion of complementarity-determining regions through intervening framework regions. Substantial progress in exploiting human, butterfly (Pieris brassicae) and bacterial systems to design and select mimetics using display technologies has been made in the past 10 years, and one of these mimetics [Kalbitor® (Dyax)] has made its way to market. Many challenges lie ahead to develop mimetics for various biomedical applications, especially those for which conventional antibodies are ineffective, and this review describes the current characteristics, construction and applications of antibody mimetics compared to animal-sourced antibodies. The possible limitations of mimetics and future perspectives are also discussed.

Therapeutic benefits of Nanoparticles in Stroke

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Stavros ePanagiotou

2015-05-01

Full Text Available Stroke represents one of the major causes of death and disability worldwide, for which no effective treatments are available. The thrombolytic drug alteplase (tissue plasminogen activator or tPA is the only treatment for acute ischemic stroke but its use is limited by several factors including short therapeutic window, selective efficacy and subsequent haemorrhagic complications. Numerous preclinical studies have reported very promising results using neuroprotective agents but they have failed at clinical trials because of either safety issues or lack of efficacy. The delivery of many potentially therapeutic neuroprotectants and diagnostic compounds to the brain is restricted by the blood-brain barrier (BBB. Nanoparticles (NPs, which can readily cross the BBB without compromising its integrity, have immense applications in the treatment of ischemic stroke. In this review, potential uses of NPs will be summarized for the treatment of ischemic stroke. Additionally, an overview of targeted NPs will be provided, which could be used in the diagnosis of stroke. Finally, the potential limitations of using NPs in medical applications will be mentioned. Since the use of NPs in stroke therapy is now emerging and is still in development, this review is far from comprehensive or conclusive. Instead, examples of NPs and their current use will be provided, as well as the potentials of NPs in an effort to meet the high demand of new therapies in stroke.

Synthesis of Biocompatible Nanoparticulate Coordination Polymers for Diagnostic and Therapeutic Applications

Science.gov (United States)

Kandanapitiye, Murthi S.

The combination of nanotechnology with medicinal chemistry has developed into a burgeoning research area. Nanomaterials (NMs) could be seamlessly interfaced with various facets in biology, biochemistry, medicinal chemistry and environmental chemistry that may not be available to the same material in the bulk scale. This dissertation research has focused on the development of nanoparticulate coordination polymers for diagnostic and therapeutic applications. Modern imaging techniques include X-ray computed tomography (CT), magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET). We have successfully developed several types of nanoparticulate diagnostics and therapeutics that have some potential usefulness in biomedicine. Synthesis and characterization of nanoparticulate based PET (Positron emission tomography)/SPECT (Single photon emission computed tomography) are discussed in chapter 3. In chapter 4, preparation and potential utility of non-gadolinium based MRI contrast agent are reported for T1-weighted application. As far as the solely effectiveness of relaxation is concerned, Gd-based T 1-weighted MRI contrast agents have excellent enhancement of image contrast but they have risks of biological toxicity. Consequently, the search for T 1-weighted CAs with high efficacy and low toxicity has gained attention toward the Mn(II) and Fe(III). Fe(III) is considered to be more toxic to cells because free ferric or ferrous ions can catalyze the production of reactive oxygen species via the Fenton reactions. Paramagnetic chelates of Mn(II) could be employed as T1-weighted CAs. However, it is challenging to design and synthesize highly stable Mn(II) complexes that could maintain the integrity when administered to living system. Chapter 4 describes the synthesis and utility of nanoparticulate Mn analogue of Prussian blue (K2Mn 3[FeII(CN)6]2) as an effective T1 MRI contrast agent for cellular imaging X

Preclinical and clinical development of siRNA-based therapeutics.

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Ozcan, Gulnihal; Ozpolat, Bulent; Coleman, Robert L; Sood, Anil K; Lopez-Berestein, Gabriel

2015-06-29

The discovery of RNA interference, first in plants and Caenorhabditis elegans and later in mammalian cells, led to the emergence of a transformative view in biomedical research. Knowledge of the multiple actions of non-coding RNAs has truly allowed viewing DNA, RNA and proteins in novel ways. Small interfering RNAs (siRNAs) can be used as tools to study single gene function both in vitro and in vivo and are an attractive new class of therapeutics, especially against undruggable targets for the treatment of cancer and other diseases. Despite the potential of siRNAs in cancer therapy, many challenges remain, including rapid degradation, poor cellular uptake and off-target effects. Rational design strategies, selection algorithms, chemical modifications and nanocarriers offer significant opportunities to overcome these challenges. Here, we review the development of siRNAs as therapeutic agents from early design to clinical trial, with special emphasis on the development of EphA2-targeting siRNAs for ovarian cancer treatment. Copyright © 2015 Elsevier B.V. All rights reserved.

Opioid withdrawal syndrome: emerging concepts and novel therapeutic targets.

