Identification and Prioritization of Important Attributes of Disease-Modifying Drugs in Decision Making among Patients with Multiple Sclerosis: A Nominal Group Technique and Best-Worst Scaling.

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Kremer, Ingrid E H; Evers, Silvia M A A; Jongen, Peter J; van der Weijden, Trudy; van de Kolk, Ilona; Hiligsmann, Mickaël

2016-01-01

Understanding the preferences of patients with multiple sclerosis (MS) for disease-modifying drugs and involving these patients in clinical decision making can improve the concordance between medical decisions and patient values and may, subsequently, improve adherence to disease-modifying drugs. This study aims first to identify which characteristics-or attributes-of disease-modifying drugs influence patients´ decisions about these treatments and second to quantify the attributes' relative importance among patients. First, three focus groups of relapsing-remitting MS patients were formed to compile a preliminary list of attributes using a nominal group technique. Based on this qualitative research, a survey with several choice tasks (best-worst scaling) was developed to prioritize attributes, asking a larger patient group to choose the most and least important attributes. The attributes' mean relative importance scores (RIS) were calculated. Nineteen patients reported 34 attributes during the focus groups and 185 patients evaluated the importance of the attributes in the survey. The effect on disease progression received the highest RIS (RIS = 9.64, 95% confidence interval: [9.48-9.81]), followed by quality of life (RIS = 9.21 [9.00-9.42]), relapse rate (RIS = 7.76 [7.39-8.13]), severity of side effects (RIS = 7.63 [7.33-7.94]) and relapse severity (RIS = 7.39 [7.06-7.73]). Subgroup analyses showed heterogeneity in preference of patients. For example, side effect-related attributes were statistically more important for patients who had no experience in using disease-modifying drugs compared to experienced patients (p decision making would be needed and requires eliciting individual preferences.

Tumour necrosis factor inhibitors versus combination intensive therapy with conventional disease modifying anti-rheumatic drugs in established rheumatoid arthritis: TACIT non-inferiority randomised controlled trial.

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Scott, David L; Ibrahim, Fowzia; Farewell, Vern; O'Keeffe, Aidan G; Walker, David; Kelly, Clive; Birrell, Fraser; Chakravarty, Kuntal; Maddison, Peter; Heslin, Margaret; Patel, Anita; Kingsley, Gabrielle H

2015-03-13

To determine whether intensive combinations of synthetic disease modifying drugs can achieve similar clinical benefits at lower costs to high cost biologics such as tumour necrosis factor inhibitors in patients with active rheumatoid arthritis resistant to initial methotrexate and other synthetic disease modifying drugs. Open label pragmatic randomised multicentre two arm non-inferiority trial over 12 months. 24 rheumatology clinics in England. Patients with rheumatoid arthritis who were eligible for treatment with tumour necrosis factor inhibitors according to current English guidance were randomised to either the tumour necrosis factor inhibitor strategy or the combined disease modifying drug strategy. Biologic strategy: start tumour necrosis factor inhibitor; second biologic in six month for non-responders. Alternative strategy: start combination of disease modifying drugs; start tumour necrosis factor inhibitors after six months in non-responders. reduction in disability at 12 months measured with patient recorded heath assessment questionnaire (range 0.00-3.00) with a 0.22 non-inferiority margin for combination treatment versus the biologic strategy. quality of life, joint damage, disease activity, adverse events, and costs. Intention to treat analysis used multiple imputation methods for missing data. 432 patients were screened: 107 were randomised to tumour necrosis factor inhibitors and 101 started taking; 107 were randomised to the combined drug strategy and 104 started taking the drugs. Initial assessments were similar; 16 patients were lost to follow-up (seven with the tumour necrosis factor inhibitor strategy, nine with the combined drug strategy); 42 discontinued the intervention but were followed-up (19 and 23, respectively). The primary outcome showed mean falls in scores on the health assessment questionnaire of -0.30 with the tumour necrosis factor inhibitor strategy and -0.45 with the alternative combined drug strategy. The difference between

Adherence to Disease Modifying Drugs among Patients with Multiple Sclerosis in Germany: A Retrospective Cohort Study.

Directory of Open Access Journals (Sweden)

Kerstin Hansen

Full Text Available Long-term therapies such as disease modifying therapy for Multiple Sclerosis (MS demand high levels of medication adherence in order to reach acceptable outcomes. The objective of this study was to describe adherence to four disease modifying drugs (DMDs among statutorily insured patients within two years following treatment initiation. These drugs were interferon beta-1a i.m. (Avonex, interferon beta-1a s.c. (Rebif, interferon beta-1b s.c. (Betaferon and glatiramer acetate s.c. (Copaxone.This retrospective cohort study used pharmacy claims data from the data warehouse of the German Institute for Drug Use Evaluation (DAPI from 2001 through 2009. New or renewed DMD prescriptions in the years 2002 to 2006 were identified and adherence was estimated during 730 days of follow-up by analyzing the medication possession ratio (MPR as proxy for compliance and persistence defined as number of days from initiation of DMD therapy until discontinuation or interruption.A total of 52,516 medication profiles or therapy cycles (11,891 Avonex, 14,060 Betaferon, 12,353 Copaxone and 14,212 Rebif from 50,057 patients were included into the analysis. Among the 4 cohorts, no clinically relevant differences were found in available covariates. The Medication Possession Ratio (MPR measured overall compliance, which was 39.9% with a threshold MPR≥0.8. There were small differences in the proportion of therapy cycles during which a patient was compliant for the following medications: Avonex (42.8%, Betaferon (40.6%, Rebif (39.2%, and Copaxone (37%. Overall persistence was 32.3% at the end of the 24 months observation period, i.e. during only one third of all included therapy cycles patients did not discontinue or interrupt DMD therapy. There were also small differences in the proportion of therapy cycles during which a patient was persistent as follows: Avonex (34.2%, Betaferon (33.4%, Rebif (31.7% and Copaxone (29.8%.Two years after initiating MS-modifying therapy, only

The Impact of Conventional and Biological Disease Modifying Antirheumatic Drugs on Bone Biology. Rheumatoid Arthritis as a Case Study.

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Barreira, Sofia Carvalho; Fonseca, João Eurico

2016-08-01

The bone and the immune system have a very tight interaction. Systemic immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA), induce bone loss, leading to a twofold increase in osteoporosis and an increase of fragility fracture risk of 1.35-2.13 times. This review focuses on the effects of conventional and biological disease modifying antirheumatic drugs (DMARDs) on bone biology, in the context of systemic inflammation, with a focus on RA. Published evidence supports a decrease in osteoclastic activity induced by DMARDs, which leads to positive effects on bone mineral density (BMD). It is unknown if this effect could be translated into fracture risk reduction. The combination with antiosteoclastic drugs can have an additional benefit.

Biologic and oral disease-modifying antirheumatic drug monotherapy in rheumatoid arthritis

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Emery, Paul; Sebba, Anthony; Huizinga, Tom W J

2013-01-01

Clinical evidence demonstrates coadministration of tumour necrosis factor inhibitor (TNFi) agents and methotrexate (MTX) is more efficacious than administration of TNFi agents alone in patients with rheumatoid arthritis, leading to the perception that coadministration of MTX with all biologic agents or oral disease-modifying antirheumatic drugs is necessary for maximum efficacy. Real-life registry data reveal approximately one-third of patients taking biologic agents use them as monotherapy. Additionally, an analysis of healthcare claims data showed that when MTX was prescribed in conjunction with a biologic agent, as many as 58% of patients did not collect the MTX prescription. Given this discrepancy between perception and real life, we conducted a review of the peer-reviewed literature and rheumatology medical congress abstracts to determine whether data support biologic monotherapy as a treatment option for patients with rheumatoid arthritis. Our analysis suggests only for tocilizumab is there evidence that the efficacy of biologic monotherapy is comparable with combination therapy with MTX. PMID:23918035

Drug development in Parkinson's disease: from emerging molecules to innovative drug delivery systems.

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Garbayo, E; Ansorena, E; Blanco-Prieto, M J

2013-11-01

Current treatments for Parkinson's disease (PD) are aimed at addressing motor symptoms but there is no therapy focused on modifying the course of the disease. Successful treatment strategies have been so far limited and brain drug delivery remains a major challenge that restricts its treatment. This review provides an overview of the most promising emerging agents in the field of PD drug discovery, discussing improvements that have been made in brain drug delivery for PD. It will be shown that new approaches able to extend the length of the treatment, to release the drug in a continuous manner or to cross the blood-brain barrier and target a specific region are still needed. Overall, the results reviewed here show that there is an urgent need to develop both symptomatic and disease-modifying treatments, giving priority to neuroprotective treatments. Promising perspectives are being provided in this field by rasagiline and by neurotrophic factors like glial cell line-derived neurotrophic factor. The identification of disease-relevant genes has also encouraged the search for disease-modifying therapies that function by identifying molecularly targeted drugs. The advent of new molecular and cellular targets like α-synuclein, leucine-rich repeat serine/threonine protein kinase 2 or parkin, among others, will require innovative delivery therapies. In this regard, drug delivery systems (DDS) have shown great potential for improving the efficacy of conventional and new PD therapy and reducing its side effects. The new DDS discussed here, which include microparticles, nanoparticles and hydrogels among others, will probably open up possibilities that extend beyond symptomatic relief. However, further work needs to be done before DDS become a therapeutic option for PD patients. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Drug delivery systems with modified release for systemic and biophase bioavailability.

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Leucuta, Sorin E

2012-11-01

This review describes the most important new generations of pharmaceutical systems: medicines with extended release, controlled release pharmaceutical systems, pharmaceutical systems for the targeted delivery of drug substances. The latest advances and approaches for delivering small molecular weight drugs and other biologically active agents such as proteins and nucleic acids require novel delivery technologies, the success of a drug being many times dependent on the delivery method. All these dosage forms are qualitatively superior to medicines with immediate release, in that they ensure optimal drug concentrations depending on specific demands of different disease particularities of the body. Drug delivery of these pharmaceutical formulations has the benefit of improving product efficacy and safety, as well as patient convenience and compliance. This paper describes the biopharmaceutical, pharmacokinetic, pharmacologic and technological principles in the design of drug delivery systems with modified release as well as the formulation criteria of prolonged and controlled release drug delivery systems. The paper presents pharmaceutical prolonged and controlled release dosage forms intended for different routes of administration: oral, ocular, transdermal, parenteral, pulmonary, mucoadhesive, but also orally fast dissolving tablets, gastroretentive drug delivery systems, colon-specific drug delivery systems, pulsatile drug delivery systems and carrier or ligand mediated transport for site specific or receptor drug targeting. Specific technologies are given on the dosage forms with modified release as well as examples of marketed products, and current research in these areas.

Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2013 update of the EULAR recommendations for the management of rheumatoid arthritis

NARCIS (Netherlands)

Nam, Jackie L.; Ramiro, Sofia; Gaujoux-Viala, Cecile; Takase, Kaoru; Leon-Garcia, Mario; Emery, Paul; Gossec, Laure; Landewe, Robert; Smolen, Josef S.; Buch, Maya H.

2014-01-01

To update the evidence for the efficacy of biological disease-modifying antirheumatic drugs (bDMARD) in patients with rheumatoid arthritis (RA) to inform the European League Against Rheumatism(EULAR) Task Force treatment recommendations. Medline, Embase and Cochrane databases were searched for

Antidepressant Drug Treatment in Association with Multiple Sclerosis Disease-Modifying Therapy: Using Explorys in the MS Population.

Science.gov (United States)

Mirsky, Matthew M; Marrie, Ruth Ann; Rae-Grant, Alexander

2016-01-01

Background: The Explorys Enterprise Performance Management (EPM) database contains de-identified clinical data for 50 million patients. Multiple sclerosis (MS) disease-modifying therapies (DMTs), specifically interferon beta (IFNβ) treatments, may potentiate depression. Conflicting data have emerged, and a large-scale claims-based study by Patten et al. did not support such an association. This study compares the results of Patten et al. with those using the EPM database. Methods: "Power searches" were built to test the relationship between antidepressant drug use and DMT in the MS population. Searches were built to produce a cohort of individuals diagnosed as having MS in the past 3 years taking a specific DMT who were then given any antidepressant drug. The antidepressant drug therapy prevalence was tested in the MS population on the following DMTs: IFNβ-1a, IFNβ-1b, combined IFNβ, glatiramer acetate, natalizumab, fingolimod, and dimethyl fumarate. Results: In patients with MS, the rate of antidepressant drug use in those receiving DMTs was 40.60% to 44.57%. The rate of antidepressant drug use for combined IFNβ DMTs was 41.61% (males: 31.25%-39.62%; females: 43.10%-47.33%). Antidepressant drug use peaked in the group aged 45 to 54 years for five of six DMTs. Conclusions: We found no association between IFNβ treatment and antidepressant drug use in the MS population compared with other DMTs. The EPM database has been validated against the Patten et al. data for future use in the MS population.

Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate or other traditional disease-modifying anti-rheumatic drugs

DEFF Research Database (Denmark)

Singh, Jasvinder A; Hossain, Alomgir; Tanjong Ghogomu, Elizabeth

2016-01-01

, tocilizumab) and small molecule tofacitinib, versus comparator (MTX, DMARD, placebo (PL), or a combination) in adults with rheumatoid arthritis who have failed to respond to methotrexate (MTX) or other disease-modifying anti-rheumatic drugs (DMARDs), i.e., MTX/DMARD incomplete responders (MTX.......78)) were similarly inconclusive and downgraded to low quality for both imprecision and indirectness.Main results text shows the results for tofacitinib and differences between medications. AUTHORS' CONCLUSIONS: Based primarily on RCTs of 6 months' to 12 months' duration, there is moderate quality evidence...

[Therapeutic Concepts for Treatment of Patients with Non-infectious Uveitis Biologic Disease Modifying Antirheumatic Drugs].

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Walscheid, Karoline; Pleyer, Uwe; Heiligenhaus, Arnd

2018-04-12

Biologic disease modifying antirheumatic drugs (bDMARDs) can be highly efficient in the treatment of various non-infectious uveitis entities. Currently, the TNF-α-inhibitor Adalimumab is the only in-label therapeutic option, whereas, all other bDMARDs need to be given as an off-label therapy. bDMARDs are indicated in diseases refractory to conventional synthetic DMARD therapy and/or systemic steroids, or in patients in whom treatment with those is not possible due to side effects. Therapeutic mechanisms currently employed are cytokine-specific (interferons, inhibition of TNF-α or of interleukin [IL]-1-, IL-6- or IL-17-signalling), inhibit T cell costimulation (CTLA-4 fusion protein), or act via depletion of B cells (anti-CD20). All bDMARDs need to be administered parenterally, and therapy is initiated by the treating internal specialist only after interdisciplinary coordination of all treating subspecialties and after exclusion of contraindications. Regular clinical and laboratory monitoring is mandatory for all patients while under bDMARD therapy. Georg Thieme Verlag KG Stuttgart · New York.

The impact of adjusted work conditions and disease-modifying drugs on work ability in multiple sclerosis.

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Wickström, Anne; Fagerström, Maria; Wickström, Lucas; Granåsen, Gabriel; Dahle, Charlotte; Vrethem, Magnus; Sundström, Peter

2017-07-01

Multiple sclerosis (MS) is a neurological disorder that causes significantly reduced ability to work, and the Expanded Disability Status Scale (EDSS) is one of the main predictors for reduced work ability. To investigate how work requirements, flexible work conditions and disease-modifying drugs (DMDs) influence the work ability in relation to different EDSS grades in two MS populations. Work ability was studied in two MS populations: one in the southern and one in the northern part of Sweden, both demographically similar. In the latter population, more active work-promoting interventions have been practised and second-generation DMDs have been widely used from the onset of disease for several years. The proportion of MS patients who participated in the workforce or studied was significantly higher in the northern compared with the southern population ( p work conditions and were able to work more hours per week. Higher EDSS was associated with lower reduction in number of worked hours per week in the northern population ( p = 0.042). Our data indicated that treatment strategy and adjusted work conditions have impact on work ability in MS.

New FDA-Approved Disease-Modifying Therapies for Multiple Sclerosis.

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English, Clayton; Aloi, Joseph J

2015-04-01

Interferon injectables and glatiramer acetate have served as the primary disease-modifying treatments for multiple sclerosis (MS) since their introduction in the 1990s and are first-line treatments for relapsing-remitting forms of MS (RRMS). Many new drug therapies were launched since early 2010, expanding the drug treatment options considerably in a disease state that once had a limited treatment portfolio. The purpose of this review is to critically evaluate the safety profile and efficacy data of disease-modifying agents for MS approved by the US Food and Drug Administration (FDA) from 2010 to the present and provide cost and available pharmacoeconomic data about each new treatment. Peer-reviewed clinical trials, pharmacoeconomic studies, and relevant pharmacokinetic/pharmacologic studies were identified from MEDLINE (January 2000-December 2014) by using the search terms multiple sclerosis, fingolimod, teriflunomide, alemtuzumab, dimethyl fumarate, pegylated interferon, peginterferon beta-1a, glatiramer 3 times weekly, and pharmacoeconomics. Citations from available articles were also reviewed for additional references. The databases publically available at www.clinicaltrials.gov and www.fda.gov were searched for unpublished studies or studies currently in progress. A total of 5 new agents and 1 new dosage formulation were approved by the FDA for the treatment of RRMS since 2010. Peginterferon beta-1a and high-dose glatiramer acetate represent 2 new effective injectable options for MS that reduce burden of administration seen with traditional interferon and low-dose glatiramer acetate. Fingolimod, teriflunomide, and dimethyl fumarate represent new oral agents available for MS, and their efficacy in reducing annualized relapse rates is 48% to 55%, 22% to 36.3%, and 44% to 53%, respectively, compared with placebo. Alemtuzumab is a biologic given over a 2-year span that reduced annualized relapse rates by 55% in treatment-naive patients and by 49% in patients

Disease-modifying anti-rheumatic drug use in pregnant women with rheumatic diseases: a systematic review of the risk of congenital malformations.

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Baldwin, Corisande; Avina-Zubieta, Antonio; Rai, Sharan K; Carruthers, Erin; De Vera, Mary A

2016-01-01

Despite the high incidence of rheumatic diseases during the reproductive years, little is known about the impact of disease-modifying anti-rheumatic drug (DMARD) use during pregnancy. Our objective was to systematically review and appraise evidence in women with rheumatic disease on the use of traditional and biologic DMARDs during pregnancy and the risk of congenital malformation outcomes. We conducted a systematic search of MEDLINE, EMBASE, and INTERNATIONAL PHARMACEUTICAL ABSTRACTS databases. Inclusion criteria were: 1) study sample including women with rheumatic disease; 2) use of traditional and/or biologic DMARDs during pregnancy; and 3) congenital malformation outcome(s) reported. We extracted information on study design, data source, number of exposed pregnancies, type of DMARD, number of live births, and number of congenital malformations. Altogether, we included 79 studies; the majority were based on designs that did not involve a comparison group, including 26 case reports, 17 case series, 20 cross-sectional studies, and 4 surveys. Studies that had a comparator group included 1 case control, 10 cohort studies, and 1 controlled trial. Hydroxychloroquine and azathioprine represent the most studied traditional DMARD exposures and, among biologics, most of the reports were on infliximab and etanercept. This is the first systematic review on the use of both traditional and biologic DMARDs during pregnancy among women with rheumatic diseases and congenital malformation outcomes, with a focus on study design and quality. Findings confirm the limited number of studies, as well as the need to improve study designs.

Efficacy of conventional synthetic disease-modifying antirheumatic drugs, glucocorticoids and tofacitinib: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis

NARCIS (Netherlands)

Gaujoux-Viala, Cécile; Nam, Jackie; Ramiro, Sofia; Landewé, Robert; Buch, Maya H.; Smolen, Josef S.; Gossec, Laure

2014-01-01

To update a previous systematic review assessing the efficacy of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in rheumatoid arthritis (RA). Two systematic reviews of the literature using PubMed, Embase and the Cochrane library were performed from 2009 until January 2013 to

Inorganically modified diatomite as a potential prolonged-release drug carrier.

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Janićijević, Jelena; Krajišnik, Danina; Calija, Bojan; Dobričić, Vladimir; Daković, Aleksandra; Krstić, Jugoslav; Marković, Marija; Milić, Jela

2014-09-01

Inorganic modification of diatomite was performed with the precipitation product of partially neutralized aluminum sulfate solution at three different mass ratios. The starting and the modified diatomites were characterized by SEM-EDS, FTIR, thermal analysis and zeta potential measurements and evaluated for drug loading capacity in adsorption batch experiments using diclofenac sodium (DS) as a model drug. In vitro drug release studies were performed in phosphate buffer pH6.8 from comprimates containing: the drug adsorbed onto the selected modified diatomite sample (DAMD), physical mixture of the drug with the selected modified diatomite sample (PMDMD) and physical mixture of the drug with the starting diatomite (PMDD). In vivo acute toxicity testing of the modified diatomite samples was performed on mice. High adsorbent loading of the selected modified diatomite sample (~250mg/g in 2h) enabled the preparation of comprimates containing adsorbed DS in the amount near to its therapeutic dose. Drug release studies demonstrated prolonged release of DS over a period of 8h from both DAMD comprimates (18% after 8h) and PMDMD comprimates (45% after 8h). The release kinetics for DAMD and PMDMD comprimates fitted well with Korsmeyer-Peppas and Bhaskar models, indicating that the release mechanism was a combination of non-Fickian diffusion and ion exchange process. Copyright © 2014 Elsevier B.V. All rights reserved.

A novel fluoride anion modified gelatin nanogel system for ultrasound-triggered drug release.

Science.gov (United States)

Wu, Daocheng; Wan, Mingxi

2008-01-01

Controlled drug release, especially tumor-targeted drug release, remains a great challenge. Here, we prepare a novel fluoride anion-modified gelatin nanogel system and investigate its characteristics of ultrasound-triggered drug release. Adriamycin gelatin nanogel modified with fluoride anion (ADM-GNMF) was prepared by a modified co-precipitation method with fluoride anion and sodium sulfate. The loading and encapsulation efficiency of the anti-neoplastic agent adriamycin (ADM) were measured by high performance liquid chromatography (HPLC). The size and shape of ADM-GNMF were determined by electron microscopy and photo-correlation spectroscopy. The size distribution and drug release efficiency of ADM-GNMF, before and after sonication, were measured by two designed measuring devices that consisted of either a submicron particle size analyzer and an ultrasound generator as well as an ultrasound generator, automatic sampler, and HPLC. The ADM-GNMF was stable in solution with an average diameter of 46+/-12 nm; the encapsulation and loading efficiency of adriamycin were 87.2% and 6.38%, respectively. The ultrasound-triggered drug release and size change were most efficient at a frequency of 20 kHz, power density of 0.4w/cm2, and a 1~2 min duration. Under this ultrasound-triggered condition, 51.5% of drug in ADM-GNMF was released within 1~2 min, while the size of ADM-GNMF changed from 46 +/- 12 nm to 1212 +/- 35 nm within 1~2 min of sonication and restored to its previous size in 2~3 min after the ultrasound stopped. In contrast, 8.2% of drug in ADM-GNMF was released within 2~3 min without sonication, and only negligible size changes were found. The ADM-GNMF system efficiently released the encompassed drug in response to ultrasound, offering a novel and promising controlled drug release system for targeted therapy for cancer or other diseases.

The Neuroprotective Disease-Modifying Potential of Psychotropics in Parkinson's Disease

Directory of Open Access Journals (Sweden)

Edward C. Lauterbach

2012-01-01

Full Text Available Neuroprotective treatments in Parkinson's disease (PD have remained elusive. Psychotropics are commonly prescribed in PD without regard to their pathobiological effects. The authors investigated the effects of psychotropics on pathobiological proteins, proteasomal activity, mitochondrial functions, apoptosis, neuroinflammation, trophic factors, stem cells, and neurogenesis. Only findings replicated in at least 2 studies were considered for these actions. Additionally, PD-related gene transcription, animal model, and human neuroprotective clinical trial data were reviewed. Results indicate that, from a PD pathobiology perspective, the safest drugs (i.e., drugs least likely to promote cellular neurodegenerative mechanisms balanced against their likelihood of promoting neuroprotective mechanisms include pramipexole, valproate, lithium, desipramine, escitalopram, and dextromethorphan. Fluoxetine favorably affects transcription of multiple genes (e.g., MAPT, GBA, CCDC62, HIP1R, although it and desipramine reduced MPTP mouse survival. Haloperidol is best avoided. The most promising neuroprotective investigative priorities will involve disease-modifying trials of the safest agents alone or in combination to capture salutary effects on H3 histone deacetylase, gene transcription, glycogen synthase kinase-3, α-synuclein, reactive oxygen species (ROS, reactive nitrogen species (RNS, apoptosis, inflammation, and trophic factors including GDNF and BDNF.

Efficacy of VX-509 (decernotinib) in combination with a disease-modifying antirheumatic drug in patients with rheumatoid arthritis

DEFF Research Database (Denmark)

Genovese, Mark C.; Yang, Fang; Østergaard, Mikkel

2016-01-01

Objective To assess early effects on joint structures of VX-509 in combination with stable disease-modifying antirheumatic drug (DMARD) therapy using MRI in adults with rheumatoid arthritis (RA). Methods This phase II, placebo-controlled, double-blind, dose-ranging study randomised patients with RA......), and the RA MRI scoring (RAMRIS) system. Results ACR20 response at week 12 was 63.6%, 60.0% and 60.0% in the VX-509 100-mg, 200-mg and 300-mg groups, respectively, compared with 25.0% in the placebo group. DAS28-CRP scores decreased in a dose-dependent manner with increasing VX-509 doses. Decreases in RAMRIS...... to a DMARD alone. MRI responses were detected at week 12. Treatment was generally well tolerated. Trial registration number NCT01754935; results....

One For All? Hitting multiple Alzheimer’s Disease targets with one drug

Directory of Open Access Journals (Sweden)

Rebecca Ellen Hughes

2016-04-01

Full Text Available Alzheimer’s disease is a complex and multifactorial disease for which the mechanism is still not fully understood. As new insights into disease progression are discovered, new drugs must be designed to target those aspects of the disease that cause neuronal damage rather than just the symptoms currently addressed by single target drugs. It is becoming possible to target several aspects of the disease pathology at once using multi-target drugs. Intended as a introduction for non-experts, this review describes the key multi-target drug design approaches, namely structure-based, in silico, and data-mining, to evaluate what is preventing compounds progressing through the clinic to the market. Repurposing current drugs using their off-target effects reduces the cost of development, time to launch and also the uncertainty associated with safety and pharmacokinetics. The most promising drugs currently being investigated for repurposing to Alzheimer’s Disease are rasagiline, originally developed for the treatment of Parkinson’s Disease, and liraglutide, an antidiabetic. Rational drug design can combine pharmacophores of multiple drugs, systematically change functional groups, and rank them by virtual screening. Hits confirmed experimentally are rationally modified to generate an effective multi-potent lead compound. Examples from this approach are ASS234 with properties similar to rasagiline, and donecopride, a hybrid of an acetylcholinesterase inhibitor and a 5-HT4 receptor agonist with pro-cognitive effects. Exploiting these interdisciplinary approaches, public-private collaborative lead factories promise faster delivery of new drugs to the clinic.

Long term effectiveness of RA-1, a standardized Ayurvedic medicine as a monotherapy and in combination with disease modifying anti-rheumatic drugs in the treatment of rheumatoid arthritis.

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Chopra, Arvind; Saluja, Manjit; Kianifard, Toktam; Chitre, Deepa; Venugopalan, Anuradha

2018-03-08

Data on long term use of Ayurvedic drugs is sparse. They may prove useful if combined with modern medicine in certain clinical situations (integrative medicine). We present the results of a long term observational study of RA-1 (Ayurvedic drug) used in the treatment of rheumatoid arthritis (RA). On completion of a 16 week randomized controlled study, 165 consenting volunteer patients were enrolled into a three year open label phase (OLP) study. Patients were symptomatic with persistent active disease and naïve for disease modifying anti-rheumatic drugs (DMARD). 57 patients were on fixed low dose prednisone. Patients were examined every 10-14 weeks in a routine rheumatology practice using standard care norms. They continued RA-1 (Artrex ™, 2 tablets twice daily) throughout the study period and were generally advised to lead a healthy life style. Based on clinical judgment, rheumatologist added DMARD and/or steroids (modified if already in use) to patients with inadequate response; chloroquine and/or methotrexate commonly used. Treatment response was assessed using American College of Rheumatology (ACR) efficacy measures and ACR 20% improvement index standard update statistical software (SAS and SPSS) were used; significant at p Ayurveda Foundation. Published by Elsevier B.V. All rights reserved.

Drug Delivery Systems for Imaging and Therapy of Parkinson's Disease.

Science.gov (United States)

Gunay, Mine Silindir; Ozer, A Yekta; Chalon, Sylvie

2016-01-01

Although a variety of therapeutic approaches are available for the treatment of Parkinson's disease, challenges limit effective therapy. Among these challenges are delivery of drugs through the blood brain barier to the target brain tissue and the side effects observed during long term administration of antiparkinsonian drugs. The use of drug delivery systems such as liposomes, niosomes, micelles, nanoparticles, nanocapsules, gold nanoparticles, microspheres, microcapsules, nanobubbles, microbubbles and dendrimers is being investigated for diagnosis and therapy. This review focuses on formulation, development and advantages of nanosized drug delivery systems which can penetrate the central nervous system for the therapy and/or diagnosis of PD, and highlights future nanotechnological approaches. It is esential to deliver a sufficient amount of either therapeutic or radiocontrast agents to the brain in order to provide the best possible efficacy or imaging without undesired degradation of the agent. Current treatments focus on motor symptoms, but these treatments generally do not deal with modifying the course of Parkinson's disease. Beyond pharmacological therapy, the identification of abnormal proteins such as α -synuclein, parkin or leucine-rich repeat serine/threonine protein kinase 2 could represent promising alternative targets for molecular imaging and therapy of Parkinson's disease. Nanotechnology and nanosized drug delivery systems are being investigated intensely and could have potential effect for Parkinson's disease. The improvement of drug delivery systems could dramatically enhance the effectiveness of Parkinson's Disease therapy and reduce its side effects.

Multimodal drugs and their future for Alzheimer's and Parkinson's disease.

Science.gov (United States)

Van der Schyf, Cornelis J; Geldenhuys, Werner J

2011-01-01

This chapter discusses the rationale for developing multimodal or multifunctional drugs (also called designed multiple ligands or DMLs) aimed at disease-modifying treatment strategies for the most common neurodegenerative diseases Alzheimer's and Parkinson's disease (AD and PD). Both the prevalence and incidence of AD and PD have seen consistent and dramatic increases, a disconcerting phenomenon which, ironically, has been attributed to extended life expectancy brought about by better health care globally. In spite of these statistics, the development and introduction to the clinic of new therapies proven to prevent or delay the onset of AD and PD have been disappointing. Evidence has accumulated to suggest that the etiopathology of these diseases is extremely complex, with an array of potential drug targets located within a number of deleterious biochemical pathways. Therefore, in these diseases, it is unlikely that the complex pathoetiological cascade leading to disease initiation or progression will be mitigated by any one drug acting on a single pathway or target. The pursuit of novel DMLs may offer far better outcomes. Although certainly not the only, and perhaps not even the best, approach but farthest along the drug development pipeline in the DML paradigm are drugs that combine inhibition of monoamine oxidase with associated etiological targets unique to either AD or PD. These compounds will constitute the major focus of this chapter, which will also explore radically new paradigms that seek to combine cognitive enhancers with proneurogenesis compounds. Copyright © 2011 Elsevier Inc. All rights reserved.

Ofatumumab, a human anti-CD20 monoclonal antibody, for treatment of rheumatoid arthritis with an inadequate response to one or more disease-modifying antirheumatic drugs: results of a randomized, double-blind, placebo-controlled, phase I/II study

DEFF Research Database (Denmark)

Østergaard, Mikkel; Baslund, Bo; Rigby, William

2010-01-01

To investigate the safety and efficacy of ofatumumab, a novel human anti-CD20 monoclonal antibody (mAb), in patients with active rheumatoid arthritis (RA) whose disease did not respond to > or = 1 disease-modifying antirheumatic drug....

Infections in patients with multiple sclerosis: Implications for disease-modifying therapy.

Science.gov (United States)

Celius, E G

2017-11-01

Patients with multiple sclerosis have an increased risk of infections compared to the general population. The increased risk has been described for decades and is not alone attributed to the use of disease-modifying drugs, but secondary to the disability. The introduction of more potent immunomodulatory drugs may cause an additional challenge, and depending on the mechanism of action, a treatment-induced increased risk of bacterial, viral, fungal or parasitic infections is observed. The choice of treatment in the individual patient with infections and multiple sclerosis must be guided by the drugs' specific mechanism of action, the drug-specific risk of infection and comorbidities. Increased monitoring and follow-up through treatment registries is warranted to increase our understanding and thereby improve management. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Drug Repositioning: An Opportunity to Develop Novel Treatments for Alzheimer’s Disease

Directory of Open Access Journals (Sweden)

Clive Ballard

2013-10-01

Full Text Available Alzheimer’s Disease (AD is the most common cause of dementia, affecting approximately two thirds of the 35 million people worldwide with the condition. Despite this, effective treatments are lacking, and there are no drugs that elicit disease modifying effects to improve outcome. There is an urgent need to develop and evaluate more effective pharmacological treatments. Drug repositioning offers an exciting opportunity to repurpose existing licensed treatments for use in AD, with the benefit of providing a far more rapid route to the clinic than through novel drug discovery approaches. This review outlines the current most promising candidates for repositioning in AD, their supporting evidence and their progress through trials to date. Furthermore, it begins to explore the potential of new transcriptomic and microarray techniques to consider the future of drug repositioning as a viable approach to drug discovery.

The modified nanocrystalline cellulose for hydrophobic drug delivery

Energy Technology Data Exchange (ETDEWEB)

Qing, Weixia [Institute of Environmental and Analytical Sciences, College of Chemistry and Chemical Engineering, Henan University, Kaifeng 475004 (China); Medical College, Henan University, Kaifeng 475004 (China); Wang, Yong [Institute of Environmental and Analytical Sciences, College of Chemistry and Chemical Engineering, Henan University, Kaifeng 475004 (China); Wang, Youyou [Institute of Environmental and Analytical Sciences, College of Chemistry and Chemical Engineering, Henan University, Kaifeng 475004 (China); Key Lab of Natural Medicine and Immun-engineering of Henan Province, Henan University, Kaifeng 475004 (China); Zhao, Dongbao [Institute of Environmental and Analytical Sciences, College of Chemistry and Chemical Engineering, Henan University, Kaifeng 475004 (China); Liu, Xiuhua, E-mail: ll514527@163.com [Institute of Environmental and Analytical Sciences, College of Chemistry and Chemical Engineering, Henan University, Kaifeng 475004 (China); Key Lab of Natural Medicine and Immun-engineering of Henan Province, Henan University, Kaifeng 475004 (China); Zhu, Jinhua [Institute of Environmental and Analytical Sciences, College of Chemistry and Chemical Engineering, Henan University, Kaifeng 475004 (China)

2016-03-15

Graphical abstract: - Highlights: • Torispherical NCC was synthesized through the improvements on the hydrolysis method. • NCC was firstly modified with CTMAB as a drug carrier. • Luteolin and luteoloside loading CTMAB-coated NCC were studied. - Abstract: In this work, torispherical nanocrystalline cellulose (NCC) was synthesized, and firstly modified with a cationic surfactant cetyltrimethylammonium bromide (CTMAB). It was proved that the kinetics of NCC adsorbing CTMAB followed the pseudo-second-order kinetics equation, and the adsorption isotherm model followed Freundlich which was multi molecular layer adsorption model. The morphology and structure of NCC and CTMAB-coated NCC were characterized by transmission electron microscopy (TEM) and X-ray powder diffraction (XRD). Stabilities of NCC and CTMAB-coated NCC were assayed by zeta potential. The results showed that NCC in CTMAB solution was well-dispersed and stable. Moreover, the drug loading and release performance of CTMAB-coated NCC were studied using luteolin (LUT) and luteoloside (LUS) as model drugs.

The modified nanocrystalline cellulose for hydrophobic drug delivery

International Nuclear Information System (INIS)

Qing, Weixia; Wang, Yong; Wang, Youyou; Zhao, Dongbao; Liu, Xiuhua; Zhu, Jinhua

2016-01-01

Graphical abstract: - Highlights: • Torispherical NCC was synthesized through the improvements on the hydrolysis method. • NCC was firstly modified with CTMAB as a drug carrier. • Luteolin and luteoloside loading CTMAB-coated NCC were studied. - Abstract: In this work, torispherical nanocrystalline cellulose (NCC) was synthesized, and firstly modified with a cationic surfactant cetyltrimethylammonium bromide (CTMAB). It was proved that the kinetics of NCC adsorbing CTMAB followed the pseudo-second-order kinetics equation, and the adsorption isotherm model followed Freundlich which was multi molecular layer adsorption model. The morphology and structure of NCC and CTMAB-coated NCC were characterized by transmission electron microscopy (TEM) and X-ray powder diffraction (XRD). Stabilities of NCC and CTMAB-coated NCC were assayed by zeta potential. The results showed that NCC in CTMAB solution was well-dispersed and stable. Moreover, the drug loading and release performance of CTMAB-coated NCC were studied using luteolin (LUT) and luteoloside (LUS) as model drugs.

Illegal Drugs and Heart Disease

Science.gov (United States)

... Venous Thromboembolism Aortic Aneurysm More Illegal Drugs and Heart Disease Updated:May 3,2018 Most illegal drugs can ... www.dea.gov/druginfo/factsheets.shtml Alcohol and Heart Disease Caffeine and Heart Disease Tobacco and Heart Disease ...

Potential drug-drug and drug-disease interactions in well-functioning community-dwelling older adults.

Science.gov (United States)

Hanlon, J T; Perera, S; Newman, A B; Thorpe, J M; Donohue, J M; Simonsick, E M; Shorr, R I; Bauer, D C; Marcum, Z A

2017-04-01

There are few studies examining both drug-drug and drug-disease interactions in older adults. Therefore, the objective of this study was to describe the prevalence of potential drug-drug and drug-disease interactions and associated factors in community-dwelling older adults. This cross-sectional study included 3055 adults aged 70-79 without mobility limitations at their baseline visit in the Health Aging and Body Composition Study conducted in the communities of Pittsburgh PA and Memphis TN, USA. The outcome factors were potential drug-drug and drug-disease interactions as per the application of explicit criteria drawn from a number of sources to self-reported prescription and non-prescription medication use. Over one-third of participants had at least one type of interaction. Approximately one quarter (25·1%) had evidence of had one or more drug-drug interactions. Nearly 10·7% of the participants had a drug-drug interaction that involved a non-prescription medication. % The most common drug-drug interaction was non-steroidal anti-inflammatory drugs (NSAIDs) affecting antihypertensives. Additionally, 16·0% had a potential drug-disease interaction with 3·7% participants having one involving non-prescription medications. The most common drug-disease interaction was aspirin/NSAID use in those with history of peptic ulcer disease without gastroprotection. Over one-third (34·0%) had at least one type of drug interaction. Each prescription medication increased the odds of having at least one type of drug interaction by 35-40% [drug-drug interaction adjusted odds ratio (AOR) = 1·35, 95% confidence interval (CI) = 1·27-1·42; drug-disease interaction AOR = 1·30; CI = 1·21-1·40; and both AOR = 1·45; CI = 1·34-1·57]. A prior hospitalization increased the odds of having at least one type of drug interaction by 49-84% compared with those not hospitalized (drug-drug interaction AOR = 1·49, 95% CI = 1·11-2·01; drug-disease interaction AOR = 1·69, CI = 1·15-2�

MS Disease-Modifying Medications

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... disease-modifying therapies Approval: 2014 US; 2014 CAN Pregnancy Category C (see footnote, page 11) Rash, headache, fever, nasal congestion, nausea, urinary tract infection, fatigue, insomnia, upper respiratory tract infection, herpes viral ...