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Rehni, Ashish K; Jaggi, Amteshwar S; Singh, Nirmal

2013-02-01

Opioid withdrawal syndrome is a debilitating manifestation of opioid dependence and responds poorly to the available clinical therapies. Studies from various in vivo and in vitro animal models of opioid withdrawal syndrome have led to understanding of its pathobiology which includes complex interrelated pathways leading to adenylyl cyclase superactivation based central excitation. Advancements in the elucidation of opioid withdrawal syndrome mechanisms have revealed a number of key targets that have been hypothesized to modulate clinical status. The present review discusses the neurobiology of opioid withdrawal syndrome and its therapeutic target recptors like calcitonin gene related peptide receptors (CGRP), N-methyl-D-aspartate (NMDA) receptors, gamma aminobutyric acid receptors (GABA), G-proteingated inwardly rectifying potassium (GIRK) channels and calcium channels. The present review further details the potential role of second messengers like calcium (Ca2+) / calmodulin-dependent protein kinase (CaMKII), nitric oxide synthase, cytokines, arachidonic acid metabolites, corticotropin releasing factor, fos and src kinases in causing opioid withdrawal syndrome. The exploitation of these targets may provide effective therapeutic agents for the management of opioid dependence-induced abstinence syndrome.

Investigating immune system aging: system dynamics and agent-based modeling

OpenAIRE

Figueredo, Grazziela; Aickelin, Uwe

2010-01-01

System dynamics and agent based simulation models can\\ud both be used to model and understand interactions of entities within a population. Our modeling work presented here is concerned with understanding the suitability of the different types of simulation for the immune system aging problems and comparing their results. We are trying to answer questions such as: How fit is the immune system given a certain age? Would an immune boost be of therapeutic value, e.g. to improve the effectiveness...

Linezolid in the treatment of drug-resistant tuberculosis: the challenge of its narrow therapeutic index.

Science.gov (United States)

Wasserman, Sean; Meintjes, Graeme; Maartens, Gary

2016-10-01

Linezolid is an oxazolidinone with potent activity against M tuberculosis, and improves culture conversion and cure rates when added to treatment regimens for drug resistant tuberculosis. However, linezolid has a narrow therapeutic window, and the optimal dosing strategy that minimizes the substantial toxicity associated with linezolid's prolonged use in tuberculosis treatment has not been determined, limiting the potential impact of this anti-mycobacterial agent. This paper aims to review and summarize the current knowledge on linezolid for the treatment of drug-resistant tuberculosis. The focus is on the pharmacokinetic-pharmacodynamic determinants of linezolid's efficacy and toxicity in tuberculosis, and how this relates to defining an optimal dose. Mechanisms of linezolid toxicity and resistance, and the potential role of therapeutic drug monitoring are also covered. Expert commentary: Prospective pharmacokinetic-pharmacodynamic studies are required to define optimal therapeutic targets and to inform improved linezolid dosing strategies for drug-resistant tuberculosis.

Recovering valuable metals from recycled photovoltaic modules.

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Yi, Youn Kyu; Kim, Hyun Soo; Tran, Tam; Hong, Sung Kil; Kim, Myong Jun

2014-07-01

Recovering valuable metals such as Si, Ag, Cu, and Al has become a pressing issue as end-of-life photovoltaic modules need to be recycled in the near future to meet legislative requirements in most countries. Of major interest is the recovery and recycling of high-purity silicon (> 99.9%) for the production of wafers and semiconductors. The value of Si in crystalline-type photovoltaic modules is estimated to be -$95/kW at the 2012 metal price. At the current installed capacity of 30 GW/yr, the metal value in the PV modules represents valuable resources that should be recovered in the future. The recycling of end-of-life photovoltaic modules would supply > 88,000 and 207,000 tpa Si by 2040 and 2050, respectively. This represents more than 50% of the required Si for module fabrication. Experimental testwork on crystalline Si modules could recover a > 99.98%-grade Si product by HNO3/NaOH leaching to remove Al, Ag, and Ti and other metal ions from the doped Si. A further pyrometallurgical smelting at 1520 degrees C using CaO-CaF2-SiO2 slag mixture to scavenge the residual metals after acid leaching could finally produce > 99.998%-grade Si. A process based on HNO3/NaOH leaching and subsequent smelting is proposed for recycling Si from rejected or recycled photovoltaic modules. Implications: The photovoltaic industry is considering options of recycling PV modules to recover metals such as Si, Ag, Cu, Al, and others used in the manufacturing of the PV cells. This is to retain its "green" image and to comply with current legislations in several countries. An evaluation of potential resources made available from PV wastes and the technologies used for processing these materials is therefore of significant importance to the industry. Of interest are the costs of processing and the potential revenues gained from recycling, which should determine the viability of economic recycling of PV modules in the future.

Mechanism of action of direct-acting antiviral agents in treatment of chronic hepatitis C

Directory of Open Access Journals (Sweden)

WEN Xiaoyu

2016-09-01

Full Text Available With the development and launch of direct-acting antiviral agents (DAAs in the world in recent years, therapeutic regimens for chronic hepatitis C are constantly evolving. DAAs will also be launched in China in the near future. DAAs mainly target at the non-structural proteins of HCV and can inhibit HCV RNA replication. This article introduces the targets, mechanism of action, and resistance characteristics of different DAAs, as well as their current research and development in China and the results of phase Ⅲ clinical studies, in order to provide a reference for combined therapeutic strategies with DAAs in the treatment for chronic hepatitis C.

Development and therapeutic application of internally emitting radiopharmaceuticals

International Nuclear Information System (INIS)

Adelstein, S.J.; Bloomer, W.D.

1980-01-01

This project is concerned with developing the potential of alpha-emitting radionuclides as agents for radiotherapy. Among the available α-emitters, astatine-211 appears most promising for testing the efficacy of α-emitters for therapeutic applications because: (1) it has some chemical similarities to iodine, an element that can readily be incorporated into numerous proteins and peptides; (2) it has a half life that is long enough to permit chemical manipulation yet short enough to minimize destruction of healthy cells; and (3) α-emission is associated with 100% of its decays. If appropriate biological carriers can be labeled with an alpha emitter such as 211 At, they could be of great utility in several areas of therapeutic medicine where elimination of specific cell populations is desired. While previous attempts to astatinate proteins using standard iodination techniques have been unsuccessful, effective labeling of proteins with astatine by first synthesizing an aryl astatide and then coupling this compound to the protein via an acylation has been achieved. Undergoing current investigation are several different aryl astatide-followed-by-acylation approaches including an astatinated Bolton-Hunter type reagent using concanavalin A (ConA) and melanocyte stimulating hormone (MSH) as model compounds

World`s Most Valuable Brand Resonation With Categories of Different Customer Needs

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Kaspars VIKSNE

2017-09-01

Full Text Available One of the key performance indicators of brand success is its value. Brand value is an outcome of brand`s performance in market, and is largely depended from brand`s ability to satisfy certain customer needs. For the greatest success in the world`s market brand should resonate its ability to satisfy some of customer`s most universal needs. In this paper authors strives to find out which of the needs world`s most successful brands are resonating with. Therefore paper goal is to is to determine what customer needs world`s most valuable brands are primarily satisfying. First part of paper authors briefly evaluate Maslow theory of needs. In second part of paper authors identify main challenges of brand valuation, and briefly describe today`s most valuable brands. In third part of paper authors analyzes if resonating certain human need in brand makes it to be more valuable. In last part of paper authors summarizes the main findings and gives recommendations for better marketing practices to other brands whose owners have high market ambitions. In order to attain the paper`s goal, authors will use following research methods: Comparative analysis for comparing brands in different brand rankings; Content analysis for determining what need satisfaction brand advertisements resonate; Data analysis for quantify the results gathered from content analysis

Efficacy of antidotes (midazolam, atropine and HI-6) on nerve agent induced molecular and neuropathological changes.

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RamaRao, Golime; Afley, Prachiti; Acharya, Jyothiranjan; Bhattacharya, Bijoy Krishna

2014-04-04

Recent alleged attacks with nerve agent sarin on civilians in Syria indicate their potential threat to both civilian and military population. Acute nerve agent exposure can cause rapid death or leads to multiple and long term neurological effects. The biochemical changes that occur following nerve agent exposure needs to be elucidated to understand the mechanisms behind their long term neurological effects and to design better therapeutic drugs to block their multiple neurotoxic effects. In the present study, we intend to study the efficacy of antidotes comprising of HI-6 (1-[[[4-(aminocarbonyl)-pyridinio]-methoxy]-methyl]-2-[(hydroxyimino) methyl] pyridinium dichloride), atropine and midazolam on soman induced neurodegeneration and the expression of c-Fos, Calpain, and Bax levels in discrete rat brain areas. Therapeutic regime consisting of HI-6 (50 mg/kg, i.m), atropine (10 mg/kg, i.m) and midazolam (5 mg/kg, i.m) protected animals against soman (2×LD50, s.c) lethality completely at 2 h and 80% at 24 h. HI-6 treatment reactivated soman inhibited plasma and RBC cholinesterase up to 40%. Fluoro-Jade B (FJ-B) staining of neurodegenerative neurons showed that soman induced significant necrotic neuronal cell death, which was reduced by this antidotal treatment. Soman increased the expression of neuronal proteins including c-Fos, Bax and Calpain levels in the hippocampus, cerebral cortex and cerebellum regions of the brain. This therapeutic regime also reduced the soman induced Bax, Calpain expression levels to near control levels in the different brain regions studied, except a mild induction of c-Fos expression in the hippocampus. Rats that received antidotal treatment after soman exposure were protected from mortality and showed reduction in the soman induced expression of c-Fos, Bax and Calpain and necrosis. Results highlight the need for timely administration of better antidotes than standard therapy in order to prevent the molecular and biochemical changes and

A Monte Carlo Study of dose enhancement according to the enhancement agents

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Kim, Jung Hoon; Kim, Chang Soo [Dept. of Radiological Science, College of Health Sciences, Catholic University of Pusan, Busan (Korea, Republic of); Hwang, Chul Hwan [Dept. of Radiation Oncology, Pusan National University Hospital, Busan (Korea, Republic of)