Drug induced lung disease

International Nuclear Information System (INIS)

Schaefer-Prokop, Cornelia; Eisenhuber, Edith

2010-01-01

There is an ever increasing number of drugs that can cause lung disease. Imaging plays an important role in the diagnosis, since the clinical symptoms are mostly nonspecific. Various HRCT patterns can be correlated - though with overlaps - to lung changes caused by certain groups of drugs. Alternative diagnosis such as infection, edema or underlying lung disease has to be excluded by clinical-radiological means. Herefore is profound knowledge of the correlations of drug effects and imaging findings essential. History of drug exposure, suitable radiological findings and response to treatment (corticosteroids and stop of medication) mostly provide the base for the diagnosis. (orig.)

Barriers and facilitators to disease-modifying antirheumatic drug use in patients with inflammatory rheumatic diseases: a qualitative theory-based study.

Science.gov (United States)

Voshaar, Marieke; Vriezekolk, Johanna; van Dulmen, Sandra; van den Bemt, Bart; van de Laar, Mart

2016-10-21

Although disease-modifying anti-rheumatic drugs (DMARDs) are the cornerstone of treatment for inflammatory rheumatic diseases, medication adherence to DMARDs is often suboptimal. Effective interventions to improve adherence to DMARDs are lacking, and new targets are needed to improve adherence. The aim of the present study was to explore patients' barriers and facilitators of optimal DMARD use. These factors might be used as targets for adherence interventions. In a mixed method study design, patients (n = 120) with inflammatory arthritis (IA) completed a questionnaire based on an existing adapted Theoretical Domains Framework (TDF) to identify facilitators and barriers of DMARD use. A subgroup of these patients (n = 21) participated in focus groups to provide insights into their facilitators and barriers. The answers to the questionnaires and responses of the focus groups were thematically coded by three researchers independently and subsequently categorized. The barriers and facilitators that were reported by IA patients presented large inter-individual variations. The identified barriers and facilitators could be captured in the following domains based on an adapted TDF: (i) knowledge, (ii) emotions, (iii) attention, memory, and decision processes, (iv) social influences, (v) beliefs about capability, (vi) beliefs about consequences, (vii) motivation and goals, (viii) goal conflict, (ix) environmental context and resources, and (x) skills. Patients with IA have a variety of barriers and facilitators with regard to their DMARD use. All of these barriers and facilitators could be categorized into adapted domains of the TDF. Interventions that address individual facilitators and barriers, based on capability, opportunity, and motivation, are needed to develop strategies for medication adherence that are tailored to individual patient needs.

Gelatin modified lipid nanoparticles for anti- viral drug delivery.

Science.gov (United States)

K S, Joshy; S, Snigdha; Kalarikkal, Nandakumar; Pothen, Laly A; Thomas, Sabu

2017-10-01

The major challenges to clinical application of zidovudine are its moderate aqueous solubility and relative short half-life and serious side effects due to frequent administrations. We investigated the preparation of zidovudine-loaded nanoparticles based on lipids which were further modified with the polymer gelatin. Formulation and stability of the modified nanoparticles were analysed from the physico-chemical characterizations. The interactions of nanoparticles with blood components were tested by haemolysis and aggregation studies. The drug content and entrapment efficiencies were assessed by UV analysis. The effect of nanoparticles on protein adsorption was assessed by native polyacrylamide gel electrophoresis (PAGE). In vitro release studies showed a sustained release profile of zidovudine. In vitro cytotoxicity and cellular uptake of the zidovudine-loaded nanoparticles were performed in MCF-7 and neuro 2a brain cells. The enhanced cellular internalization of drug loaded modified nanoparticles in both the cell lines were revealed by fluorescence microscopy. Hence the present study focuses on the feasibility of zidovudine-loaded polymer modified lipid nanoparticles as carriers for safe and efficient HIV/AIDS therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

The marked and rapid therapeutic effect of tofacitinib in combination with subcutaneous methotrexate in a rheumatoid arthritis patient with poor prognostic factors who is resistant to standard disease-modifying antirheumatic drugs and biologicals: A clinical case

Directory of Open Access Journals (Sweden)

N. V. Demidova

2016-01-01

Full Text Available Today, it is generally accepted that it is necessary to achieve clinical remission in rheumatoid arthritis (RA or as minimum a low disease activity. The paper describes a clinical case of a female patient diagnosed with RA who was observed to have inefficiency of standard disease-modifying antirheumatic therapy with methotrexate 25 mg/week, secondary inefficiency of tumor necrosis factor-α inhibitors (adalimumab, and inefficiency/poor tolerance of the interlukin-6 receptor antagonist tocilizumab. This determined the need to use fofacitinib (TOFA, a drug with another mechanism of action. TOFA is the first agent from a new group of immunomodulatory and anti-inflammatory drugs, intracellular kinase inhibitors. Disease remission could be achieved during therapy with TOFA, which enables one to consider this synthetic drug as a therapy option that potentially competes with therapy with biologicals.

Perspectives and experiences of Dutch multiple sclerosis patients and multiple sclerosis-specialized neurologists on injectable disease-modifying treatment

NARCIS (Netherlands)

Visser, Leo H.; Heerings, Marco A.; Jongen, Peter J.; van der Hiele, Karin

2016-01-01

Background: The adherence to treatment with injectable disease-modifying drugs (DMDs) in multiple sclerosis (MS) may benefit from adequate information provision and management of expectations. The communication between patients and physicians is very important in this respect. The current study

Adherence to synthetic disease-modifying Antirheumatic Drugs in Rheumatoid Arthritis: Results of the OBSERVAR Study.

Science.gov (United States)

Juan Mas, Antonio; Castañeda, Santos; Cantero Santamaría, José I; Baquero, José L; Del Toro Santos, Francisco J

2017-12-27

Treatment compliance with disease-modifying antirheumatic drugs (DMARD) is essential to achieve the therapeutic goals in rheumatoid arthritis (RA). However, despite the need for good compliance, there is evidence that patients with RA frequently fail to use DMARD for the control of RA. Thus, the main objective of the OBSERVAR study is to evaluate the reasons for the lack of therapeutic adherence to synthetic DMARD in these patients. A Delphi process involving 18 randomly selected Spanish rheumatologists determined the level of agreement with 66 causes of noncompliance selected from the literature in relation to synthetic DMARD in RA. The reasons for noncompliance were consistent in 75.7%, although 3 reasons (4.5%) were highly consistent: 1) not knowing what to do in the case of an adverse event with DMARD; 2) not having undergone adherence screening by health personnel for early detection of "noncompliant patients"; and 3) not having undergone interventions or strategies that improve adherence. In order to improve adherence to RA treatment with synthetic DMARD, the patient should be adequately informed of each new treatment introduced, the patient's compliance profile should be incorporated into the clinical routine and the patient's motivation for therapeutic compliance be reinforced through the methods available to us. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

A new proposal for randomized start design to investigate disease-modifying therapies for Alzheimer disease.

Science.gov (United States)

Zhang, Richard Y; Leon, Andrew C; Chuang-Stein, Christy; Romano, Steven J

2011-02-01

The increasing prevalence of Alzheimer disease (AD) and lack of effective agents to attenuate progression have accelerated research and development of disease modifying (DM) therapies. The traditional parallel group design and single time point analysis used in the support of past AD drug approvals address symptomatic benefit over relatively short treatment durations. More recent trials investigating disease modification are by necessity longer in duration and require larger sample sizes. Nevertheless, trial design and analysis remain mostly unchanged and may not be adequate to meet the objective of demonstrating disease modification. Randomized start design (RSD) has been proposed as an option to study DM effects, but its application in AD trials may have been hampered by certain methodological challenges. To address the methodological issues that have impeded more extensive use of RSD in AD trial and to encourage other researchers to develop novel design and analysis methodologies to better ascertain DM effects for the next generation of AD therapies, we propose a stepwise testing procedure to evaluate potential DM effects of novel AD therapies. Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-cog) is used for illustration. We propose to test three hypotheses in a stepwise sequence. The three tests pertain to treatment difference at two separate time points and a difference in the rate of change. Estimation is facilitated by the Mixed-effects Model for Repeated Measures approach. The required sample size is estimated using Monte Carlo simulations and by modeling ADAS-cog data from prior longitudinal AD studies. The greatest advantage of the RSD proposed in this article is its ability to critically address the question on a DM effect. The AD trial using the new approach would be longer (12-month placebo period plus 12-month delay-start period; total 24-month duration) and require more subjects (about 1000 subjects per arm for the non-inferiority margin

[Drug treatment of early-stage (de novo and "honeymoon") Parkinson disease].

Science.gov (United States)

Cesaro, P; Defebvre, L

2014-04-01

In this article, we discuss the management of motor symptoms during the early phases of Parkinson's disease, excluding that of any other clinical manifestation. We relied primarily upon recently published data and do not describe older publications relating to anticholinergic drugs or amantadine. The initial pharmacological treatment of idiopathic Parkinson's disease (IPD) is symptomatic and remains based upon dopaminergic drugs. However, the development of new drugs has broadened the range of strategic options and improved overall patient management. Announcing the diagnosis is a critical moment, as pointed out by patients' associations. Patients should be advised to maintain personal, professional, social and physical activities as long as possible. The potential benefit of early pharmacological treatment should be explained, focusing on the possible disease-modifying effect of drugs such as rasagiline. According to current guidelines, L-Dopa is preferred in patients above 65years of age, while those below 65 should be treated with dopamine agonists. Like monoamine oxidase inhibitors B (MAOI-B), synthetic dopamine agonists exhibit several advantages: easy-to-use treatment with a once-daily administration, delayed L-Dopa initiation, significant efficacy on motor symptoms (although lower than that of L-Dopa). MOAI can be prescribed in association with L-Dopa or dopamine agonists. Rasagiline also delays L-Dopa initiation, and consequently motor complications. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Therapeutic Drug Monitoring in Rheumatic Diseases

Directory of Open Access Journals (Sweden)

NG Hoi-Yan Alexandra

2016-12-01

Full Text Available The ultimate goal of treating rheumatic disease is to achieve rapid suppression of inflammation, while at the same time minimizing the toxicities from rheumatic drugs. Different patients have different individual pharmacokinetics that can affect the drug level. Moreover, different factors, such as renal function, age or even different underlying diseases, can affect the drug level. Therefore, giving the same dosage of drugs to different patients may result in different drug levels. This article will review the usefulness of therapeutic drug monitoring in maximizing drug efficacy, while reducing the risk of toxicities in Hydroxychloroquine, Mycophenolate Mofetil, Tacrolimus and Tumor Necrosis Factor inhibitors (TNF Inhibitors.

Molecular property diagnostic suite (MPDS): Development of disease-specific open source web portals for drug discovery.

Science.gov (United States)

Nagamani, S; Gaur, A S; Tanneeru, K; Muneeswaran, G; Madugula, S S; Consortium, Mpds; Druzhilovskiy, D; Poroikov, V V; Sastry, G N

2017-11-01

Molecular property diagnostic suite (MPDS) is a Galaxy-based open source drug discovery and development platform. MPDS web portals are designed for several diseases, such as tuberculosis, diabetes mellitus, and other metabolic disorders, specifically aimed to evaluate and estimate the drug-likeness of a given molecule. MPDS consists of three modules, namely data libraries, data processing, and data analysis tools which are configured and interconnected to assist drug discovery for specific diseases. The data library module encompasses vast information on chemical space, wherein the MPDS compound library comprises 110.31 million unique molecules generated from public domain databases. Every molecule is assigned with a unique ID and card, which provides complete information for the molecule. Some of the modules in the MPDS are specific to the diseases, while others are non-specific. Importantly, a suitably altered protocol can be effectively generated for another disease-specific MPDS web portal by modifying some of the modules. Thus, the MPDS suite of web portals shows great promise to emerge as disease-specific portals of great value, integrating chemoinformatics, bioinformatics, molecular modelling, and structure- and analogue-based drug discovery approaches.

Genetic Modifiers of Sickle Cell Disease

Science.gov (United States)

Steinberg, Martin H.; Sebastiani, Paola

2015-01-01

Sickle cell anemia is associated with unusual clinical heterogeneity for a Mendelian disorder. Fetal hemoglobin concentration and coincident ∝ thalassemia, both which directly affect the sickle erythrocyte, are the major modulators of the phenotype of disease. Understanding the genetics underlying the heritable subphenotypes of sickle cell anemia would be prognostically useful, could inform personalized therapeutics, and might help the discovery of new “druggable” pathophysiologic targets. Genotype-phenotype association studies have been used to identify novel genetic modifiers. In the future, whole genome sequencing with its promise of discovering hitherto unsuspected variants could add to our understanding of the genetic modifiers of this disease. PMID:22641398

Microbiome and metabolome modifying effects of several cardiovascular disease interventions in apo-E-/- mice.

Science.gov (United States)

Ryan, Paul M; London, Lis E E; Bjorndahl, Trent C; Mandal, Rupasri; Murphy, Kiera; Fitzgerald, Gerald F; Shanahan, Fergus; Ross, R Paul; Wishart, David S; Caplice, Noel M; Stanton, Catherine

2017-03-13

There is strong evidence indicating that gut microbiota have the potential to modify, or be modified by the drugs and nutritional interventions that we rely upon. This study aims to characterize the compositional and functional effects of several nutritional, neutraceutical, and pharmaceutical cardiovascular disease interventions on the gut microbiome, through metagenomic and metabolomic approaches. Apolipoprotein-E-deficient mice were fed for 24 weeks either high-fat/cholesterol diet alone (control, HFC) or high-fat/cholesterol in conjunction with one of three dietary interventions, as follows: plant sterol ester (PSE), oat β-glucan (OBG) and bile salt hydrolase-active Lactobacillus reuteri APC 2587 (BSH), or the drug atorvastatin (STAT). The gut microbiome composition was then investigated, in addition to the host fecal and serum metabolome. We observed major shifts in the composition of the gut microbiome of PSE mice, while OBG and BSH mice displayed more modest fluctuations, and STAT showed relatively few alterations. Interestingly, these compositional effects imparted by PSE were coupled with an increase in acetate and reduction in isovalerate (p metabolome, including alterations in several acylcarnitines previously associated with a state of metabolic dysfunction (p < 0.05). We observed functional alterations in microbial and host-derived metabolites, which may have important implications for systemic metabolic health, suggesting that cardiovascular disease interventions may have a significant impact on the microbiome composition and functionality. This study indicates that the gut microbiome-modifying effects of novel therapeutics should be considered, in addition to the direct host effects.

Modified local diatomite as potential functional drug carrier--A model study for diclofenac sodium.

Science.gov (United States)

Janićijević, Jelena; Krajišnik, Danina; Čalija, Bojan; Vasiljević, Bojana Nedić; Dobričić, Vladimir; Daković, Aleksandra; Antonijević, Milan D; Milić, Jela

2015-12-30

Diatomite makes a promising candidate for a drug carrier because of its high porosity, large surface area, modifiable surface chemistry and biocompatibility. Herein, refined diatomite from Kolubara coal basin, which complied with the pharmacopoeial requirements for heavy metals content and microbiological quality, was used as a starting material. Inorganic modification of the starting material was performed through a simple, one-step procedure. Significant increase in adsorbent loading with diclofenac sodium (DS) was achieved after the modification process (∼373mg/g) which enabled the preparation of comprimates containing therapeutic dose of the adsorbed drug. Adsorption of DS onto modified diatomite resulted in the alteration of the drug's XRD pattern and FTIR spectrum. In vitro drug release studies in phosphate buffer pH 7.5 demonstrated prolonged DS release over 8h from comprimates containing DS adsorbed on modified diatomite (up to 37% after 8h) and those containing physical mixture of the same composition (up to 45% after 8h). The results of in vivo toxicity testing on mice pointed on potential safety of both unmodified (starting) and modified diatomite. All these findings favor the application of diatomite as a potential functional drug carrier. Copyright © 2015 Elsevier B.V. All rights reserved.

Determination of drug lipophilicity by phosphatidylcholine-modified microemulsion high-performance liquid chromatography.

Science.gov (United States)

Xuan, Xueyi; Xu, Liyuan; Li, Liangxing; Gao, Chongkai; Li, Ning

2015-07-25

A new biomembrane-mimetic liquid chromatographic method using a C8 stationary phase and phosphatidylcholine-modified (PC-modified) microemulsion mobile phase was used to estimate unionized and ionized drugs lipophilicity expressed as an n-octanol/water partition coefficient (logP and logD). The introduction of PC into sodium dodecyl sulfate (SDS) microemulsion yielded a good correlation between logk and logD (R(2)=0.8). The optimal composition of the PC-modified microemulsion liquid chromatography (PC-modified MELC) mobile phase was 0.2% PC-3.0% SDS-6.0% n-butanol-0.8% ethyl acetate-90.0% water (pH 7.0) for neutral and ionized molecules. The interactions between the analytes and system described by this chromatographic method is more similar to biological membrane than the n-octanol/water partition system. The result in this paper suggests that PC-modified MELC can serve as a possible alternative to the shake-flask method for high-throughput unionized and ionized drugs lipophilicity determination and simulation of biological processes. Copyright © 2015 Elsevier B.V. All rights reserved.

Multi-Drug-Loaded Microcapsules with Controlled Release for Management of Parkinson's Disease.

Science.gov (United States)

Baek, Jong-Suep; Choo, Chee Chong; Qian, Cheng; Tan, Nguan Soon; Shen, Zexiang; Loo, Say Chye Joachim

2016-07-01

Parkinson's disease (PD) is a progressive disease of the nervous system, and is currently managed through commercial tablets that do not sufficiently enable controlled, sustained release capabilities. It is hypothesized that a drug delivery system that provides controlled and sustained release of PD drugs would afford better management of PD. Hollow microcapsules composed of poly-l-lactide (PLLA) and poly (caprolactone) (PCL) are prepared through a modified double-emulsion technique. They are loaded with three PD drugs, i.e., levodopa (LD), carbidopa (CD), and entacapone (ENT), at a ratio of 4:1:8, similar to commercial PD tablets. LD and CD are localized in both the hollow cavity and PLLA/PCL shell, while ENT is localized in the PLLA/PCL shell. Release kinetics of hydrophobic ENT is observed to be relatively slow as compared to the other hydrophilic drugs. It is further hypothesized that encapsulating ENT into PCL as a surface coating onto these microcapsules can aid in accelerating its release. Now, these spray-coated hollow microcapsules exhibit similar release kinetics, according to Higuchi's rate, for all three drugs. The results suggest that multiple drug encapsulation of LD, CD, and ENT in gastric floating microcapsules could be further developed for in vivo evaluation for the management of PD. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Simultaneous Response in Several Domains in Patients with Psoriatic Disease Treated with Etanercept as Monotherapy or in Combination with Conventional Synthetic Disease-modifying Antirheumatic Drugs.

Science.gov (United States)

Behrens, Frank; Meier, Lothar; Prinz, Jörg C; Jobst, Jürgen; Lippe, Ralph; Löschmann, Peter-Andreas; Lorenz, Hanns-Martin

2018-04-01

To evaluate patients with psoriatic arthritis (PsA) receiving etanercept (ETN) monotherapy or ETN plus conventional synthetic disease-modifying antirheumatic drugs (csDMARD) to determine the proportion achieving a clinically meaningful response in arthritis, psoriasis, and quality of life simultaneously. A prospective, multicenter, 52-week observational study in patients with active PsA evaluated treatment with ETN in clinical practice (ClinicalTrials.gov: NCT00293722). This analysis assessed simultaneous achievement of 3 treatment targets: low disease activity (LDA) based on 28-joint count Disease Activity Score (DAS28); body surface area (BSA) involvement ≤ 3%; and a score > 45 on the Medical Outcomes Study Short Form-12 (SF-12) physical component summary. Of 579 patients, 380 received ETN monotherapy and 199 received combination ETN plus csDMARD. At 52 weeks, data for all 3 disease domains were available for 251 patients receiving monotherapy and 151 receiving combination therapy. In the monotherapy and combination therapy groups, 61 (24.3%) and 37 (24.5%) patients, respectively, achieved all 3 treatment targets simultaneously. A significantly greater proportion of patients receiving monotherapy versus combination therapy achieved SF-12 > 45 (43.0% vs 31.8%; p < 0.05) and DAS28 LDA (72.5% vs 62.3%; p < 0.05). Conversely, BSA ≤ 3% was reached by a significantly greater proportion receiving combination therapy (75.5% vs 56.6%; p < 0.001). However, baseline BSA involvement was higher for the monotherapy group. While nearly half the patients achieved arthritis and psoriasis treatment targets simultaneously and one-fourth reached all 3 treatment targets, combining ETN and csDMARD did not substantially improve clinical response compared with ETN monotherapy in this real-world PsA patient population.

Antithyroid Drug Therapy for Graves' Disease and Implications for Recurrence

Science.gov (United States)

Fu, Jing; Xu, Yuan

2017-01-01

Graves' disease (GD) is the most common cause of hyperthyroidism worldwide. Current therapeutic options for GD include antithyroid drugs (ATD), radioactive iodine, and thyroidectomy. ATD treatment is generally well accepted by patients and clinicians due to some advantages including normalizing thyroid function in a short time, hardly causing hypothyroidism, and ameliorating immune disorder while avoiding radiation exposure and invasive procedures. However, the relatively high recurrence rate is a major concern for ATD treatment, which is associated with multiple influencing factors like clinical characteristics, treatment strategies, and genetic and environmental factors. Of these influencing factors, some are modifiable but some are nonmodifiable. The recurrence risk can be reduced by adjusting the modifiable factors as much as possible. The titration regimen for 12–18 months is the optimal strategy of ATD. Levothyroxine administration after successful ATD treatment was not recommended. The addition of immunosuppressive drugs might be helpful to decrease the recurrence rate of GD patients after ATD withdrawal, whereas further studies are needed to address the safety and efficacy. This paper reviewed the current knowledge of ATD treatment and mainly focused on influencing factors for recurrence in GD patients with ATD treatment. PMID:28529524

Drugs Approved for Gestational Trophoblastic Disease

Science.gov (United States)

This page lists cancer drugs approved by the Food and Drug Administration (FDA) for gestational trophoblastic disease. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

The Effect of Disease-Modifying Drugs on Brain Atrophy in Relapsing-Remitting Multiple Sclerosis: A Meta-Analysis.

Directory of Open Access Journals (Sweden)

Pierre Branger

Full Text Available The quantification of brain atrophy in relapsing-remitting multiple sclerosis (RRMS may serve as a marker of disease progression and treatment response. We compared the association between first-line (FL or second-line (SL disease-modifying drugs (DMDs and brain volume changes over time in RRMS.We reviewed clinical trials in RRMS between January 1, 1995 and June 1, 2014 that assessed the effect of DMDs and reported data on brain atrophy in Medline, Embase, the Cochrane database and meeting abstracts. First, we designed a meta-analysis to directly compare the percentage brain volume change (PBVC between FLDMDs and SLDMDs at 24 months. Second, we conducted an observational and longitudinal linear regression analysis of a 48-month follow-up period. Sensitivity analyses considering PBVC between 12 and 48 months were also performed.Among the 272 studies identified, 117 were analyzed and 35 (18,140 patients were included in the analysis. Based on the meta-analysis, atrophy was greater for the use of an FLDMD than that of an SLDMD at 24 months (primary endpoint mean difference, -0.86; 95% confidence interval: -1.57--0.15; P = 0.02. Based on the linear regression analysis, the annual PBVC significantly differed between SLDMDs and placebo (-0.27%/y and -0.50%/y, respectively, P = 0.046 but not between FLDMDs (-0.33%/y and placebo (P = 0.11 or between FLDMDs and SLDMDs (P = 0.49. Based on sensitivity analysis, the annual PBVC was reduced for SLDMDs compared with placebo (-0.14%/y and -0.56%/y, respectively, P<0.001 and FLDMDs (-0.46%/y, P<0.005, but no difference was detected between FLDMDs and placebo (P = 0.12.SLDMDs were associated with reduced PBVC slope over time in RRMS, regardless of the period considered. These results provide new insights into the mechanisms underlying atrophy progression in RRMS.

Safety and effectiveness of tacrolimus add-on therapy for rheumatoid arthritis patients without an adequate response to biological disease-modifying anti-rheumatic drugs (DMARDs): Post-marketing surveillance in Japan.

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Takeuchi, Tsutomu; Ishida, Kota; Shiraki, Katsuhisa; Yoshiyasu, Takashi

2018-01-01

Post-marketing surveillance (PMS) was conducted to assess the safety and effectiveness of tacrolimus (TAC) add-on therapy for patients with rheumatoid arthritis (RA) and an inadequate response to biological disease-modifying anti-rheumatic drugs (DMARDs). Patients with RA from 180 medical sites across Japan were registered centrally with an electronic investigation system. The observational period was 24 weeks from the first day of TAC administration concomitantly with biological DMARDs. Safety and effectiveness populations included 624 and 566 patients, respectively. Patients were predominantly female (81.1%), with a mean age of 61.9 years. Overall, 125 adverse drug reactions (ADRs) occurred in 94 patients (15.1%), and 15 serious ADRs occurred in 11 patients (1.8%). These incidences were lower compared with previously reported incidences after TAC treatment in PMS, and all of the observed ADRs were already known. A statistically significant improvement was observed in the primary effectiveness variable of Simplified Disease Activity Index after TAC treatment; 62.7% of patients achieved remission or low disease activity at week 24. TAC is well tolerated and effective when used as an add-on to biological DMARDs in Japanese patients with RA who do not achieve an adequate response to biological DMARDs in a real-world clinical setting.

Tofacitinib 5 mg Twice Daily in Patients with Rheumatoid Arthritis and Inadequate Response to Disease-Modifying Antirheumatic Drugs: A Comprehensive Review of Phase 3 Efficacy and Safety.

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Bird, Paul; Bensen, William; El-Zorkany, Bassel; Kaine, Jeffrey; Manapat-Reyes, Bernadette Heizel; Pascual-Ramos, Virginia; Witcombe, David; Soma, Koshika; Zhang, Richard; Thirunavukkarasu, Krishan

2018-05-24

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We performed a comprehensive review of phase 3 studies of tofacitinib 5 mg twice daily (BID) (approved dose in many countries) in patients with moderate to severe RA and inadequate response to prior disease-modifying antirheumatic drugs. A search of PubMed and ClinicalTrials.gov identified 5 studies: ORAL Solo (NCT00814307), ORAL Sync (NCT00856544), ORAL Standard (included adalimumab 40 mg once every 2 weeks; NCT00853385), ORAL Scan (NCT00847613), and ORAL Step (NCT00960440). Efficacy and safety data for tofacitinib 5 mg BID, placebo, and adalimumab were analyzed. Across the 5 studies, 1216 patients received tofacitinib 5 mg BID, 681 received placebo, and 204 received adalimumab. At month 3, tofacitinib demonstrated significantly higher 20%, 50%, and 70% improvement in American College of Rheumatology response criteria (ACR20, ACR50, and ACR70, respectively) response rates, greater improvement in Health Assessment Questionnaire-Disability Index, and a higher proportion of Disease Activity Score-defined remission than placebo. Frequencies of adverse events (AEs), serious AEs, and discontinuations due to AEs were similar for tofacitinib and placebo at month 3; serious infection events were more frequent for tofacitinib. In ORAL Standard, although not powered for formal comparisons, tofacitinib and adalimumab had numerically similar efficacy and AEs; serious AEs and serious infection events were more frequent with tofacitinib. Tofacitinib 5 mg BID reduced RA signs and symptoms and improved physical function versus placebo in patients with inadequate response to prior disease-modifying antirheumatic drugs. Tofacitinib 5 mg BID had a consistent, manageable safety profile across studies, with no new safety signals identified.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where

Clinical Trials for Disease-Modifying Therapies in Alzheimer's Disease: A Primer, Lessons Learned, and a Blueprint for the Future.

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Cummings, Jeffrey; Ritter, Aaron; Zhong, Kate

2018-03-16

Alzheimer's disease (AD) has no currently approved disease-modifying therapies (DMTs), and treatments to prevent, delay the onset, or slow the progression are urgently needed. A delay of 5 years if available by 2025 would decrease the total number of patients with AD by 50% in 2050. To meet the definition of DMT, an agent must produce an enduring change in the course of AD; clinical trials of DMTs have the goal of demonstrating this effect. AD drug discovery entails target identification followed by high throughput screening and lead optimization of drug-like compounds. Once an optimized agent is available and has been assessed for efficacy and toxicity in animals, it progresses through Phase I testing with healthy volunteers, Phase II learning trials to establish proof-of-mechanism and dose, and Phase III confirmatory trials to demonstrate efficacy and safety in larger populations. Phase III is followed by Food and Drug Administration review and, if appropriate, market access. Trial populations include cognitively normal at-risk participants in prevention trials, mildly impaired participants with biomarker evidence of AD in prodromal AD trials, and subjects with cognitive and functional impairment in AD dementia trials. Biomarkers are critical in trials of DMTs, assisting in participant characterization and diagnosis, target engagement and proof-of-pharmacology, demonstration of disease-modification, and monitoring side effects. Clinical trial designs include randomized, parallel group; delayed start; staggered withdrawal; and adaptive. Lessons learned from completed trials inform future trials and increase the likelihood of success.

A novel approach to delayed-start analyses for demonstrating disease-modifying effects in Alzheimer's disease.

Directory of Open Access Journals (Sweden)

Hong Liu-Seifert

Full Text Available One method for demonstrating disease modification is a delayed-start design, consisting of a placebo-controlled period followed by a delayed-start period wherein all patients receive active treatment. To address methodological issues in previous delayed-start approaches, we propose a new method that is robust across conditions of drug effect, discontinuation rates, and missing data mechanisms. We propose a modeling approach and test procedure to test the hypothesis of noninferiority, comparing the treatment difference at the end of the delayed-start period with that at the end of the placebo-controlled period. We conducted simulations to identify the optimal noninferiority testing procedure to ensure the method was robust across scenarios and assumptions, and to evaluate the appropriate modeling approach for analyzing the delayed-start period. We then applied this methodology to Phase 3 solanezumab clinical trial data for mild Alzheimer's disease patients. Simulation results showed a testing procedure using a proportional noninferiority margin was robust for detecting disease-modifying effects; conditions of high and moderate discontinuations; and with various missing data mechanisms. Using all data from all randomized patients in a single model over both the placebo-controlled and delayed-start study periods demonstrated good statistical performance. In analysis of solanezumab data using this methodology, the noninferiority criterion was met, indicating the treatment difference at the end of the placebo-controlled studies was preserved at the end of the delayed-start period within a pre-defined margin. The proposed noninferiority method for delayed-start analysis controls Type I error rate well and addresses many challenges posed by previous approaches. Delayed-start studies employing the proposed analysis approach could be used to provide evidence of a disease-modifying effect. This method has been communicated with FDA and has been

Orphan diseases: state of the drug discovery art.

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Volmar, Claude-Henry; Wahlestedt, Claes; Brothers, Shaun P

2017-06-01

Since 1983 more than 300 drugs have been developed and approved for orphan diseases. However, considering the development of novel diagnosis tools, the number of rare diseases vastly outpaces therapeutic discovery. Academic centers and nonprofit institutes are now at the forefront of rare disease R&D, partnering with pharmaceutical companies when academic researchers discover novel drugs or targets for specific diseases, thus reducing the failure risk and cost for pharmaceutical companies. Considerable progress has occurred in the art of orphan drug discovery, and a symbiotic relationship now exists between pharmaceutical industry, academia, and philanthropists that provides a useful framework for orphan disease therapeutic discovery. Here, the current state-of-the-art of drug discovery for orphan diseases is reviewed. Current technological approaches and challenges for drug discovery are considered, some of which can present somewhat unique challenges and opportunities in orphan diseases, including the potential for personalized medicine, gene therapy, and phenotypic screening.

Classifying PML risk with disease modifying therapies.

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Berger, Joseph R

2017-02-01

To catalogue the risk of PML with the currently available disease modifying therapies (DMTs) for multiple sclerosis (MS). All DMTs perturb the immune system in some fashion. Natalizumab, a highly effective DMT, has been associated with a significant risk of PML. Fingolimod and dimethyl fumarate have also been unquestionably associated with a risk of PML in the MS population. Concerns about PML risk with other DMTs have arisen due to their mechanism of action and pharmacological parallel to other agents with known PML risk. A method of contextualizing PML risk for DMTs is warranted. Classification of PML risk was predicated on three criteria:: 1) whether the underlying condition being treated predisposes to PML in the absence of the drug; 2) the latency from initiation of the drug to the development of PML; and 3) the frequency with which PML is observed. Among the DMTs, natalizumab occupies a place of its own with respect to PML risk. Significantly lesser degrees of risk exist for fingolimod and dimethyl fumarate. Whether PML will be observed with other DMTs in use for MS, such as, rituximab, teriflunomide, and alemtuzumab, remains uncertain. A logical classification for stratifying DMT PML risk is important for both the physician and patient in contextualizing risk/benefit ratios. As additional experience accumulates regarding PML and the DMTs, this early effort will undoubtedly require revisiting. Copyright © 2016 Elsevier B.V. All rights reserved.

Wildlife disease prevalence in human-modified landscapes.

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Brearley, Grant; Rhodes, Jonathan; Bradley, Adrian; Baxter, Greg; Seabrook, Leonie; Lunney, Daniel; Liu, Yan; McAlpine, Clive

2013-05-01

Human-induced landscape change associated with habitat loss and fragmentation places wildlife populations at risk. One issue in these landscapes is a change in the prevalence of disease which may result in increased mortality and reduced fecundity. Our understanding of the influence of habitat loss and fragmentation on the prevalence of wildlife diseases is still in its infancy. What is evident is that changes in disease prevalence as a result of human-induced landscape modification are highly variable. The importance of infectious diseases for the conservation of wildlife will increase as the amount and quality of suitable habitat decreases due to human land-use pressures. We review the experimental and observational literature of the influence of human-induced landscape change on wildlife disease prevalence, and discuss disease transmission types and host responses as mechanisms that are likely to determine the extent of change in disease prevalence. It is likely that transmission dynamics will be the key process in determining a pathogen's impact on a host population, while the host response may ultimately determine the extent of disease prevalence. Finally, we conceptualize mechanisms and identify future research directions to increase our understanding of the relationship between human-modified landscapes and wildlife disease prevalence. This review highlights that there are rarely consistent relationships between wildlife diseases and human-modified landscapes. In addition, variation is evident between transmission types and landscape types, with the greatest positive influence on disease prevalence being in urban landscapes and directly transmitted disease systems. While we have a limited understanding of the potential influence of habitat loss and fragmentation on wildlife disease, there are a number of important areas to address in future research, particularly to account for the variability in increased and decreased disease prevalence. Previous studies

Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014

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Schneider, Lon S.; Mangialasche, Francesca; Andreasen, Niels; Feldman, Howard; Giacobini, Ezio; Jones, Roy; Mantua, Valentina; Mecocci, Patrizia; Pani, Luca; Winblad, Bengt; Kivipelto, Miia

2014-01-01

The modern era of drug development for Alzheimer’s disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer’s disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here we review the development of treatments for Alzheimer’s disease during the past 30 years, considering the drugs, potential targets, late-stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late-stage Alzheimer’s disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta-analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild to moderate Alzheimer’s disease criteria, recently extending to early or prodromal Alzheimer disease or ‘mild cognitive impairment due to Alzheimer’s disease’, for drugs considered to be disease modifying. The duration of trials has remained at 6 to 12 months for drugs intended to improve symptoms; 18- to 24-month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities

Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series

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Nigrovic, Peter A.; Mannion, Melissa; Prince, Femke H. M.; Zeft, Andrew; Rabinovich, C. Egla; van Rossum, Marion A. J.; Cortis, Elisabetta; Pardeo, Manuela; Miettunen, Paivi M.; Janow, Ginger; Birmingham, James; Eggebeen, Aaron; Janssen, Erin; Shulman, Andrew I.; Son, Mary Beth; Hong, Sandy; Jones, Karla; Ilowite, Norman T.; Cron, Randy Q.; Higgins, Gloria C.

2011-01-01

To examine the safety and efficacy of the interleukin-1 (IL-1) receptor antagonist anakinra as first-line therapy for systemic juvenile idiopathic arthritis (JIA). Patients with systemic JIA receiving anakinra as part of initial disease-modifying antirheumatic drug (DMARD) therapy were identified

[Acupuncture Therapy versus Disease-modifying Antirheumatic Drugs for the Treatment of Ankylosing Spondylitis--a Meta-analysis].

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Lv, Zheng-tao; Zhou, Xiang; Chen, An-min

2015-01-01

We conducted a meta-analysis evaluating the efficacy and safety of acupuncture compared to disease-modifying antirheumatic drugs in patients with ankylosing spondylitis. Four databases including Pubmed, EMBASE, Cochrane library, and ISI Web of Science were searched in December 2014, taking also the reference section into account. Randomized controlled trials that aimed to assess the efficacy of acupuncture therapy were identified. The inclusion criteria for the outcome measurements were the clinical effect, ESR, occipital wall test, chest expansion, CRP and finger ground distance. Finally, six studies met these inclusion criteria. Two reviewers screened each article independently and were blinded to the findings of each other. We analyzed data from 6 RCTs involving 541 participants. Acupuncture therapy could further improve the clinical effect (OR = 3.01; 95% CI, 1.48-6.13; P = 0.002) and reduce ESR level (SMD = -0.77; 95% CI, -1.46 to -0.08; P = 0.03) compared to DMARDs; a combination of acupuncture and DMARDs could further improve clinical effect (OR = 3.20, 95% CI, 1.36-7.54; P = 0.008), occipital-wall distance (SMD = -0.84; 95% CI, -1.37 to -0.31; P = 0.002), chest expansion (SMD = 0.38; 95% CI, 0.16-0.60; P = 0.0009), and finger-ground distance (SMD = -0.48; 95% CI, -0.87 to -0.09; P = 0.02) as compared to DMARDs treatment alone. Our findings support that acupuncture therapy could be an option to relieve symptoms associated with AS. These results should be interpreted cautiously due to the generally poor methodological qualities of the included trials. © 2015 S. Karger GmbH, Freiburg.

Drug management in the elderly adult with chronic kidney disease: a review for the primary care physician.

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Ponticelli, Claudio; Sala, Gabriele; Glassock, Richard J

2015-05-01

With advancing age, the functional reserve of many organs tends to decrease. In particular, the lean body mass, the levels of serum albumin, the blood flow to the liver, and the glomerular filtration rate are reduced in elderly individuals and can be further impaired by the concomitant presence of acute or chronic kidney disease. Moreover, patients with kidney disease are often affected by comorbid processes and are prescribed multiple medications. The aging process also modifies some drug interactions, including the affinity of some drugs for their receptor, the number of receptors, and the cell responses upon receptor activation. Therefore, older patients with kidney disease are particularly susceptible to the risks of adverse drug reactions. Planning a pharmacological regimen in such patients is confounded by the paucity of information available on the pharmacokinetic and pharmacodynamic profiles of a large number of drugs commonly used in this group of patients. Finally, many aged patients suffer from unintentional poor compliance. In this review, the problems physicians face in designing safe and effective medication management in elderly individuals are discussed, paying attention to those more frequently used, which may be potentially harmful in patients with kidney disease. The risks of overdosing and underdosing are outlined, and some recommendations to reduce the risk of adverse drug reactions are provided. A review of the literature covering the field of drug management in older patients with kidney disease was performed by selecting those articles published between January 1, 1990, and December 1, 2014, using PubMed as a search engine with the keywords elderly, kidney disease, drugs, drug interaction, and renal function. Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

[Application of fuzzy mathematics on modifying taste of oral solution of traditional Chinese drug].

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Wang, Youjie; Feng, Yi; Zhang, Bo

2009-01-01

To apply Fuzzy mathematical methods to choose the best taste modifying prescription of oral solution of traditional Chinese drug. Jin-Fukang oral solution was used as a model drug. The oral solution was prepared in different taste modifying prescriptions, whose tastes were evaluated by the fuzzy quality synthetic evaluation system. Compound-sweeteners with Sucralose and Erythritol was the best choice. Fuzzy integrated evaluation can be used to evaluate the taste of traditional Chinese medicinal pharmaceuticals, which overcame the artificial factors and achieve more objective conclusion.

Efficacy and safety of tofacitinib following inadequate response to conventional synthetic or biological disease-modifying antirheumatic drugs.