2017-03-15

Dose enhancement effects at megavoltage (MV) X and γ-ray energies, and the effects of different energy levels on incident energy, dose enhancement agents, and concentrations were analyzed using Monte Carlo simulations. Gold, gadolinium, Iodine, and iron oxide (Fe2O3) were compared as dose enhancement agents. For incident energy, 4, 6, 10 and 15 MV X-ray spectra produced by a linear accelerator and a Co60 γ-ray were used. The dose enhancement factor (DEF) was calculated using an ICRU Slab phantom for concentrations of 7, 18, and 30 mg/g. The DEF was higher at higher concentrations of dose enhancement agents and at lower incident energies. The calculated DEF ranged from 1.035 to 1.079, and dose enhancement effects were highest for iron oxide, followed by iodine, gadolinium, and gold. Thus, this study contributes to improving the therapeutic ratio by delivering larger doses of radiation to tumor volume, and provides data to support further in vivo and in vitro studies.

Emerging therapeutic potential of graviola and its constituents in cancers.

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Qazi, Asif Khurshid; Siddiqui, Jawed A; Jahan, Rahat; Chaudhary, Sanjib; Walker, Larry A; Sayed, Zafar; Jones, Dwight T; Batra, Surinder K; Macha, Muzafar A

2018-04-05

Cancer remains a leading cause of death in the USA and around the world. Although the current synthetic inhibitors used in targeted therapies have improved patient prognosis, toxicity and development of resistance to these agents remain a challenge. Plant-derived natural products and their derivatives have historically been used to treat various diseases, including cancer. Several leading chemotherapeutic agents are directly or indirectly based on botanical natural products. Beyond these important drugs, however, a number of crude herbal or botanical preparations have also shown promising utility for cancer and other disorders. One such natural resource is derived from certain plants of the family Annonaceae, which are widely distributed in tropical and subtropical regions. Among the best known of these is Annona muricata, also known as soursop, graviola or guanabana. Extracts from the fruit, bark, seeds, roots and leaves of graviola, along with several other Annonaceous species, have been extensively investigated for anticancer, anti-inflammatory and antioxidant properties. Phytochemical studies have identified the acetogenins, a class of bioactive polyketide-derived constituents, from the extracts of Annonaceous species, and dozens of these compounds are present in different parts of graviola. This review summarizes current literature on the therapeutic potential and molecular mechanism of these constituents from A.muricata against cancer and many non-malignant diseases. Based on available data, there is good evidence that these long-used plants could have both chemopreventive and therapeutic potential. Appropriate attention to safety studies will be important to assess their effectiveness on various diseases caused or promoted by inflammation.

Application of Disposable Bag Bioreactors in Tissue Engineering and for the Production of Therapeutic Agents

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Eibl, R.; Eibl, D.

In order to increase process efficiency, many pharmaceutical and biotechnology companies have introduced disposable bag technology over the last 10 years. Because this technology also greatly reduces the risk of cross-contamination, disposable bags are preferred in applications in which an absolute or improved process safety is a necessity, namely the production of functional tissue for implantation (tissue engineering), the production of human cells for the treatment of cancer and immune system diseases (cellular therapy), the production of viruses for gene therapies, the production of therapeutic proteins, and veterinary as well as human vaccines.

An alternative approach to recovering valuable metals from zinc phosphating sludge.

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Kuo, Yi-Ming

2012-01-30

This study used a vitrification process (with good potential for commercialization) to recover valuable metals from Zn phosphating sludge. The involved vitrification process achieves two major goals: it transformed hazardous Zn phosphating sludge into inert slag and it concentrated Fe (83.5%) and Zn (92.8%) into ingot and fine particulate-phase material, respectively. The Fe content in the ingot was 278,000 mg/kg, making the ingot a potential raw material for iron making. The fine particulate-phase material (collected from flue gas) contained abundant Zn (544,000 mg/kg) in the form of ZnO. The content (67.7%) of ZnO was high, so it can be directly sold to refineries. The recovered coarse particulate-phase material, with insufficient amount of ZnO, can be recycled as a feeding material for Zn re-concentration. Therefore, the vitrification process can not only treat hazardous materials but also effectively recover valuable metals. Copyright © 2011 Elsevier B.V. All rights reserved.