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Charles-Schoeman, Christina; Burmester, Gerd; Nash, Peter; Zerbini, Cristiano A F; Soma, Koshika; Kwok, Kenneth; Hendrikx, Thijs; Bananis, Eustratios; Fleischmann, Roy

2016-07-01

Biological disease-modifying antirheumatic drugs (bDMARDs) have shown diminished clinical response following an inadequate response (IR) to ≥1 previous bDMARD. Here, tofacitinib was compared with placebo in patients with an IR to conventional synthetic DMARDs (csDMARDs; bDMARD-naive) and in patients with an IR to bDMARDs (bDMARD-IR). Data were taken from phase II and phase III studies of tofacitinib in patients with rheumatoid arthritis (RA). Patients received tofacitinib 5 or 10 mg twice daily, or placebo, as monotherapy or with background methotrexate or other csDMARDs. Efficacy endpoints and incidence rates of adverse events (AEs) of special interest were assessed. 2812 bDMARD-naive and 705 bDMARD-IR patients were analysed. Baseline demographics and disease characteristics were generally similar between treatment groups within subpopulations. Across subpopulations, improvements in efficacy parameters at month 3 were generally significantly greater for both tofacitinib doses versus placebo. Clinical response was numerically greater with bDMARD-naive versus bDMARD-IR patients (overlapping 95% CIs). Rates of safety events of special interest were generally similar between tofacitinib doses and subpopulations; however, patients receiving glucocorticoids had more serious AEs, discontinuations due to AEs, serious infection events and herpes zoster. Numerically greater clinical responses and incidence rates of AEs of special interest were generally reported for tofacitinib 10 mg twice daily versus tofacitinib 5 mg twice daily (overlapping 95% CIs). Tofacitinib demonstrated efficacy in both bDMARD-naive and bDMARD-IR patients with RA. Clinical response to tofacitinib was generally numerically greater in bDMARD-naive than bDMARD-IR patients. The safety profile appeared similar between subpopulations. (NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385). Published by the BMJ Publishing Group Limited

Financing drug discovery for orphan diseases.

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Fagnan, David E; Gromatzky, Austin A; Stein, Roger M; Fernandez, Jose-Maria; Lo, Andrew W

2014-05-01

Recently proposed 'megafund' financing methods for funding translational medicine and drug development require billions of dollars in capital per megafund to de-risk the drug discovery process enough to issue long-term bonds. Here, we demonstrate that the same financing methods can be applied to orphan drug development but, because of the unique nature of orphan diseases and therapeutics (lower development costs, faster FDA approval times, lower failure rates and lower correlation of failures among disease targets) the amount of capital needed to de-risk such portfolios is much lower in this field. Numerical simulations suggest that an orphan disease megafund of only US$575 million can yield double-digit expected rates of return with only 10-20 projects in the portfolio. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Strontium ranelate is a drug to treat osteoarthrosis

Directory of Open Access Journals (Sweden)

Oksana Anatolyevna Nikitinskaya

2013-01-01

Full Text Available To prevent disease progression in patients with osteoarthosis (OA remains a challenging problem. Despite the proposed drug, non-drug, and surgical treatments for OA, there is a clinical need for medications that have a structure-modifying effect and are able to delay or prevent cartilage degradation and to alleviate the clinical manifestations of the disease. A 3-year international randomized clinical trial has demonstrated strong evidence for the symptomand structure-modifying effect of strontium ranelate in female and male patients with clinical primary knee OA. The clinical use of the drug opens up new prospects for preventing the progression of the disease in patients with knee and hip OA.

Synthesis and characterization of modified starch/polybutadiene as novel transdermal drug delivery system.

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Saboktakin, Mohammad Reza; Akhyari, Shahab; Nasirov, Fizuli A

2014-08-01

Transdermal drug delivery systems are topically administered medicaments in the form of patches that deliver drugs for systemic effects at a predetermined and controlled rate. It works very simply in which drug is applied inside the patch and it is worn on skin for long period of time. Polymer matrix, drug, permeation enhancers are the main components of transdermal drug delivery systems. The objective of the present study was to develop the modified starch and 1,4-cis polybutadiene nanoparticles as novel polymer matrix system. We have been studied the properties of a novel transdermal drug delivery system with clonidine as drug model. Copyright © 2014 Elsevier B.V. All rights reserved.

Modifiable risk factors in periodontitis: at the intersection of aging and disease.

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Reynolds, Mark A

2014-02-01

Chronic inflammation is a prominent feature of aging and of common age-related diseases, including atherosclerosis, cancer and periodontitis. This volume examines modifiable risk factors for periodontitis and other chronic inflammatory diseases. Oral bacterial communities and viral infections, particularly with cytomegalovirus and other herpesviruses, elicit distinct immune responses and are central in the initiation of periodontal diseases. Risk of disease is dynamic and changes in response to complex interactions of genetic, environmental and stochastic factors over the lifespan. Many modifiable risk factors, such as smoking and excess caloric intake, contribute to increases in systemic markers of inflammation and can modify gene regulation through a variety of biologic mechanisms (e.g. epigenetic modifications). Periodontitis and other common chronic inflammatory diseases share multiple modifiable risk factors, such as tobacco smoking, psychological stress and depression, alcohol consumption, obesity, diabetes, metabolic syndrome and osteoporosis. Interventions that target modifiable risk factors have the potential to improve risk profiles for periodontitis as well as for other common chronic diseases. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Dissolution-modulating mechanism of pH modifiers in solid dispersion containing weakly acidic or basic drugs with poor water solubility.

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Tran, Phuong Ha-Lien; Tran, Thao Truong-Dinh; Lee, Kyoung-Ho; Kim, Dong-Jin; Lee, Beom-Jin

2010-05-01

Although the solid dispersion method has been known to increase the dissolution rate of poorly water-soluble drugs by dispersing them in hydrophilic carriers, one obstacle of the solid dispersion method is its limited solubilization capacity, especially for pH-dependent soluble drugs. pH-modified solid dispersion, in which pH modifiers are incorporated, may be a useful method for increasing the dissolution rate of weakly acidic or basic drugs. Sufficient research, including the most recent reports, was undertaken in this review. How could the inclusion of the pH the pH modifiers in the solid dispersion system change drug structural behaviors, molecular interactions, microenvironmental pH, and/or release rate of pH modifiers, relating with the enhanced dissolution of weakly acidic or weakly basic drugs with poor water solubility? These questions have been investigated to determine the dissolution-modulating mechanism of pH modifiers in solid dispersion containing weakly acidic or basic drugs. It is believed that step-by-step mechanistic approaches could provide the ultimate solution for solubilizing several poorly water-soluble drugs with pH-dependent solubility from a solid dispersion system, as well as provide ideas for developing future dosage systems.

Established and novel disease-modifying treatments in multiple sclerosis.

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Cross, A H; Naismith, R T

2014-04-01

Multiple sclerosis (MS) is a presumed autoimmune disorder of the central nervous system, resulting in inflammatory demyelination and axonal and neuronal injury. New diagnostic criteria that incorporate magnetic resonance imaging have resulted in earlier and more accurate diagnosis of MS. Several immunomodulatory and immunosuppressive therapeutic agents are available for relapsing forms of MS, which allow individualized treatment based upon the benefits and risks. Disease-modifying therapies introduced in the 1990s, the beta-interferons and glatiramer acetate, have an established track record of efficacy and safety, although they require administration via injection. More recently, monoclonal antibodies have been engineered to act through specific mechanisms such as blocking alpha-4 integrin interactions (natalizumab) or lysing cells bearing specific markers, for example CD52 (alemtuzumab) or CD20 (ocrelizumab and ofatumumab). These agents can be highly efficacious, but sometimes have serious potential complications (natalizumab is associated with progressive multifocal leukoencephalopathy; alemtuzumab is associated with the development of new autoimmune disorders). Three new oral therapies (fingolimod, teriflunomide and dimethyl fumarate, approved for MS treatment from 2010 onwards) provide efficacy, tolerability and convenience; however, as yet, there are no long-term postmarketing efficacy and safety data in a general MS population. Because of this lack of long-term data, in some cases, therapy is currently initiated with the older, safer injectable medications, but patients are monitored closely with the plan to switch therapies if there is any indication of a suboptimal response or intolerance or lack of adherence to the initial therapy. For patients with MS who present with highly inflammatory and potentially aggressive disease, the benefit-to-risk ratio may support initiating therapy using a drug with greater potential efficacy despite greater risks (e

Analysis of recent failures of disease modifying therapies in Alzheimer's disease suggesting a new methodology for future studies.

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Amanatkar, Hamid Reza; Papagiannopoulos, Bill; Grossberg, George Thomas

2017-01-01

Pharmaceutical companies and the NIH have invested heavily in a variety of potential disease-modifying therapies for Alzheimer's disease (AD) but unfortunately all double-blind placebo-controlled Phase III studies of these drugs have failed to show statistically significant results supporting their clinical efficacy on cognitive measures. These negative results are surprising as most of these medications have the capability to impact the biomarkers which are associated with progression of Alzheimer's disease. Areas covered: This contradiction prompted us to review all study phases of Intravenous Immunoglobulin (IVIG), Bapineuzumab, Solanezumab, Avagacestat and Dimebolin to shed more light on these recent failures. We critically analyzed these studies, recommending seven lessons from these failures which should not be overlooked. Expert commentary: We suggest a new methodology for future treatment research in Alzheimer's disease considering early intervention with more focus on cognitive decline as a screening tool, more sophisticated exclusion criteria with more reliance on biomarkers, stratification of subjects based on the rate of cognitive decline aiming less heterogeneity, and a longer study duration with periodic assessment of cognition and activities of daily living during the study and also after a washout period.

An evaluation of adherence in patients with multiple sclerosis newly initiating treatment with a self-injectable or an oral disease-modifying drug

Directory of Open Access Journals (Sweden)

Munsell M

2016-12-01

Full Text Available Michael Munsell,1 Molly Frean,1 Joseph Menzin,1 Amy L Phillips2 1Boston Health Economics, Inc., Waltham, MA, USA; 2Health Economics & Outcomes Research, EMD Serono Inc., Rockland, MA, USA Objective: As the multiple sclerosis (MS disease-modifying drug (DMD treatment options have expanded to include oral therapies, it is important to understand whether route of administration is associated with DMD adherence. The objective of this study was to compare adherence to DMDs in patients with MS newly initiating treatment with a self-injectable versus an oral DMD. Methods: This retrospective database study used IMS Health Real World Data Adjudicated Claims – US data between July 1, 2010 and June 30, 2014. Adherence was measured by medication possession ratio (MPR, calculated as the total number of treated days divided by the total number of days from the first treated day until the end of 12-month follow-up. A binary measure representing adherence (MPR ≥0.8 versus nonadherence (MPR <0.8 to therapy was used. Logistic regression evaluated the likelihood of adherence to index DMD type (self-injectable vs oral. Covariates included patient baseline characteristics (ie, age, sex, comorbidities and index DMD type. Results: The analysis included 7,207 self-injectable and 1,175 oral DMD-treated patients with MS. In unadjusted analyses, the proportion of patients adherent to therapy (MPR ≥0.8 did not differ significantly between the self-injectable (54.1% and the oral DMD cohorts (53.0%; P=0.5075. After controlling for covariates, index DMD type was not a significant predictor of adherence (odds ratio [OR] 1.062; 95% confidence interval [CI]: 0.937–1.202; P=0.3473. Higher likelihood of adherence was associated with male sex (OR 1.20; 95% CI: 1.085–1.335; P=0.0005 and age groups older than 18–34 years (ORs 1.220–1.331; P<0.01. Depression was associated with a lower likelihood of adherence (OR 0.618; 95% CI: 0.511–0.747; P<0.0001. Conclusion: Male

A short history of anti-rheumatic therapy - VI. Rheumatoid arthritis drugs

Directory of Open Access Journals (Sweden)

G. Pasero

2011-09-01

Full Text Available The treatment of rheumatoid arthritis traditionally includes symptomatic drugs, showing a prompt action on pain and infl ammation, but without any infl uence on disease progression, and other drugs that could modify the disease course and occasionally induce clinical remission (DMARDs or disease modifying anti-rheumatic drugs. This review describes the historical steps that led to the use of the main DMARDs in rheumatoid arthritis, such as gold salts, sulphasalazine, chloroquine and hydroxychloroquine, D-penicillamine, and other immunoactive drugs, including methotrexate, azathioprine, cyclosporin and lefl unomide. The historical evolution of use of these drugs is then discussed, including the strategy of progressive (“therapeutic pyramid” or of more aggressive treatment, through the simultaneous use of two or more DMARDs (“combination therapy”.

Mucoadhesive Cyclodextrin-Modified Thiolated Poly(aspartic acid as a Potential Ophthalmic Drug Delivery System

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Mária Budai-Szűcs

2018-02-01

Full Text Available Thiolated poly(aspartic acid is known as a good mucoadhesive polymer in aqueous ophthalmic formulations. In this paper, cyclodextrin-modified thiolated poly(aspartic acid was synthesized for the incorporation of prednisolone, a lipophilic ophthalmic drug, in an aqueous in situ gellable mucoadhesive solution. This polymer combines the advantages of cyclodextrins and thiolated polymers. The formation of the cyclodextrin-drug complex in the gels was analyzed by X-ray powder diffraction. The ocular applicability of the polymer was characterized by means of physicochemical, rheological and drug diffusion tests. It was established that the chemical bonding of the cyclodextrin molecule did not affect the complexation of prednisolone, while the polymer solution preserved its in situ gellable and good mucoadhesive characteristics. The chemical immobilization of cyclodextrin modified the diffusion profile of prednisolone and prolonged drug release was observed. The combination of free and immobilized cyclodextrins provided the best release profile because the free complex can diffuse rapidly, while the bonded complex ensures a prolonged action.

Ultrasound-mediated drug delivery using liposomes modified with a thermosensitive polymer.

Science.gov (United States)

Ninomiya, Kazuaki; Kawabata, Shinya; Tashita, Hiroyuki; Shimizu, Nobuaki

2014-01-01

Ultrasound-mediated drug delivery was established using liposomes that were modified with the thermosensitive polymer (TSP) poly(NIPMAM-co-NIPAM), which sensitized the liposomes to high temperatures. TSP-modified liposomes (TSP liposomes) released encapsulated calcein under 1 MHz ultrasound irradiation at 0.5 W/cm(2) for 120 s as well as the case under incubation at 42 °C for 15 min. In addition, uptake of the drug released from TSP liposomes by cancer cells was enhanced by ultrasound irradiation. In a cell injury assay using doxorubicin (DOX)-loaded TSP liposomes and ultrasound irradiation, cell viability of HepG2 cells at 6 h after ultrasound irradiation (1 MHz, 0.5 W/cm(2) for 30 s) with DOX-loaded TSP liposomes (TSP/lipid ratio=1) was 60%, which was significantly lower than that of the control conditions such as DOX-loaded TSP liposomes alone and DOX-loaded intact liposomes under ultrasound irradiation. Copyright © 2013 Elsevier B.V. All rights reserved.

77 FR 59930 - Clinical Development Programs for Disease-Modifying Agents for Peripheral Neuropathy; Public...

Science.gov (United States)

2012-10-01

...] Clinical Development Programs for Disease-Modifying Agents for Peripheral Neuropathy; Public Workshop... to the clinical development of disease-modifying agents for the treatment of peripheral neuropathy... disease-modifying products for the management of peripheral neuropathy. Date and Time: The public workshop...

Leukotrienes and leukotriene modifiers in pediatric allergic diseases

African Journals Online (AJOL)

Ehab

... 12(1):3-12. 3. Leukotrienes and leukotriene modifiers in pediatric allergic diseases ... childhood allergic diseases. This review ... produce cysteinyl-LTs and LTB4 spontaneously in vitro.8. Although nonleukocyte cells generally do not have sufficient 5-LO and FLAP to synthesize .... uninterrupted sleep in these patients.55.

Issues surrounding orphan disease and orphan drug policies in Europe.

Science.gov (United States)

Denis, Alain; Mergaert, Lut; Fostier, Christel; Cleemput, Irina; Simoens, Steven

2010-01-01

An orphan disease is a disease with a very low prevalence. Although there are 5000-7000 orphan diseases, only 50 orphan drugs (i.e. drugs developed to treat orphan diseases) were marketed in the EU by the end of 2008. In 2000, the EU implemented policies specifically designed to stimulate the development of orphan drugs. While decisions on orphan designation and the marketing authorization of orphan drugs are made at the EU level, decisions on drug reimbursement are made at the member state level. The specific features of orphan diseases and orphan drugs make them a high-priority issue for policy makers. The aim of this article is to identify and discuss several issues surrounding orphan disease and drug policies in Europe. The present system of orphan designation allows for drugs for non-orphan diseases to be designated as orphan drugs. The economic factors underlying orphan designation can be questioned in some cases, as a low prevalence of a certain indication does not equal a low return on investment for the drug across its indications. High-quality evidence about the clinical added value of orphan drugs is rarely available at the time of marketing authorization, due to the low number of patients. A balance must be struck between ethical and economic concerns. To this effect, there is a need to initiate a societal dialogue on this issue, to clarify what society wants and accepts in terms of ethical and economic consequences. The growing budgetary impact of orphan drugs puts pressure on drug expenditure. Indications can be extended for an orphan drug and the total prevalence across indications is not considered. Finally, cooperation needs to be fostered in the EU, particularly through a standardized approach to the creation and use of registries. These issues require further attention from researchers, policy makers, health professionals, patients, pharmaceutical companies and other stakeholders with a view to optimizing orphan disease and drug policies in

Triple-Component Drug-Loaded Nanocomposites Prepared Using a Modified Coaxial Electrospinning

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Wei Qian

2013-01-01

Full Text Available Triple-component nanocomposites for improved sustained drug release profiles are successfully fabricated through a modified coaxial electrospinning process, in which only organic solvent N,N-dimethylacetamide was used as sheath fluid. Using polyacrylonitrile (PAN as filament-forming matrix, ibuprofen (IBU as functional ingredient, and polyvinylpyrrolidone (PVP as the additional component, the IBU/PVP/PAN triple-component nanocomposites had uniform structure and an average diameter of 620±120 nm and 650±120 nm when the contents of PVP in the nanofibers were 10.5% and 22.7%, respectively. The optimal sheath-to-core flow rate ratio was 0.11 under a total sheath and core fluid flow rate of 1.0 mL/h. Compared with the IBU/PAN composite nanofibers, the triple-component composites could release 92.1% and 97.8% of the contained IBU, significantly larger than a value of 73.4% from the former. The inclusion of PVP in the IBU/PAN could effectively avoid the entrapment of IBU in the insoluble PAN molecules, facilitating the in vitro release of IBU. The modified coaxial process and the resulted multiple component nanocomposites would provide new way for developing novel drug sustained materials and transdermal drug delivery systems.

EDITORIAL Drugs for Neglected Diseases Initiative

African Journals Online (AJOL)

Dr.Kofi-Tsekpo

disease, and malaria have a devastating impact on humanity, yet R&D for new drugs for these diseases has been progressively marginalised because they are not considered a lucrative investment. DNDi, a needs-driven initiative, keeps the needs of patients suffering from neglected diseases paramount in its search for.

Large-scale computational drug repositioning to find treatments for rare diseases.

Science.gov (United States)

Govindaraj, Rajiv Gandhi; Naderi, Misagh; Singha, Manali; Lemoine, Jeffrey; Brylinski, Michal

2018-01-01

Rare, or orphan, diseases are conditions afflicting a small subset of people in a population. Although these disorders collectively pose significant health care problems, drug companies require government incentives to develop drugs for rare diseases due to extremely limited individual markets. Computer-aided drug repositioning, i.e., finding new indications for existing drugs, is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research. Structure-based matching of drug-binding pockets is among the most promising computational techniques to inform drug repositioning. In order to find new targets for known drugs ultimately leading to drug repositioning, we recently developed e MatchSite, a new computer program to compare drug-binding sites. In this study, e MatchSite is combined with virtual screening to systematically explore opportunities to reposition known drugs to proteins associated with rare diseases. The effectiveness of this integrated approach is demonstrated for a kinase inhibitor, which is a confirmed candidate for repositioning to synapsin Ia. The resulting dataset comprises 31,142 putative drug-target complexes linked to 980 orphan diseases. The modeling accuracy is evaluated against the structural data recently released for tyrosine-protein kinase HCK. To illustrate how potential therapeutics for rare diseases can be identified, we discuss a possibility to repurpose a steroidal aromatase inhibitor to treat Niemann-Pick disease type C. Overall, the exhaustive exploration of the drug repositioning space exposes new opportunities to combat orphan diseases with existing drugs. DrugBank/Orphanet repositioning data are freely available to research community at https://osf.io/qdjup/.

Lactoferrin-modified rotigotine nanoparticles for enhanced nose-to-brain delivery: LESA-MS/MS-based drug biodistribution, pharmacodynamics, and neuroprotective effects

Directory of Open Access Journals (Sweden)

Yan X

2018-01-01

Full Text Available Xiuju Yan,1,* Lixiao Xu,1,* Chenchen Bi,1 Dongyu Duan,1 Liuxiang Chu,1 Xin Yu,1 Zimei Wu,1 Aiping Wang,1,2 Kaoxiang Sun1,2 1School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University, Ministry of Education, Yantai University, Yantai, Shandong Province, 2State Key Laboratory of Long-Acting and Targeting Drug Delivery System, Shandong Luye Pharmaceutical Co., Ltd, Yantai, Shandong Province, People’s Republic of China *These authors contributed equally to this work Introduction: Efficient delivery of rotigotine into the brain is crucial for obtaining maximum therapeutic efficacy for Parkinson’s disease (PD. Therefore, in the present study, we prepared lactoferrin-modified rotigotine nanoparticles (Lf-R-NPs and studied their biodistribution, pharmacodynamics, and neuroprotective effects following nose-to-brain delivery in the rat 6-hydroxydopamine model of PD.Materials and methods: The biodistribution of rotigotine nanoparticles (R-NPs and Lf-R-NPs after intranasal administration was assessed by liquid extraction surface analysis coupled with tandem mass spectrometry. Contralateral rotations were quantified to evaluate pharmacodynamics. Tyrosine hydroxylase and dopamine transporter immunohistochemistry were performed to compare the neuroprotective effects of levodopa, R-NPs, and Lf-R-NPs.Results: Liquid extraction surface analysis coupled with tandem mass spectrometry analysis, used to examine rotigotine biodistribution, showed that Lf-R-NPs more efficiently supplied rotigotine to the brain (with a greater sustained amount of the drug delivered to this organ, and with more effective targeting to the striatum than R-NPs. The pharmacodynamic study revealed a significant difference (P<0.05 in contralateral rotations between rats treated with Lf-R-NPs and those treated with R-NPs. Furthermore, Lf

Financing drug discovery for orphan diseases

OpenAIRE

Fagnan, David Erik; Gromatzky, Austin A.; Stein, Roger Mark; Fernandez, Jose-Maria; Lo, Andrew W.

2014-01-01

Recently proposed ‘megafund’ financing methods for funding translational medicine and drug development require billions of dollars in capital per megafund to de-risk the drug discovery process enough to issue long-term bonds. Here, we demonstrate that the same financing methods can be applied to orphan drug development but, because of the unique nature of orphan diseases and therapeutics (lower development costs, faster FDA approval times, lower failure rates and lower correlation of failures...

An investigation of effects of modification processes on physical properties and mechanism of drug release for sustaining drug release from modified rice

Energy Technology Data Exchange (ETDEWEB)

Ngo, Vuong Duy; Luu, Thinh Duc; Van Vo, Toi [Pharmaceutical Engineering Laboratory, Biomedical Engineering Department, International University, Vietnam National University, Ho Chi Minh City (Viet Nam); Tran, Van-Thanh [Faculty of Pharmacy, University of Medicine and Pharmacy, Ho Chi Minh City (Viet Nam); Duan, Wei [School of Medicine, Deakin University, Pigdons Road, Waurn Ponds, Victoria (Australia); Tran, Phuong Ha-Lien, E-mail: phuong.tran1@deakin.edu.au [School of Medicine, Deakin University, Pigdons Road, Waurn Ponds, Victoria (Australia); Tran, Thao Truong-Dinh, E-mail: ttdthao@hcmiu.edu.vn [Pharmaceutical Engineering Laboratory, Biomedical Engineering Department, International University, Vietnam National University, Ho Chi Minh City (Viet Nam)

2016-10-01

The aim of this study was to investigate the effect of modification processes on physical properties and explain the mechanism of sustained drug release from modified rice (MR). Various types of Vietnamese rice were introduced in the study as the matrices of sustained release dosage form. Rice was thermally modified in water for a determined temperature at different times with a simple process. Then tablets containing MR and isradipine, the model drug, were prepared to investigate the capability of sustained drug release. Scanning electron microscopy (SEM) was used to determine different morphologies between MR formulations. Flow property of MR was analyzed by Hausner ratio and Carr's indices. The dissolution rate and swelling/erosion behaviors of tablets were evaluated at pH 1.2 and pH 6.8 at 37 ± 0.5 °C. The matrix tablet containing MR showed a sustained release as compared to the control. The SEM analyses and swelling/erosion studies indicated that the morphology as well as swelling/erosion rate of MR were modulated by modification time, drying method and incubation. It was found that the modification process was crucial because it could highly affect the granule morphologies and hence, leading to the change of flowability and swelling/erosion capacity for sustained release of drug. - Highlights: • Modification process affected granule morphologies and flowability of modified rice. • Modification process affected swelling/erosion capacity for drug sustained release. • Freeze-drying could decrease the erosion as well as increase the swelling rate.

An investigation of effects of modification processes on physical properties and mechanism of drug release for sustaining drug release from modified rice

International Nuclear Information System (INIS)

Ngo, Vuong Duy; Luu, Thinh Duc; Van Vo, Toi; Tran, Van-Thanh; Duan, Wei; Tran, Phuong Ha-Lien; Tran, Thao Truong-Dinh

2016-01-01

The aim of this study was to investigate the effect of modification processes on physical properties and explain the mechanism of sustained drug release from modified rice (MR). Various types of Vietnamese rice were introduced in the study as the matrices of sustained release dosage form. Rice was thermally modified in water for a determined temperature at different times with a simple process. Then tablets containing MR and isradipine, the model drug, were prepared to investigate the capability of sustained drug release. Scanning electron microscopy (SEM) was used to determine different morphologies between MR formulations. Flow property of MR was analyzed by Hausner ratio and Carr's indices. The dissolution rate and swelling/erosion behaviors of tablets were evaluated at pH 1.2 and pH 6.8 at 37 ± 0.5 °C. The matrix tablet containing MR showed a sustained release as compared to the control. The SEM analyses and swelling/erosion studies indicated that the morphology as well as swelling/erosion rate of MR were modulated by modification time, drying method and incubation. It was found that the modification process was crucial because it could highly affect the granule morphologies and hence, leading to the change of flowability and swelling/erosion capacity for sustained release of drug. - Highlights: • Modification process affected granule morphologies and flowability of modified rice. • Modification process affected swelling/erosion capacity for drug sustained release. • Freeze-drying could decrease the erosion as well as increase the swelling rate.

Long-Term Outcomes in Puerto Ricans with Rheumatoid Arthritis (RA) Receiving Early Treatment with Disease-Modifying Anti-Rheumatic Drugs using the American College of Rheumatology Definition of Early RA.

Science.gov (United States)

Varela-Rosario, Noemí; Arroyo-Ávila, Mariangelí; Fred-Jiménez, Ruth M; Díaz-Correa, Leyda M; Pérez-Ríos, Naydi; Rodríguez, Noelia; Ríos, Grissel; Vilá, Luis M

2017-01-01

Early treatment of rheumatoid arthritis (RA) results in better long-term outcomes. However, the optimal therapeutic window has not been clearly established. To determine the clinical outcome of Puerto Ricans with RA receiving early treatment with conventional and/or biologic disease-modifying anti-rheumatic drugs (DMARDs) based on the American College of Rheumatology (ACR) definition of early RA. A cross-sectional study was performed in a cohort of Puerto Ricans with RA. Demographic features, clinical manifestations, disease activity, functional status, and pharmacotherapy were determined. Early treatment was defined as the initiation of DMARDs (conventional and/or biologic) in less than 6 months from the onset of symptoms attributable to RA. Patients who received early (disease duration was 14.9 years and 337 (87.0%) patients were women. One hundred and twenty one (31.3%) patients received early treatment. In the multivariate analysis adjusted for age and sex, early treatment was associated with better functional status, lower probability of joint deformities, intra-articular injections and joint replacement surgeries, and lower scores in the physician's assessments of global health, functional impairment and physical damage of patients. Using the ACR definition of early RA, this group of patients treated with DMARDs within 6 months of disease had better long-term outcomes with less physical damage and functional impairment.

Drugs and drug delivery systems targeting amyloid-β in Alzheimer's disease

Directory of Open Access Journals (Sweden)

Morgan Robinson

2015-07-01

Full Text Available Alzheimer's disease (AD is a devastating neurodegenerative disorder with no cure and limited treatment solutions that are unable to target any of the suspected causes. Increasing evidence suggests that one of the causes of neurodegeneration is the overproduction of amyloid beta (Aβ and the inability of Aβ peptides to be cleared from the brain, resulting in self-aggregation to form toxic oligomers, fibrils and plaques. One of the potential treatment options is to target Aβ and prevent self-aggregation to allow for a natural clearing of the brain. In this paper, we review the drugs and drug delivery systems that target Aβ in relation to Alzheimer's disease. Many attempts have been made to use anti-Aβ targeting molecules capable of targeting Aβ (with much success in vitro and in vivo animal models, but the major obstacle to this technique is the challenge posed by the blood brain barrier (BBB. This highly selective barrier protects the brain from toxic molecules and pathogens and prevents the delivery of most drugs. Therefore novel Aβ aggregation inhibitor drugs will require well thought-out drug delivery systems to deliver sufficient concentrations to the brain.

Discontinuing disease-modifying therapy in progressive multiple sclerosis: can we stop what we have started?

LENUS (Irish Health Repository)

Lonergan, Roisin

2012-02-01

Disease-modifying therapy is ineffective in disabled patients (Expanded Disability Status Scale [EDSS] > 6.5) with secondary progressive multiple sclerosis (MS) without relapses, or in primary progressive MS. Many patients with secondary progressive MS who initially had relapsing MS continue to use disease-modifying therapies. The enormous associated costs are a burden to health services. Regular assessment is recommended to guide discontinuation of disease-modifying therapies when no longer beneficial, but this is unavailable to many patients, particularly in rural areas. The objectives of this study are as follows: 1. To observe use of disease-modifying therapies in patients with progressive multiple sclerosis and EDSS > 6.5. 2. To examine approaches used by a group of international MS experts to stopping-disease modifying therapies in patients with secondary progressive MS without relapses. During an epidemiological study in three regions of Ireland (southeast Dublin city, and Wexford and Donegal Counties), we recorded details of disease-modifying therapies in patients with progressive MS and EDSS > 6.5. An e-questionnaire was sent to 26 neurologists with expert knowledge of MS, asking them to share their approach to stopping disease-modifying therapies in patients with secondary progressive MS. Three hundred and thirty-six patients were studied: 88 from southeast Dublin, 99 from Wexford and 149 from Donegal. Forty-four had EDSS > 6.5: 12 were still using disease-modifying therapies. Of the surveyed neurologists, 15 made efforts to stop disease-modifying therapies in progressive multiple sclerosis, but most did not insist. A significant proportion (12 of 44 patients with progressive MS and EDSS > 6.5) was considered to be receiving therapy without benefit. Eleven of the 12 were from rural counties, reflecting poorer access to neurology services. The costs of disease-modifying therapies in this group (>170,000 euro yearly) could be re-directed towards development

The Impact of Disease and Drugs on Hip Fracture Risk.

Science.gov (United States)

Leavy, Breiffni; Michaëlsson, Karl; Åberg, Anna Cristina; Melhus, Håkan; Byberg, Liisa

2017-01-01

We report the risks of a comprehensive range of disease and drug categories on hip fracture occurrence using a strict population-based cohort design. Participants included the source population of a Swedish county, aged ≥50 years (n = 117,494) including all incident hip fractures during 1 year (n = 477). The outcome was hospitalization for hip fracture (ICD-10 codes S72.0-S72.2) during 1 year (2009-2010). Exposures included: prevalence of (1) inpatient diseases [International Classification of Diseases (ICD) codes A00-T98 in the National Patient Register 1987-2010] and (2) prescribed drugs dispensed in 2010 or the year prior to fracture. We present age- and sex-standardized risk ratios (RRs), risk differences (RDs) and population attributable risks (PARs) of disease and drug categories in relation to hip fracture risk. All disease categories were associated with increased risk of hip fracture. Largest risk ratios and differences were for mental and behavioral disorders, diseases of the blood and previous fracture (RRs between 2.44 and 3.00; RDs (per 1000 person-years) between 5.0 and 6.9). For specific drugs, strongest associations were seen for antiparkinson (RR 2.32 [95 % CI 1.48-1.65]; RD 5.2 [1.1-9.4]) and antidepressive drugs (RR 1.90 [1.55-2.32]; RD 3.1 [2.0-4.3]). Being prescribed ≥10 drugs during 1 year incurred an increased risk of hip fracture, whereas prescription of cardiovascular drugs or ≤5 drugs did not appear to increase risk. Diseases inferring the greatest PARs included: cardiovascular diseases PAR 22 % (95 % CI 14-29) and previous injuries (PAR 21 % [95 % CI 16-25]; for specific drugs, antidepressants posed the greatest risk (PAR 16 % [95 % CI 12.0-19.3]).

Drug development for airway diseases: looking forward

NARCIS (Netherlands)

Holgate, Stephen; Agusti, Alvar; Strieter, Robert M.; Anderson, Gary P.; Fogel, Robert; Bel, Elisabeth; Martin, Thomas R.; Reiss, Theodore F.

2015-01-01

Advancing drug development for airway diseases beyond the established mechanisms and symptomatic therapies requires redefining the classifications of airway diseases, considering systemic manifestations, developing new tools and encouraging collaborations

Targeting cysteine proteases in trypanosomatid disease drug discovery.

Science.gov (United States)

Ferreira, Leonardo G; Andricopulo, Adriano D

2017-12-01

Chagas disease and human African trypanosomiasis are endemic conditions in Latin America and Africa, respectively, for which no effective and safe therapy is available. Efforts in drug discovery have focused on several enzymes from these protozoans, among which cysteine proteases have been validated as molecular targets for pharmacological intervention. These enzymes are expressed during the entire life cycle of trypanosomatid parasites and are essential to many biological processes, including infectivity to the human host. As a result of advances in the knowledge of the structural aspects of cysteine proteases and their role in disease physiopathology, inhibition of these enzymes by small molecules has been demonstrated to be a worthwhile approach to trypanosomatid drug research. This review provides an update on drug discovery strategies targeting the cysteine peptidases cruzain from Trypanosoma cruzi and rhodesain and cathepsin B from Trypanosoma brucei. Given that current chemotherapy for Chagas disease and human African trypanosomiasis has several drawbacks, cysteine proteases will continue to be actively pursued as valuable molecular targets in trypanosomatid disease drug discovery efforts. Copyright © 2017. Published by Elsevier Inc.

Fungal endophytes: modifiers of plant disease.

Science.gov (United States)

Busby, Posy E; Ridout, Mary; Newcombe, George

2016-04-01

Many recent studies have demonstrated that non-pathogenic fungi within plant microbiomes, i.e., endophytes ("endo" = within, "phyte" = plant), can significantly modify the expression of host plant disease. The rapid pace of advancement in endophyte ecology warrants a pause to synthesize our understanding of endophyte disease modification and to discuss future research directions. We reviewed recent literature on fungal endophyte disease modification, and here report on several emergent themes: (1) Fungal endophyte effects on plant disease span the full spectrum from pathogen antagonism to pathogen facilitation, with pathogen antagonism most commonly reported. (2) Agricultural plant pathosystems are the focus of research on endophyte disease modification. (3) A taxonomically diverse group of fungal endophytes can influence plant disease severity. And (4) Fungal endophyte effects on plant disease severity are context-dependent. Our review highlights the importance of fungal endophytes for plant disease across a broad range of plant pathosystems, yet simultaneously reveals that complexity within plant microbiomes presents a significant challenge to disentangling the biotic environmental factors affecting plant disease severity. Manipulative studies integrating eco-evolutionary approaches with emerging molecular tools will be poised to elucidate the functional importance of endophytes in natural plant pathosystems that are fundamental to biodiversity and conservation.

Drugs of abuse and Parkinson's disease.

Science.gov (United States)

Mursaleen, Leah R; Stamford, Jonathan A

2016-01-04

The term "drug of abuse" is highly contextual. What constitutes a drug of abuse for one population of patients does not for another. It is therefore important to examine the needs of the patient population to properly assess the status of drugs of abuse. The focus of this article is on the bidirectional relationship between patients and drug abuse. In this paper we will introduce the dopaminergic systems of the brain in Parkinson's and the influence of antiparkinsonian drugs upon them before discussing this synergy of condition and medication as fertile ground for drug abuse. We will then examine the relationship between drugs of abuse and Parkinson's, both beneficial and deleterious. In summary we will draw the different strands together and speculate on the future merit of current drugs of abuse as treatments for Parkinson's disease. Copyright © 2015 Elsevier Inc. All rights reserved.

Delayed wound healing and postoperative surgical site infections in patients with rheumatoid arthritis treated with or without biological disease-modifying antirheumatic drugs.

Science.gov (United States)

Tada, Masahiro; Inui, Kentaro; Sugioka, Yuko; Mamoto, Kenji; Okano, Tadashi; Kinoshita, Takuya; Hidaka, Noriaki; Koike, Tatsuya

2016-06-01

Biological disease-modifying antirheumatic drugs (bDMARDs) have become more popular for treating rheumatoid arthritis (RA). Whether or not bDMARDs increase the postoperative risk of surgical site infection (SSI) has remained controversial. We aimed to clarify the effects of bDMARDs on the outcomes of elective orthopedic surgery. We used multivariate logistic regression analysis to analyze risk factors for SSI and delayed wound healing among 227 patients with RA (mean age, 65.0 years; disease duration, 16.9 years) after 332 elective orthopedic surgeries. We also attempted to evaluate the effects of individual medications on infection. Rates of bDMARD and conventional synthetic DMARD (csDMARD) administration were 30.4 and 91.0 %, respectively. Risk factors for SSI were advanced age (odds ratio [OR], 1.11; P = 0.045), prolonged surgery (OR, 1.02; P = 0.03), and preoperative white blood cell count >10,000/μL (OR, 3.66; P = 0.003). Those for delayed wound healing were advanced age (OR, 1.16; P = 0.001), prolonged surgery (OR, 1.02; P = 0.007), preoperative white blood cell count >10,000/μL (OR, 4.56; P = 0.02), and foot surgery (OR, 6.60; P = 0.001). Risk factors for SSI and medications did not significantly differ. No DMARDs were risk factors for any outcome examined. Biological DMARDs were not risk factors for postoperative SSI. Foot surgery was a risk factor for delayed wound healing.

RGD-modified lipid disks as drug carriers for tumor targeted drug delivery

Science.gov (United States)

Gao, Jie; Xie, Cao; Zhang, Mingfei; Wei, Xiaoli; Yan, Zhiqiang; Ren, Yachao; Ying, Man; Lu, Weiyue

2016-03-01

Melittin, the major component of the European bee venom, is a potential anticancer candidate due to its lytic properties. However, in vivo applications of melittin are limited due to its main side effect, hemolysis, especially when applied through intravenous administration. The polyethylene glycol-stabilized lipid disk is a novel type of nanocarrier, and the rim of lipid disks has a high affinity to amphiphilic peptides. In our study, a c(RGDyK) modified lipid disk was developed as a tumor targeted drug delivery system for melittin. Cryo-TEM was used to confirm the shape and size of lipid disks with or without c(RGDyK) modification. In vitro and in vivo hemolysis analyses revealed that the hemolysis effect significantly decreased after melittin associated with lipid disks. Importantly, the results of our in vivo biodistribution and tumor growth inhibitory experiments showed that c(RGDyK) modification increased the distribution of lipid disks in the tumor and the anticancer efficacy of melittin loaded lipid disks. Thus, we successfully achieved a targeted drug delivery system for melittin and other amphiphilic peptides with a good therapeutic effect and low side effects.

Systematic evaluation of drug-disease relationships to identify leads for novel drug uses.