Pharmacological and therapeutic directions in ADHD: Specificity in the PFC

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Levy Florence

2008-02-01

Full Text Available Abstract Background Recent directions in the treatment of ADHD have involved both a broadening of pharmacological perspectives to include nor-adrenergic as well as dopaminergic agents. A review of animal and human studies of pharmacological and therapeutic directions in ADHD suggests that the D1 receptor is a specific site for dopaminergic regulation of the PFC, but optimal levels of dopamine (DA are required for beneficial effects on working memory. Animal and human studies indicate that the alpha-2A receptor is also important for prefrontal regulation, leaving open the question of the relative importance of these receptor sites. The therapeutic effects of ADHD medications in the prefrontal cortex have focused attention on the development of working memory capacity in ADHD. Hypothesis The actions of dopaminergic vs noradrenergic agents, currently available for the treatment of ADHD have overlapping, but different actions in the prefrontal cortex (PFC and subcortical centers. While stimulants act on D1 receptors in the dorsolateral prefrontal cortex, they also have effects on D2 receptors in the corpus striatum and may also have serotonergic effects at orbitofrontal areas. At therapeutic levels, dopamine (DA stimulation (through DAT transporter inhibition decreases noise level acting on subcortical D2 receptors, while NE stimulation (through alpha-2A agonists increases signal by acting preferentially in the PFC possibly on DAD1 receptors. On the other hand, alpha-2A noradrenergic transmission is more limited to the prefrontal cortex (PFC, and thus less likely to have motor or stereotypic side effects, while alpha-2B and alpha-2C agonists may have wider cortical effects. The data suggest a possible hierarchy of specificity in the current medications used in the treatment of ADHD, with guanfacine likely to be most specific for the treatment of prefrontal attentional and working memory deficits. Stimulants may have broader effects on both vigilance

Guidelines for Rational Cancer Therapeutics

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Byunghee Yoo

2017-12-01

Full Text Available Traditionally, cancer therapy has relied on surgery, radiation therapy, and chemotherapy. In recent years, these interventions have become increasingly replaced or complemented by more targeted approaches that are informed by a deeper understanding of the underlying biology. Still, the implementation of fully rational patient-specific drug design appears to be years away. Here, we present a vision of rational drug design for cancer that is defined by two major components: modularity and image guidance. We suggest that modularity can be achieved by combining a nanocarrier and an oligonucleotide component into the therapeutic. Image guidance can be incorporated into the nanocarrier component by labeling with a specific imaging reporter, such as a radionuclide or contrast agent for magnetic resonance imaging. While limited by the need for additional technological advancement in the areas of cancer biology, nanotechnology, and imaging, this vision for the future of cancer therapy can be used as a guide to future research endeavors.

Efficacy of anti-inflammatory, antibiotic and pleiotropic agents in reversing nitrogen mustard-induced injury in ex vivo cultured rabbit cornea.

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Goswami, Dinesh G; Kant, Rama; Tewari-Singh, Neera; Agarwal, Rajesh

2018-09-01

Vesicating agent, Sulfur mustard (SM), causes devastating eye injury; however, there are no effective antidotes available. Using nitrogen mustard (NM), a bi-functional analog of SM, we have earlier reported that NM-induced corneal injury in ex vivo rabbit cornea organ culture model parallels corneal injury reported with SM. Using this model, we have demonstrated the therapeutic efficacy of dexamethasone (DEX), doxycycline (DOX) and silibinin (SB) in reversing NM (2h exposure)-induced corneal injuries when added immediately after washing NM. In the present study, we further examined the efficacy of similar/higher doses of these agents when added immediately, 2, or 4h after washing NM following its 2h exposure. All three treatment agents caused a reversal in established NM-induced injury biomarkers when added immediately or 2h after washing NM following its 2h exposure; however, when treatments were carried out 4h after washing NM, there was no significant effect. Together, our results further show the beneficial effect of these agents in reversing NM-induced corneal injury and indicate the time window for effective treatment. This could be useful towards future development of targeted therapeutics against vesicant-induced ocular injury. Copyright © 2017 Elsevier B.V. All rights reserved.

Chemotherapy and novel therapeutics before radical prostatectomy for high-risk clinically localized prostate cancer.

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Cha, Eugene K; Eastham, James A

2015-05-01

Although both surgery and radiation are potential curative options for men with clinically localized prostate cancer, a significant proportion of men with high-risk and locally advanced disease will demonstrate biochemical and potentially clinical progression of their disease. Neoadjuvant systemic therapy before radical prostatectomy (RP) is a logical strategy to improve treatment outcomes for men with clinically localized high-risk prostate cancer. Furthermore, delivery of chemotherapy and other systemic agents before RP affords an opportunity to explore the efficacy of these agents with pathologic end points. Neoadjuvant chemotherapy, primarily with docetaxel (with or without androgen deprivation therapy), has demonstrated feasibility and safety in men undergoing RP, but no study to date has established the efficacy of neoadjuvant chemotherapy or neoadjuvant chemohormonal therapies. Other novel agents, such as those targeting the vascular endothelial growth factor receptor, epidermal growth factor receptor, platelet-derived growth factor receptor, clusterin, and immunomodulatory therapeutics, are currently under investigation. Copyright © 2015 Elsevier Inc. All rights reserved.

Nucleic acid aptamer-guided cancer therapeutics and diagnostics: the next generation of cancer medicine.