Science.gov (United States)

Chiang, A P; Butte, A J

2009-11-01

Drug repositioning refers to the discovery of alternative uses for drugs--uses that are different from that for which the drugs were originally intended. One challenge in this effort lies in choosing the indication for which a drug of interest could be prospectively tested. We systematically evaluated a drug treatment-based view of diseases in order to address this challenge. Suggestions for novel drug uses were generated using a "guilt by association" approach. When compared with a control group of drug uses, the suggested novel drug uses generated by this approach were significantly enriched with respect to previous and ongoing clinical trials.

Macrophage models of Gaucher disease for evaluating disease pathogenesis and candidate drugs.

Science.gov (United States)

Aflaki, Elma; Stubblefield, Barbara K; Maniwang, Emerson; Lopez, Grisel; Moaven, Nima; Goldin, Ehud; Marugan, Juan; Patnaik, Samarjit; Dutra, Amalia; Southall, Noel; Zheng, Wei; Tayebi, Nahid; Sidransky, Ellen

2014-06-11

Gaucher disease is caused by an inherited deficiency of glucocerebrosidase that manifests with storage of glycolipids in lysosomes, particularly in macrophages. Available cell lines modeling Gaucher disease do not demonstrate lysosomal storage of glycolipids; therefore, we set out to develop two macrophage models of Gaucher disease that exhibit appropriate substrate accumulation. We used these cellular models both to investigate altered macrophage biology in Gaucher disease and to evaluate candidate drugs for its treatment. We generated and characterized monocyte-derived macrophages from 20 patients carrying different Gaucher disease mutations. In addition, we created induced pluripotent stem cell (iPSC)-derived macrophages from five fibroblast lines taken from patients with type 1 or type 2 Gaucher disease. Macrophages derived from patient monocytes or iPSCs showed reduced glucocerebrosidase activity and increased storage of glucocerebroside and glucosylsphingosine in lysosomes. These macrophages showed efficient phagocytosis of bacteria but reduced production of intracellular reactive oxygen species and impaired chemotaxis. The disease phenotype was reversed with a noninhibitory small-molecule chaperone drug that enhanced glucocerebrosidase activity in the macrophages, reduced glycolipid storage, and normalized chemotaxis and production of reactive oxygen species. Macrophages differentiated from patient monocytes or patient-derived iPSCs provide cellular models that can be used to investigate disease pathogenesis and facilitate drug development. Copyright © 2014, American Association for the Advancement of Science.

The use of random-effects models to identify health care center-related characteristics modifying the effect of antipsychotic drugs.

Science.gov (United States)

Nordon, Clementine; Battin, Constance; Verdoux, Helene; Haro, Josef Maria; Belger, Mark; Abenhaim, Lucien; van Staa, Tjeerd Pieter

2017-01-01

A case study was conducted, exploring methods to identify drugs effects modifiers, at a health care center level. Data were drawn from the Schizophrenia Outpatient Health Outcome cohort, including hierarchical information on 6641 patients, recruited from 899 health care centers from across ten European countries. Center-level characteristics included the following: psychiatrist's gender, age, length of practice experience, practice setting and type, countries' Healthcare System Efficiency score, and psychiatrist density in the country. Mixed multivariable linear regression models were used: 1) to estimate antipsychotic drugs' effectiveness (defined as the association between patients' outcome at 3 months - dependent variable, continuous - and antipsychotic drug initiation at baseline - drug A vs other antipsychotic drug); 2) to estimate the similarity between clustered data (using the intra-cluster correlation coefficient); and 3) to explore antipsychotic drug effects modification by center-related characteristics (using the addition of an interaction term). About 23% of the variance found for patients' outcome was explained by unmeasured confounding at a center level. Psychiatrists' practice experience was found to be associated with patient outcomes ( p =0.04) and modified the relative effect of "drug A" ( p <0.001), independent of center- or patient-related characteristics. Mixed models may be useful to explore how center-related characteristics modify drugs' effect estimates, but require numerous assumptions.

HYDROXYCARBAMINE: FROM AN OLD DRUG USED IN MALIGNANT HEMOPATHIES TO A CURRENT STANDARD IN SICKLE CELL DISEASE

Directory of Open Access Journals (Sweden)

Giovanna Cannas

2017-02-01

Full Text Available While hydroxycarbamine (hydroxyurea, HU has less and less indications in malignant hemopathies, it represents the only widely used drug which modifies sickle cell disease pathogenesis. Clinical experience with HU for patients with sickle cell disease has been accumulated over the past 25 years in Western countries. The review of the literature provides increasing support of safety and efficacy in both children and adults for reducing acute vaso-occlusive events including pain episodes and acute chest syndrome. HU has become the standard-of-care for sickle cell anemia, but remains underused. Barriers to its use should be identified and overcome.

Magnetic silica hybrids modified with guanidine containing co-polymers for drug delivery applications

Energy Technology Data Exchange (ETDEWEB)

Timin, Alexander S., E-mail: a_timin@mail.ru [Inorganic Chemistry Department, Ivanovo State University of Chemistry and Technology (ISUCT), 7, Sheremetevsky prosp., 153000 Ivanovo (Russian Federation); RASA Center in Tomsk, Tomsk Polytechnic University, 30, Lenin Avenue, 634500 Tomsk (Russian Federation); Khashirova, Svetlana Yu. [Kabardino-Balkar State University, ul. Chernyshevskogo 173, Nal' chik, 360004 Kabardino-Balkaria (Russian Federation); Rumyantsev, Evgeniy V.; Goncharenko, Alexander A. [Inorganic Chemistry Department, Ivanovo State University of Chemistry and Technology (ISUCT), 7, Sheremetevsky prosp., 153000 Ivanovo (Russian Federation)

2016-07-01

Guanidine containing co-polymers grafted onto silica nanoparticles to form core-shell structure were prepared by sol-gel method in the presence of γ-Fe{sub 2}O{sub 3} nanoparticles. The morphological features for uncoated and coated silica particles have been characterized with scanning electron microscopy. The results show that the polymer coated silicas exhibit spherical morphology with rough polymeric surface covered by γ-Fe{sub 2}O{sub 3} nanoparticles. The grafting amount of guanidine containing co-polymers evaluated by thermogravimetric analysis was in the range from 17 to 30%. Then, the drug loading properties and cumulative release of silica hybrids modified with guanidine containing co-polymers were evaluated using molsidomine as a model drug. It was shown that after polymer grafting the loading content of molsidomine could reach up to 3.42 ± 0.21 and 2.34 ± 0.14 mg/g respectively. The maximum drug release of molsidomine is achieved at pH 1.6 (approximately 71–75% release at 37 °C), whereas at pH 7.4 drug release is lower (50.4–59.6% release at 37 °C). These results have an important implication that our magneto-controlled silica hybrids modified with guanidine containing co-polymers are promising as drug carriers with controlled behaviour under influence of magnetic field. - Highlights: • Polymer coated silica hybrids containing γ-Fe{sub 2}O{sub 3} were prepared via sol–gel method. • Polymer grafting influences pH-response and surface properties of final products. • Molsidomine as a model drug was effectively loaded into polymer coated silicas. • The drug loading depends on the nature of grafted polymer and its content.

Tofacitinib with conventional synthetic disease-modifying antirheumatic drugs in Chinese patients with rheumatoid arthritis: Patient-reported outcomes from a Phase 3 randomized controlled trial.

Science.gov (United States)

Li, Zhanguo; An, Yuan; Su, Houheng; Li, Xiangpei; Xu, Jianhua; Zheng, Yi; Li, Guiye; Kwok, Kenneth; Wang, Lisy; Wu, Qizhe

2018-02-01

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We assess the effect of tofacitinib + conventional synthetic disease-modifying anti rheumatic drugs (csDMARDs) on patient-reported outcomes in Chinese patients with RA and inadequate response to DMARDs. This analysis of data from the Phase 3 study ORAL Sync included Chinese patients randomized 4 : 4 : 1 : 1 to receive tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, placebo→tofacitinib 5 mg twice daily, or placebo→tofacitinib 10 mg twice daily, with csDMARDs. Placebo non-responders switched to tofacitinib at 3 months; the remaining placebo patients switched at 6 months. Least squares mean changes from baseline were reported for Health Assessment Questionnaire-Disability Index (HAQ-DI), patient assessment of arthritis pain (Pain), patient global assessment of disease activity (PtGA), physician global assessment of disease activity (PGA), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores, Short Form 36 (SF-36), and Work Limitations Questionnaire (WLQ), using a mixed-effects model for repeated measures. Overall, 216 patients were included (tofacitinib 5 mg twice daily, n = 86; tofacitinib 10 mg twice daily, n = 86; placebo→tofacitinib 5 mg twice daily, n = 22; placebo→tofacitinib 10 mg twice daily, n = 22). At month 3, tofacitinib elicited significant improvements in HAQ-DI, Pain, PtGA, PGA and SF-36 Physical Component Summary scores. Improvements were generally maintained through 12 months. Tofacitinib 5 and 10 mg twice daily + csDMARDs resulted in improvements in health-related quality of life, physical function and Pain through 12 months in Chinese patients with RA. © 2018 The Authors. International Journal of Rheumatic Diseases published by Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

Drug: D07478 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available D07478 Drug Aurotioprol; Allochrysine (TN) ... C3H6AuO4S2.Na ... Anti-inflammatory ... DG01912 ... Gold... preparations ... DG01985 ... Disease modifying anti-rheumatic drugs (DMARDs) ... DG01912 ... Gold preparat...ions ATC code: M01CB05 ... Gold preparation ... CAS: 27279-43-2 PubChem: 96024436 NIKKAJI: J35.087G ...

Design, Synthesis, and Biological Evaluation of 2-(Benzylamino-2-HydroxyalkylIsoindoline-1,3-Diones Derivatives as Potential Disease-Modifying Multifunctional Anti-Alzheimer Agents

Directory of Open Access Journals (Sweden)

Dawid Panek

2018-02-01

Full Text Available The complex nature of Alzheimer’s disease calls for multidirectional treatment. Consequently, the search for multi-target-directed ligands may lead to potential drug candidates. The aim of the present study is to seek multifunctional compounds with expected activity against disease-modifying and symptomatic targets. A series of 15 drug-like various substituted derivatives of 2-(benzylamino-2-hydroxyalkylisoindoline-1,3-diones was designed by modification of cholinesterase inhibitors toward β-secretase inhibition. All target compounds have been synthesized and tested against eel acetylcholinesterase (eeAChE, equine serum butyrylcholinesterase (eqBuChE, human β-secretase (hBACE-1, and β-amyloid (Aβ-aggregation. The most promising compound, 12 (2-(5-(benzylamino-4-hydroxypentylisoindoline-1,3-dione, displayed inhibitory potency against eeAChE (IC50 = 3.33 μM, hBACE-1 (43.7% at 50 μM, and Aβ-aggregation (24.9% at 10 μM. Molecular modeling studies have revealed possible interaction of compound 12 with the active sites of both enzymes—acetylcholinesterase and β-secretase. In conclusion: modifications of acetylcholinesterase inhibitors led to the discovery of a multipotent anti-Alzheimer’s agent, with moderate and balanced potency, capable of inhibiting acetylcholinesterase, a symptomatic target, and disease-modifying targets: β-secretase and Aβ-aggregation.

Drug delivery from hydrophobic-modified mesoporous silicas: Control via modification level and site-selective modification

International Nuclear Information System (INIS)

Tang Qunli; Chen Yuxi; Chen Jianghua; Li Jin; Xu Yao; Wu Dong; Sun Yuhan

2010-01-01

Dimethylsilyl (DMS) modified mesoporous silicas were successfully prepared via co-condensation and post-grafting modification methods. The post-grafting modification was carried out by the reaction of the as-synthesized MCM-41 material (before CTAB removal) with diethoxydimethylsinale (DEDMS). N 2 adsorption-desorption and 29 Si MAS NMR characterization demonstrated that different amount of DMS groups were successfully incorporated into the co-condensation modified samples, and the functional DMS groups were placed selectively on the pore openings and external pore surfaces in the post-grafting modified samples. Subsequently, the controlled drug delivery properties from the resulting DMS-modified mesoporous silicas were investigated in detail. The drug adsorption experiments showed that the adsorption capacities were mainly depended on the content of silanol group (CSG) in the corresponding carriers. The in vitro tests exhibited that the incorporation of DMS groups greatly retarded the ibuprofen release rate. Moreover, the ibuprofen release profiles could be well modulated by varying DMS modification levels and site-selective distribution of functional groups in mesoporous carriers. - The distribution of DMS groups on the pore surfaces of the mesostructures strongly affects the drug release rate. The P-M41-1 and the P-M41-2 possess the close DMS modification levels as the C-M41-10, but the ibuprofen release rates from the P-M41-1 and P-M41-2 are much slower than that from the C-M41-10.

Allosteric regulation of epigenetic modifying enzymes.

Science.gov (United States)

Zucconi, Beth E; Cole, Philip A

2017-08-01

Epigenetic enzymes including histone modifying enzymes are key regulators of gene expression in normal and disease processes. Many drug development strategies to target histone modifying enzymes have focused on ligands that bind to enzyme active sites, but allosteric pockets offer potentially attractive opportunities for therapeutic development. Recent biochemical studies have revealed roles for small molecule and peptide ligands binding outside of the active sites in modulating the catalytic activities of histone modifying enzymes. Here we highlight several examples of allosteric regulation of epigenetic enzymes and discuss the biological significance of these findings. Copyright © 2017 Elsevier Ltd. All rights reserved.

Structural Genomics and Drug Discovery for Infectious Diseases

International Nuclear Information System (INIS)

Anderson, W.F.

2009-01-01

The application of structural genomics methods and approaches to proteins from organisms causing infectious diseases is making available the three dimensional structures of many proteins that are potential drug targets and laying the groundwork for structure aided drug discovery efforts. There are a number of structural genomics projects with a focus on pathogens that have been initiated worldwide. The Center for Structural Genomics of Infectious Diseases (CSGID) was recently established to apply state-of-the-art high throughput structural biology technologies to the characterization of proteins from the National Institute for Allergy and Infectious Diseases (NIAID) category A-C pathogens and organisms causing emerging, or re-emerging infectious diseases. The target selection process emphasizes potential biomedical benefits. Selected proteins include known drug targets and their homologs, essential enzymes, virulence factors and vaccine candidates. The Center also provides a structure determination service for the infectious disease scientific community. The ultimate goal is to generate a library of structures that are available to the scientific community and can serve as a starting point for further research and structure aided drug discovery for infectious diseases. To achieve this goal, the CSGID will determine protein crystal structures of 400 proteins and protein-ligand complexes using proven, rapid, highly integrated, and cost-effective methods for such determination, primarily by X-ray crystallography. High throughput crystallographic structure determination is greatly aided by frequent, convenient access to high-performance beamlines at third-generation synchrotron X-ray sources.

DR2DI: a powerful computational tool for predicting novel drug-disease associations

Science.gov (United States)

Lu, Lu; Yu, Hua

2018-05-01

Finding the new related candidate diseases for known drugs provides an effective method for fast-speed and low-risk drug development. However, experimental identification of drug-disease associations is expensive and time-consuming. This motivates the need for developing in silico computational methods that can infer true drug-disease pairs with high confidence. In this study, we presented a novel and powerful computational tool, DR2DI, for accurately uncovering the potential associations between drugs and diseases using high-dimensional and heterogeneous omics data as information sources. Based on a unified and extended similarity kernel framework, DR2DI inferred the unknown relationships between drugs and diseases using Regularized Kernel Classifier. Importantly, DR2DI employed a semi-supervised and global learning algorithm which can be applied to uncover the diseases (drugs) associated with known and novel drugs (diseases). In silico global validation experiments showed that DR2DI significantly outperforms recent two approaches for predicting drug-disease associations. Detailed case studies further demonstrated that the therapeutic indications and side effects of drugs predicted by DR2DI could be validated by existing database records and literature, suggesting that DR2DI can be served as a useful bioinformatic tool for identifying the potential drug-disease associations and guiding drug repositioning. Our software and comparison codes are freely available at https://github.com/huayu1111/DR2DI.

DR2DI: a powerful computational tool for predicting novel drug-disease associations

Science.gov (United States)

Lu, Lu; Yu, Hua

2018-04-01

Finding the new related candidate diseases for known drugs provides an effective method for fast-speed and low-risk drug development. However, experimental identification of drug-disease associations is expensive and time-consuming. This motivates the need for developing in silico computational methods that can infer true drug-disease pairs with high confidence. In this study, we presented a novel and powerful computational tool, DR2DI, for accurately uncovering the potential associations between drugs and diseases using high-dimensional and heterogeneous omics data as information sources. Based on a unified and extended similarity kernel framework, DR2DI inferred the unknown relationships between drugs and diseases using Regularized Kernel Classifier. Importantly, DR2DI employed a semi-supervised and global learning algorithm which can be applied to uncover the diseases (drugs) associated with known and novel drugs (diseases). In silico global validation experiments showed that DR2DI significantly outperforms recent two approaches for predicting drug-disease associations. Detailed case studies further demonstrated that the therapeutic indications and side effects of drugs predicted by DR2DI could be validated by existing database records and literature, suggesting that DR2DI can be served as a useful bioinformatic tool for identifying the potential drug-disease associations and guiding drug repositioning. Our software and comparison codes are freely available at https://github.com/huayu1111/DR2DI.

Development of Drug Loaded Nanoparticles Binding to Hydroxyapatite Based on a Bisphosphonate Modified Nonionic Surfactant

Directory of Open Access Journals (Sweden)

Jiabin Zhang

2015-01-01

Full Text Available This study aimed at development of drug loaded nanoparticles which could bind to hydroxyapatite (HA to construct drug or growth factor releasing bone graft substitutes. To this end, the terminal hydroxyl group of a nonionic surfactant Brij 78 (polyoxyethylene (20 stearyl ether was first modified with pamidronate (Pa. Using Pa-Brij 78 as both a surfactant and an affinity ligand to HA, three different Pa surface functionalized nanoparticles were prepared, named as solid lipid nanoparticles (Pa-SNPs, nanoemulsions (Pa-NEMs, and PLGA nanoparticles (Pa-PNPs. A model drug curcumin was successfully encapsulated in the three nanoparticles. The sizes of Pa-NEM and Pa-PNP were around 150 nm and the size of Pa-SNP was around 90 nm with polydispersity indexes (PDIs less than 0.20. Drug encapsulation efficiencies of the three nanoparticles were all greater than 85%. Furthermore, the order of binding affinity of the nanoparticles to HA was Pa-PNP>Pa-NEM=Pa-SNP. After lyophilization, the sizes of the three nanoparticles were increased about 0.5–2.0-fold but their binding affinities to HA were almost the same as the fresh prepared nanoparticles. In conclusion, a Pa-modified Brij 78 was synthesized and used for fabrication of a series of drug loaded nanoparticles to construct drug-eluting HA-based bone graft substitutes.

Biologic disease-modifying anti-rheumatic drugs and the risk of non-vertebral osteoporotic fractures in patients with rheumatoid arthritis aged 50 years and over.

Science.gov (United States)

Roussy, J-P; Bessette, L; Bernatsky, S; Rahme, E; Lachaine, J

2013-09-01

Prevention of bone mineral density loss in rheumatoid arthritis (RA) has been associated with use of biologic disease-modifying anti-rheumatic drugs (DMARDs). However, in this study, we could not demonstrate a reduction in the risk of non-vertebral fractures. Additional research is required to clarify the impact of biologic DMARDs on fracture risk in RA. Small studies have suggested biologic DMARDs preserve bone mineral density at 6-12 months. Our objective was to determine the association between biologic DMARD use and the risk of non-vertebral osteoporotic fractures in RA subjects aged ≥50 years. A nested case-control study was conducted using Quebec physician billing and hospital discharge data. RA subjects were identified from International Classification of Disease-9/10 codes in billing and hospitalisation data and followed from cohort entry until the earliest of non-vertebral osteoporotic fracture, death, or end of study period. Controls were matched to cases (4:1 ratio) on age, sex, and date of cohort entry. Biologic DMARD exposure was defined as being on treatment for ≥180 days pre-fracture (index). Conditional logistic regression was used, adjusting for indicators of RA severity, comorbidity, drugs influencing fracture risk, and measures of health care utilisation. Over the study period, 1,515 cases were identified (6,023 controls). The most frequent fracture site was hip/femur (42.3%). In total, 172 subjects (49 cases and 123 controls) were exposed to biologic DMARDs. The median duration of exposure was 735 (interquartile range (IQR), 564) and 645 (IQR, 903) days in cases and controls, respectively. We were unable to demonstrate an association between biologic DMARDs and fracture risk (odds ratio, 1.03; 95% confidence interval, 0.42-2.53). RA duration significantly increased the fracture risk. Despite the positive impact of biologic DMARDs on bone remodelling observed in small studies, we were unable to demonstrate a reduction in the risk of non

Public acceptance of drug use for non-disease conditions

DEFF Research Database (Denmark)

Møldrup, Claus; Hansen, Rikke Rie

2006-01-01

OBJECTIVE: This article deals with the issue of ordinary healthy people using drugs to improve or enhance non-disease conditions. The objective is to illuminate the extent of public acceptance of this practice. RESEARCH DESIGN AND METHODS: The results are based on two studies: a classically...... of drugs for non-disease conditions. Men in particular look favourably on the use of drugs by healthy individuals. People with less education find this type of drug use unacceptable to a greater extent than those with more education, who are more positive. If we look at political affiliation, a pattern...

A modifier of Huntington's disease onset at the MLH1 locus.

Science.gov (United States)

Lee, Jong-Min; Chao, Michael J; Harold, Denise; Abu Elneel, Kawther; Gillis, Tammy; Holmans, Peter; Jones, Lesley; Orth, Michael; Myers, Richard H; Kwak, Seung; Wheeler, Vanessa C; MacDonald, Marcy E; Gusella, James F

2017-10-01

Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by an expanded CAG repeat in HTT. Many clinical characteristics of HD such as age at motor onset are determined largely by the size of HTT CAG repeat. However, emerging evidence strongly supports a role for other genetic factors in modifying the disease pathogenesis driven by mutant huntingtin. A recent genome-wide association analysis to discover genetic modifiers of HD onset age provided initial evidence for modifier loci on chromosomes 8 and 15 and suggestive evidence for a locus on chromosome 3. Here, genotyping of candidate single nucleotide polymorphisms in a cohort of 3,314 additional HD subjects yields independent confirmation of the former two loci and moves the third to genome-wide significance at MLH1, a locus whose mouse orthologue modifies CAG length-dependent phenotypes in a Htt-knock-in mouse model of HD. Both quantitative and dichotomous association analyses implicate a functional variant on ∼32% of chromosomes with the beneficial modifier effect that delays HD motor onset by 0.7 years/allele. Genomic DNA capture and sequencing of a modifier haplotype localize the functional variation to a 78 kb region spanning the 3'end of MLH1 and the 5'end of the neighboring LRRFIP2, and marked by an isoleucine-valine missense variant in MLH1. Analysis of expression Quantitative Trait Loci (eQTLs) provides modest support for altered regulation of MLH1 and LRRFIP2, raising the possibility that the modifier affects regulation of both genes. Finally, polygenic modification score and heritability analyses suggest the existence of additional genetic modifiers, supporting expanded, comprehensive genetic analysis of larger HD datasets. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Regulation of drug-metabolizing enzymes in infectious and inflammatory disease: implications for biologics-small molecule drug interactions.

Science.gov (United States)

Mallick, Pankajini; Taneja, Guncha; Moorthy, Bhagavatula; Ghose, Romi

2017-06-01

Drug-metabolizing enzymes (DMEs) are primarily down-regulated during infectious and inflammatory diseases, leading to disruption in the metabolism of small molecule drugs (smds), which are increasingly being prescribed therapeutically in combination with biologics for a number of chronic diseases. The biologics may exert pro- or anti-inflammatory effect, which may in turn affect the expression/activity of DMEs. Thus, patients with infectious/inflammatory diseases undergoing biologic/smd treatment can have complex changes in DMEs due to combined effects of the disease and treatment. Areas covered: We will discuss clinical biologics-SMD interaction and regulation of DMEs during infection and inflammatory diseases. Mechanistic studies will be discussed and consequences on biologic-small molecule combination therapy on disease outcome due to changes in drug metabolism will be highlighted. Expert opinion: The involvement of immunomodulatory mediators in biologic-SMDs is well known. Regulatory guidelines recommend appropriate in vitro or in vivo assessments for possible interactions. The role of cytokines in biologic-SMDs has been documented. However, the mechanisms of drug-drug interactions is much more complex, and is probably multi-factorial. Studies aimed at understanding the mechanism by which biologics effect the DMEs during inflammation/infection are clinically important.

Unexpected exacerbations following initiation of disease-modifying drugs in neuromyelitis optica spectrum disorder: Which factor is responsible, anti-aquaporin 4 antibodies, B cells, Th1 cells, Th2 cells, Th17 cells, or others?

Science.gov (United States)

Kira, Jun-Ichi

2017-08-01

Some disease-modifying drugs for multiple sclerosis, which mainly act on T cells, are ineffective for neuromyelitis optica spectrum disorder and induce unexpected relapses. These include interferon beta, glatiramer acetate, fingolimod, natalizumab, and alemtuzumab. The cases reported here suggest that dimethyl fumarate, which reduces the number of Th1 and Th17 cells and induces IL-4-producing Th2 cells, is also unsuitable for neuromyelitis optica spectrum disorder, irrespective of anti-aquaporin 4 IgG serostatus. Although oral dimethyl fumarate with manageable adverse effects is easy to initiate in the early course of multiple sclerosis, special attention should be paid for atypical demyelinating cases.

Ultrasound-detected bone erosion is a relapse risk factor after discontinuation of biologic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis whose ultrasound power Doppler synovitis activity and clinical disease activity are well controlled.

Science.gov (United States)

Kawashiri, Shin-Ya; Fujikawa, Keita; Nishino, Ayako; Okada, Akitomo; Aramaki, Toshiyuki; Shimizu, Toshimasa; Umeda, Masataka; Fukui, Shoichi; Suzuki, Takahisa; Koga, Tomohiro; Iwamoto, Naoki; Ichinose, Kunihiro; Tamai, Mami; Mizokami, Akinari; Nakamura, Hideki; Origuchi, Tomoki; Ueki, Yukitaka; Aoyagi, Kiyoshi; Maeda, Takahiro; Kawakami, Atsushi

2017-05-25

In the present study, we explored the risk factors for relapse after discontinuation of biologic disease-modifying antirheumatic drug (bDMARD) therapy in patients with rheumatoid arthritis (RA) whose ultrasound power Doppler (PD) synovitis activity and clinical disease activity were well controlled. In this observational study in clinical practice, the inclusion criteria were based on ultrasound disease activity and clinical disease activity, set as low or remission (Disease Activity Score in 28 joints based on erythrocyte sedimentation rate Ultrasound was performed in 22 joints of bilateral hands at discontinuation for evaluating synovitis severity and presence of bone erosion. Patients with a maximum PD score ≤1 in each joint were enrolled. Forty patients with RA were consecutively recruited (November 2010-March 2015) and discontinued bDMARD therapy. Variables at the initiation and discontinuation of bDMARD therapy that were predictive of relapse during the 12 months after discontinuation were assessed. The median patient age was 54.5 years, and the median disease duration was 3.5 years. Nineteen (47.5%) patients relapsed during the 12 months after the discontinuation of bDMARD therapy. Logistic regression analysis revealed that only the presence of bone erosion detected by ultrasound at discontinuation was predictive of relapse (OR 8.35, 95% CI 1.78-53.2, p = 0.006). No clinical characteristics or serologic biomarkers were significantly different between the relapse and nonrelapse patients. The ultrasound synovitis scores did not differ significantly between the groups. Our findings are the first evidence that ultrasound bone erosion may be a relapse risk factor after the discontinuation of bDMARD therapy in patients with RA whose PD synovitis activity and clinical disease activity are well controlled.

[Development of anti-Alzheimer's disease drug based on beta-amyloid hypothesis].

Science.gov (United States)

Sugimoto, Hachiro

2010-04-01

Currently, there are five anti-Alzheimer's disease drugs approved. These are tacrine, donepezil, rivastigmine, galantamine, and memantine. The mechanism of the first four drugs is acetylcholinesterase inhibition, while memantine is an NMDA-receptor antagonist. However, these drugs do not cure Alzheimer's, but are only symptomatic treatments. Therefore, a cure for Alzheimer's disease is truly needed. Alzheimer's disease is a progressive neurodegenerative disease characterized by cognitive deficits. The cause of the disease is not well understood, but research indicates that the aggregation of beta-amyloid is the fundamental cause. This theory suggests that beta-amyloid aggregation causes neurotoxicity. Therefore, development of the next anti-Alzheimer's disease drug is based on the beta-amyloid theory. We are now studying natural products, such as mulberry leaf extracts and curcumin derivatives, as potential cure for Alzheimer's disease. In this report, we describe some data about these natural products and derivatives.

Health Technology Assessment Of Orphan Drugs : The example of Pompe disease

NARCIS (Netherlands)

T.A. Kanters (Tim A.)

2016-01-01

markdownabstractIn recent decades, the development of orphan drugs, i.e. drugs for rare diseases, is stimulated by regulations in various countries. However, the generally high prices of orphan drugs confront policy makers with difficult reimbursement decisions. The orphan disease investigated in

Fragment-based drug discovery as alternative strategy to the drug development for neglected diseases.

Science.gov (United States)

Mello, Juliana da Fonseca Rezende E; Gomes, Renan Augusto; Vital-Fujii, Drielli Gomes; Ferreira, Glaucio Monteiro; Trossini, Gustavo Henrique Goulart

2017-12-01

Neglected diseases (NDs) affect large populations and almost whole continents, representing 12% of the global health burden. In contrast, the treatment available today is limited and sometimes ineffective. Under this scenery, the Fragment-Based Drug Discovery emerged as one of the most promising alternatives to the traditional methods of drug development. This method allows achieving new lead compounds with smaller size of fragment libraries. Even with the wide Fragment-Based Drug Discovery success resulting in new effective therapeutic agents against different diseases, until this moment few studies have been applied this approach for NDs area. In this article, we discuss the basic Fragment-Based Drug Discovery process, brief successful ideas of general applications and show a landscape of its use in NDs, encouraging the implementation of this strategy as an interesting way to optimize the development of new drugs to NDs. © 2017 John Wiley & Sons A/S.

Distribution of Podoplanin in Synovial Tissues in Rheumatoid Arthritis Patients Using Biologic or Conventional Disease-Modifying Anti-Rheumatic Drugs.

Science.gov (United States)

Takakubo, Yuya; Oki, Hiroharu; Naganuma, Yasushi; Saski, Kan; Sasaki, Akiko; Tamaki, Yasunobu; Suran, Yang; Konta, Tsuneo; Takagi, Michiaki

2017-01-01

Podoplanin (PDPN) mediates tumor cell migration and invasion, which phenomena might also play a role in severe rheumatoid arthritis (RA). Therefore, the precise cellular distribution of PDPN and it's relationships with inflammation was studied in RA treated with biologic disease-modifying anti-rheumatic drugs (DMARD) or conventional DMARDs (cDMARD). PDPN+ cells were immunostained by NZ-1 mAb, and scored (3+; >50%/ area, 2+; 20%- 50%, 1+; 5%-20%, 0: <5%) in synovial tissues from RA treated with biologic DMARDs (BIO, n=20) or cDMARD (n=20) for comparison with osteoarthritis (OA, n=5), followed by cell grading of inflammation and cell-typing. Inflammatory synovitis score was 1.4 in both BIO and cDMARD, compared to only 0.2 in OA. PDPN+ cells were found in the lining layer (BIO 1.6, cDMARD 1.3, OA 0.2) and lymphoid aggregates (BIO 0.6, cDMRD 0.7, OA 0.2), and correlated with RA-inflammation in BIO- and cDMARD-groups in both area (r=0.7/0.9, r=0.6/0.7, respectively p<0.05). PDPN was expressed in CD68+ type A macrophage-like and 5B5+ type B fibroblast-like cells in the lining layer, and in IL- 17+ cells in lymphoid aggregates in RA. PDPN was markedly increased in the immunologically inflamed RA synovitis, which was surgically treated due to BIO- and cDMARD-resistant RA. PDPN may have potential of a new marker of residual arthritis in local joints for inflammation-associated severe RA. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Comparison of preferences of healthcare professionals and MS patients for attributes of disease-modifying drugs: A best-worst scaling.

Science.gov (United States)

Kremer, Ingrid E H; Evers, Silvia M A A; Jongen, Peter J; Hiligsmann, Mickaël

2018-02-01

The choice between disease-modifying drugs (DMDs) for the treatment of multiple sclerosis (MS) becomes more often a shared decision between the patient and the neurologist and MS nurse. This study aimed to assess which DMD attributes are most important for the healthcare professionals in selecting a DMD for a patient. Subsequently, within this perspective, the neurologists' and nurses' perspectives were compared. Lastly, the healthcare professionals' perspective was compared with the patients' perspective to detect any differences that may need attention in the communication about DMDs. A best-worst scaling (BWS) was conducted among 27 neurologists and 33 MS nurses treating patients with MS to determine the importance of 27 DMD attributes. These attributes were identified through three focus groups with MS patients in a previous study (N=19). Relative importance scores (RISs) were estimated for each attribute. Multivariable linear regression analyses were used to compare the different perspectives. According to the neurologists and nurses, safety of the DMD was the most important DMD attribute in the treatment decision, closely followed by effect on disability progression, quality of life and relapse rate. Patients with MS agreed with the importance of the last three attributes, but valued safety significantly lower (b=-2.59, P<.001). This study suggests that, overall, neurologists and nurses regard the same DMD attributes as important as MS patients with the notable exception of safety. This study provides valuable information for the development of interventions to support shared decision making and highlights which attributes of DMDs may need additional attention. © 2017 The Authors Health Expectations Published by John Wiley & Sons Ltd.

Advanced and controlled drug delivery systems in clinical disease management

NARCIS (Netherlands)

Brouwers, JRBJ

1996-01-01

Advanced and controlled drug delivery systems are important for clinical disease management. In this review the most important new systems which have reached clinical application are highlighted. Microbiologically controlled drug delivery is important for gastrointestinal diseases like ulcerative

[Non steroidal anti-inflammatory drugs and rheumatic diseases].

Science.gov (United States)

Cossermelli, W; Pastor, E H

1995-01-01

Nonsteroidal anti-inflammatory drugs (NSAID) comprise an important class of medicaments that reduced the symptoms of inflamation in rheumatic disease. This article emphasizes similarities and class characteristics of the NSAID, mechanisms of action, and drug-interactions.

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

Science.gov (United States)

2013-04-11

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

Pharmacological approaches for Alzheimer's disease: neurotransmitter as drug targets.

Science.gov (United States)

Prakash, Atish; Kalra, Jaspreet; Mani, Vasudevan; Ramasamy, Kalavathy; Majeed, Abu Bakar Abdul

2015-01-01

Alzheimer's disease (AD) is the most common CNS disorder occurring worldwide. There is neither proven effective prevention for AD nor a cure for patients with this disorder. Hence, there is an urgent need to develop safer and more efficacious drugs to help combat the tremendous increase in disease progression. The present review is an attempt at discussing the treatment strategies and drugs under clinical trials governing the modulation of neurotransmitter. Therefore, looking at neurotransmitter abnormalities, there is an urge for developing the pharmacological approaches aimed at correcting those abnormalities and dysfunctioning. In addition, this review also discusses the drugs that are in Phase III trials for the treatment of AD. Despite advances in treatment strategies aimed at correcting neurotransmitter abnormalities, there exists a need for the development of drug therapies focusing on the attempts to remove the pathogenomic protein deposits, thus combating the disease progression.

Investigation of Fatty Acid Ketohydrazone Modified Liposome’s Properties as a Drug Carrier

Directory of Open Access Journals (Sweden)

Keita Hayashi

2015-01-01

Full Text Available pH-responsive liposomes were prepared by modifying the liposome with acid-cleaving amphiphiles. Palmitic ketohydrazone (P-KH or stearic ketohydrazone (S-KH, composed of hydrophilic sugar headgroup and hydrophobic acyl chain, was used as a modifier of the DMPC liposome. Because the ketohydrazone group of P-KH or S-KH was cleaved at low pH conditions (modified liposomes was observed probably via an endocytic pathway. The membrane properties of these liposomes were characterized, focusing on the variation of both polarity (measured by Laurdan and membrane fluidity (measured by DPH at low pH condition. The interface of the P-KH modified liposome at acidic pH was found to become more hydrophobic and less fluidic as compared with that at neutral pH; that is, P-KH modified liposome became more rigid structure. Therefore, it seems that the P-KH modified liposome could protect encapsulated drugs from the enzymes in the lysosome. This study shows the novel approach about design of pH-responsive liposomes based on the membrane properties.

Structural genomics of infectious disease drug targets: the SSGCID

International Nuclear Information System (INIS)

Stacy, Robin; Begley, Darren W.; Phan, Isabelle; Staker, Bart L.; Van Voorhis, Wesley C.; Varani, Gabriele; Buchko, Garry W.; Stewart, Lance J.; Myler, Peter J.

2011-01-01

An introduction and overview of the focus, goals and overall mission of the Seattle Structural Genomics Center for Infectious Disease (SSGCID) is given. The Seattle Structural Genomics Center for Infectious Disease (SSGCID) is a consortium of researchers at Seattle BioMed, Emerald BioStructures, the University of Washington and Pacific Northwest National Laboratory that was established to apply structural genomics approaches to drug targets from infectious disease organisms. The SSGCID is currently funded over a five-year period by the National Institute of Allergy and Infectious Diseases (NIAID) to determine the three-dimensional structures of 400 proteins from a variety of Category A, B and C pathogens. Target selection engages the infectious disease research and drug-therapy communities to identify drug targets, essential enzymes, virulence factors and vaccine candidates of biomedical relevance to combat infectious diseases. The protein-expression systems, purified proteins, ligand screens and three-dimensional structures produced by SSGCID constitute a valuable resource for drug-discovery research, all of which is made freely available to the greater scientific community. This issue of Acta Crystallographica Section F, entirely devoted to the work of the SSGCID, covers the details of the high-throughput pipeline and presents a series of structures from a broad array of pathogenic organisms. Here, a background is provided on the structural genomics of infectious disease, the essential components of the SSGCID pipeline are discussed and a survey of progress to date is presented

An Evidence-Based Assessment of the Clinical Significance of Drug-Drug Interactions Between Disease-Modifying Antirheumatic Drugs and Non-Antirheumatic Drugs According to Rheumatologists and Pharmacists

NARCIS (Netherlands)

van Roon, Eric N.; van den Bemt, Patricia M. L. A.; Jansen, Tim L. Th. A.; Houtman, Nella M.; van de Laar, Mart A. F. J.; Brouwers, Jacobus R. B. J.

Background: Clinically relevant drug-drug interactions (DDIs) must be recognized in a timely manner and managed appropriately to prevent adverse drug reactions or therapeutic failure. Because the evidence for most DDIs is based on case reports or poorly documented clinical information, there is a

Drug dosing in chronic kidney disease.

Science.gov (United States)

Gabardi, Steven; Abramson, Stuart

2005-05-01

Patients with chronic kidney disease (CKD) are at high risk for adverse drug reactions and drug-drug interactions. Drug dosing in these patients often proves to be a difficult task. Renal dysfunction-induced changes in human pathophysiology regularly results may alter medication pharmacodynamics and handling. Several pharmacokinetic parameters are adversely affected by CKD, secondary to a reduced oral absorption and glomerular filtration; altered tubular secretion; and reabsorption and changes in intestinal, hepatic, and renal metabolism. In general, drug dosing can be accomplished by multiple methods; however, the most common recommendations are often to reduce the dose or expand the dosing interval, or use both methods simultaneously. Some medications need to be avoided all together in CKD either because of lack of efficacy or increased risk of toxicity. Nevertheless, specific recommendations are available for dosing of certain medications and are an important resource, because most are based on clinical or pharmacokinetic trials.

Improving drug delivery technology for treating neurodegenerative diseases.

Science.gov (United States)

Choonara, Yahya E; Kumar, Pradeep; Modi, Girish; Pillay, Viness

2016-07-01

Neurodegenerative diseases (NDs) represent intricate challenges for efficient uptake and transport of drugs to the brain mainly due to the restrictive blood-brain barrier (BBB). NDs are characterized by the loss of neuronal subtypes as sporadic and/or familial and several mechanisms of neurodegeneration have been identified. This review attempts to recap, organize and concisely evaluate the advanced drug delivery systems designed for treating common NDs. It highlights key research gaps and opinionates on new neurotherapies to overcome the BBB as an addition to the current treatments of countering oxidative stress, inflammation and apoptotic mechanisms. Current treatments do not fully address the biological, drug and therapeutic factors faced. This has led to the development of vogue treatments such as nose-to-brain technologies, bio-engineered systems, fusion protein chaperones, stem cells, gene therapy, use of natural compounds, neuroprotectants and even vaccines. However, failure of these treatments is mainly due to the BBB and non-specific delivery in the brain. In order to increase neuroavailability various advanced drug delivery systems provide promising alternatives that are able to augment the treatment of Alzheimer's disease and Parkinson's disease. However, much work is still required in this field beyond the preclinical testing phase.

In silico studies in drug research against neurodegenerative diseases.

Science.gov (United States)

Makhouri, Farahnaz Rezaei; Ghasemi, Jahan B

2017-08-22

Neurodegenerative diseases such as Alzheimer's disease (AD), progressive neurodegenerative forms of Huntington's disease, Parkinson's disease (PD), amyotrophic lateral sclerosis, spinal cerebellar ataxias, and spinal and bulbar muscular atrophy are described by slow and selective dysfunction and degeneration of neurons and axons in the central nervous system (CNS). Computer-aided or in silico design methods have matured into powerful tools for reducing the number of ligands that should be screened in experimental assays. In the present review, the authors provide a basic background about neurodegenerative diseases and in silico techniques in the drug research. Furthermore, they review the various in silico studies reported against various targets in neurodegenerative diseases, including homology modeling, molecular docking, virtual high-throughput screening, quantitative structure activity relationship (QSAR), hologram quantitative structure activity relationship (HQSAR), 3D pharmacophore mapping, proteochemometrics modeling (PCM), fingerprints, fragment-based drug discovery, Monte Carlo simulation, molecular dynamic (MD) simulation, quantum-mechanical methods for drug design, support vector machines, and machine learning approaches. Neurodegenerative diseases have a multifactorial pathoetiological origin, so scientists have become persuaded that a multi-target therapeutic strategy aimed at the simultaneous targeting of multiple proteins (and therefore etiologies) involved in the development of a disease is recommended in future. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Beyond the neurotransmitter-focused approach in treating Alzheimer's disease: drugs targeting beta-amyloid and tau protein.

Science.gov (United States)

Panza, Francesco; Solfrizzi, Vincenzo; Frisardi, Vincenza; Imbimbo, Bruno P; Capurso, Cristiano; D'Introno, Alessia; Colacicco, Anna M; Seripa, Davide; Vendemiale, Gianluigi; Capurso, Antonio; Pilotto, Alberto

2009-12-01

Drugs currently used to treat Alzheimer's Disease (AD) have limited therapeutic value and do not affect the main neuropathological hallmarks of the disease, i.e., senile plaques and neurofibrillar tangles. Senile plaques are mainly formed of beta-amyloid (Abeta), a 42-aminoacid peptide. Neurofibrillar tangles are composed of paired helical filaments of hyperphosphorylated tau protein. New, potentially disease-modifying, therapeutic approaches are targeting Abeta and tau protein. Drugs directed against Abeta include active and passive immunization, that have been found to accelerate Abeta clearance from the brain. The most developmentally advanced monoclonal antibody directly targeting Abeta is bapineuzumab, now being studied in a large Phase III clinical trial. Compounds that interfere with proteases regulating Abeta formation from amyloid precursor protein (APP) are also actively pursued. The discovery of inhibitors of beta-secretase, the enzyme that regulates the first step of the amyloidogenic metabolism of APP, has been revealed to be particularly difficult due to inherent medicinal chemistry problems, and only one compound (CTS-21166) has reached clinical testing. Conversely, several compounds that inhibit gamma-secretase, the pivotal enzyme that generates Abeta, have been identified, the most advanced being LY-450139 (semagacestat), now in Phase III clinical development. Compounds that stimulate alpha-secretase, the enzyme responsible for the non-amyloidogenic metabolism of APP, are also being developed, and one of them, EHT-0202, has recently entered Phase II testing. Potent inhibitors of Abeta aggregation have also been identified, and one of such compounds, PBT-2, has provided encouraging neuropsychological results in a recently completed Phase II study. Therapeutic approaches directed against tau protein include inhibitors of glycogen synthase kinase- 3 (GSK-3), the enzyme responsible for tau phosphorylation and tau protein aggregation inhibitors. NP-12

Quantity and economic value of unused oral anti-cancer and biological disease-modifying anti-rheumatic drugs among outpatient pharmacy patients who discontinue therapy.

Science.gov (United States)

Bekker, C L; Melis, E J; Egberts, A C G; Bouvy, M L; Gardarsdottir, H; van den Bemt, B J F

2018-03-24

Patients sometimes discontinue the use of expensive oral anti-cancer drug (OACD) or biological disease-modifying anti-rheumatic drug (bDMARD) therapies early, leading to medication waste if the patient has not used all dispensed medication. To determine the proportion of patients who have unused OACDs or bDMARDs after therapy discontinuation, and the quantity and economic value of these unused medications. Furthermore, patients' reasons for therapy discontinuation and their disposal method for unused medications were determined. In a retrospective follow-up study using a Dutch outpatient pharmacy database, patients (≥18 years) who did not refill an OACD or bDMARD prescription, dispensed between November 2015 and February 2016, within two weeks of the prescription end date were contacted by phone and asked about their unused medication and reasons thereof. The economic value was calculated using Dutch medication prices. Data were descriptively analyzed in STATA13. The database included 1173 patients, of whom 159 likely had discontinued therapy and were contacted. Of these, 88 patients were excluded (39 refilled, 47 missing, and 2 other). Of the 71 patients who had discontinued therapy, 39 (54.9%) had unused medications, comprising 22 OACD users (mean age 63.0 (SD ± 15.9) years, 50.0% female) and 17 bDMARD users (mean age 50.7 (SD ± 13.5) years, 47.1% female). A total of 59 packages were unused, with a total value of €60,341. Unused OACD packages and bDMARD packages had median values of €179 (IQR €24-2487) and €992 (IQR €681-1093), respectively. Patients primarily discontinued therapy due to adverse or insufficient effects. This study illustrates that more than half of patients discontinuing OACD or bDMARD therapies have unused medication. This emphasizes the need for waste-reducing interventions. Copyright © 2018 Elsevier Inc. All rights reserved.

Advanced Therapeutic Strategies for Chronic Lung Disease Using Nanoparticle-Based Drug Delivery

Directory of Open Access Journals (Sweden)

Ji Young Yhee

2016-09-01

Full Text Available Chronic lung diseases include a variety of obstinate and fatal diseases, including asthma, chronic obstructive pulmonary disease (COPD, cystic fibrosis (CF, idiopathic pulmonary fibrosis (IPF, and lung cancers. Pharmacotherapy is important for the treatment of chronic lung diseases, and current progress in nanoparticles offers great potential as an advanced strategy for drug delivery. Based on their biophysical properties, nanoparticles have shown improved pharmacokinetics of therapeutics and controlled drug delivery, gaining great attention. Herein, we will review the nanoparticle-based drug delivery system for the treatment of chronic lung diseases. Various types of nanoparticles will be introduced, and recent innovative efforts to utilize the nanoparticles as novel drug carriers for the effective treatment of chronic lung diseases will also be discussed.

Drug: D08521 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available D08521 Drug Sodium aurothiosulfate (INN); Gold sodium thiosulfate, dihydrate; Cryt...ioro (TN) ... AuS4O6. 3Na. 2H2O D08521.gif ... Anti-inflammatory ... DG01912 ... Gold preparations ... DG01985 ... Disease m...odifying anti-rheumatic drugs (DMARDs) ... DG01912 ... Gold preparations ATC code: M01CB02 ... Gold preparation ... CAS: 10210-36-3 PubChem: 96025206 ChEMBL: CHEMBL3833379 ...

The effect of tofacitinib on function and quality of life indicators in patients with rheumatoid arthritis resistant to synthetic and biological disease-modifying antirheumatic drugs in real clinical practice: Results of a multicenter observational study

Directory of Open Access Journals (Sweden)

D. E. Karateev

2017-01-01

Full Text Available Tofacitinib (TOFA, a representative of a new class of targeted synthetic disease-modifying antirheumatic drugs (s-DMARD, is a promising drug for treating rheumatoid arthritis (RA and other immune inflammatory diseases.Objective: to evaluate the efficiency and safety of therapy with TOFA in combination with methotrexate (MTX and other s-DMARDs in real clinical practice in patients with active RA and previous ineffective therapy.Patients and methods. A 6-month Russian multicenter study of function and quality of life enrolled 101 patients with resistant RA: 18 men and 83 women; mean age, 51.03±11.28 years; mean disease duration, 105.4±81.43 months; rheumatoid factor-positive individuals (89.1%; and anticyclic citrullinated peptide antibody-positive ones (74.7%. 93 (92,1% of these patients completed a 24-week study. TOFA was used as both second-line drug (after failure of therapy with s-DMARD (n=74 and as a third-line drug (after failure of therapy with s-DMARDs and biological agents (BAs (n=74. The tools RAPID3, HAQ, and EQ-5D were used to determine disease outcomes from a patient's assessment.Results. All the three tools demonstrated significant positive changes at 3–6 months following therapy initiation. RAPID3 scores for the status of a patient achieving a low disease activity or remission coincided with the mean DAS28-ESR and SDAI scores in 60% and 68% of cases, respectively. The achievement rates of the minimally clinically significant improvement (ΔHAQ≥0.22 and functional remission (HAQ≤0.5 at 6 months of TOFA therapy were 79.6 and 30.1%, respectively. The mean change value in EQ-5D scores over 6 months was -0.162±0.21. There were no significant between the groups of patients who used TOFA as a second- or third-line agent in the majority of indicators, except EQ-5D scores at 6 months.Conclusions. The results of our multicenter study using considerable Russian material confirmed the pronounced positive effect of TOFA used

Providing patients with information about disease-modifying anti-rheumatic drugs: Individually or in groups? A pilot randomized controlled trial comparing adherence and satisfaction.

Science.gov (United States)

Homer, Dawn; Nightingale, Peter; Jobanputra, Paresh

2009-06-01

Communicating information about disease-modifying anti-rheumatic drugs (DMARDs) before patients start treatment is a key role for some rheumatology clinical nurse specialists. This is done in our unit to promote understanding of the risks and benefits of drug therapy and encourage timely and reliable use of DMARDs. Information is routinely provided individually but this can lead to delays in starting treatment because of limited nursing resources. In this randomized trial we tested the feasibility of giving patients, who were about to start on a DMARD, information about the drug in groups and compared this with information given individually. Adults with a clinical diagnosis of rheumatoid arthritis or psoriatic arthritis who were referred to the nursing team for counselling about starting on methotrexate, sulfasalazine or leflunomide were included. Patients who had previously taken a DMARD were not excluded and those consenting were randomized to receive drug information individually or in groups (of three to six patients). We provided all patients with written materials about the relevant drug and discussed the risks and benefits of drug use verbally. Patients allocated to group counselling received this intervention in a teaching room, with a slide presentation. The primary outcome was adherence with medication use, ascertained by pill counts, self-report diaries and prescription dispensation. Secondary outcomes included satisfaction with information about medicines (SIMS) by questionnaire; time taken to provide information; adherence to scheduled hospital appointments and blood monitoring schedules; and DMARD continuation rates at four and twelve months. Of 127 eligible patients referred for counselling about DMARDs, 62 consented to take part: 32 were randomized to receive drug information individually and 30 to receiving it in groups. Patients allocated to the two different interventions were comparable for age and diagnoses at baseline but more patients

Chronotherapeutic drug delivery systems: an approach to circadian rhythms diseases.

Science.gov (United States)

Sunil, S A; Srikanth, M V; Rao, N Sreenivasa; Uhumwangho, M U; Latha, K; Murthy, K V Ramana

2011-11-01

The purpose of writing this review on chronotherapeutic drug delivery systems (ChrDDs) is to review the literatures with special focus on ChrDDs and the various dosage forms, techniques that are used to target the circadian rhythms (CR) of various diseases. Many functions of the human body vary considerably in a day. ChrDDs refers to a treatment method in which in vivo drug availability is timed to match circadian rhythms of disease in order to optimize therapeutic outcomes and minimize side effects. Several techniques have been developed but not many dosage forms for all the diseases are available in the market. ChrDDs are gaining importance in the field of pharmaceutical technology as these systems reduce dosing frequency, toxicity and deliver the drug that matches the CR of that particular disease when the symptoms are maximum to worse. Finally, the ultimate benefit goes to the patient due the compliance and convenience of the dosage form. Some diseases that follow circadian rhythms include cardiovascular diseases, asthma, arthritis, ulcers, diabetes etc. ChrDDs in the market were also discussed and the current technologies used to formulate were also stated. These technologies include Contin® , Chronotopic®, Pulsincaps®, Ceform®, Timerx®, Oros®, Codas®, Diffucaps®, Egalet®, Tablet in capsule device, Core-in-cup tablet technology. A coated drug-core tablet matrix, A bi-layered tablet, Multiparticulate-based chronotherapeutic drug delivery systems, Chronoset and Controlled release microchips.

Design and Synthesis of Epigenetic Drugs

DEFF Research Database (Denmark)

Leurs, Ulrike

2014-01-01

of histone- and DNA-modifying enzymes can lead to the development of diseases such as cancer. The histone demethylases of the KDM4 family have been implicated in a wide range of diseases, and are hence important drug targets. KDM4s belong to the bigger family of 2-OG oxygenases, an enzyme class sharing high...

Nanocarrier mediated retinal drug delivery: overcoming ocular barriers to treat posterior eye diseases.

Science.gov (United States)

Bisht, Rohit; Mandal, Abhirup; Jaiswal, Jagdish K; Rupenthal, Ilva D

2018-03-01

Effective drug delivery to the retina still remains a challenge due to ocular elimination mechanisms and complex barriers that selectively limit the entry of drugs into the eye. To overcome these barriers, frequent intravitreal injections are currently used to achieve high drug concentrations in vitreous and retina. However, these repetitive injections may result in several side effects. Recent advancements in the field of nanoparticle-based drug delivery could overcome some of these unmet needs and various preclinical studies conducted to date have demonstrated promising results of nanotherapies in the treatment of retinal diseases. Compared to the majority of commercially available ocular implants, the biodegradable nature of most nanoparticles (NPs) avoids the need for surgical implantation and removal after the release of the payload. In addition, the sustained drug release from NPs over an extended period of time reduces the need for frequent intravitreal injections and the risk of associated side effects. The nanometer size and highly modifiable surface properties make NPs excellent candidates for targeted ocular drug delivery. Studies have shown that nanocarriers enhance the intravitreal half-life and thus bioavailability of a number of drugs including proteins and peptides. In addition, they have shown promising results in delivering genetic material to the retinal tissues by protecting it from possible intravitreal degradation. This review covers the various challenges associated with drug delivery to the posterior segment of the eye, particularly the retina, and highlights the application of nanocarriers to overcome these challenges in context with recent advances in preclinical studies. WIREs Nanomed Nanobiotechnol 2018, 10:e1473. doi: 10.1002/wnan.1473 This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Implantable Materials and Surgical Technologies > Nanomaterials and Implants. © 2017 Wiley Periodicals

The effect of comedication with conventional synthetic disease modifying antirheumatic drugs on TNF inhibitor drug survival in patients with ankylosing spondylitis and undifferentiated spondyloarthritis

DEFF Research Database (Denmark)

Lie, Elisabeth; Kristensen, Lars Erik; Forsblad-d'Elia, Helena

2015-01-01

on patients with a clinical diagnosis of AS or uSpA starting treatment with adalimumab, etanercept or infliximab as their first TNFi during 2003-2010 were retrieved from the Swedish national biologics register and linked to national population based registers. Five-year drug survival was analysed by Cox......, and the associations were retained when adjusting for erythrocyte sedimentation rate, C-reactive protein, patient global, swollen joints, uveitis, psoriasis and inflammatory bowel disease. CONCLUSIONS: In this large register study of patients with AS and uSpA, use of csDMARD comedication was associated with better 5...

Potential of chromatin modifying compounds for the treatment of Alzheimer's disease.

Science.gov (United States)

Karagiannis, Tom C; Ververis, Katherine

2012-01-01

Alzheimer's disease is a very common progressive neurodegenerative disorder affecting the learning and memory centers in the brain. The hallmarks of disease are the accumulation of β-amyloid neuritic plaques and neurofibrillary tangles formed by abnormally phosphorylated tau protein. Alzheimer's disease is currently incurable and there is an intense interest in the development of new potential therapies. Chromatin modifying compounds such as sirtuin modulators and histone deacetylase inhibitors have been evaluated in models of Alzheimer's disease with some promising results. For example, the natural antioxidant and sirtuin 1 activator resveratrol has been shown to have beneficial effects in animal models of disease. Similarly, numerous histone deacetylase inhibitors including Trichostatin A, suberoylanilide hydroxamic acid, valproic acid and phenylbutyrate reduction have shown promising results in models of Alzheimer's disease. These beneficial effects include a reduction of β-amyloid production and stabilization of tau protein. In this review we provide an overview of the histone deacetylase enzymes, with a focus on enzymes that have been identified to have an important role in the pathobiology of Alzheimer's disease. Further, we discuss the potential for pharmacological intervention with chromatin modifying compounds that modulate histone deacetylase enzymes.

Potential of chromatin modifying compounds for the treatment of Alzheimer's disease

Directory of Open Access Journals (Sweden)

Tom C. Karagiannis

2012-02-01

Full Text Available Alzheimer's disease is a very common progressive neurodegenerative disorder affecting the learning and memory centers in the brain. The hallmarks of disease are the accumulation of β-amyloid neuritic plaques and neurofibrillary tangles formed by abnormally phosphorylated tau protein. Alzheimer's disease is currently incurable and there is an intense interest in the development of new potential therapies. Chromatin modifying compounds such as sirtuin modulators and histone deacetylase inhibitors have been evaluated in models of Alzheimer's disease with some promising results. For example, the natural antioxidant and sirtuin 1 activator resveratrol has been shown to have beneficial effects in animal models of disease. Similarly, numerous histone deacetylase inhibitors including Trichostatin A, suberoylanilide hydroxamic acid, valproic acid and phenylbutyrate reduction have shown promising results in models of Alzheimer's disease. These beneficial effects include a reduction of β-amyloid production and stabilization of tau protein. In this review we provide an overview of the histone deacetylase enzymes, with a focus on enzymes that have been identified to have an important role in the pathobiology of Alzheimer's disease. Further, we discuss the potential for pharmacological intervention with chromatin modifying compounds that modulate histone deacetylase enzymes.

Emerging drugs for gastroesophageal reflux disease

NARCIS (Netherlands)

Boeckxstaens, G. E.

2009-01-01

Proton pump inhibitors (PPIs) are very effective and safe drugs for the treatment of erosive and non-erosive gastroesophageal reflux disease (GERD). Nevertheless, a significant proportion of GERD patients (30 - 40%) continue to suffer from symptoms during PPI treatment, which has stimulated the

Demographic, genetic, and environmental factors that modify disease course.

Science.gov (United States)

Marrie, Ruth Ann

2011-05-01

As with susceptibility to disease, it is likely that multiple factors interact to influence the phenotype of multiple sclerosis and long-term disease outcomes. Such factors may include genetic factors, socioeconomic status, comorbid diseases, and health behaviors, as well as environmental exposures. An improved understanding of the influence of these factors on disease course may reap several benefits, such as improved prognostication, allowing us to tailor disease management with respect to intensity of disease-modifying therapies and changes in specific health behaviors, in the broad context of coexisting health issues. Such information can facilitate appropriately adjusted comparisons within and between populations. Elucidation of these factors will require careful study of well-characterized populations in which the roles of multiple factors are considered simultaneously. Copyright © 2011 Elsevier Inc. All rights reserved.

Development and validation of modified disease activity scores in rheumatoid arthritis

DEFF Research Database (Denmark)

Baker, Joshua F; Conaghan, Philip G; Smolen, Josef S

2014-01-01

-CDAI) were generated for each subject in the validation cohort. The M-DAS28, M-SDAI, and M-CDAI scores were compared to conventional scores of disease activity with regard to associations with MRI measures of synovitis and radiographic progression, assessed using Pearson's and Spearman's correlations, linear......OBJECTIVE: To develop and validate composite disease activity scores, based on widely available clinical measures, that would demonstrate improved correlation with detection of synovitis on magnetic resonance imaging (MRI) and radiographic progression, in comparison with conventional measures.......15 × SJC28 + 0.22 × EvGA + 1 and M-SDAI = CRP + SJC28 + EvGA. Both modified and conventional disease activity scores correlated significantly with MRI measures of synovitis. Modified scores showed superior correlation with synovitis, as compared to conventional scores, at all time points (P

Repurposing of Copper(II)-chelating Drugs for the Treatment of Neurodegenerative Diseases.

Science.gov (United States)

Lanza, Valeria; Milardi, Danilo; Di Natale, Giuseppe; Pappalardo, Giuseppe

2018-02-12

There is mounting urgency to find new drugs for the treatment of neurodegenerative disorders. A large number of reviews have exhaustively described either the molecular or clinical aspects of neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's (PD). Conversely, reports outlining how known drugs in use for other diseases can also be effective as therapeutic agents in neurodegenerative diseases are less reported. This review focuses on the current uses of some copper(II) chelating molecules as potential drug candidates in neurodegeneration. Starting from the well-known harmful relationships existing between the dyshomeostasis and mis-management of metals and AD onset, we surveyed the experimental work reported in the literature, which deals with the repositioning of metal-chelating drugs in the field of neurodegenerative diseases. The reviewed papers were retrieved from common literature and their selection was limited to those describing the biomolecular aspects associated with neuroprotection. In particular, we emphasized the copper(II) coordination abilities of the selected drugs. Copper, together with zinc and iron, are known to play a key role in regulating neuronal functions. Changes in copper homeostasis are crucial for several neurodegenerative disorders. The studies included in this review may provide an overview on the current strategies aimed at repurposing copper (II) chelating drugs for the treatment of neurodegenerative disorders. Starting from the exemplary case of clioquinol repurposing, we discuss the challenge and the opportunities that repurposing of other metal-chelating drugs may provide (e.g. PBT-2, metformin and cyclodipeptides) in the treatment of neurodegenerative disease. In order to improve the success rate of drug repositioning, comprehensive studies on the molecular mechanism and therapeutic efficacy are still required. The present review upholds that drug repurposing makes significant advantages over drug discovery since

Disease-modifying anti-rheumatic drugs til behandling af ankyloserende spondylitis

DEFF Research Database (Denmark)

Madsen, Ole Rintek; Egsmose, Charlotte

2009-01-01

Ankylosing spondylitis (AS) is an inflammatory disorder affecting the axial skeleton, peripheral joints, entheses and extra-articular sites. Patients with early disease, a higher level of erythrocyte sedimentation rate and/or peripheral arthritis might benefit from sulfasalazine. Otherwise...

Efficacy and safety of golimumab as add-on therapy to disease-modifying antirheumatic drugs in rheumatoid arthritis: results of the GO-MORE study in Spain.

Science.gov (United States)

Alonso, Alberto; González, Carlos M; Ballina, Javier; García Vivar, María L; Gómez-Reino, Juan J; Marenco, Jose Luis; Fernández-Nebro, Antonio; Ordás, Carmen; Cea-Calvo, Luis; Arteaga, María J; Sanmartí, Raimon

2015-01-01

To assess the efficacy and safety of golimumab in the 140 patients included in Spain as the first part of the GO-MORE trial, a multinational study involving patients with active rheumatoid arthritis (RA) despite treatment with different disease-modifying antirheumatic drugs (DMARDs). The patients received subcutaneous golimumab 50mg once a month during 6 months. The primary endpoint was the percentage of individuals with a good or moderate EULAR DAS28-ESR response after 6 months of treatment. A total of 140 patients were included. Of these, 76.4% had very active disease (DAS28-ESR>5.1). 76.4% were taking methotrexate, 40.0% other DMARDs in monotherapy or combined, and 65.0% received corticosteroids. After 6 months, 82.9% of the patients showed a good or moderate EULAR response, 41.4% had low disease activity, and 30.7% were in remission. The percentage of responders one month after the first dose was 69.3%. The efficacy was similar in patients treated with methotrexate or other DMARDs, with different methotrexate doses, with or without corticosteroids, or in subjects who had failed one or more DMARDs. The response to golimumab was observed from the first dose. Golimumab was well tolerated and its safety profile was consistent with the findings of previous studies. Serious adverse events were reported in 11 patients (7.9%). The addition of subcutaneous golimumab 50 mg once a month to different DMARDs in patients with active RA yielded a moderate or good response after 6 months in 82.9% of the cases. The response was observed early, from the start of the second month, after a single dose of golimumab. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Pharmacogenomics to Revive Drug Development in Cardiovascular Disease.

Science.gov (United States)

Dubé, Marie-Pierre; de Denus, Simon; Tardif, Jean-Claude

2016-02-01

Investment in cardiovascular drug development is on the decline as large cardiovascular outcomes trials require considerable investments in time, efforts and financial resources. Pharmacogenomics has the potential to help revive the cardiovascular drug development pipeline by providing new and better drug targets at an earlier stage and by enabling more efficient outcomes trials. This article will review some of the recent developments highlighting the value of pharmacogenomics for drug development. We discuss how genetic biomarkers can enable the conduct of more efficient clinical outcomes trials by enriching patient populations for good responders to the medication. In addition, we assess past drug development programs which support the added value of selecting drug targets that have established genetic evidence supporting the targeted mechanism of disease. Finally, we discuss how pharmacogenomics can provide valuable evidence linking a drug target to clinically relevant outcomes, enabling novel drug discovery and drug repositioning opportunities.

Gender and images of heart disease in Scandinavian drug advertising.

Science.gov (United States)

Riska, Elianne; Heikell, Thomas

2007-01-01

This study examines the construction of the "heart disease candidate" in advertisements for cardiovascular drugs in Scandinavian medical journals. All advertisements for cardiovascular drugs (n = 603) in Scandinavian medical journals (Denmark, Finland, Norway, and Sweden) in 2005 were collected. Only advertisements that portray users (n = 289, 48% of the advertisements) were analyzed. The results show that coronary candidacy is constructed as a male condition in half of the advertisements for cardiovascular drugs. The advertisements suggest a gendering of heart disease: men are the major victims of heart failure and cardiac insufficiency, and women are in need of cholesterol-lowering drugs. The cardiovascular drug advertisements portray a restoration of men's hyperactive agency, valorized by means of sporty images, by drawing on masculinity as a fixed trait and behavior. Hypercholesterolemia as a woman's disease reproduces the tyranny of slimness for women: Only women's stoutness is medicalized, and there are no pictures of heavy men. The findings point to the public health implications of gendered images of coronary candidacy in medical advertising.

The systems containing clays and clay minerals from modified drug release: a review.

Science.gov (United States)

Rodrigues, Luís Alberto de Sousa; Figueiras, Ana; Veiga, Francisco; de Freitas, Rivelilson Mendes; Nunes, Lívio César Cunha; da Silva Filho, Edson Cavalcanti; da Silva Leite, Cleide Maria

2013-03-01

Clays are materials commonly used in the pharmaceutical industry, either as ingredients or as active ingredients. It was observed that when they are administered concurrently, they may interact with drugs reducing their absorption. Therefore, such interactions can be used to achieve technological and biopharmaceutical advantages, regarding the control of release. This review summarizes bibliographic (articles) and technological (patents) information on the use of systems containing clays and clay minerals in modified drug delivery. In this area, formulations such natural clay, commercial clay, synthetic clay, composites clay-polymers, nanocomposites clay-polymers, films and hidrogels composites clay-polymers are used to slow/extend or vectorize the release of drugs and consequently they increase their bioavailability. Finally, this review summarizes the fields of technology and biopharmaceutical applications, where clays are applied. Copyright © 2012 Elsevier B.V. All rights reserved.

Cardiovascular disease among people with drug use disorders

DEFF Research Database (Denmark)

Thylstrup, Birgitte; Clausen, Thomas; Hesse, Morten

2015-01-01

Objectives To present the prevalence and incidence of cardiovascular disease (CVD) in a national cohort of patients seeking treatment for drug use disorders (DUD). Methods This is a longitudinal record linkage study of consecutive DUD treatment admissions between 2000 and 2006 from Denmark. Results...... treatment (SHR = 1.15, p = 0.022). The use of amphetamines was negatively associated with the risk of CVD within this cohort (SHR = 0.75, p = 0.001). Conclusions Patients injecting drugs using prescribed methadone were at elevated risk for cardiovascular disease and should be monitored for CVD. Opioid...... medications should be evaluated in terms of their cardiovascular sequelae....

Modulation at Age of Onset in Tunisian Huntington Disease Patients: Implication of New Modifier Genes

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Dorra Hmida-Ben Brahim

2014-01-01

Full Text Available Huntington’s disease (HD is an autosomal dominant neurodegenerative disorder. The causative mutation is an expansion of more than 36 CAG repeats in the first exon of IT15 gene. Many studies have shown that the IT15 interacts with several modifier genes to regulate the age at onset (AO of HD. Our study aims to investigate the implication of CAG expansion and 9 modifiers in the age at onset variance of 15 HD Tunisian patients and to establish the correlation between these modifiers genes and the AO of this disease. Despite the small number of studied patients, this report consists of the first North African study in Huntington disease patients. Our results approve a specific effect of modifiers genes in each population.

A network-based classification model for deriving novel drug-disease associations and assessing their molecular actions.

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Min Oh

Full Text Available The growing number and variety of genetic network datasets increases the feasibility of understanding how drugs and diseases are associated at the molecular level. Properly selected features of the network representations of existing drug-disease associations can be used to infer novel indications of existing drugs. To find new drug-disease associations, we generated an integrative genetic network using combinations of interactions, including protein-protein interactions and gene regulatory network datasets. Within this network, network adjacencies of drug-drug and disease-disease were quantified using a scored path between target sets of them. Furthermore, the common topological module of drugs or diseases was extracted, and thereby the distance between topological drug-module and disease (or disease-module and drug was quantified. These quantified scores were used as features for the prediction of novel drug-disease associations. Our classifiers using Random Forest, Multilayer Perceptron and C4.5 showed a high specificity and sensitivity (AUC score of 0.855, 0.828 and 0.797 respectively in predicting novel drug indications, and displayed a better performance than other methods with limited drug and disease properties. Our predictions and current clinical trials overlap significantly across the different phases of drug development. We also identified and visualized the topological modules of predicted drug indications for certain types of cancers, and for Alzheimer's disease. Within the network, those modules show potential pathways that illustrate the mechanisms of new drug indications, including propranolol as a potential anticancer agent and telmisartan as treatment for Alzheimer's disease.

Determining the Molecular Pathways Underlying the Protective Effect of Non-Steroidal Anti-Inflammatory Drugs for Alzheimer's Disease: A Bioinformatics Approach

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Alejo J Nevado-Holgado

Full Text Available Alzheimer's disease (AD represents a substantial unmet need, due to increasing prevalence in an ageing society and the absence of a disease modifying therapy. Epidemiological evidence shows a protective effect of non steroidal anti inflammatory (NSAID drugs, and genome wide association studies (GWAS show consistent linkage to inflammatory pathways; both observations suggesting anti-inflammatory compounds might be effective in AD therapy although clinical trials to date have not been positive.In this study, we use pathway enrichment and fuzzy logic to identify pathways (KEGG database simultaneously affected in both AD and by NSAIDs (Sulindac, Piroxicam, Paracetamol, Naproxen, Nabumetone, Ketoprofen, Diclofenac and Aspirin. Gene expression signatures were derived for disease from both blood (n = 344 and post-mortem brain (n = 690, and for drugs from immortalised human cell lines exposed to drugs of interest as part of the Connectivity Map platform. Using this novel approach to combine datasets we find striking overlap between AD gene expression in blood and NSAID induced changes in KEGG pathways of Ribosome and Oxidative Phosphorylation. No overlap was found in non NSAID comparison drugs. In brain we find little such overlap, although Oxidative Phosphorylation approaches our pre-specified significance level.These findings suggest that NSAIDs might have a mode of action beyond inflammation and moreover that their therapeutic effects might be mediated in particular by alteration of Oxidative Phosphorylation and possibly the Ribosome pathway. Mining of such datasets might prove increasingly productive as they increase in size and richness. Keywords: Alzheimer's disease, NSAID, Inflammation, Fuzzy logic, Ribosome

[Experience of rapid drug desensitization therapy in the treatment of mycobacterial disease].

Science.gov (United States)

Sasaki, Yuka; Kurashima, Atsuyuki; Morimoto, Kozo; Okumura, Masao; Watanabe, Masato; Yoshiyama, Takashi; Ogata, Hideo; Gotoh, Hajime; Kudoh, Shoji; Suzuki, Hiroaki

2014-11-01

Drugs for tuberculosis and non-tuberculosis mycobacterial diseases are limited. In particular, no new drugs for non-tuberculosis mycobacterial disease have been developed in recent years. Antimycobacterial drugs have many adverse reactions, for which drug desensitization therapy has been used. Rapid drug desensitization (RDD) therapy, including antituberculosis drugs and clarithromycin, has been implemented in many regions in Europe and the United States. We investigated the validity of RDD therapy in Japan. We report our experience with RDD therapy in 13 patients who developed severe drug allergy to antimycobacterial treatment. The desensitization protocol reported by Holland and Cernandas was adapted. The underlying diseases were 7 cases of pulmonary Mycobacterium avium complex disease and 6 cases of pulmonary tuberculosis. Isoniazid was readministered in 2 (100%) of 2 patients; rifampicin, in 8 (67.7%) of 12 patients; ethambutol, in 4 (67.7%) of 6 patients; and clarithromycin, in 2 (100%) of 2 patients. In Japan, the desensitization therapy recommended by the Treatment Committee of the Japanese Society for Tuberculosis have been implemented generally. We think RDD therapy is effective and safe as the other desensitization therapy. We will continue to investigate the efficiency of RDD therapy in patients who had discontinued antimycobacterial treatment because of the drug allergic reaction.

Chitosan nanoparticles as a modified diclofenac drug release system

Science.gov (United States)

Duarte Junior, Anivaldo Pereira; Tavares, Eraldo José Madureira; Alves, Taís Vanessa Gabbay; de Moura, Márcia Regina; da Costa, Carlos Emmerson Ferreira; Silva Júnior, José Otávio Carréra; Ribeiro Costa, Roseane Maria

2017-08-01

This study evaluated a modified nanostructured release system employing diclofenac as a drug model. Biodegradable chitosan nanoparticles were prepared with chitosan concentrations between 0.5 and 0.8% ( w/ v) by template polymerization method using methacrylic acid in aqueous solution. Chitosan-poly(methacrylic acid) (CS-PMAA) nanoparticles showed uniform size around 50-100 nm, homogeneous morphology, and spherical shape. Raw material and chitosan nanoparticles were characterized by thermal analysis, Fourier transform infrared spectroscopy (FT-IR), and transmission electron microscopy (TEM), confirming the interaction between chitosan and methacrylic acid during nanoparticles preparation. Diclofenac sorption on the chitosan nanoparticles surface was achieved by incubation in water/ethanol (1:1) drug solution in concentrations of 0.5 and 0.8 mg/mL. The diclofenac amount sorbed per gram of CS-PMAA nanoparticles, when in a 0.5 mg/mL sodium diclofenac solution, was as follows: 12.93, 15, 20.87, and 29.63 mg/g for CS-PMAA nanoparticles 0.5, 0.6, 0.7, and 0.8% ( w/ v), respectively. When a 0.8 mg/mL sodium diclofenac solution was used, higher sorption efficiencies were obtained: For CS-PMAA nanoparticles with chitosan concentrations of 0.5, 0.6, 0.7, and 0.8% ( w/ v), the sorption efficiencies were 33.39, 49.58, 55.23, and 67.2 mg/g, respectively. Diclofenac sorption kinetics followed a second-order kinetics. Drug release from nanoparticles occurred in a period of up to 48 h and obeyed Korsmeyer-Peppas model, which was characterized mainly by Fickian diffusion transport. [Figure not available: see fulltext.

Hemostimulating efficiency of non-steroid anti-inflammatory drugs under modified irradiation conditions

International Nuclear Information System (INIS)

Zhvoronkov, L.P.; Sklobovskaya, I.Eh.

1988-01-01

Non-steroid anti-inflammatory drugs (NSAID) were found to have hemostimulating effect in mice after irradiation. This effect was rather definite under irradiation conditions modified by dose fractioning or radioprotective chemicals. NSAID application during fractionated irradiation with midlethal integral dose leads to almost complete recovery of bone marrow hemopoiesis by the 9th day of radiation illness. NSAID usage combined with chemical radioprotectors provides effective hemopoiesis stimulation leading to survival increase in animals, irradiated with absolutely lethal doses. (author)

Drug therapy in patients with Parkinson’s disease

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Müller Thomas

2012-05-01

Full Text Available Abstract Parkinson`s disease (PD is a progressive, disabling neurodegenerative disorder with onset of motor and non-motor features. Both reduce quality of life of PD patients and cause caregiver burden. This review aims to provide a survey of possible therapeutic options for treatment of motor and non motor symptoms of PD and to discuss their relation to each other. MAO-B-Inhibitors, NMDA antagonists, dopamine agonists and levodopa with its various application modes mainly improve the dopamine associated motor symptoms in PD. This armentarium of PD drugs only partially influences the onset and occurrence of non motor symptoms. These PD features predominantly result from non dopaminergic neurodegeneration. Autonomic features, such as seborrhea, hyperhidrosis, orthostatic syndrome, salivation, bladder dysfunction, gastrointestinal disturbances, and neuropsychiatric symptoms, such as depression, sleep disorders, psychosis, cognitive dysfunction with impaired execution and impulse control may appear. Drug therapy of these non motor symptoms complicates long-term PD drug therapy due to possible occurrence of drug interactions, - side effects, and altered pharmacokinetic behaviour of applied compounds. Dopamine substituting compounds themselves may contribute to onset of these non motor symptoms. This complicates the differentiation from the disease process itself and influences therapeutic options, which are often limited because of additional morbidity with necessary concomitant drug therapy.

Guidance for Modifying the Definition of Diseases: A Checklist.

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Doust, Jenny; Vandvik, Per O; Qaseem, Amir; Mustafa, Reem A; Horvath, Andrea R; Frances, Allen; Al-Ansary, Lubna; Bossuyt, Patrick; Ward, Robyn L; Kopp, Ina; Gollogly, Laragh; Schunemann, Holger; Glasziou, Paul

2017-07-01

No guidelines exist currently for guideline panels and others considering changes to disease definitions. Panels frequently widen disease definitions, increasing the proportion of the population labeled as unwell and potentially causing harm to patients. We set out to develop a checklist of issues, with guidance, for panels to consider prior to modifying a disease definition. We assembled a multidisciplinary, multicontinent working group of 13 members, including members from the Guidelines International Network, Grading of Recommendations Assessment, Development and Evaluation working group, and the World Health Organisation. We used a 5-step process to develop the checklist: (1) a literature review of issues, (2) a draft outline document, (3) a Delphi process of feedback on the list of issues, (4) a 1-day face-to-face meeting, and (5) further refinement of the checklist. The literature review identified 12 potential issues. From these, the group developed an 8-item checklist that consisted of definition changes, number of people affected, trigger, prognostic ability, disease definition precision and accuracy, potential benefits, potential harms, and the balance between potential harms and benefits. The checklist is accompanied by an explanation of each item and the types of evidence to assess each one. We used a panel's recent consideration of a proposed change in the definition of gestational diabetes mellitus (GDM) to illustrate use of the checklist. We propose that the checklist be piloted and validated by groups developing new guidelines. We anticipate that the use of the checklist will be a first step to guidance and better documentation of definition changes prior to introducing modified disease definitions.

Pharmaceutical cocrystals as an opportunity to modify drug properties: From the idea to application. A review.