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Xiang, Dongxi; Shigdar, Sarah; Qiao, Greg; Wang, Tao; Kouzani, Abbas Z; Zhou, Shu-Feng; Kong, Lingxue; Li, Yong; Pu, Chunwen; Duan, Wei

2015-01-01

Conventional anticancer therapies, such as chemo- and/or radio-therapy are often unable to completely eradicate cancers due to abnormal tumor microenvironment, as well as increased drug/radiation resistance. More effective therapeutic strategies for overcoming these obstacles are urgently in demand. Aptamers, as chemical antibodies that bind to targets with high affinity and specificity, are a promising new and novel agent for both cancer diagnostic and therapeutic applications. Aptamer-based cancer cell targeting facilitates the development of active targeting in which aptamer-mediated drug delivery could provide promising anticancer outcomes. This review is to update the current progress of aptamer-based cancer diagnosis and aptamer-mediated active targeting for cancer therapy in vivo, exploring the potential of this novel form of targeted cancer therapy.

New method for studying the efficiency of chelating agents of the polyamine acid series for internal decontamination

International Nuclear Information System (INIS)

Lafuma, J.; Nenot, J.C.; Morin, M.

1968-01-01

We followed the biological fate of a complex formed on one side with either a rare earth (cerium-144) or a transuranium element (plutonium-239), and on the other side with a chelating agent of the polyamino acid series (EDTA, BAETA, DTPA, TTHA). This method allowed to study: 1 - the in vivo stability of the various complexes and to compare them; 2 - the stability of the complexes as a function of the isotope - chelating agent weight relationships; 3 - the metabolism of the chelating agents resulting in stable complexes, i. e. DTPA and TTHA mainly. This simple method brought out the higher efficiency, of DTPA in chelating rare earths and plutonium and for therapeutic purposes. (authors) [fr

Investigation of Acute Toxicity of a Chemical Warfare Agent in Kidneys

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Turgut Topal

2007-08-01

Full Text Available One of the most important chemical warfare agents, sulfur mustard (SM causes crucial acute and chronic toxic effects. Lung, skin, eye and kidneys are the most affected organs. In this work, it was investigated if increased nitric oxide (NO and peroxynitrite are involved in nitrogen mustard (NM induced kidney damage. In this experimen, aminoguanidine (AG as inducible nitric oxide synthase (iNOS inhibitor and ebselen as peroxynitrite scavenger were used. NM administration resulted in important oxidant and antioxidant changes as well as tissue damage in kidneys. Therapeutic agents showed significant protection and reduced oxidant parameteres leading to tissue healing was observed. Results of this study suggest that drugs with similar properties can be used to protect kidney damage caused by NM. [TAF Prev Med Bull. 2007; 6(4: 227-232

Investigation of Acute Toxicity of a Chemical Warfare Agent in Kidneys

Directory of Open Access Journals (Sweden)

Turgut Topal

2007-08-01

Full Text Available One of the most important chemical warfare agents, sulfur mustard (SM causes crucial acute and chronic toxic effects. Lung, skin, eye and kidneys are the most affected organs. In this work, it was investigated if increased nitric oxide (NO and peroxynitrite are involved in nitrogen mustard (NM induced kidney damage. In this experimen, aminoguanidine (AG as inducible nitric oxide synthase (iNOS inhibitor and ebselen as peroxynitrite scavenger were used. NM administration resulted in important oxidant and antioxidant changes as well as tissue damage in kidneys. Therapeutic agents showed significant protection and reduced oxidant parameteres leading to tissue healing was observed. Results of this study suggest that drugs with similar properties can be used to protect kidney damage caused by NM. [TAF Prev Med Bull 2007; 6(4.000: 227-232

Therapeutics of Ebola hemorrhagic fever: whole-genome transcriptional analysis of successful disease mitigation.

Science.gov (United States)

Yen, Judy Y; Garamszegi, Sara; Geisbert, Joan B; Rubins, Kathleen H; Geisbert, Thomas W; Honko, Anna; Xia, Yu; Connor, John H; Hensley, Lisa E

2011-11-01

The mechanisms of Ebola (EBOV) pathogenesis are only partially understood, but the dysregulation of normal host immune responses (including destruction of lymphocytes, increases in circulating cytokine levels, and development of coagulation abnormalities) is thought to play a major role. Accumulating evidence suggests that much of the observed pathology is not the direct result of virus-induced structural damage but rather is due to the release of soluble immune mediators from EBOV-infected cells. It is therefore essential to understand how the candidate therapeutic may be interrupting the disease process and/or targeting the infectious agent. To identify genetic signatures that are correlates of protection, we used a DNA microarray-based approach to compare the host genome-wide responses of EBOV-infected nonhuman primates (NHPs) responding to candidate therapeutics. We observed that, although the overall circulating immune response was similar in the presence and absence of coagulation inhibitors, surviving NHPs clustered together. Noticeable differences in coagulation-associated genes appeared to correlate with survival, which revealed a subset of distinctly differentially expressed genes, including chemokine ligand 8 (CCL8/MCP-2), that may provide possible targets for early-stage diagnostics or future therapeutics. These analyses will assist us in understanding the pathogenic mechanisms of EBOV infection and in identifying improved therapeutic strategies.