Science.gov (United States)

Sokal, Agnieszka; Pindelska, Edyta

2017-12-26

The properties of many drugs which have been available on the pharmaceutical market for a long time still need to be improved. Cocrystals are the solid state drug modification which can improve such properties as low solubility, stability and mechanical properties (e.g. compressibility). In this paper examples how to use cocrystals to modify properties of API (Active Pharmaceutical Ingredient) will be reported. Additionally, in this review the way from an idea of the new cocrystal to drug dosage form registration will be shortly described. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Non-steroidal anti-inflammatory drug use and the risk of Parkinson's disease

DEFF Research Database (Denmark)

Manthripragada, Angelika D; Schernhammer, Eva S; Qiu, Jiaheng

2011-01-01

Experimental evidence supports a preventative role for non-steroidal anti-inflammatory drugs (NSAIDs) in Parkinson's disease (PD).......Experimental evidence supports a preventative role for non-steroidal anti-inflammatory drugs (NSAIDs) in Parkinson's disease (PD)....

A comparison of discontinuation rates of tofacitinib and biologic disease-modifying anti-rheumatic drugs in rheumatoid arthritis: a systematic review and Bayesian network meta-analysis.

Science.gov (United States)

Park, Sun-Kyeong; Lee, Min-Young; Jang, Eun-Jin; Kim, Hye-Lin; Ha, Dong-Mun; Lee, Eui-Kyung

2017-01-01

The purpose of this study was to compare the discontinuation rates of tofacitinib and biologics (tumour necrosis factor inhibitors (TNFi), abatacept, rituximab, and tocilizumab) in rheumatoid arthritis (RA) patients considering inadequate responses (IRs) to previous treatment(s). Randomised controlled trials of tofacitinib and biologics - reporting at least one total discontinuation, discontinuation due to lack of efficacy (LOE), and discontinuation due to adverse events (AEs) - were identified through systematic review. The analyses were conducted for patients with IRs to conventional synthetic disease-modifying anti-rheumatic drugs (cDMARDs) and for patients with biologics-IR, separately. Bayesian network meta-analysis was used to estimate rate ratio (RR) of a biologic relative to tofacitinib with 95% credible interval (CrI), and probability of RR being tofacitinib and biologics in the cDMARDs-IR group. In the biologics-IR group, however, TNFi (RR 0.17, 95% CrI 0.01-3.61, P[RRtofacitinib did. Despite the difference, discontinuation cases owing to LOE and AEs revealed that tofacitinib was comparable to the biologics. The comparability of discontinuation rate between tofacitinib and biologics was different based on previous treatments and discontinuation reasons: LOE, AEs, and total (due to other reasons). Therefore, those factors need to be considered to decide the optimal treatment strategy.

Identification of attractive drug targets in neglected-disease pathogens using an in silico approach.

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Gregory J Crowther

Full Text Available BACKGROUND: The increased sequencing of pathogen genomes and the subsequent availability of genome-scale functional datasets are expected to guide the experimental work necessary for target-based drug discovery. However, a major bottleneck in this has been the difficulty of capturing and integrating relevant information in an easily accessible format for identifying and prioritizing potential targets. The open-access resource TDRtargets.org facilitates drug target prioritization for major tropical disease pathogens such as the mycobacteria Mycobacterium leprae and Mycobacterium tuberculosis; the kinetoplastid protozoans Leishmania major, Trypanosoma brucei, and Trypanosoma cruzi; the apicomplexan protozoans Plasmodium falciparum, Plasmodium vivax, and Toxoplasma gondii; and the helminths Brugia malayi and Schistosoma mansoni. METHODOLOGY/PRINCIPAL FINDINGS: Here we present strategies to prioritize pathogen proteins based on whether their properties meet criteria considered desirable in a drug target. These criteria are based upon both sequence-derived information (e.g., molecular mass and functional data on expression, essentiality, phenotypes, metabolic pathways, assayability, and druggability. This approach also highlights the fact that data for many relevant criteria are lacking in less-studied pathogens (e.g., helminths, and we demonstrate how this can be partially overcome by mapping data from homologous genes in well-studied organisms. We also show how individual users can easily upload external datasets and integrate them with existing data in TDRtargets.org to generate highly customized ranked lists of potential targets. CONCLUSIONS/SIGNIFICANCE: Using the datasets and the tools available in TDRtargets.org, we have generated illustrative lists of potential drug targets in seven tropical disease pathogens. While these lists are broadly consistent with the research community's current interest in certain specific proteins, and suggest

Drug discovery for Chagas disease should consider Trypanosoma cruzi strain diversity

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Bianca Zingales

2014-09-01

Full Text Available This opinion piece presents an approach to standardisation of an important aspect of Chagas disease drug discovery and development: selecting Trypanosoma cruzi strains for in vitro screening. We discuss the rationale for strain selection representing T. cruzi diversity and provide recommendations on the preferred parasite stage for drug discovery, T. cruzi discrete typing units to include in the panel of strains and the number of strains/clones for primary screens and lead compounds. We also consider experimental approaches for in vitro drug assays. The Figure illustrates the current Chagas disease drug-discovery and development landscape.

Electrocatalytic oxidation of some anti-inflammatory drugs on a nickel hydroxide-modified nickel electrode

Energy Technology Data Exchange (ETDEWEB)

Hajjizadeh, M. [Department of Chemistry, Faculty of Science, K. N. Toosi University of Technology, P.O. Box 16315-1618, Tehran (Iran, Islamic Republic of); Jabbari, A. [Department of Chemistry, Faculty of Science, K. N. Toosi University of Technology, P.O. Box 16315-1618, Tehran (Iran, Islamic Republic of)], E-mail: jabbari@kntu.ac.ir; Heli, H.; Moosavi-Movahedi, A.A. [Institute of Biochemistry and Biophysics, University of Tehran, Tehran (Iran, Islamic Republic of); Haghgoo, S. [Center of Quality Control of Drug, Tehran (Iran, Islamic Republic of)

2007-12-31

The electrocatalytic oxidation of several anti-inflammatory drugs (mefenamic acid, diclofenac and indomethacin) was investigated on a nickel hydroxide-modified nickel (NHMN) electrode in alkaline solution. This oxidation process and its kinetics were studied using cyclic voltammetry, chronoamperometry, and electrochemical impedance spectroscopy techniques. Voltammetric studies indicated that in the presence of drugs, the anodic peak current of low-valence nickel species increases, followed by a decrease in the corresponding cathodic current. This pattern indicates that drugs were oxidized on the redox mediator immobilized on the electrode surface via an electrocatalytic mechanism. A mechanism based on the electrochemical generation of Ni(III) active sites and their subsequent consumption by drugs was also investigated. The corresponding rate law under the control of charge transfer was developed and kinetic parameters were derived. In this context, the charge-transfer resistance accessible both theoretically and through impedancemetry was used as a criterion. The rate constants of the catalytic oxidation of drugs and the electron-transfer coefficients are reported. A sensitive, simple and time-saving amperometric procedure was developed for the analysis of these drugs in bulk form and for the direct assay of tablets, using the NHMN electrode.

Electrocatalytic oxidation of some anti-inflammatory drugs on a nickel hydroxide-modified nickel electrode

International Nuclear Information System (INIS)

Hajjizadeh, M.; Jabbari, A.; Heli, H.; Moosavi-Movahedi, A.A.; Haghgoo, S.

2007-01-01

The electrocatalytic oxidation of several anti-inflammatory drugs (mefenamic acid, diclofenac and indomethacin) was investigated on a nickel hydroxide-modified nickel (NHMN) electrode in alkaline solution. This oxidation process and its kinetics were studied using cyclic voltammetry, chronoamperometry, and electrochemical impedance spectroscopy techniques. Voltammetric studies indicated that in the presence of drugs, the anodic peak current of low-valence nickel species increases, followed by a decrease in the corresponding cathodic current. This pattern indicates that drugs were oxidized on the redox mediator immobilized on the electrode surface via an electrocatalytic mechanism. A mechanism based on the electrochemical generation of Ni(III) active sites and their subsequent consumption by drugs was also investigated. The corresponding rate law under the control of charge transfer was developed and kinetic parameters were derived. In this context, the charge-transfer resistance accessible both theoretically and through impedancemetry was used as a criterion. The rate constants of the catalytic oxidation of drugs and the electron-transfer coefficients are reported. A sensitive, simple and time-saving amperometric procedure was developed for the analysis of these drugs in bulk form and for the direct assay of tablets, using the NHMN electrode

Orphan drugs for rare diseases: is it time to revisit their special market access status?

Science.gov (United States)

Simoens, Steven; Cassiman, David; Dooms, Marc; Picavet, Eline

2012-07-30

Orphan drugs are intended for diseases with a very low prevalence, and many countries have implemented legislation to support market access of orphan drugs. We argue that it is time to revisit the special market access status of orphan drugs. Indeed, evidence suggests that there is no societal preference for treating rare diseases. Although society appears to assign a greater value to severity of disease, this criterion is equally relevant to many common diseases. Furthermore, the criterion of equity in access to treatment, which underpins orphan drug legislation, puts more value on health improvement in rare diseases than in common diseases and implies that population health is not maximized. Finally, incentives for the development, pricing and reimbursement of orphan drugs have created market failures, including monopolistic prices and the artificial creation of rare diseases. We argue that, instead of awarding special market access status to orphan drugs, there is scope to optimize research and development (R&D) of orphan drugs and to control prices of orphan drugs by means of, for example, patent auctions, advance purchase commitments, pay-as-you-go schemes and dose-modification studies. Governments should consider carefully the right incentive strategy for R&D of orphan drugs in rare diseases.

Drug Induced Steatohepatitis: An Uncommon Culprit of a Common Disease

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Liane Rabinowich

2015-01-01

Full Text Available Nonalcoholic fatty liver disease (NAFLD is a leading cause of liver disease in developed countries. Its frequency is increasing in the general population mostly due to the widespread occurrence of obesity and the metabolic syndrome. Although drugs and dietary supplements are viewed as a major cause of acute liver injury, drug induced steatosis and steatohepatitis are considered a rare form of drug induced liver injury (DILI. The complex mechanism leading to hepatic steatosis caused by commonly used drugs such as amiodarone, methotrexate, tamoxifen, valproic acid, glucocorticoids, and others is not fully understood. It relates not only to induction of the metabolic syndrome by some drugs but also to their impact on important molecular pathways including increased hepatocytes lipogenesis, decreased secretion of fatty acids, and interruption of mitochondrial β-oxidation as well as altered expression of genes responsible for drug metabolism. Better familiarity with this type of liver injury is important for early recognition of drug hepatotoxicity and crucial for preventing severe forms of liver injury and cirrhosis. Moreover, understanding the mechanisms leading to drug induced hepatic steatosis may provide much needed clues to the mechanism and potential prevention of the more common form of metabolic steatohepatitis.

In Silico Chemogenomics Drug Repositioning Strategies for Neglected Tropical Diseases.

Science.gov (United States)

Andrade, Carolina Horta; Neves, Bruno Junior; Melo-Filho, Cleber Camilo; Rodrigues, Juliana; Silva, Diego Cabral; Braga, Rodolpho Campos; Cravo, Pedro Vitor Lemos

2018-03-08

Only ~1% of all drug candidates against Neglected Tropical Diseases (NTDs) have reached clinical trials in the last decades, underscoring the need for new, safe and effective treatments. In such context, drug repositioning, which allows finding novel indications for approved drugs whose pharmacokinetic and safety profiles are already known, is emerging as a promising strategy for tackling NTDs. Chemogenomics is a direct descendent of the typical drug discovery process that involves the systematic screening of chemical compounds against drug targets in high-throughput screening (HTS) efforts, for the identification of lead compounds. However, different to the one-drug-one-target paradigm, chemogenomics attempts to identify all potential ligands for all possible targets and diseases. In this review, we summarize current methodological development efforts in drug repositioning that use state-of-the-art computational ligand- and structure-based chemogenomics approaches. Furthermore, we highlighted the recent progress in computational drug repositioning for some NTDs, based on curation and modeling of genomic, biological, and chemical data. Additionally, we also present in-house and other successful examples and suggest possible solutions to existing pitfalls. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Baricitinib in Patients with Rheumatoid Arthritis and an Inadequate Response to Conventional Disease-Modifying Antirheumatic Drugs in United States and Rest of World: A Subset Analysis.

Science.gov (United States)

Wells, Alvin F; Greenwald, Maria; Bradley, John D; Alam, Jahangir; Arora, Vipin; Kartman, Cynthia E

2018-06-01

This article evaluates the efficacy and safety of baricitinib 4 mg versus placebo in United States including Puerto Rico (US) and rest of the world (ROW) subpopulations using data pooled from RA-BEAM and RA-BUILD, which enrolled patients with moderate-to-severe adult-onset rheumatoid arthritis (RA). In RA-BEAM, patients with an inadequate response (IR) to methotrexate, at least one X-ray erosion, and high sensitivity C-reactive protein (hsCRP) ≥ 6 mg/L were randomized to placebo or orally administered baricitinib 4 mg daily or subcutaneously administered adalimumab 40 mg every other week. In RA-BUILD, patients with an IR to at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD) and with hsCRP ≥ 3.6 mg/L were randomized to placebo or baricitinib 2 or 4 mg daily. Patients in both trials were biologic naive. In this post hoc analysis, data from both studies were pooled (714 baricitinib 4 mg-treated, 716 placebo-treated patients). Overall, 188 US and 1242 ROW patients were included. Subgroups differed in baseline characteristics including race, weight, age, time since RA diagnosis, current corticosteroid use, and previous csDMARD use. At weeks 12 and 24, baricitinib-treated patients had larger responses compared to placebo-treated patients for multiple efficacy outcomes: American College of Rheumatology 20/50/70 response, low disease activity, remission, Disease Activity Score 28-C-reactive protein, and Health Assessment Questionnaire-Disability Index. Overall, similar efficacy was observed in US and ROW subgroups with no notable safety differences between subgroups at weeks 12 or 24. Baricitinib 4 mg was efficacious compared to placebo in US and ROW subpopulations. Safety was similar between subgroups. Eli Lilly & Company and Incyte Corporation. ClinicalTrials.gov identifiers, NCT01721057; NCT01710358.

Drug Delivery Nanoparticles in Skin Cancers

Science.gov (United States)

Dianzani, Chiara; Zara, Gian Paolo; Maina, Giovanni; Pettazzoni, Piergiorgio; Pizzimenti, Stefania; Rossi, Federica; Gigliotti, Casimiro Luca; Ciamporcero, Eric Stefano; Daga, Martina; Barrera, Giuseppina

2014-01-01

Nanotechnology involves the engineering of functional systems at nanoscale, thus being attractive for disciplines ranging from materials science to biomedicine. One of the most active research areas of the nanotechnology is nanomedicine, which applies nanotechnology to highly specific medical interventions for prevention, diagnosis, and treatment of diseases, including cancer disease. Over the past two decades, the rapid developments in nanotechnology have allowed the incorporation of multiple therapeutic, sensing, and targeting agents into nanoparticles, for detection, prevention, and treatment of cancer diseases. Nanoparticles offer many advantages as drug carrier systems since they can improve the solubility of poorly water-soluble drugs, modify pharmacokinetics, increase drug half-life by reducing immunogenicity, improve bioavailability, and diminish drug metabolism. They can also enable a tunable release of therapeutic compounds and the simultaneous delivery of two or more drugs for combination therapy. In this review, we discuss the recent advances in the use of different types of nanoparticles for systemic and topical drug delivery in the treatment of skin cancer. In particular, the progress in the treatment with nanocarriers of basal cell carcinoma, squamous cell carcinoma, and melanoma has been reported. PMID:25101298

Developing Disease-Modifying Treatments in Alzheimer's Disease - A Perspective from Roche and Genentech.

Science.gov (United States)

Doody, R

2017-01-01

Alzheimer's disease (AD) is a chronic neurodegenerative disease for which no preventative or disease-modifying treatments currently exist. Pathological hallmarks include amyloid plaques and neurofibrillary tangles composed of hyper-phosphorylated tau protein. Evidence suggests that both pathologies are self-propagating once established. However, the lag time between neuropathological changes in the brain and the onset of even subtle clinical symptomatology means that patients are often diagnosed late when pathology, and neurodegeneration secondary to these changes, may have been established for several years. Complex pathological pathways associated with susceptibility to AD and changes that occur downstream of the neuropathologic process further contribute to the challenging endeavour of developing novel disease-modifying therapy. Recognising this complexity, effective management of AD must include reliable screening and early diagnosis in combination with effective therapeutic management of the pathological processes. Roche and Genentech are committed to addressing these unmet needs through developing a comprehensive portfolio of diagnostics and novel therapies. Beginning with the most scientifically supported targets, this approach includes two targeted amyloid-β monoclonal antibody therapies, crenezumab and gantenerumab, and an anti-tau monoclonal antibody, RO7105705, as well as a robust biomarker platform to aid in the early identification of people at risk or in the early stages of AD. Identification and implementation of diagnostic tools will support the enrolment of patients into clinical trials; furthermore, these tools should also support evaluation of the clinical efficacy and safety profile of the novel therapeutic agents tested in these trials. This review discusses the therapeutic agents currently under clinical development.

Clinical course and therapeutic approach to varicella zoster virus infection in children with rheumatic autoimmune diseases under immunosuppression

OpenAIRE

Leuvenink, Raphael; Aeschlimann, Florence; Baer, Walter; Berthet, Gerald; Cannizzaro, Elvira; Hofer, Michael; Kaiser, Daniela; Schroeder, Silke; Heininger, Ulrich; Woerner, Andreas

2016-01-01

Background To analyze the clinical presentation and complications of varicella zoster virus (VZV) infection in children with rheumatic diseases treated with immunosuppressive medication such as biological disease-modifying antirheumatic drugs (bDMARDs) and/or conventional disease-modifying antirheumatic drugs (cDMARDs), and to analyze the therapeutic approach to VZV infections with respect to the concomitant immunosuppressive treatment. Methods Retrospective multicenter study using the Swiss ...

CLC-2 single nucleotide polymorphisms (SNPs) as potential modifiers of cystic fibrosis disease severity

Science.gov (United States)

Blaisdell, Carol J; Howard, Timothy D; Stern, Augustus; Bamford, Penelope; Bleecker, Eugene R; Stine, O Colin

2004-01-01

Background Cystic fibrosis (CF) lung disease manifest by impaired chloride secretion leads to eventual respiratory failure. Candidate genes that may modify CF lung disease severity include alternative chloride channels. The objectives of this study are to identify single nucleotide polymorphisms (SNPs) in the airway epithelial chloride channel, CLC-2, and correlate these polymorphisms with CF lung disease. Methods The CLC-2 promoter, intron 1 and exon 20 were examined for SNPs in adult CF dF508/dF508 homozygotes with mild and severe lung disease (forced expiratory volume at one second (FEV1) > 70% and < 40%). Results PCR amplification of genomic CLC-2 and sequence analysis revealed 1 polymorphism in the hClC -2 promoter, 4 in intron 1, and none in exon 20. Fisher's analysis within this data set, did not demonstrate a significant relationship between the severity of lung disease and SNPs in the CLC-2 gene. Conclusions CLC-2 is not a key modifier gene of CF lung phenotype. Further studies evaluating other phenotypes associated with CF may be useful in the future to assess the ability of CLC-2 to modify CF disease severity. PMID:15507145

CLC-2 single nucleotide polymorphisms (SNPs as potential modifiers of cystic fibrosis disease severity

Directory of Open Access Journals (Sweden)

Bleecker Eugene R

2004-10-01

Full Text Available Abstract Background Cystic fibrosis (CF lung disease manifest by impaired chloride secretion leads to eventual respiratory failure. Candidate genes that may modify CF lung disease severity include alternative chloride channels. The objectives of this study are to identify single nucleotide polymorphisms (SNPs in the airway epithelial chloride channel, CLC-2, and correlate these polymorphisms with CF lung disease. Methods The CLC-2 promoter, intron 1 and exon 20 were examined for SNPs in adult CF dF508/dF508 homozygotes with mild and severe lung disease (forced expiratory volume at one second (FEV1 > 70% and Results PCR amplification of genomic CLC-2 and sequence analysis revealed 1 polymorphism in the hClC -2 promoter, 4 in intron 1, and none in exon 20. Fisher's analysis within this data set, did not demonstrate a significant relationship between the severity of lung disease and SNPs in the CLC-2 gene. Conclusions CLC-2 is not a key modifier gene of CF lung phenotype. Further studies evaluating other phenotypes associated with CF may be useful in the future to assess the ability of CLC-2 to modify CF disease severity.

The expert meeting dedicated to the discussion of results of a local open-label multicenter observational study of the efficiency and safety of tofacitinib in patients with active rheumatoid arthritis with the inefficiency of disease-modifying antirheumatic drugs and to the elaboration of recommendations for the use for tofacitinib in the therapy of rheumatoid arthritis

Directory of Open Access Journals (Sweden)

2016-01-01

Full Text Available The expert meeting dedicated to the discussion of results of a local open-label multicenter observational study of the efficiency and safety of tofacitinib in patients with active rheumatoid arthritis with the inefficiency of disease-modifying antirheumatic drugs and to the elaboration of recommendations for the use for tofacitinib in the therapy of rheumatoid arthritis.

eRepo-ORP: Exploring the Opportunity Space to Combat Orphan Diseases with Existing Drugs.

Science.gov (United States)

Brylinski, Michal; Naderi, Misagh; Govindaraj, Rajiv Gandhi; Lemoine, Jeffrey

2017-12-10

About 7000 rare, or orphan, diseases affect more than 350 million people worldwide. Although these conditions collectively pose significant health care problems, drug companies seldom develop drugs for orphan diseases due to extremely limited individual markets. Consequently, developing new treatments for often life-threatening orphan diseases is primarily contingent on financial incentives from governments, special research grants, and private philanthropy. Computer-aided drug repositioning is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research. Here, we present eRepo-ORP, a comprehensive resource constructed by a large-scale repositioning of existing drugs to orphan diseases with a collection of structural bioinformatics tools, including eThread, eFindSite, and eMatchSite. Specifically, a systematic exploration of 320,856 possible links between known drugs in DrugBank and orphan proteins obtained from Orphanet reveals as many as 18,145 candidates for repurposing. In order to illustrate how potential therapeutics for rare diseases can be identified with eRepo-ORP, we discuss the repositioning of a kinase inhibitor for Ras-associated autoimmune leukoproliferative disease. The eRepo-ORP data set is available through the Open Science Framework at https://osf.io/qdjup/. Copyright © 2017. Published by Elsevier Ltd.

A novel neurotrophic drug for cognitive enhancement and Alzheimer's disease.

Directory of Open Access Journals (Sweden)

Qi Chen

Full Text Available Currently, the major drug discovery paradigm for neurodegenerative diseases is based upon high affinity ligands for single disease-specific targets. For Alzheimer's disease (AD, the focus is the amyloid beta peptide (Aß that mediates familial Alzheimer's disease pathology. However, given that age is the greatest risk factor for AD, we explored an alternative drug discovery scheme that is based upon efficacy in multiple cell culture models of age-associated pathologies rather than exclusively amyloid metabolism. Using this approach, we identified an exceptionally potent, orally active, neurotrophic molecule that facilitates memory in normal rodents, and prevents the loss of synaptic proteins and cognitive decline in a transgenic AD mouse model.

Electrochemical studies of ropinirole, an anti-Parkinson's disease drug

Indian Academy of Sciences (India)

The oxidation behaviour of a potent anti-Parkinson's disease drug ropinirole hydrochloride was investigated over a wide pH range in aqueous solution at glassy carbon electrode using cyclic and square-wave voltammetry. The oxidation of drug is a pH dependent irreversible process and occurs in two steps.

Oral disease-modifying therapies for multiple sclerosis in the Middle Eastern and North African (MENA) region: an overview.

Science.gov (United States)

Deleu, Dirk; Mesraoua, Boulenouar; Canibaño, Beatriz; Melikyan, Gayane; Al Hail, Hassan; El-Sheikh, Lubna; Ali, Musab; Al Hussein, Hassan; Ibrahim, Faiza; Hanssens, Yolande

2018-06-18

The introduction of new disease-modifying therapies (DMTs) for remitting-relapsing multiple sclerosis (RRMS) has considerably transformed the landscape of therapeutic opportunities for this chronic disabling disease. Unlike injectable drugs, oral DMTs promote patient satisfaction and increase therapeutic adherence. This article reviews the salient features about the mode of action, efficacy, safety, and tolerability profile of approved oral DMTs in RRMS, and reviews their place in clinical algorithms in the Middle East and North Africa (MENA) region. A systematic review was conducted using a comprehensive search of MEDLINE, PubMed, Cochrane Database of Systematic Reviews (period January 1, 1995-January 31, 2018). Additional searches of the American Academy of Neurology and European Committee for Treatment and Research in Multiple Sclerosis abstracts from 2012-2017 were performed, in addition to searches of the Food and Drug Administration and European Medicines Agency websites, to obtain relevant safety information on these DMTs. Four oral DMTs: fingolimod, teriflunomide, dimethyl fumarate, and cladribine have been approved by the regulatory agencies. Based on the number needed to treat (NNT), the potential role of these DMTs in the management of active and highly active or rapidly evolving RRMS is assessed. Finally, the place of the oral DMTs in clinical algorithms in the MENA region is reviewed.

Cerivastatin Nano-Liposome as a Potential Disease Modifying Approach for the Treatment of Pulmonary Arterial Hypertension.

Science.gov (United States)

Lee, Young; Pai, S Balakrishna; Bellamkonda, Ravi V; Thompson, David H; Singh, Jaipal

2018-04-25

In this study, we have investigated nano-liposome as an approach to tailor the pharmacology of cerivastatin as a disease modifying drug for pulmonary arterial hypertension (PAH). Cerivastatin encapsulated liposomes with an average diameter of 98±27 nm were generated by thin film and freeze-thaw process. The nano-liposomes demonstrated sustained drug release kinetics in vitro and inhibited proliferation of pulmonary artery smooth muscle cells with significantly less cellular cytotoxicity as compared to free cerivastatin. When delivered by inhalation to a rat model of monocrotalin induced PAH, cerivastatin significantly reduced pulmonary artery pressure from 55.13±9.82 mmHg to 35.56±6.59 mmHg (P < 0.001) and diminished pulmonary artery wall thickening. Echocardiography showed that cerivastatin significantly reduced right ventricle thickening (0.34±0.02 cm monocrotalin vs. 0.26±0.02 cm cerivastatin; P < 0.001) and increased pulmonary artery acceleration time (13.98±1.14 ms monocrotalin vs. 21.07±2.80 ms cerivastatin; P < 0.001). Nano-liposomal cerivastatin was equally effective or slightly better than cerivastatin in reducing pulmonary artery pressure (67.06±13.64 mmHg monocrotalin; 46.31±7.64 mmHg cerivastatin vs. 37.32±9.50 mmHg liposomal cerivastatin) and improving parameters of right ventricular function as measured by increasing pulmonary artery acceleration time (24.68±3.92 ms monocrotalin; 32.59±6.10 ms cerivastatin vs. 34.96±7.51 ms liposomal cerivastatin). More importantly, the rate and magnitude of toxic cerivastatin metabolite lactone generation from the intratracheally administered nano-liposomes was significantly lower as compared to intravenously administered free cerivastatin. These studies show that nano-liposome encapsulation improved in vitro and in vivo pharmacological and safety profile of cerivastatin and may represent a safer approach as a disease modifying therapy for PAH. The American Society for Pharmacology and Experimental

Structure of a complex of uridine phosphorylase from Yersinia pseudotuberculosis with the modified bacteriostatic antibacterial drug determined by X-ray crystallography and computer analysis

Energy Technology Data Exchange (ETDEWEB)

Balaev, V. V.; Lashkov, A. A., E-mail: alashkov83@gmail.com; Gabdoulkhakov, A. G.; Seregina, T. A.; Dontsova, M. V.; Mikhailov, A. M. [Russian Academy of Sciences, Shubnikov Institute of Crystallography (Russian Federation)

2015-03-15

Pseudotuberculosis and bubonic plague are acute infectious diseases caused by the bacteria Yersinia pseudotuberculosis and Yersinia pestis. These diseases are treated, in particular, with trimethoprim and its modified analogues. However, uridine phosphorylases (pyrimidine nucleoside phosphorylases) that are present in bacterial cells neutralize the action of trimethoprim and its modified analogues on the cells. In order to reveal the character of the interaction of the drug with bacterial uridine phosphorylase, the atomic structure of the unligated molecule of uridine-specific pyrimidine nucleoside phosphorylase from Yersinia pseudotuberculosis (YptUPh) was determined by X-ray diffraction at 1.7 Å resolution with high reliability (R{sub work} = 16.2, R{sub free} = 19.4%; r.m.s.d. of bond lengths and bond angles are 0.006 Å and 1.005°, respectively; DPI = 0.107 Å). The atoms of the amino acid residues of the functionally important secondary-structure elements—the loop L9 and the helix H8—of the enzyme YptUPh were located. The three-dimensional structure of the complex of YptUPh with modified trimethoprim—referred to as 53I—was determined by the computer simulation. It was shown that 53I is a pseudosubstrate of uridine phosphorylases, and its pyrimidine-2,4-diamine group is located in the phosphate-binding site of the enzyme YptUPh.

Structure of a complex of uridine phosphorylase from Yersinia pseudotuberculosis with the modified bacteriostatic antibacterial drug determined by X-ray crystallography and computer analysis

International Nuclear Information System (INIS)

Balaev, V. V.; Lashkov, A. A.; Gabdoulkhakov, A. G.; Seregina, T. A.; Dontsova, M. V.; Mikhailov, A. M.

2015-01-01

Pseudotuberculosis and bubonic plague are acute infectious diseases caused by the bacteria Yersinia pseudotuberculosis and Yersinia pestis. These diseases are treated, in particular, with trimethoprim and its modified analogues. However, uridine phosphorylases (pyrimidine nucleoside phosphorylases) that are present in bacterial cells neutralize the action of trimethoprim and its modified analogues on the cells. In order to reveal the character of the interaction of the drug with bacterial uridine phosphorylase, the atomic structure of the unligated molecule of uridine-specific pyrimidine nucleoside phosphorylase from Yersinia pseudotuberculosis (YptUPh) was determined by X-ray diffraction at 1.7 Å resolution with high reliability (R work = 16.2, R free = 19.4%; r.m.s.d. of bond lengths and bond angles are 0.006 Å and 1.005°, respectively; DPI = 0.107 Å). The atoms of the amino acid residues of the functionally important secondary-structure elements—the loop L9 and the helix H8—of the enzyme YptUPh were located. The three-dimensional structure of the complex of YptUPh with modified trimethoprim—referred to as 53I—was determined by the computer simulation. It was shown that 53I is a pseudosubstrate of uridine phosphorylases, and its pyrimidine-2,4-diamine group is located in the phosphate-binding site of the enzyme YptUPh

Structure of a complex of uridine phosphorylase from Yersinia pseudotuberculosis with the modified bacteriostatic antibacterial drug determined by X-ray crystallography and computer analysis

Science.gov (United States)

Balaev, V. V.; Lashkov, A. A.; Gabdoulkhakov, A. G.; Seregina, T. A.; Dontsova, M. V.; Mikhailov, A. M.

2015-03-01

Pseudotuberculosis and bubonic plague are acute infectious diseases caused by the bacteria Yersinia pseudotuberculosis and Yersinia pestis. These diseases are treated, in particular, with trimethoprim and its modified analogues. However, uridine phosphorylases (pyrimidine nucleoside phosphorylases) that are present in bacterial cells neutralize the action of trimethoprim and its modified analogues on the cells. In order to reveal the character of the interaction of the drug with bacterial uridine phosphorylase, the atomic structure of the unligated molecule of uridine-specific pyrimidine nucleoside phosphorylase from Yersinia pseudotuberculosis ( YptUPh) was determined by X-ray diffraction at 1.7 Å resolution with high reliability ( R work = 16.2, R free = 19.4%; r.m.s.d. of bond lengths and bond angles are 0.006 Å and 1.005°, respectively; DPI = 0.107 Å). The atoms of the amino acid residues of the functionally important secondary-structure elements—the loop L9 and the helix H8—of the enzyme YptUPh were located. The three-dimensional structure of the complex of YptUPh with modified trimethoprim—referred to as 53I—was determined by the computer simulation. It was shown that 53I is a pseudosubstrate of uridine phosphorylases, and its pyrimidine-2,4-diamine group is located in the phosphate-binding site of the enzyme YptUPh.

Summary of recommendations for the design of clinical trials and the registration of drugs used in the treatment of asthma

DEFF Research Database (Denmark)

Holgate, S T; Bousquet, J; Chung, K F

2004-01-01

With new drugs being introduced to treat asthma it is timely to review criteria that can be used to assess efficacy in clinical trials. Anti-asthma drugs are classified into symptoms-modifying, symptom preventers and disease modifying agents. Attention is drawn to the types of experimental eviden...

Drugs for Neglected Diseases initiative model of drug development for neglected diseases: current status and future challenges.

Science.gov (United States)

Ioset, Jean-Robert; Chang, Shing

2011-09-01

The Drugs for Neglected Diseases initiative (DNDi) is a patients' needs-driven organization committed to the development of new treatments for neglected diseases. Created in 2003, DNDi has delivered four improved treatments for malaria, sleeping sickness and visceral leishmaniasis. A main DNDi challenge is to build a solid R&D portfolio for neglected diseases and to deliver preclinical candidates in a timely manner using an original model based on partnership. To address this challenge DNDi has remodeled its discovery activities from a project-based academic-bound network to a fully integrated process-oriented platform in close collaboration with pharmaceutical companies. This discovery platform relies on dedicated screening capacity and lead-optimization consortia supported by a pragmatic, structured and pharmaceutical-focused compound sourcing strategy.

Polyethyleneimine-modified iron oxide nanoparticles for brain tumor drug delivery using magnetic targeting and intra-carotid administration

OpenAIRE

Chertok, Beata; David, Allan E.; Yang, Victor C.

2010-01-01

This study aimed to examine the applicability of polyethyleneimine (PEI)-modified magnetic nanoparticles (GPEI) as a potential vascular drug/gene carrier to brain tumors. In vitro, GPEI exhibited high cell association and low cell toxicity – properties which are highly desirable for intracellular drug/gene delivery. In addition, a high saturation magnetization of 93 emu/g Fe was expected to facilitate magnetic targeting of GPEI to brain tumor lesions. However, following intravenous administra...

Non-steroidal anti-inflammatory drugs and cyclooxygenase in Alzheimer's disease

NARCIS (Netherlands)

Hoozemans, Jeroen J. M.; Veerhuis, Robert; Rozemuller, Annemieke J. M.; Eikelenboom, Piet

2003-01-01

Epidemiological studies indicate that anti-inflammatory drugs, especially the non-steroidal anti-inflammatory drugs (NSAIDs), decrease the risk of developing Alzheimer's disease (AD). Their beneficial effects may be due to interference in the chronic inflammatory reaction, that takes place in AD.

Scientific and Regulatory Considerations in Solid Oral Modified Release Drug Product Development.

Science.gov (United States)

Li, Min; Sander, Sanna; Duan, John; Rosencrance, Susan; Miksinski, Sarah Pope; Yu, Lawrence; Seo, Paul; Rege, Bhagwant

2016-11-01

This review presents scientific and regulatory considerations for the development of solid oral modified release (MR) drug products. It includes a rationale for patient-focused development based on Quality-by-Design (QbD) principles. Product and process understanding of MR products includes identification and risk-based evaluation of critical material attributes (CMAs), critical process parameters (CPPs), and their impact on critical quality attributes (CQAs) that affect the clinical performance. The use of various biopharmaceutics tools that link the CQAs to a predictable and reproducible clinical performance for patient benefit is emphasized. Product and process understanding lead to a more comprehensive control strategy that can maintain product quality through the shelf life and the lifecycle of the drug product. The overall goal is to develop MR products that consistently meet the clinical objectives while mitigating the risks to patients by reducing the probability and increasing the detectability of CQA failures.

Meningococcal disease and future drug targets

DEFF Research Database (Denmark)

Gammelgaard, L K; Colding, H; Hartzen, S H

2011-01-01

recent data and current knowledge on molecular mechanisms of meningococcal disease and explains how host immune responses ultimately may aggravate neuropathology and the clinical prognosis. Within this context, particular importance is paid to the endotoxic components that provide potential drug targets...... for novel neuroprotective adjuvants, which are needed in order to improve the clinical management of meningoencephalitis and patient prognosis....

Drug sales data analysis for outbreak detection of infectious diseases: a systematic literature review.

Science.gov (United States)

Pivette, Mathilde; Mueller, Judith E; Crépey, Pascal; Bar-Hen, Avner

2014-11-18

This systematic literature review aimed to summarize evidence for the added value of drug sales data analysis for the surveillance of infectious diseases. A search for relevant publications was conducted in Pubmed, Embase, Scopus, Cochrane Library, African Index Medicus and Lilacs databases. Retrieved studies were evaluated in terms of objectives, diseases studied, data sources, methodologies and performance for real-time surveillance. Most studies compared drug sales data to reference surveillance data using correlation measurements or indicators of outbreak detection performance (sensitivity, specificity, timeliness of the detection). We screened 3266 articles and included 27 in the review. Most studies focused on acute respiratory and gastroenteritis infections. Nineteen studies retrospectively compared drug sales data to reference clinical data, and significant correlations were observed in 17 of them. Four studies found that over-the-counter drug sales preceded clinical data in terms of incidence increase. Five studies developed and evaluated statistical algorithms for selecting drug groups to monitor specific diseases. Another three studies developed models to predict incidence increase from drug sales. Drug sales data analyses appear to be a useful tool for surveillance of gastrointestinal and respiratory disease, and OTC drugs have the potential for early outbreak detection. Their utility remains to be investigated for other diseases, in particular those poorly surveyed.

Muscarinic Acetylcholine Receptor Subtypes as Potential Drug Targets for the Treatment of Schizophrenia, Drug Abuse and Parkinson's Disease

DEFF Research Database (Denmark)

Dencker, Ditte; Thomsen, Morgane; Wörtwein, Gitta

2011-01-01

's disease and drug abuse. Dopaminergic systems are regulated by cholinergic, especially muscarinic, input. Not surprisingly, increasing evidence implicates muscarinic acetylcholine receptor-mediated pathways as potential targets for the treatment of these disorders classically viewed as "dopamine based...... site. Such agents may lead to the development of novel classes of drugs useful for the treatment of psychosis, drug abuse and Parkinson's disease. The present review highlights recent studies carried out using muscarinic receptor knock-out mice and new subtype-selective allosteric ligands to assess...... the roles of M(1), M(4), and M(5) receptors in various central processes that are under strong dopaminergic control. The outcome of these studies opens new perspectives for the use of novel muscarinic drugs for several severe disorders of the CNS....

Remission of Grave's disease after oral anti-thyroid drug treatment.

Science.gov (United States)

Ishtiaq, Osama; Waseem, Sabiha; Haque, M Naeemul; Islam, Najmul; Jabbar, Abdul

2009-11-01

To evaluate remission rate of anti-thyroid drug treatment in patients with Grave's disease, and to study the factors associated with remission. A cross sectional study. The Endocrine Department of the Aga Khan University Hospital, Karachi from 1999 to 2000. Seventy four patients of Grave's disease were recruited who were prescribed medical treatment. Grave's disease was diagnosed in the presence of clinical and biochemical hyperthyroidism along with anti-microsomal (AMA) and anti-thyroglobulin antibodies (ATA) and thyroid scan. These patients were prescribed oral anti-thyroid drugs using titration regime and followed at 3, 6, 12 and 18 months. Patients were categorized into two groups: "remission group" and "treatment failure group" and results were compared using a chi-square test, t-test and logistic regression model with significance at p disease on initial presentation.

Disease-threat model explains acceptance of genetically modified products

Directory of Open Access Journals (Sweden)

Prokop Pavol

2013-01-01

Full Text Available Natural selection favoured survival of individuals who were able to avoid disease. The behavioural immune system is activated especially when our sensory system comes into contact with disease-connoting cues and/or when these cues resemble disease threat. We investigated whether or not perception of modern risky technologies, risky behaviour, expected reproductive goals and food neophobia are associated with the behavioural immune system related to specific attitudes toward genetically modified (GM products. We found that respondents who felt themselves more vulnerable to infectious diseases had significantly more negative attitudes toward GM products. Females had less positive attitudes toward GM products, but engaging in risky behaviours, the expected reproductive goals of females and food neophobia did not predict attitudes toward GM products. Our results suggest that evolved psychological mechanisms primarily designed to protect us against pathogen threat are activated by modern technologies possessing potential health risks.