A Prokinetic Agent with a Dual Effect – Itopride – In the Treatment of Dysmotility

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Petr Dite

2014-12-01

Full Text Available A wide range of dyspeptic symptoms in clinical practice reflect the high prevalence of functional disorders of the gastrointestinal (GI tract. Prokinetic agents are the current mainstay in the therapy of functional dyspepsia. One of these drugs is itopride. We evaluated therapeutic efficacy of itopride according to the literature review. The therapeutic potential of itopride is connected with a dual effect: influencing of enzyme acetylcholinesterase activity and blocking dopamine D2 receptors. After the itopride administration, the contractility of smooth muscle in the upper GI tract increases. Itopride is a drug with rapid absorption from the small bowel; its peak serum concentration occurs 35 minutes after oral administration. Itopride does not pass the blood-brain barrier and does not affect the heart rate by influencing the QT segment. Itopride is a safe prokinetic agent with positive influence on the symptoms of functional dyspepsia such as postprandial fullness, bloating, and gastric emptying. Itopride could also be used for the therapy of the mild form of gastro-oesophageal reflux.

Long-Term Impact of Immunosuppressants at Therapeutic Doses on Male Reproductive System in Unilateral Nephrectomized Rats: A Comparative Study

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Yehui Chen

2013-01-01

Full Text Available Cyclosporine, tacrolimus, and sirolimus are commonly used in renal transplant recipients to prevent rejection. However, information for comparative effects of these agents on the male productive system is extremely limited and controversial. In a physiologically and clinically relevant rat model of unilateral nephrectomy, we demonstrated that long-term oral administration of both cyclosporine and sirolimus at doses equivalent to the therapeutic levels used for postrenal transplant patients significantly affects testicular development and the hypothalamic-pituitary-gonadal axis accompanied by profound histological changes of testicular structures on both light and electron microscopic examinations. Spermatogenesis was also severely impaired as indicated by low total sperm counts along with reduction of sperm motility and increase in sperm abnormality after treatment with these agents, which may lead to male infertility. On the other hand, treatment with therapeutic dose of tacrolimus only induced mild reduction of sperm count without histological evidence of testicular injury. The current study clearly demonstrates that commonly used immunosuppressants have various impacts on male reproductive system even at therapeutic levels. Our data provide useful information for the assessment of male infertility in renal transplant recipients who wish to father children. Clinical trials to address these issues should be urged.

Introduction to thematic minireview series: Development of human therapeutics based on induced pluripotent stem cell (iPSC) technology.

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Rao, Mahendra; Gottesfeld, Joel M

2014-02-21

With the advent of human induced pluripotent stem cell (hiPSC) technology, it is now possible to derive patient-specific cell lines that are of great potential in both basic research and the development of new therapeutics for human diseases. Not only do hiPSCs offer unprecedented opportunities to study cellular differentiation and model human diseases, but the differentiated cell types obtained from iPSCs may become therapeutics themselves. These cells can also be used in the screening of therapeutics and in toxicology assays for potential liabilities of therapeutic agents. The remarkable achievement of transcription factor reprogramming to generate iPSCs was recognized by the award of the Nobel Prize in Medicine to Shinya Yamanaka in 2012, just 6 years after the first publication of reprogramming methods to generate hiPSCs (Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. (2007) Cell 131, 861-872). This minireview series highlights both the promises and challenges of using iPSC technology for disease modeling, drug screening, and the development of stem cell therapeutics.

The potential therapeutic value for bereaved relatives participating in research: An exploratory study.

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Germain, Alison; Mayland, Catriona R; Jack, Barbara A

2016-10-01

Conducting research with the bereaved presents an immediate ethical challenge, as they are undoubtedly a vulnerable group, associated with high levels of distress and susceptible to both physical and mental health issues. A comprehensive understanding of the potential therapeutic benefits for bereaved relatives participating in palliative care research is limited, and therefore the ethics of engaging this group remain questionable. This paper describes a secondary analysis of qualitative data collected in the Care of the Dying Evaluation (CODE) project, examining the experiences of patients who died at home. It explores the motivations and potential benefits for bereaved relatives participating in research with reference to the recently developed concepts in bereavement theory. Cognitive interviews were conducted with 15 bereaved relatives and secondary analysis using a content analysis framework was employed to classify the data. The results center around six recurring concepts identified as adaptive in current bereavement theory: an opportunity to share the narrative accounts of the final hours of their relative's life; a search for sense and meaning in loss; an ongoing bond/attachment with the deceased; altruistic motivations; oscillation between loss and restorative orientations; and a sense of resilience. Overall, the participants found that taking part in the research was valuable and that it could be described as offering therapeutic benefits. The need for bereaved relatives to take part in research studies should be encouraged, as they provide an accurate proxy for the patient's experience of end-of-life care while also providing a valuable account of their own perspective as family member and carer. In addition, we highlight the need for ethics committees to be aware of the potential benefits for bereaved relatives participating in research of this kind.