Ceramic/polymer nanocomposites with tunable drug delivery capability at specific disease sites.

Science.gov (United States)

Liu, Huinan; Webster, Thomas J

2010-06-01

Pharmaceutical agents are often used to stimulate new bone formation for the treatment of bone injuries or diseases (such as osteoporosis). However, there are several problems associated with current orthopedic drug delivery methods. First, conventional systemic administration of pharmaceutical agents may not effectively reach targeted sites and, thus, they can cause nonspecific bone formation in areas not affected by injury or disease. Second, even if intentionally delivered or implanted locally to the damaged bone tissue, these agents tend to rapidly diffuse into adjacent tissues due to weak physical bonding to their drug carriers, which limits their potential to promote prolonged bone formation in targeted areas of bone disease. Therefore, in this study, biodegradable ceramic/polymer nanocomposites were explored as novel drug carriers for orthopedic applications to prolong local drug release and, thus, improve drug effectiveness at bone disease sites. Specifically, a bone morphogenetic protein (BMP-7) derived peptide (DIF-7c) was used as a model drug in this study and was first loaded onto nanocrystalline hydroxyapatite (nano-HA) by either covalent chemical attachment or physical adsorption. These drug-carrying nano-HA particles were then dispersed into a degradable polymer (poly-lactide-co-glycolide or PLGA) matrix to create an implantable system capable of long-term drug release. The aminophase silane covalent chemical immobilization process was utilized in this study. These nanocomposite-based drug delivery systems were then characterized for drug loading efficiency and in vitro drug release. Results demonstrated that DIF-7c was successfully immobilized onto nano-HA placed in PLGA. Moreover, a greater prolonged two-phase release profile (of more than 3 months) was achieved when using aminophase silane chemical immobilization to nano-HA particles. Since previous studies have demonstrated greater in vivo bone growth on nano- compared with micron-HA particles

World health dilemmas: Orphan and rare diseases, orphan drugs and orphan patients.

Science.gov (United States)

Kontoghiorghe, Christina N; Andreou, Nicholas; Constantinou, Katerina; Kontoghiorghes, George J

2014-09-26

According to global annual estimates hunger/malnutrition is the major cause of death (36 of 62 million). Cardiovascular diseases and cancer (5.44 of 13.43 million) are the major causes of death in developed countries, while lower respiratory tract infections, human immunodeficiency virus infection/acquired immunodeficiency syndrome, diarrhoeal disease, malaria and tuberculosis (10.88 of 27.12 million) are the major causes of death in developing countries with more than 70% of deaths occurring in children. The majority of approximately 800 million people with other rare diseases, including 100000 children born with thalassaemia annually receive no treatment. There are major ethical dilemmas in dealing with global health issues such as poverty and the treatment of orphan and rare diseases. Of approximately 50000 drugs about 10% are orphan drugs, with annual sales of the latter approaching 100 billion USD. In comparison, the annual revenue in 2009 from the top 12 pharmaceutical companies in Western countries was 445 billion USD and the top drug, atorvastatin, reached 100 billion USD. In the same year, the total government expenditure for health in the developing countries was 410 billion USD with only 6%-7% having been received as aid from developed countries. Drugs cost the National Health Service in the United Kingdom more than 20 billion USD or 10% of the annual health budget. Uncontrollable drug prices and marketing policies affect global health budgets, clinical practice, patient safety and survival. Fines of 5.3 billion USD were imposed on two pharmaceutical companies in the United States, the regulatory authority in France was replaced and clinicians were charged with bribery in order to overcome recent illegal practises affecting patient care. High expenditure for drug development is mainly related to marketing costs. However, only 2 million USD was spent developing the drug deferiprone (L1) for thalassaemia up to the stage of multicentre clinical trials. The

World health dilemmas: Orphan and rare diseases, orphan drugs and orphan patients

Science.gov (United States)

Kontoghiorghe, Christina N; Andreou, Nicholas; Constantinou, Katerina; Kontoghiorghes, George J

2014-01-01

According to global annual estimates hunger/malnutrition is the major cause of death (36 of 62 million). Cardiovascular diseases and cancer (5.44 of 13.43 million) are the major causes of death in developed countries, while lower respiratory tract infections, human immunodeficiency virus infection/acquired immunodeficiency syndrome, diarrhoeal disease, malaria and tuberculosis (10.88 of 27.12 million) are the major causes of death in developing countries with more than 70% of deaths occurring in children. The majority of approximately 800 million people with other rare diseases, including 100000 children born with thalassaemia annually receive no treatment. There are major ethical dilemmas in dealing with global health issues such as poverty and the treatment of orphan and rare diseases. Of approximately 50000 drugs about 10% are orphan drugs, with annual sales of the latter approaching 100 billion USD. In comparison, the annual revenue in 2009 from the top 12 pharmaceutical companies in Western countries was 445 billion USD and the top drug, atorvastatin, reached 100 billion USD. In the same year, the total government expenditure for health in the developing countries was 410 billion USD with only 6%-7% having been received as aid from developed countries. Drugs cost the National Health Service in the United Kingdom more than 20 billion USD or 10% of the annual health budget. Uncontrollable drug prices and marketing policies affect global health budgets, clinical practice, patient safety and survival. Fines of 5.3 billion USD were imposed on two pharmaceutical companies in the United States, the regulatory authority in France was replaced and clinicians were charged with bribery in order to overcome recent illegal practises affecting patient care. High expenditure for drug development is mainly related to marketing costs. However, only 2 million USD was spent developing the drug deferiprone (L1) for thalassaemia up to the stage of multicentre clinical trials. The

Modifiable Cardiovascular Disease Risk Factors among Indigenous Populations

Directory of Open Access Journals (Sweden)

Adam A. Lucero

2014-01-01

Full Text Available Objective. To identify modifiable cardio-metabolic and lifestyle risk factors among indigenous populations from Australia (Aboriginal Australians/Torres Strait Islanders, New Zealand (Māori, and the United States (American Indians and Alaska Natives that contribute to cardiovascular disease (CVD. Methods. National health surveys were identified where available. Electronic databases identified sources for filling missing data. The most relevant data were identified, organized, and synthesized. Results. Compared to their non-indigenous counterparts, indigenous populations exhibit lower life expectancies and a greater prevalence of CVD. All indigenous populations have higher rates of obesity and diabetes, hypertension is greater for Māori and Aboriginal Australians, and high cholesterol is greater only among American Indians/Alaska Natives. In turn, all indigenous groups exhibit higher rates of smoking and dangerous alcohol behaviour as well as consuming less fruits and vegetables. Aboriginal Australians and American Indians/Alaska Natives also exhibit greater rates of sedentary behaviour. Conclusion. Indigenous groups from Australia, New Zealand, and the United States have a lower life expectancy then their respective non-indigenous counterparts. A higher prevalence of CVD is a major driving force behind this discrepancy. A cluster of modifiable cardio-metabolic risk factors precede CVD, which, in turn, is linked to modifiable lifestyle risk factors.

Review on potential phytocompounds in drug development for Parkinson disease: A pharmacoinformatic approach

Directory of Open Access Journals (Sweden)

S. Vijayakumar

Full Text Available Parkinson's disease (PD is caused by human physiological function and is ranked as the second most common neurodegenerative disorder. One of the prominent therapies currently available for PD is the use of dopamine agonists which mimic the natural action of dopamine in the brain and stimulate dopamine receptors directly. Currently, available pharmaceutical drugs provide only temporary relief of the disease. Phytocompounds have been identified as promising target of research in the quest for new pharmaceutical compounds as they can produce secondary metabolites with novel chemical structure. In this review the drug development of Parkinson disease has been analyzed using computational tools. Keywords: Parkinson disease, Phytocompounds, Computational methods, Drug development and design

Orphan drugs in development for Huntington's disease: challenges and progress

Directory of Open Access Journals (Sweden)

Burgunder JM

2015-02-01

Full Text Available Jean-Marc Burgunder1–4 1Swiss Huntington’s Disease Centre, Department of Neurology, University of Bern, Bern, Switzerland; 2Department of Neurology, West China Hospital, Sichuan University, Chengdu, 3Department of Neurology, Xiangya Hospital, Central South University, Changsha, 4Department of Neurology, Sun Yat-sen University, Guangzhou, People’s Republic of China Abstract: Huntington’s disease is a monogenic disorder encompassing a variable phenotype with progressive cognitive, psychiatric, and movement disorders. Knowledge of the mechanisms involved in this disorder has made substantial advances since the discovery of the gene mutation. The dynamic mutation is the expansion of a CAG (cytosine-adenine-guanine repeat in the huntingtin (HTT gene, which is transcribed into an abnormal protein with an elongated polyglutamine tract. Polyglutamine HTT accumulates and is changed in its function in multifaceted ways related to the numerous roles of the normal protein. The protein is expressed in numerous areas of the brain and also in other organs. The major brain region involved in the disease process is the striatum, but it is clear that other systems are involved as well. This accumulated knowledge has now led to the development of treatment strategies based on specific molecular pathways for symptomatic and disease course-modifying treatment. The most proximal way to handle the disturbed protein is to hinder the gene transcription, translation, and/or to increase protein clearance. Other mechanisms now being approached include modulation of energy and intracellular signaling, induction of factors potentially leading to neuroprotection, as well as modulation of glial function. Several clinical trials based on these approaches are now under way, and it is becoming clear that a future disease-modifying therapy will be a combination of several approaches harmonized with symptomatic treatments. In this review, some of the most promising and

Modifying release characteristics from 3D printed drug-eluting products

DEFF Research Database (Denmark)

Boetker, Johan; Water, Jorrit; Aho, Johanna

2016-01-01

Abstract This work describes an approach to modify the release of active compound from a 3D printed model drug product geometry intended for flexible dosing and precision medication. The production of novel polylactic acid and hydroxypropyl methylcellulose based feed materials containing...... nitrofurantoin for 3D printing purposes is demonstrated. Nitrofurantoin, Metolose® and polylactic acid were successfully co-extruded with up to 40% Metolose® content, and subsequently 3D printed into model disk geometries (ø10 mm, h = 2 mm). Thermal analysis with differential scanning calorimetry and solid phase...... identification with Raman spectroscopy showed that nitrofurantoin remained in its original solid form during both hot-melt extrusion and subsequent 3D printing. Rheological measurements of the different compositions showed that the flow properties were sensitive to the amount of undissolved particles present...

Studying Disease Occurrence and Drug Effects in Children: A global approach

NARCIS (Netherlands)

O.U. Osokogu (Osemeke)

2017-01-01

markdownabstractChildhood diseases result from different causes and exhibit different characteristics. The occurrence of such diseases can be estimated from electronic healthcare records but the characteristics of both the diseases and the databases should be considered. Licensed drugs have limited

A Modified Murine Embryonic Stem Cell Test for Evaluating the Teratogenic Effects of Drugs on Early Embryogenesis.

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Ruoxing Yu

Full Text Available Mammalian fetal development is easily disrupted by exogenous agents, making it essential to test new drug candidates for embryotoxicity and teratogenicity. To standardize the testing of drugs that might be used to treat pregnant women, the U.S. Food and Drug Administration (FDA formulated special grade categories, labeled A, B, C, D and X, that define the level of risk associated with the use of a specific drug during pregnancy. Drugs in categories (Cat. D and X are those with embryotoxic and/or teratogenic effects on humans and animals. However, which stages of pregnancy are affected by these agents and their molecular mechanisms are unknown. We describe here an embryonic stem cell test (EST that classifies FDA pregnancy Cat.D and Cat.X drugs into 4 classes based on their differing effects on primitive streak formation. We show that ~84% of Cat.D and Cat.X drugs target this period of embryogenesis. Our results demonstrate that our modified EST can identify how a drug affects early embryogenesis, when it acts, and its molecular mechanism. Our test may thus be a useful addition to the drug safety testing armamentarium.

The use of random-effects models to identify health care center-related characteristics modifying the effect of antipsychotic drugs

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Nordon C

2017-12-01

Full Text Available Clementine Nordon,1 Constance Battin,1 Helene Verdoux,2 Josef Maria Haro,3 Mark Belger,4 Lucien Abenhaim,1 Tjeerd Pieter van Staa5 On behalf of the IMI GetReal WP2 Group 1Epidemiological Research, Analytica LASER, Paris, 2Population Health Research Center, Team Pharmaco-Epidemiology, UMR 1219, Bordeaux-2 University, INSERM, Bordeaux, France; 3Parc Sanitari Sant Joan de Deu, CIBERSAM, University of Barcelona, Barcelona, Spain; 4Eli Lilly and Company Limited, Erl Wood Manor, Windlesham, 5Farr Institute, University of Manchester, Manchester, UK Purpose: A case study was conducted, exploring methods to identify drugs effects modifiers, at a health care center level.Patients and methods: Data were drawn from the Schizophrenia Outpatient Health Outcome cohort, including hierarchical information on 6641 patients, recruited from 899 health care centers from across ten European countries. Center-level characteristics included the following: psychiatrist’s gender, age, length of practice experience, practice setting and type, countries’ Healthcare System Efficiency score, and psychiatrist density in the country. Mixed multivariable linear regression models were used: 1 to estimate antipsychotic drugs’ effectiveness (defined as the association between patients’ outcome at 3 months – dependent variable, continuous – and antipsychotic drug initiation at baseline – drug A vs other antipsychotic drug; 2 to estimate the similarity between clustered data (using the intra-cluster correlation coefficient; and 3 to explore antipsychotic drug effects modification by center-related characteristics (using the addition of an interaction term.Results: About 23% of the variance found for patients’ outcome was explained by unmeasured confounding at a center level. Psychiatrists’ practice experience was found to be associated with patient outcomes (p=0.04 and modified the relative effect of “drug A” (p<0.001, independent of center- or patient

Influence of Anti-TNF and Disease Modifying Antirheumatic Drugs Therapy on Pulmonary Forced Vital Capacity Associated to Ankylosing Spondylitis: A 2-Year Follow-Up Observational Study

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Alberto Daniel Rocha-Muñoz

2015-01-01

Full Text Available Objective. To evaluate the effect of anti-TNF agents plus synthetic disease modifying antirheumatic drugs (DMARDs versus DMARDs alone for ankylosing spondylitis (AS with reduced pulmonary function vital capacity (FVC%. Methods. In an observational study, we included AS who had FVC% <80% at baseline. Twenty patients were taking DMARDs and 16 received anti-TNF + DMARDs. Outcome measures: changes in FVC%, BASDAI, BASFI, 6-minute walk test (6MWT, Borg scale after 6MWT, and St. George’s Respiratory Questionnaire at 24 months. Results. Both DMARDs and anti-TNF + DMARDs groups had similar baseline values in FVC%. Significant improvement was achieved with anti-TNF + DMARDs in FVC%, at 24 months, when compared to DMARDs alone (P=0.04. Similarly, patients in anti-TNF + DMARDs group had greater improvement in BASDAI, BASFI, Borg scale, and 6MWT when compared to DMARDs alone. After 2 years of follow-up, 14/16 (87.5% in the anti-TNF + DMARDs group achieved the primary outcome: FVC% ≥80%, compared with 11/20 (55% in the DMARDs group (P=0.04. Conclusions. Patients with anti-TNF + DMARDs had a greater improvement in FVC% and cardiopulmonary scales at 24 months compared with DMARDs. This preliminary study supports the fact that anti-TNF agents may offer additional benefits compared to DMARDs in patients with AS who have reduced FVC%.

In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis.

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Pascal Trouvé

Full Text Available Cystic Fibrosis is the most common lethal autosomal recessive disorder in the white population, affecting among other organs, the lung, the pancreas and the liver. Whereas Cystic Fibrosis is a monogenic disease, many studies reveal a very complex relationship between genotype and clinical phenotype. Indeed, the broad phenotypic spectrum observed in Cystic Fibrosis is far from being explained by obvious genotype-phenotype correlations and it is admitted that Cystic Fibrosis disease is the result of multiple factors, including effects of the environment as well as modifier genes. Our objective was to highlight new modifier genes with potential implications in the lung, pancreatic and liver outcomes of the disease. For this purpose we performed a system biology approach which combined, database mining, literature mining, gene expression study and network analysis as well as pathway enrichment analysis and protein-protein interactions. We found that IFI16, CCNE2 and IGFBP2 are potential modifiers in the altered lung function in Cystic Fibrosis. We also found that EPHX1, HLA-DQA1, HLA-DQB1, DSP and SLC33A1, GPNMB, NCF2, RASGRP1, LGALS3 and PTPN13, are potential modifiers in pancreas and liver, respectively. Associated pathways indicate that immune system is likely involved and that Ubiquitin C is probably a central node, linking Cystic Fibrosis to liver and pancreatic disease. We highlight here new modifier genes with potential implications in Cystic Fibrosis. Nevertheless, our in silico analysis requires functional analysis to give our results a physiological relevance.

Global Trends in Alzheimer Disease Clinical Development: Increasing the Probability of Success.

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Sugino, Haruhiko; Watanabe, Akihito; Amada, Naoki; Yamamoto, Miho; Ohgi, Yuta; Kostic, Dusan; Sanchez, Raymond

2015-08-01

Alzheimer disease (AD) is a growing global health and economic issue as elderly populations increase dramatically across the world. Despite the many clinical trials conducted, currently no approved disease-modifying treatment exists. In this commentary, the present status of AD drug development and the grounds for collaborations between government, academia, and industry to accelerate the development of disease-modifying AD therapies are discussed. Official government documents, literature, and news releases were surveyed by MEDLINE and website research. Currently approved anti-AD drugs provide only short-lived symptomatic improvements, which have no effect on the underlying pathogenic mechanisms or progression of the disease. The failure to approve a disease-modifying drug for AD may be because the progression of AD in the patient populations enrolled in clinical studies was too advanced for drugs to demonstrate cognitive and functional improvements. The US Food and Drug Administration and the European Medicines Agency recently published draft guidance for industry which discusses approaches for conducting clinical studies with patients in early AD stages. For successful clinical trials in early-stage AD, however, it will be necessary to identify biomarkers highly correlated with the clinical onset and the longitudinal progress of AD. In addition, because of the high cost and length of clinical AD studies, support in the form of global initiatives and collaborations between government, industry, and academia is needed. In response to this situation, national guidance and international collaborations have been established. Global initiatives are focusing on 2025 as a goal to provide new treatment options, and early signs of success in biomarker and drug development are already emerging. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

A comparative analysis of the impact of a positive list system on new chemical entity drugs and incrementally modified drugs in South Korea.

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Ha, DongMun; Choi, Yong; Kim, Dae Up; Chung, Kyu Hyuck; Lee, Eui-Kyung

2011-07-01

Medical costs in South Korea have risen, in part due to increased demand and consumption of pharmaceutical products by an aging population and also because of the introduction of newer, more expensive drugs. In an effort to stabilize the financing of health insurance and alleviate the financial burden on individuals, the government implemented a policy changing the national health insurance drug-listing system from a negative list system to a positive list system (PLS). The goal of this study was to compare differences in drug-listing rates for new chemical entities (NCEs) and incrementally modified drugs (IMDs) after South Korea introduced the PLS in December 2006. Parameters significantly affecting NCE and IMD listings were also identified. New drug-listing data for 2007 and 2008 were obtained from the databases of the Health Insurance Review Agency and the Ministry of Health and Welfare. Descriptive analyses on the reimbursement rate and logistic regression analysis were conducted. Statistical significance was tested for all results, and P system by decreasing the drug-listing rate and lengthening the period for reimbursement determinations. These effects were more pronounced for NCE listings than for IMD listings. Crown Copyright © 2011. Published by EM Inc USA. All rights reserved.

Rare diseases and orphan drugs

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Domenica Taruscio

2011-01-01

Full Text Available According to the Regulation (EC N. 141/2000 of the European Parliament and of the Council, rare diseases are life-threatening or chronically debilitating conditions, affecting no more than 5 in 10 000 persons in the European Community. It is estimated that between 6000 to 8000 distinct rare diseases affect up to 6% of the total EU population. Therefore, these conditions can be considered rare if taken individually but they affect a significant proportion of the European population when considered as a single group. Several initiatives have been undertaken at international, European and national level to tackle public health as well as research issues related to the prevention, diagnosis, treatment and surveillance of these diseases. The development of innovative and effective medical products for their diagnosis and treatment is frequently hampered by several factors, including the limited knowledge of their natural history, the difficulties in setting up clinical studies due to the limited numbers of patients affected by a specific disease, the weak interest of sponsors due to the restricted market opportunities. Therefore, incentives and other facilitations have been adopted in many parts of the world, including in the EU, in order to facilitate the development and commercialization of diagnostic tools and treatments devoted to rare diseases. This paper illustrates mainly the European initiatives and will discuss the problematic and controversial aspects surrounding orphan drugs. Finally, activities and measures adopted in Italy are presented.

Adverse drug reactions associated with the use of disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis

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Jorge Enrique Machado-Alba

2014-12-01

Full Text Available This study describes the adverse drug reactions (ADRs and their incidence in patients with rheumatoid arthritis who were treated in the Colombian health system. A retrospective cohort study was conducted using information from all patients who were diagnosed with rheumatoid arthritis and attended specialized health care centers in the cities of Bogotá, Cali, Manizales, Medellin, and Pereira between 1 December 2009 and 30 August 2013. The ADRs were obtained from medical records and the pharmacovigilance system registry and sorted by frequency and affected tissue according to World Health Organization Adverse Reaction Terminology (WHO-ART. A total of 949 reports of ADRs were obtained from 419 patients (32.8 ADRs per 100 patient-years; these patients were from a cohort of 1 364 patients being treated for rheumatoid arthritis and followed up for an average of 23.8 months (± 12.9. The cohort was mostly female (366, 87.4% and had a mean age of 52.7 years (± 13.1. The highest numbers of ADRs were reported following the use of tocilizumab, rituximab, and infliximab (28.8, 23.1, and 13.3 reports per 100 patient-years respectively. The most frequently reported ADRs were elevated transaminase levels and dyspepsia. Overall, 87.7% of ADRs were classified as type A, 36.6% as mild, 40.7% as moderate, and 22.7% as severe. As a result, 73.2% of patients who experienced an ADR stopped taking their drugs. The occurrence of ADRs in patients treated for rheumatoid arthritis is common, especially in those associated with the use of biotechnologically produced anti-rheumatic drugs. This outcome should be studied in future research and monitoring is needed to reduce the risks in these patients.

Electrochemical determination of xanthine oxidase inhibitor drug in urate lowering therapy using graphene nanosheets modified electrode

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Raj, M. Amal; John, S. Abraham

2014-01-01

We report the electrochemical determination of urate lowering therapeutic drug, allopurinol (AP) using the electrochemically reduced graphene oxide (ERGO) modified glassy carbon electrode (GCE). The ERGO modified GCE was fabricated by self–assembling graphene oxide (GO) on 1,6-hexadiamine (HDA) modified GCE by the electrostatic interaction between the positively charged amine group and the negatively charged GO layers followed by the electrochemical reduction of GO layers at negative potential. XPS results confirmed the attachment of GO and its electrochemical reduction. The electrochemical behavior of AP was examined at ERGO modified electrode in the presence of ascorbic acid (AA) and uric acid (UA). It was found that ERGO modified electrode not only enhanced the oxidation currents of AP, AA and UA but also showed stable signals for them for repetitive potential cycles. The present modified electrode was successfully used to determine these analytes simultaneously in a mixture. Selective determination of AP in the presence of high concentrations of AA and UA was also demonstrated at ERGO modified GCE. Using amperometry, detections of 40 and 200 nM of UA and AP were achieved and the detection limits were found to be 9.0 × 10 −9 M and 1.1 × 10 −7 M, respectively (S/N = 3). Further, the practical application of the present modified electrode was demonstrated by simultaneously determining the concentrations of AA, UA and AP in human blood serum and urine samples

Anti-thyroid drugs in pediatric Graves′ disease

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Mathew John

2015-01-01

Full Text Available Graves′ disease is the most common cause of hyperthyroidism in children. Most children and adolescents are treated with anti-thyroid drugs as the initial modality. Studies have used Methimazole, Carbimazole and Propylthiouracil (PTU either as titration regimes or as block and replacement regimes. The various studies of anti-thyroid drug (ATD treatment of Graves′ disease in pediatric patients differ in terms of the regimes, remission rate, duration of therapy for adequate remission, follow up and adverse effects of ATD. Various studies show that lower thyroid hormone levels, prolonged duration of treatment, lower levels of TSH receptor antibodies, smaller goiter and increased age of child predicted higher chance of remission after ATD. A variable number of patients experience minor and major adverse effects limiting initial and long term treatment with ATD. The adverse effects of various ATD seem to more in children compared to that of adults. In view of liver injury including hepatocellular failure need of liver transplantation associated with PTU, the use has been restricted in children. The rate of persistent remission with ATD following discontinuation is about 30%. Radioactive iodine therapy is gaining more acceptance in older children with Graves′s disease in view of the limitations of ATD. For individual patients, risk-benefit ratio of ATD should be weighed against benefits of radioactive iodine therapy and patient preferences.

Cyclodextrin-Modified Porous Silicon Nanoparticles for Efficient Sustained Drug Delivery and Proliferation Inhibition of Breast Cancer Cells.

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Correia, Alexandra; Shahbazi, Mohammad-Ali; Mäkilä, Ermei; Almeida, Sérgio; Salonen, Jarno; Hirvonen, Jouni; Santos, Hélder A

2015-10-21

Over the past decade, the potential of polymeric structures has been investigated to overcome many limitations related to nanosized drug carriers by modulating their toxicity, cellular interactions, stability, and drug-release kinetics. In this study, we have developed a successful nanocomposite consisting of undecylenic acid modified thermally hydrocarbonized porous silicon nanoparticles (UnTHCPSi NPs) loaded with an anticancer drug, sorafenib, and surface-conjugated with heptakis(6-amino-6-deoxy)-β-cyclodextrin (HABCD) to show the impact of the surface polymeric functionalization on the physical and biological properties of the drug-loaded nanoparticles. Cytocompatibility studies showed that the UnTHCPSi-HABCD NPs were not toxic to breast cancer cells. HABCD also enhanced the suspensibility and both the colloidal and plasma stabilities of the UnTHCPSi NPs. UnTHCPSi-HABCD NPs showed a significantly increased interaction with breast cancer cells compared to bare NPs and also sustained the drug release. Furthermore, the sorafenib-loaded UnTHCPSi-HABCD NPs efficiently inhibited cell proliferation of the breast cancer cells.

Budget impact analysis of drugs for ultra-orphan non-oncological diseases in Europe.

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Schlander, Michael; Adarkwah, Charles Christian; Gandjour, Afschin

2015-02-01

Ultra-orphan diseases (UODs) have been defined by a prevalence of less than 1 per 50,000 persons. However, little is known about budget impact of ultra-orphan drugs. For analysis, the budget impact analysis (BIA) had a time horizon of 10 years (2012-2021) and a pan-European payer's perspective, based on prevalence data for UODs for which patented drugs are available and/or for which drugs are in clinical development. A total of 18 drugs under patent protection or orphan drug designation for non-oncological UODs were identified. Furthermore, 29 ultra-orphan drugs for non-oncological diseases under development that have the potential of reaching the market by 2021 were found. Total budget impact over 10 years was estimated to be €15,660 and €4965 million for approved and pipeline ultra-orphan drugs, respectively (total: €20,625 million). The analysis does not support concerns regarding an uncontrolled growth in expenditures for drugs for UODs.

Nuclear track microfilters in controlled drug delivery against chronic skin disease

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Gopalani, D. E-mail: deflab@sancharnet.in; Jodha, A.S.; Saravanan, S.; Kumar, S

2003-06-01

Nuclear track microfilters have been developed for transdermal therapeutic system. The transdermal therapeutic method reduces the toxicity of the drug as compared to other conventional methods. For this purpose a slow drug release system containing the nuclear track microfilter was developed. This device was applied to the patients suffering from psoriasis and cellulites diseases. The delivery of the drug to the patient was confirmed through high performance liquid chromatography. The preliminary results have shown that patients are responding to drugs with minimum toxicity.

Nuclear track microfilters in controlled drug delivery against chronic skin disease

International Nuclear Information System (INIS)

Gopalani, D.; Jodha, A.S.; Saravanan, S.; Kumar, S.

2003-01-01

Nuclear track microfilters have been developed for transdermal therapeutic system. The transdermal therapeutic method reduces the toxicity of the drug as compared to other conventional methods. For this purpose a slow drug release system containing the nuclear track microfilter was developed. This device was applied to the patients suffering from psoriasis and cellulites diseases. The delivery of the drug to the patient was confirmed through high performance liquid chromatography. The preliminary results have shown that patients are responding to drugs with minimum toxicity

Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity

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Massart, Julie; Begriche, Karima; Moreau, Caroline; Fromenty, Bernard

2017-01-01

Background Obesity is often associated with nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions including fatty liver, nonalcoholic steatohepatitis (NASH) and cirrhosis. Different investigations showed or suggested that obesity and NAFLD are able to increase the risk of hepatotoxicity of different drugs. Some of these drugs could induce more frequently an acute hepatitis in obese individuals whereas others could worsen pre-existing NAFLD. Aim The main objective of the present review was to collect the available information regarding the role of NAFLD as risk factor for drug-induced hepatotoxicity. For this purpose, we performed a data-mining analysis using different queries including drug-induced liver injury (or DILI), drug-induced hepatotoxicity, fatty liver, nonalcoholic fatty liver disease (or NAFLD), steatosis and obesity. The main data from the collected articles are reported in this review and when available, some pathophysiological hypotheses are put forward. Relevance for patients Drugs that could pose a potential risk in obese patients include compounds belonging to different pharmacological classes such as acetaminophen, halothane, methotrexate, rosiglitazone, stavudine and tamoxifen. For some of these drugs, experimental investigations in obese rodents confirmed the clinical observations and unveiled different pathophysiological mechanisms which could explain why these pharmaceuticals are particularly hepatotoxic in obesity and NAFLD. Other drugs such as pentoxifylline, phenobarbital and omeprazole might also pose a risk but more investigations are required to determine whether this risk is significant or not. Because obese people often take several drugs for the treatment of different obesity-related diseases such as type 2 diabetes, hyperlipidemia and coronary heart disease, it is urgent to identify the main pharmaceuticals that can cause acute hepatitis on a fatty liver background or induce NAFLD worsening

Harnessing Cerebrospinal Fluid Biomarkers in Clinical Trials for Treating Alzheimer's and Parkinson's Diseases: Potential and Challenges

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Kim, Dana; Kim, Young-Sam; Shin, Dong Wun; Park, Chang-Shin; Kang, Ju-Hee

2016-01-01

No disease-modifying therapies (DMT) for neurodegenerative diseases (NDs) have been established, particularly for Alzheimer's disease (AD) and Parkinson's disease (PD). It is unclear why candidate drugs that successfully demonstrate therapeutic effects in animal models fail to show disease-modifying effects in clinical trials. To overcome this hurdle, patients with homogeneous pathologies should be detected as early as possible. The early detection of AD patients using sufficiently tested bio...

Modified Harrington Procedure for Acetabular Insuficiency Due to Metastatic Malignant Disease

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WI Faisham

2009-05-01

Full Text Available Extensive peri-acetabular osteolysis caused by malignant disease process is a major surgical challenge as conventional hip arthroplasty is not adequate. We describe a modified use of the Harrington procedure for acetabular insufficiency secondary to metastatic disease in twelve patients. The procedures include application of multiple threaded pins to bridge the acetabular columns, anti-protrusio cage and cemented acetabular cup. Eleven patients were able to walk pain free and achieved a mean Musculoskeletal Tumour Society Functional Score of 80 (range, 68 to 86.

Can Patients with Cardiovascular Disease Take Nonsteroidal Antiinflammatory Drugs?

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... of the American Heart Association Cardiology Patient Page Can Patients With Cardiovascular Disease Take Nonsteroidal Antiinflammatory Drugs? ... It also does not upset the gastrointestinal tract. Can People With CVD Take an NSAID? If you ...

Addictive drugs and their relationship with infectious diseases.

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Friedman, Herman; Pross, Susan; Klein, Thomas W

2006-08-01

The use of drugs of abuse, both recreationally and medicinally, may be related to serious public health concerns. There is a relationship between addictive drugs of abuse such as alcohol and nicotine in cigarette smoke, as well as illegal drugs such as opiates, cocaine and marijuana, and increased susceptibility to infections. The nature and mechanisms of immunomodulation induced by such drugs of abuse are described in this review. The effects of opiates and marijuana, using animal models as well as in vitro studies with immune cells from experimental animals and humans, have shown that immunomodulation induced by these drugs is mainly receptor-mediated, either directly by interaction with specific receptors on immune cells or indirectly by reaction with similar receptors on cells of the nervous system. Similar studies also show that cocaine and nicotine have marked immunomodulatory effects, which are mainly receptor-mediated. Both cocaine, an illegal drug, and nicotine, a widely used legal addictive component of cigarettes, are markedly immunomodulatory and increase susceptibility to infection. The nature and mechanism of immunomodulation induced by alcohol, the most widely used addictive substance of abuse, are similar but immunomodulatory effects, although not receptor-mediated. The many research studies on the effects of these drugs on immunity and increased susceptibility to infectious diseases, including AIDS, are providing a better understanding of the complex interactions between immunity, infections and substance abuse.

The availability and affordability of orphan drugs for rare diseases in China.

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Gong, Shiwei; Wang, Yingxiao; Pan, Xiaoyun; Zhang, Liang; Huang, Rui; Chen, Xin; Hu, Juanjuan; Xu, Yi; Jin, Si

2016-02-27

Orphan drugs are intended to treat, prevent or diagnose rare diseases. In recent years, China healthcare policy makers and patients have become increasingly concerned about orphan drug issues. However, very few studies have assessed the availability and affordability of orphan drugs for rare diseases in China. The aim of this study was to provide an overview of the availability and affordability of orphan drugs in China and to make suggestions to improve patient access to orphan drugs. Two components of the availability of orphan drugs were examined. Market availability was assessed by the extent to which orphan drugs were marketed in China with a comparison to orphan drugs in international markets, such as the U.S., EU and Japan. We conducted surveys and collected data from 24 tertiary public hospitals in China to measure hospital-level availability of orphan drugs. The affordability of orphan drugs was calculated using hospital dispensary prices and was expressed as days of average daily income required for the cost of a course of treatment. Affordability was also analyzed under the Chinese basic medical insurance system. Orphan drugs approved in the U.S., EU and Japan had 37.8%, 24.6% and 52.4% market availability in China, respectively. Median availability of 31 orphan drugs surveyed at the 24 tertiary public hospitals was 20.8% (very low). Within a periodic treatment course, the average treatment cost of 23 orphan drugs is approximately 4, 843. 5 USD, which equates to 505.6 days of per capita net income for an urban resident with a middle income (187.4 days for a high-income urban resident) or 1,582.8 days's income for a rural resident with a middle income (657.2 days for a high-income rural resident). Except for homoharringtonine, 22 orphan drugs for 14 rare diseases were unaffordable for the most of residents in China. With 5% out-of-pocket expenses, only three generics could be afforded by middle-income residents, whereas seven drugs for high-income urban

From research on rare diseases to new orphan drug development

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Heemstra, H.E.

2010-01-01

Rare diseases have a prevalence of lower than 5 in 10,000 inhabitants and are life-threatening or chronically debilitating. It is estimated that worldwide more than 5000 rare diseases exist, which account for over 55 million patients in the EU and the US together. However, the development of drugs

Nano materials for the Local and Targeted Delivery of Osteoarthritis Drugs

International Nuclear Information System (INIS)

Periyasamy, P.C.; Leijten, J.C.H.; Dijkstra, P.J.; Karperien, M.; Post, J.N.

2012-01-01

Nano technology has found its potential in every possible field of science and engineering. It offers a plethora of options to design tools at the nanometer scale, which can be expected to function more effectively than micro- and macro systems for specific applications. Although the debate regarding the safety of synthetic nano materials for clinical applications endures, it is a promising technology due to its potential to augment current treatments. Various materials such as synthetic polymer, biopolymers, or naturally occurring materials such as proteins and peptides can serve as building blocks for adaptive nano scale formulations. The choice of materials depends highly on the application. We focus on the use of nanoparticles for the treatment of degenerative cartilage diseases, such as osteoarthritis (OA). Current therapies for OA focus on treating the symptoms rather than modifying the disease. The usefulness of OA disease modifying drugs is hampered by side effects and lack of suitable drug delivery systems that target, deliver, and retain drugs locally. This challenge can be overcome by using nano technological formulations. We describe the different nano drug delivery systems and their potential for cartilage repair. This paper provides the reader basal understanding of nano materials and aims at drawing new perspectives on the use of existing nano technological formulations for the treatment of osteoarthritis.

The current state of GPCR-based drug discovery to treat metabolic disease.

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Sloop, Kyle W; Emmerson, Paul J; Statnick, Michael A; Willard, Francis S

2018-02-02

One approach of modern drug discovery is to identify agents that enhance or diminish signal transduction cascades in various cell types and tissues by modulating the activity of GPCRs. This strategy has resulted in the development of new medicines to treat many conditions, including cardiovascular disease, psychiatric disorders, HIV/AIDS, certain forms of cancer and Type 2 diabetes mellitus (T2DM). These successes justify further pursuit of GPCRs as disease targets and provide key learning that should help guide identifying future therapeutic agents. This report reviews the current landscape of GPCR drug discovery with emphasis on efforts aimed at developing new molecules for treating T2DM and obesity. We analyse historical efforts to generate GPCR-based drugs to treat metabolic disease in terms of causal factors leading to success and failure in this endeavour. © 2018 The British Pharmacological Society.

FDM 3D printing of modified drug-delivery systems using hot melt extrusion: a new approach for individualized therapy.

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Cunha-Filho, Marcilio; Araújo, Maísa Rp; Gelfuso, Guilherme M; Gratieri, Tais

2017-11-01

The production process of 3D-printed drugs offers unique advantages such as the possibility of individualizing the drug therapy and easily associating different drugs and release technologies in the same pharmaceutical unit. Fused deposition modeling, a 3D printing technique, seems especially interesting for pharmaceutical applications, due to its low cost, precise and reproducible control of the printed structures, and versatility for industrial and laboratory scale. This technique combined with another technology already adapted for the pharmaceutical industry, the hot melt extrusion, is able to incorporate various mechanisms of modified drug release. This special report aims to bring together data of the experimental progress achieved using the fused deposition modeling 3D printing combined with hot melt extrusion technique and its potential in drug delivery. [Formula: see text].