The advantages and challenges of using FDG PET/CT for response assessment in melanoma in the era of targeted agents and immunotherapy

Energy Technology Data Exchange (ETDEWEB)

Wong, Annie N.M.; McArthur, Grant A. [The Peter MacCallum Cancer Centre, Cancer Medicine, Melbourne (Australia); The University of Melbourne, The Sir Peter MacCallum Department of Oncology, Melbourne (Australia); Hofman, Michael S. [The Peter MacCallum Cancer Centre, Cancer Imaging, Melbourne, VIC (Australia); Hicks, Rodney J. [The University of Melbourne, The Sir Peter MacCallum Department of Oncology, Melbourne (Australia); The Peter MacCallum Cancer Centre, Cancer Imaging, Melbourne, VIC (Australia)

2017-08-15

The treatment of melanoma has been revolutionised in recent years by advances in the understanding of the genomic landscape of this disease, which has led to the development of new targeted therapeutic agents, and the ability to therapeutically manipulate the immune system through inhibition of cancer cell-T-cell interactions that prevent an adaptive immune response. While these therapeutic interventions have dramatically improved the prospects of survival for patients with advanced melanoma, they bring significant complexity to the interpretation of therapeutic response because their mechanisms and temporal profile of response vary considerably. In this review, we discuss the mode of action of these emerging therapies and their toxicities to provide a framework for the use of FDG PET/CT in therapeutic response assessment. We propose that the greatest utility of PET in assessment of response to agents that abrogate signalling related to BRAF mutation is for early assessment of resistance, while in anti-CTLA4 therapy, immunological flare can compromise early assessment of response but can identify potentially life-threatening autoimmune reactions. For anti-PD1/PDL1 therapy, the role of FDG PET/CT is more akin to its use in other solid malignancies undergoing treatment with conventional chemotherapy. However, further research is required to optimise the timing of scans and response criteria in this disease. (orig.)

The advantages and challenges of using FDG PET/CT for response assessment in melanoma in the era of targeted agents and immunotherapy

International Nuclear Information System (INIS)

Wong, Annie N.M.; McArthur, Grant A.; Hofman, Michael S.; Hicks, Rodney J.

2017-01-01

The treatment of melanoma has been revolutionised in recent years by advances in the understanding of the genomic landscape of this disease, which has led to the development of new targeted therapeutic agents, and the ability to therapeutically manipulate the immune system through inhibition of cancer cell-T-cell interactions that prevent an adaptive immune response. While these therapeutic interventions have dramatically improved the prospects of survival for patients with advanced melanoma, they bring significant complexity to the interpretation of therapeutic response because their mechanisms and temporal profile of response vary considerably. In this review, we discuss the mode of action of these emerging therapies and their toxicities to provide a framework for the use of FDG PET/CT in therapeutic response assessment. We propose that the greatest utility of PET in assessment of response to agents that abrogate signalling related to BRAF mutation is for early assessment of resistance, while in anti-CTLA4 therapy, immunological flare can compromise early assessment of response but can identify potentially life-threatening autoimmune reactions. For anti-PD1/PDL1 therapy, the role of FDG PET/CT is more akin to its use in other solid malignancies undergoing treatment with conventional chemotherapy. However, further research is required to optimise the timing of scans and response criteria in this disease. (orig.)

Agentes farmacológicos actuales en el tratamiento de la diabetes mellitus no insulinodependiente

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Arturo Hernández-Yero

1997-12-01

Full Text Available Se plantea que debido a la heterogeneidad patogénica de la diabetes mellitus no insulinodependiente, se debe considerar que diferentes agentes farmacológicos serán necesarios para tratar con éxito la enfermedad, por lo cual se realiza una revisión bibliográfica de las líneas de tratamiento actuales y en perspectivas para esta compleja entidad. Las modalidades terapéuticas actuales incluyen 5 grupos de agentes esenciales: los inhibidores de las alfaglucosidasas intestinales, las sulfonilureas, las biguanidas, la insulina y el recién incorporado grupo de las tiazolidinedionas, que si se utilizan en los comienzos de la enfermedad o en pacientes con resistencia insulínica, pudieran retrasar o prevenir el desarrollo de ésta, y pueden interferir en la reducción progresiva de la función pancreática. Se expone un grupo importante de agentes farmacológicos, así como sus posibles mecanismos de acción, sobre los cuales se ha estado investigando, para ampliar e incrementar la terapéutica de la diabetes, entre los que se encuentran los análogos de la insulina, los agentes insulinomiméticos y los preparados orales de insulina, los agentes insulinotrópicos no sulfonilureas, los análogos de la amilina, los péptidos similares al glucagón, los antagonistas alfa-2 adrenérgicos, los moduladores del metabolismo de la glucosa y algunas sustancias de origen vegetal con posibles efectos hipoglucémicos.It is stated that due to the pathogenic heterogeneity of non insulin-dependent diabetes mellitus, it should be considered that different pharmacological agents will be necessary to treat this disease successfully. To this end, a bibliographical review of the present and prospective treatment lines for this complex disease is made. The current therapeutic modalities include 5 groups of esential agents: the inhibitors of the intestinal alphaglucosidases, the sulphonylureas, the biguanides, insulin, and the newly incorporated group of