Use of tofacitinib in real clinical practice to treat patients with rheumatoid arthritis resistant to synthetic and biological disease-modifying antirheumatic drugs: Results of a multicenter observational study

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D. E. Karateev

2016-01-01

Full Text Available Tofacitinib (TOFA, a member of a new class of targeted synthetic disease-modifying antirheumatic drugs (DMARDs, is a promising medication for the treatment of rheumatoid arthritis (RA and other immunoinflammatory diseases. The paper describes the Russian experi-ence with TOFA used to treat severe RA.Patients and methods. 101 RA patients (18 men and 83 women; mean age, 51.03±11.28 years; mean disease duration, 105.4±81.43 months who were positive for rheumatoid factor (89.1% and anti-cyclic citrullinated peptide antibodies (74.7% and resistant to therapy with synthetic DMARDs (sDMARDs (80.2% and biological agents (19.8% were given TOFA at a dose of 5 mg twice daily, which could be doubled if necessary. TOFA was used alone (n=9 or in combination with methotrexate (MT (n=75 or other sDMARDs (n=17. The achievement of low disease activity (LDA and clinical remission at 3 and 6 months of treatment by DAS28-ESR SDAI, and CDAI scores, and the indices of safety and tolerability were assessed.Results. A total of 93 (92.1% of the 101 patients completed a 24-week period of the investigation. 8 (7.9% patients prematurely discontinued TOFA after an average of 2.75±0.71 months. At the end of the study, the patients achieved the primary endpoint (LDA including remission in terms of DAS28-ESR ≤3.2 (34.7%, SDAI ≤11 (47.5%, and CDAI ≤10 (48.5% and the secondary endpoints (clinical remission in terms of DAS28-ESR ≤2.6 (17.8%, SDAI ≤3.3 (8.9%, and CDAI ≤2.8 (6.9%. When TOFA was combined with MT, the discontinuation rate for the former was significantly lower (2.7% than when TOFA was used in combination with other sDMARDs (29.4% or alone (11.1%; p<0.01. At 3 and 6 months of follow-up, LDA was achieved more frequently when TOFA was combined with MT than when other treatment regimens were used. Fatal outcomes and serious adverse events (AEs, as AEs previously undescribed in the literature, were not seen during a follow-up within

Progression of motor symptoms in Parkinson's disease

Institute of Scientific and Technical Information of China (English)

Ruiping Xia; Zhi-Hong Mao

2012-01-01

Parkinson's disease (PD) is a chronic progressive neurodegenerative disease that is clinically manifested by a triad of cardinal motor symptoms - rigidity,bradykinesia and tremor - due to loss of dopaminergic neurons.The motor symptoms of PD become progressively worse as the disease advances.PD is also a heterogeneous disease since rigidity and bradykinesia are the major complaints in some patients whereas tremor is predominant in others.In recent years,many studies have investigated the progression of the hallmark symptoms over time,and the cardinal motor symptoms have different rates of progression,with the disease usually progressing faster in patients with rigidity and bradykinesia than in those with predominant tremor.The current treatment regime of dopamine-replacement therapy improves motor symptoms and alleviates disability.Increasing the dosage of dopaminergic medication is commonly used to combat the worsenirtg symptoms.However,the drug-induced involuntary body movements and motor comphcations can significantly contribute to overall disability.Further,none of the currently-available therapies can slow or halt the disease progression.Significant research efforts have been directed towards developing neuroprotective or disease-modifying agents that are intended to slow the progression.In this article,the most recent clinical studies investigating disease progression and current progress on the development of disease-modifying drug trials are reviewed.

Towards the concept of disease-modifier in post-stroke or vascular cognitive impairment: a consensus report.

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Bordet, Régis; Ihl, Ralf; Korczyn, Amos D; Lanza, Giuseppe; Jansa, Jelka; Hoerr, Robert; Guekht, Alla

2017-05-24

Vascular cognitive impairment (VCI) is a complex spectrum encompassing post-stroke cognitive impairment (PSCI) and small vessel disease-related cognitive impairment. Despite the growing health, social, and economic burden of VCI, to date, no specific treatment is available, prompting the introduction of the concept of a disease modifier. Within this clinical spectrum, VCI and PSCI remain advancing conditions as neurodegenerative diseases with progression of both vascular and degenerative lesions accounting for cognitive decline. Disease-modifying strategies should integrate both pharmacological and non-pharmacological multimodal approaches, with pleiotropic effects targeting (1) endothelial and brain-blood barrier dysfunction; (2) neuronal death and axonal loss; (3) cerebral plasticity and compensatory mechanisms; and (4) degenerative-related protein misfolding. Moreover, pharmacological and non-pharmacological treatment in PSCI or VCI requires valid study designs clearly stating the definition of basic methodological issues, such as the instruments that should be used to measure eventual changes, the biomarker-based stratification of participants to be investigated, and statistical tests, as well as the inclusion and exclusion criteria that should be applied. A consensus emerged to propose the development of a disease-modifying strategy in VCI and PSCI based on pleiotropic pharmacological and non-pharmacological approaches.

Monitoring the efficacy of drugs for neglected tropical diseases controlled by preventive chemotherapy.

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Albonico, M; Levecke, B; LoVerde, P T; Montresor, A; Prichard, R; Vercruysse, J; Webster, J P

2015-12-01

In the last decade, pharmaceutical companies, governments and global health organisations under the leadership of the World Health Organization (WHO) have pledged large-scale donations of anthelmintic drugs, including ivermectin (IVM), praziquantel (PZQ), albendazole (ALB) and mebendazole (MEB). This worldwide scale-up in drug donations calls for strong monitoring systems to detect any changes in anthelmintic drug efficacy. This review reports on the outcome of the WHO Global Working Group on Monitoring of Neglected Tropical Diseases Drug Efficacy, which consists of three subgroups: (i) soil-transmitted helminthiases (ALB and MEB); (ii) onchocerciasis and lymphatic filariasis (IVM); and (iii) schistosomiasis (PZQ). Progress of ongoing work, challenges and research needs for each of the four main drugs used in helminthic preventive chemotherapy (PC) are reported, laying the ground for appropriate implementation of drug efficacy monitoring programmes under the co-ordination and guidelines of the WHO. Best practices for monitoring drug efficacy should be made available and capacity built as an integral part of neglected tropical disease (NTD) programme monitoring. Development of a disease-specific model to predict the impact of PC programmes, to detect outliers and to solicit responses is essential. Research studies on genetic polymorphisms in relation to low-efficacy phenotypes should be carried out to identify markers of putative resistance against all NTD drugs and ultimately to develop diagnostic assays. Development of combination and co-administration of NTD drugs as well as of new drug entities to boost the armamentarium of the few drugs available for NTD control and elimination should be pursued in parallel. Copyright © 2015 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.

Re-Inventing Infectious Disease: Antibiotic Resistance and Drug Development at the Bayer Company 1945-80.

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Gradmann, Christoph

2016-04-01

This paper analyses how research on antibiotic resistance has been a driving force in the development of new antibiotics. Drug resistance, while being a problem for physicians and patients, offers attractive perspectives for those who research and develop new medicines. It imposes limits on the usability of older medicines and simultaneously modifies pathologies in a way that opens markets for new treatments. Studying resistance can thus be an important part of developing and marketing antibiotics. The chosen example is that of the German pharmaceutical company Bayer. Before World War Two, Bayer had pioneered the development of anti-infective chemotherapy, sulpha drugs in particular, but had missed the boat when it came to fungal antibiotics. Exacerbated by the effects of war, Bayer's world market presence, which had been considerable prior to the war, had plummeted. In this critical situation, the company opted for a development strategy that tried to capitalise on the problems created by the use of first-generation antibiotics. Part and parcel of this strategy was monitoring what can be called the structural change of infectious disease. In practice, this meant to focus on pathologies resulting from resistance and hospital infections. In addition, Bayer also focused on lifestyle pathologies such as athlete's foot. This paper will follow drug development and marketing at Bayer from 1945 to about 1980. In this period, Bayer managed to regain some of its previous standing in markets but could not escape from the overall crisis of anti-infective drug development from the 1970s on.

Recent progress on fabrication and drug delivery applications of nanostructured hydroxyapatite.

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Mondal, Sudip; Dorozhkin, Sergy V; Pal, Umapada

2018-07-01

Through this brief review, we provide a comprehensive historical background of the development of nanostructured hydroxyapatite (nHAp), and its application potentials for controlled drug delivery, drug conjugation, and other biomedical treatments. Aspects associated with efficient utilization of hydroxyapatite (HAp) nanostructures such as their synthesis, interaction with drug molecules, and other concerns, which need to be resolved before they could be used as a potential drug carrier in body system, are discussed. This review focuses on the evolution of perceptions, practices, and accomplishments in providing improved delivery systems for drugs until date. The pioneering developments that have presaged today's fascinating state of the art drug delivery systems based on HAp and HAp-based composite nanostructures are also discussed. Special emphasis has been given to describe the application and effectiveness of modified HAp as drug carrier agent for different diseases such as bone-related disorders, carriers for antibiotics, anti-inflammatory, carcinogenic drugs, medical imaging, and protein delivery agents. As only a very few published works made comprehensive evaluation of HAp nanostructures for drug delivery applications, we try to cover the three major areas: concepts, practices and achievements, and applications, which have been consolidated and patented for their practical usage. The review covers a broad spectrum of nHAp and HAp modified inorganic drug carriers, emphasizing some of their specific aspects those needed to be considered for future drug delivery applications. This article is categorized under: Implantable Materials and Surgical Technologies > Nanomaterials and Implants Therapeutic Approaches and Drug Discovery > Nanomedicine for Respiratory Disease Nanotechnology Approaches to Biology > Cells at the Nanoscale. © 2017 Wiley Periodicals, Inc.

New drugs for the treatment of dry eye disease

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Ridder, III, William; Karsolia,Apoorva

2015-01-01

William H Ridder III, Apoorva Karsolia Southern California College of Optometry, Marshall B Ketchum University, Fullerton, CA, USA Abstract: Dry eye disease (DED) is one of the most commonly encountered conditions for eye care practitioners. The prevalence of DED can be as high as 30% of the population. In the past decade, only one drug has been approved for the treatment of DED by the US Food and Drug Administration (FDA) in the USA (ie, Restasis® by Allergan, Inc.). The total annua...

Mast Cell Stabilizers as Host Modulatory Drugs to Prevent and Control Periodontal Disease

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Dhoom Singh Mehta

2011-01-01

Full Text Available Introduction: Mast cells are among the first cells to get in-volved in periodontal inflammation. Their numbers have been shown to be in-creased in cases of gingivitis and periodontal disease. The hypothesis: Since mast cell stabilizers like sodium cromogly-cate (SCG and nedocromil sodium (NS have been used in the prophylaxis of bronchial asthma without any significant adverse effects and also the fact that drugs like SCG show significant anti-inflammatory activities, it would be logical to use mast cell stabilizers as host modulating drugs for the treatment and prevention of peri-odontal disease. Evaluation of the hypothesis: Safety and efficacy of both SCG and NS are well documented. So, it will be systemically safe to use in humans. However, oral administration SCG or delivery of the drug by means local irrigation will not be very useful because SCG may not be secreted in the gingival crevicular fluid (GCF(as in the case of oral administraion or the drug may get washed out from periodontal pocket due to the constant flow of GCF(as in the case of irrigation. A local or targeted drug delivery of mast cell stabilizers can be used in patients with periodontal disease. Role of mast cells in periodontal disease has been dealt in-depth in many studies and articles. However, limited amount of research has been done on using mast cell stabilizers in the prevention and control of periodontal diseases. More studies are needed to study the efficacy and effective-ness of mast cell stabilizers as an adjunct to phase I therapy in the control of periodontal disease.

Disease-responsive drug delivery: the next generation of smart delivery devices.

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Wanakule, Prinda; Roy, Krishnendu

2012-01-01

With the advent of highly potent and cytotoxic drugs, it is increasingly critical that they be targeted and released only in cells of diseased tissues, while sparing physiologically normal neighbors. Simple ligand-based targeting of drug carriers, although promising, cannot always provide the required specificity to achieve this since often normal cells also express significant levels of the targeted receptors. Therefore, stimuli-responsive delivery systems are being explored to allow drug release from nano- and microcarriers and implantable devices, primarily in the presence of physiological or disease-specific pathophysiological signals. Designing smart biomaterials that respond to temperature or pH changes, protein and ligand binding, disease-specific degradation, e.g. enzymatic cleavage, has become an integral part of this approach. These strategies are used in combination with nano- and microparticle systems to improve delivery efficiency through several routes of administration, and with injectable or implantable systems for long term controlled release. This review focuses on recent developments in stimuli-responsive systems, their physicochemical properties, release profiles, efficacy, safety and biocompatibility, as well as future perspectives.

Disease-specific induced pluripotent stem cells: a platform for human disease modeling and drug discovery.

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Jang, Jiho; Yoo, Jeong-Eun; Lee, Jeong-Ah; Lee, Dongjin R; Kim, Ji Young; Huh, Yong Jun; Kim, Dae-Sung; Park, Chul-Yong; Hwang, Dong-Youn; Kim, Han-Soo; Kang, Hoon-Chul; Kim, Dong-Wook

2012-03-31

The generation of disease-specific induced pluripotent stem cell (iPSC) lines from patients with incurable diseases is a promising approach for studying disease mechanisms and drug screening. Such innovation enables to obtain autologous cell sources in regenerative medicine. Herein, we report the generation and characterization of iPSCs from fibroblasts of patients with sporadic or familial diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), juvenile-onset, type I diabetes mellitus (JDM), and Duchenne type muscular dystrophy (DMD), as well as from normal human fibroblasts (WT). As an example to modeling disease using disease-specific iPSCs, we also discuss the previously established childhood cerebral adrenoleukodystrophy (CCALD)- and adrenomyeloneuropathy (AMN)-iPSCs by our group. Through DNA fingerprinting analysis, the origins of generated disease-specific iPSC lines were identified. Each iPSC line exhibited an intense alkaline phosphatase activity, expression of pluripotent markers, and the potential to differentiate into all three embryonic germ layers: the ectoderm, endoderm, and mesoderm. Expression of endogenous pluripotent markers and downregulation of retrovirus-delivered transgenes [OCT4 (POU5F1), SOX2, KLF4, and c-MYC] were observed in the generated iPSCs. Collectively, our results demonstrated that disease-specific iPSC lines characteristically resembled hESC lines. Furthermore, we were able to differentiate PD-iPSCs, one of the disease-specific-iPSC lines we generated, into dopaminergic (DA) neurons, the cell type mostly affected by PD. These PD-specific DA neurons along with other examples of cell models derived from disease-specific iPSCs would provide a powerful platform for examining the pathophysiology of relevant diseases at the cellular and molecular levels and for developing new drugs and therapeutic regimens.

The Cost-effectiveness of Sequences of Biological Disease-modifying Antirheumatic Drug Treatment in England for Patients with Rheumatoid Arthritis Who Can Tolerate Methotrexate.

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Stevenson, Matt D; Wailoo, Allan J; Tosh, Jonathan C; Hernandez-Alava, Monica; Gibson, Laura A; Stevens, John W; Archer, Rachel J; Simpson, Emma L; Hock, Emma S; Young, Adam; Scott, David L

2017-07-01

To ascertain whether strategies of treatment with a biological disease-modifying antirheumatic drug (bDMARD) are cost-effective in an English setting. Results are presented for those patients with moderate to severe rheumatoid arthritis (RA) and those with severe RA. An economic model to assess the cost-effectiveness of 7 bDMARD was developed. A systematic literature review and network metaanalysis was undertaken to establish relative clinical effectiveness. The results were used to populate the model, together with estimates of Health Assessment Questionnaire (HAQ) score following European League Against Rheumatism response; annual costs, and utility, per HAQ band; trajectory of HAQ for patients taking bDMARD; and trajectory of HAQ for patients using nonbiologic therapy (NBT). Results were presented as those associated with the strategy with the median cost-effectiveness. Supplementary analyses were undertaken assessing the change in cost-effectiveness when only patients with the most severe prognoses taking NBT were provided with bDMARD treatment. The costs per quality-adjusted life-year (QALY) values were compared with reported thresholds from the UK National Institute for Health and Care Excellence of £20,000 to £30,000 (US$24,700 to US$37,000). In the primary analyses, the cost per QALY of a bDMARD strategy was £41,600 for patients with severe RA and £51,100 for those with moderate to severe RA. Under the supplementary analyses, the cost per QALY fell to £25,300 for those with severe RA and to £28,500 for those with moderate to severe RA. The cost-effectiveness of bDMARD in RA in England is questionable and only meets current accepted levels in subsets of patients with the worst prognoses.

Polymeric micelles for drug targeting.

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Mahmud, Abdullah; Xiong, Xiao-Bing; Aliabadi, Hamidreza Montazeri; Lavasanifar, Afsaneh

2007-11-01

Polymeric micelles are nano-delivery systems formed through self-assembly of amphiphilic block copolymers in an aqueous environment. The nanoscopic dimension, stealth properties induced by the hydrophilic polymeric brush on the micellar surface, capacity for stabilized encapsulation of hydrophobic drugs offered by the hydrophobic and rigid micellar core, and finally a possibility for the chemical manipulation of the core/shell structure have made polymeric micelles one of the most promising carriers for drug targeting. To date, three generations of polymeric micellar delivery systems, i.e. polymeric micelles for passive, active and multifunctional drug targeting, have arisen from research efforts, with each subsequent generation displaying greater specificity for the diseased tissue and/or targeting efficiency. The present manuscript aims to review the research efforts made for the development of each generation and provide an assessment on the overall success of polymeric micellar delivery system in drug targeting. The emphasis is placed on the design and development of ligand modified, stimuli responsive and multifunctional polymeric micelles for drug targeting.

Scleroglucan: A Versatile Polysaccharide for Modified Drug Delivery

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Franco Alhaique

2005-01-01

Full Text Available Scleroglucan is a natural polysaccharide, produced by fungi of the genus Sclerotium, that has been extensively studied for various commercial applications (secondary oil recovery, ceramic glazes, food, paints, etc. and also shows several interesting pharmacological properties. This review focuses its attention on the use of scleroglucan, and some derivatives, in the field of pharmaceutics and in particular for the formulation of modified-release dosage forms. The reported investigations refer mainly to the following topics: natural scleroglucan suitable for the preparation of sustained release tablets and ocular formulations; oxidized and crosslinked scleroglucan used as a matrix for dosage forms sensitive to environmental conditions; co-crosslinked scleroglucan/gellan whose delivery rate can be affected by calcium ions. Furthermore, a novel hydrogel obtained with this polysaccharide and borate ions is described, and the particular structure of this hydrogel network has been interpreted in terms of conformational analysis and molecular dynamics. Profound attention is devoted to the mechanisms involved in drug release from the tested dosage forms that depend, according to the specific preparation, on swelling and/or diffusion. Experimental data are also discussed on the basis of a mathematical approach that allows a better understanding of the behavior of the tested polymeric materials.

Is aspirin still the drug of choice for management of patients with peripheral arterial disease?

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Poredos, Pavel; Jezovnik, Mateja K

2013-03-01

Antiplatelet drugs represent one of the basic options for management of patients with different atherosclerotic diseases. Aspirin is the oldest and most often prescribed antiplatelet drug. The efficacy of aspirin depends on the clinical characteristics of the treated population and probably also on the type or location of atherosclerotic disease. It seems that it is most effective in coronary patients with clinically unstable disease, less effective in prevention of cerebrovascular incidents, and its efficacy is uncertain in peripheral artery disease (PAD) patients. One of the first meta-analyses (Antithrombotic Trialists' Collaboration - ATC) indicated that antiplatelet drugs also significantly reduce cardiovascular events in patients with PAD. However, only one third of the PAD patients included were treated with aspirin, while the rest received other anti-platelet drugs. The latest ATC meta-analysis of randomized control trials of aspirin therapy involving patients with diabetes and PAD demonstrated no benefit of aspirin in reducing cardiovascular events. Also in patients with preclinical PAD (pathological ankle brachial index) aspirin did not result in a significant reduction of vascular events. The new anti-platelet drugs prasugrel, ticagrelor and picotamide seem to be more effective than aspirin in PAD patients, particularly in diabetic patients with PAD. In conclusion, antiplatelet drugs are effective in prevention of cardiovascular events in different atherosclerotic diseases, including PAD. However, recent studies indicated that in PAD patients aspirin is less effective than in coronary artery disease. New anti-platelet drugs showed marginal superiority over aspirin without definite advantages. Aspirin thus remains the first line of antiplatelet drug for secondary prevention of cardiovascular events in PAD patients and clopidogrel as its effective alternative. Further, new studies on PAD patients are necessary to better define the role of anti

Hemolytic Disease of the Fetus and Newborn due to Intravenous Drug Use.

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Markham, Kara B; Scrape, Scott R; Prasad, Mona; Rossi, Karen Q; O'Shaughnessy, Richard W

2016-03-01

Objectives The objective is to present a pregnancy complication associated with intravenous drug use, namely, that of red blood cell alloimmunization and hemolytic disease of the fetus and newborn. Methods An observational case series is presented including women with red blood cell alloimmunization most likely secondary to intravenous drug abuse Results Five pregnancies were identified that were complicated by red blood cell alloimmunization and significant hemolytic disease of the fetus and newborn, necessitating intrauterine transfusion, an indicated preterm birth, or neonatal therapy. Conclusions As opioid abuse continues to increase in the United States, clinicians should be aware of the potential for alloimmunization to red blood cell antibodies as yet another negative outcome from intravenous drug abuse.

Patient-derived stem cells: pathways to drug discovery for brain diseases

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Alan eMackay-Sim

2013-03-01

Full Text Available The concept of drug discovery through stem cell biology is based on technological developments whose genesis is now coincident. The first is automated cell microscopy with concurrent advances in image acquisition and analysis, known as high content screening (HCS. The second is patient-derived stem cells for modelling the cell biology of brain diseases. HCS has developed from the requirements of the pharmaceutical industry for high throughput assays to screen thousands of chemical compounds in the search for new drugs. HCS combines new fluorescent probes with automated microscopy and computational power to quantify the effects of compounds on cell functions. Stem cell biology has advanced greatly since the discovery of genetic reprogramming of somatic cells into induced pluripotent stem cells (iPSCs. There is now a rush of papers describing their generation from patients with various diseases of the nervous system. Although the majority of these have been genetic diseases, iPSCs have been generated from patients with complex diseases (schizophrenia and sporadic Parkinson’s disease. Some genetic diseases are also modelled in embryonic stem cells generated from blastocysts rejected during in vitro fertilisation. Neural stem cells have been isolated from post-mortem brain of Alzheimer’s patients and neural stem cells generated from biopsies of the olfactory organ of patients is another approach. These olfactory neurosphere-derived cells demonstrate robust disease-specific phenotypes in patients with schizophrenia and Parkinson’s disease. High content screening is already in use to find small molecules for the generation and differentiation of embryonic stem cells and induced pluripotent stem cells. The challenges for using stem cells for drug discovery are to develop robust stem cell culture methods that meet the rigorous requirements for repeatable, consistent quantities of defined cell types at the industrial scale necessary for high

Uptake Mechanism of ApoE-Modified Nanoparticles on Brain Capillary Endothelial Cells as a Blood-Brain Barrier Model

OpenAIRE

Wagner, Sylvia; Zensi, Anja; Wien, Sascha L.; Tschickardt, Sabrina E.; Maier, Wladislaw; Vogel, Tikva; Worek, Franz; Pietrzik, Claus U.; Kreuter, Jörg; von Briesen, Hagen

2012-01-01

Background: The blood-brain barrier (BBB) represents an insurmountable obstacle for most drugs thus obstructing an effective treatment of many brain diseases. One solution for overcoming this barrier is a transport by binding of these drugs to surface-modified nanoparticles. Especially apolipoprotein E (ApoE) appears to play a major role in the nanoparticle-mediated drug transport across the BBB. However, at present the underlying mechanism is incompletely understood. Methodology/Principal Fi...

Increased Loading, Efficacy and Sustained Release of Silibinin, a Poorly Soluble Drug Using Hydrophobically-Modified Chitosan Nanoparticles for Enhanced Delivery of Anticancer Drug Delivery Systems

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Cha Yee Kuen

2017-11-01

Full Text Available Conventional delivery of anticancer drugs is less effective due to pharmacological drawbacks such as lack of aqueous solubility and poor cellular accumulation. This study reports the increased drug loading, therapeutic delivery, and cellular accumulation of silibinin (SLB, a poorly water-soluble phenolic compound using a hydrophobically-modified chitosan nanoparticle (pCNP system. In this study, chitosan nanoparticles were hydrophobically-modified to confer a palmitoyl group as confirmed by 2,4,6-Trinitrobenzenesulfonic acid (TNBS assay. Physicochemical features of the nanoparticles were studied using the TNBS assay, and Attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR analyses. The FTIR profile and electron microscopy correlated the successful formation of pCNP and pCNP-SLB as nano-sized particles, while Dynamic Light Scattering (DLS and Field Emission-Scanning Electron Microscopy (FESEM results exhibited an expansion in size between pCNP and pCNP-SLB to accommodate the drug within its particle core. To evaluate the cytotoxicity of the nanoparticles, a Methylthiazolyldiphenyl-tetrazolium bromide (MTT cytotoxicity assay was subsequently performed using the A549 lung cancer cell line. Cytotoxicity assays exhibited an enhanced efficacy of SLB when delivered by CNP and pCNP. Interestingly, controlled release delivery of SLB was achieved using the pCNP-SLB system, conferring higher cytotoxic effects and lower IC50 values in 72-h treatments compared to CNP-SLB, which was attributed to the hydrophobic modification of the CNP system.

Cognitive enhancers (nootropics). Part 2: drugs interacting with enzymes.

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Froestl, Wolfgang; Muhs, Andreas; Pfeifer, Andrea

2013-01-01

Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer's disease, schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing, applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To classify the compounds, a concept is proposed assigning drugs to 19 categories according to their mechanism(s) of action, in particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants, metal chelators, and disease modifying drugs meaning small molecules, vaccines, and monoclonal antibodies interacting with amyloid-β and tau. For drugs whose mechanism of action is not known, they are either classified according to structure, e.g., peptides, or their origin, e.g., natural products. This review covers the evolution of research in this field over the last 25 years.

Cognitive enhancers (nootropics). Part 1: drugs interacting with receptors.

Science.gov (United States)

Froestl, Wolfgang; Muhs, Andreas; Pfeifer, Andrea

2012-01-01

Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer's disease, schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing, applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To classify the compounds, a concept is proposed assigning drugs to 18 categories according to their mechanism(s) of action, in particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants, metal chelators, and disease-modifying drugs meaning small molecules, vaccines, and monoclonal antibodies interacting with amyloid-β and tau. For drugs, whose mechanism of action is not known, they are either classified according to structure, e.g., peptides, or their origin, e.g., natural products. The review covers the evolution of research in this field over the last 25 years.

The basics of preclinical drug development for neurodegenerative disease indications.

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Steinmetz, Karen L; Spack, Edward G

2009-06-12

Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonization. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and

Neutrophil targeted nano-drug delivery system for chronic obstructive lung diseases.

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Vij, Neeraj; Min, Taehong; Bodas, Manish; Gorde, Aakruti; Roy, Indrajit

2016-11-01

The success of drug delivery to target airway cell(s) remains a significant challenge due to the limited ability of nanoparticle (NP) systems to circumvent protective airway-defense mechanisms. The size, density, surface and physical-chemical properties of nanoparticles are the key features that determine their ability to navigate across the airway-barrier. We evaluated here the efficacy of a PEGylated immuno-conjugated PLGA-nanoparticle (PINP) to overcome this challenge and selectively deliver drug to specific inflammatory cells (neutrophils). We first characterized the size, shape, surface-properties and neutrophil targeting using dynamic laser scattering, transmission electron microscopy and flow cytometry. Next, we assessed the efficacy of neutrophil-targeted PINPs in transporting through the airway followed by specific binding and release of drug to neutrophils. Finally, our results demonstrate the efficacy of PINP mediated non-steroidal anti-inflammatory drug-(ibuprofen) delivery to neutrophils in murine models of obstructive lung diseases, based on its ability to control neutrophilic-inflammation and resulting lung disease. Copyright © 2016 Elsevier Inc. All rights reserved.

Modified vegetation indices for Ganoderma disease detection in oil palm from field spectroradiometer data

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Shafri, Helmi Z. M.; Anuar, M. Izzuddin; Saripan, M. Iqbal

2009-10-01

High resolution field spectroradiometers are important for spectral analysis and mobile inspection of vegetation disease. The biggest challenges in using this technology for automated vegetation disease detection are in spectral signatures pre-processing, band selection and generating reflectance indices to improve the ability of hyperspectral data for early detection of disease. In this paper, new indices for oil palm Ganoderma disease detection were generated using band ratio and different band combination techniques. Unsupervised clustering method was used to cluster the values of each class resultant from each index. The wellness of band combinations was assessed by using Optimum Index Factor (OIF) while cluster validation was executed using Average Silhouette Width (ASW). 11 modified reflectance indices were generated in this study and the indices were ranked according to the values of their ASW. These modified indices were also compared to several existing and new indices. The results showed that the combination of spectral values at 610.5nm and 738nm was the best for clustering the three classes of infection levels in the determination of the best spectral index for early detection of Ganoderma disease.

Efficacy of glucocorticoids, conventional and targeted synthetic disease-modifying antirheumatic drugs: a systematic literature review informing the 2016 update of the EULAR recommendations for the management of rheumatoid arthritis

NARCIS (Netherlands)

Chatzidionysiou, Katerina; Emamikia, Sharzad; Nam, Jackie; Ramiro, Sofia; Smolen, Josef; van der Heijde, Désirée; Dougados, Maxime; Bijlsma, Johannes; Burmester, Gerd; Scholte, Marieke; van Vollenhoven, Ronald; Landewé, Robert

2017-01-01

To perform a systematic literature review (SLR) informing the 2016 update of the recommendations for the management of rheumatoid arthritis (RA). An SLR for the period between 2013 and 2016 was undertaken to assess the efficacy of glucocorticoids (GCs), conventional synthetic disease-modifying

78 FR 9396 - Draft Guidance for Industry on Alzheimer's Disease: Developing Drugs for the Treatment of Early...

Science.gov (United States)

2013-02-08

...] Draft Guidance for Industry on Alzheimer's Disease: Developing Drugs for the Treatment of Early Stage... ``Alzheimer's Disease: Developing Drugs for the Treatment of Early Stage Disease.'' This guidance outlines FDA... trials that are specifically focused on the treatment of patients with established Alzheimer's disease...

Non-alcoholic fatty liver disease (NAFLD) models in drug discovery.

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Cole, Banumathi K; Feaver, Ryan E; Wamhoff, Brian R; Dash, Ajit

2018-02-01

The progressive disease spectrum of non-alcoholic fatty liver disease (NAFLD), which includes non-alcoholic steatohepatitis (NASH), is a rapidly emerging public health crisis with no approved therapy. The diversity of various therapies under development highlights the lack of consensus around the most effective target, underscoring the need for better translatable preclinical models to study the complex progressive disease and effective therapies. Areas covered: This article reviews published literature of various mouse models of NASH used in preclinical studies, as well as complex organotypic in vitro and ex vivo liver models being developed. It discusses translational challenges associated with both kinds of models, and describes some of the studies that validate their application in NAFLD. Expert opinion: Animal models offer advantages of understanding drug distribution and effects in a whole body context, but are limited by important species differences. Human organotypic in vitro and ex vivo models with physiological relevance and translatability need to be used in a tiered manner with simpler screens. Leveraging newer technologies, like metabolomics, proteomics, and transcriptomics, and the future development of validated disease biomarkers will allow us to fully utilize the value of these models to understand disease and evaluate novel drugs in isolation or combination.

Surveillance of gastrointestinal disease in France using drug sales data.

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Pivette, Mathilde; Mueller, Judith E; Crépey, Pascal; Bar-Hen, Avner

2014-09-01

Drug sales data have increasingly been used for disease surveillance during recent years. Our objective was to assess the value of drug sales data as an operational early detection tool for gastroenteritis epidemics at national and regional level in France. For the period 2008-2013, we compared temporal trends of drug sales for the treatment of gastroenteritis with trends of cases reported by a Sentinel Network of general practitioners. We benchmarked detection models to select the one with the best sensitivity, false alert proportion and timeliness, and developed a prospective framework to assess the operational performance of the system. Drug sales data allowed the detection of seasonal gastrointestinal epidemics occurring in winter with a distinction between prescribed and non-prescribed drugs. Sales of non-prescribed drugs allowed epidemic detection on average 2.25 weeks earlier than Sentinel data. These results confirm the value of drug sales data for real-time monitoring of gastroenteritis epidemic activity. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Do nonsteroidal anti-inflammatory drugs decrease the risk for Alzheimer's disease?

DEFF Research Database (Denmark)

Andersen, K; Launer, L J; Ott, A

1995-01-01

Based on reports that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the risk for Alzheimer's disease (AD), we studied the cross-sectional relation between NSAID use and the risk for AD in a population-based study of disease and disability in older people. After controlling...

Amperometric sensing of anti-HIV drug zidovudine on Ag nanofilm-multiwalled carbon nanotubes modified glassy carbon electrode

Energy Technology Data Exchange (ETDEWEB)

Rafati, Amir Abbas, E-mail: aa_rafati@basu.ac.ir; Afraz, Ahmadreza

2014-06-01

The zidovudine (ZDV) is the first drug approved for the treatment of HIV virus infection. The detection and determination of this drug are very importance in human serum because of its undesirable effects. A new ZDV sensor was fabricated on the basis of nanocomposite of silver nanofilm (Ag-NF) and multiwalled carbon nanotubes (MWCNTs) immobilized on glassy carbon electrode (GCE). The modified electrodes were characterized by scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), cyclic voltammetry (CV), and linear sweep voltammetry (LSV) techniques. Results showed that the electrodeposited silver has a nanofilm structure and further electrochemical studies showed that the prepared nanocomposite has high electrocatalytic activity and is appropriate for using in sensors. The amperometric technique under optimal conditions is used for the determination of ZDV ranging from 0.1 to 400 ppm (0.37 μM–1.5 mM) with a low detection limit of 0.04 ppm (0.15 μM) (S/N = 3) and good sensitivity. The prepared sensor possessed accurate and rapid response to ZDV and shows an average recovery of 98.6% in real samples. - Highlights: • New anti-HIV drug sensor was fabricated on the basis of nanomaterials composite. • The GCE modified by prepared hydrophilic MWCNT silver nanoparticles. • Silver nanofilm electrodeposited on MWCNT/GCE and characterized by SEM, EDX, CV and LSV • Response of electrode to ZDV was thoroughly investigated by electrochemical techniques.

Electrochemical and DFT study of an anticancer and active anthelmintic drug at carbon nanostructured modified electrode

International Nuclear Information System (INIS)

Ghalkhani, Masoumeh; Beheshtian, Javad; Salehi, Maryam

2016-01-01

The electrochemical response of mebendazole (Meb), an anticancer and effective anthelmintic drug, was investigated using two different carbon nanostructured modified glassy carbon electrodes (GCE). Although, compared to unmodified GCE, both prepared modified electrodes improved the voltammetric response of Meb, the carbon nanotubes (CNTs) modified GCE showed higher sensitivity and stability. Therefore, the CNTs-GCE was chosen as a promising candidate for the further studies. At first, the electrochemical behavior of Meb was studied by cyclic voltammetry and differential pulse and square wave voltammetry. A one step reversible, pH-dependent and adsorption-controlled process was revealed for electro-oxidation of Meb. A possible mechanism for the electrochemical oxidation of Meb was proposed. In addition, electronic structure, adsorption energy, band gap, type of interaction and stable configuration of Meb on the surface of functionalized carbon nanotubes were studied by using density functional theory (DFT). Obtained results revealed that Meb is weakly physisorbed on the CNTs and that the electronic properties of the CNTs are not significantly changed. Notably, CNTs could be considered as a suitable modifier for preparation of the modified electrode for Meb analysis. Then, the experimental parameters affecting the electrochemical response of Meb were optimized. Under optimal conditions, high sensitivity (b(Meb) = dI p,a (Meb) / d[Meb] = 19.65 μA μM −1 ), a low detection limit (LOD (Meb) = 19 nM) and a wide linear dynamic range (0.06–3 μM) was resulted for the voltammetric quantification of Meb. - Highlights: • Electrochemical oxidation mechanism of Meb was investigated. • A carbon nanostructure modified electrode was developed for the determination of Meb. • The modified electrode surface was characterized by SEM and impedance studies. • This study provides an effective chemically modified electrode with satisfactory repeatability and reproducibility

Study on radiation modifiers with zebrafish as a vertebrate model

International Nuclear Information System (INIS)

Lei Jixiao; Ni Jin; Cai Jianming; Shen Jianliang

2010-01-01

Zebrafish (Danio rerio) as a vertebrate model system has been used in a series of biomedical experiments by scientists. It offers distinctive benefits as a laboratory model system, especially for embryonic development, gene expression, drug screening and human disease model. In this paper, the typical radiation modifiers, such as Amifostine, DF-1, AG1478, Flavopiridol and DNA repair proteins involved in biomedical process by use of zebrafish have been reviewed. (authors)

Associations between Potentially Modifiable Risk Factors and Alzheimer Disease : A Mendelian Randomization Study

NARCIS (Netherlands)

Ostergaard, Soren D.; Mukherjee, Shubhabrata; Sharp, Stephen J.; Proitsi, Petroula; Lotta, Luca A.; Day, Felix; Perry, John R. B.; Boehme, Kevin L.; Walter, Stefan; Kauwe, John S.; Gibbons, Laura E.; Larson, Eric B.; Powell, John F.; Langenberg, Claudia; Crane, Paul K.; Wareham, Nicholas J.; Scott, Robert A.; van der Schouw, YT

Background Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these

Determination of Residual Nonsteroidal Anti-Inflammatory Drugs in Aqueous Sample Using Magnetic Nanoparticles Modified with Cetyltrimethylammonium Bromide by High Performance Liquid Chromatography

OpenAIRE

Khoeini Sharifabadi, Malihe; Saber-Tehrani, Mohammad; Waqif Husain, Syed; Mehdinia, Ali; Aberoomand-Azar, Parviz

2014-01-01

A simple and sensitive solid-phase extraction method for separation and preconcentration of trace amount of four nonsteroidal anti-inflammatory drugs (naproxen, indomethacin, diclofenac, and ibuprofen) using Fe3O4 magnetic nanoparticles modified with cetyltrimethylammonium bromide has been developed. For this purpose, the surface of MNPs was modified with cetyltrimethylammonium bromide (CTAB) as a cationic surfactant. Effects of different parameters influencing the extraction efficiency of dr...

A SNP in the HTT promoter alters NF-κB binding and is a bidirectional genetic modifier of Huntington disease

DEFF Research Database (Denmark)

Bečanović, Kristina; Nørremølle, Anne; Neal, Scott J

2015-01-01

Cis-regulatory variants that alter gene expression can modify disease expressivity, but none have previously been identified in Huntington disease (HD). Here we provide in vivo evidence in HD patients that cis-regulatory variants in the HTT promoter are bidirectional modifiers of HD age of onset....

Neuroproteases in peptide neurotransmission and neurodegenerative diseases: applications to drug discovery research.

Science.gov (United States)

Hook, Vivian Y H

2006-01-01

The nervous system represents a key area for development of novel therapeutic agents for the treatment of neurological and neurodegenerative diseases. Recent research has demonstrated the critical importance of neuroproteases for the production of specific peptide neurotransmitters and for the production of toxic peptides in major neurodegenerative diseases that include Alzheimer, Huntington, and Parkinson diseases. This review illustrates the successful criteria that have allowed identification of proteases responsible for converting protein precursors into active peptide neurotransmitters, consisting of dual cysteine protease and subtilisin-like protease pathways in neuroendocrine cells. These peptide neurotransmitters are critical regulators of neurologic conditions, including analgesia and cognition, and numerous behaviors. Importantly, protease pathways also represent prominent mechanisms in neurodegenerative diseases, especially Alzheimer, Huntington, and Parkinson diseases. Recent studies have identified secretory vesicle cathepsin B as a novel beta-secretase for production of the neurotoxic beta-amyloid (Abeta) peptide of Alzheimer disease. Moreover, inhibition of cathepsin B reduces Abeta peptide levels in brain. These neuroproteases potentially represent new drug targets that should be explored in future pharmaceutical research endeavors for drug discovery.

Beyond Psoriasis: Novel Uses for Biologic Response Modifiers in Pediatric Dermatology.

Science.gov (United States)

Bellodi-Schmidt, Fernanda; Shah, Kara N

2016-01-01

Dermatologists have witnessed the increasing availability of novel biologic response modifiers for the treatment of inflammatory and autoimmune diseases in recent years. The most common dermatologic indication for the use of biologic response modifiers in adults is psoriasis, but the U.S. Food and Drug Administration has not approved any of these agents for use in any dermatologic disease in children with the exception of omalizumab, and as such, use in this population is considered off-label. In this review, we focus on the use of these agents in children to treat inflammatory skin diseases other than psoriasis, including atopic dermatitis, hidradenitis suppurativa, pemphigus vulgaris, bullous pemphigoid, and toxic epidermal necrolysis, with an emphasis on the use of etanercept, infliximab, rituximab, omalizumab, and ustekinumab. By highlighting novel uses of these agents, particularly for the treatment of dermatologic conditions for which optimal therapies are yet to be established, we hope to raise awareness of the potential use of this class of medications to treat inflammatory skin diseases in children. © 2015 Wiley Periodicals, Inc.

Clustering of modifiable biobehavioral risk factors for chronic disease in US adults: a latent class analysis.

Science.gov (United States)

Leventhal, Adam M; Huh, Jimi; Dunton, Genevieve F

2014-11-01

Examining the co-occurrence patterns of modifiable biobehavioral risk factors for deadly chronic diseases (e.g. cancer, cardiovascular disease, diabetes) can elucidate the etiology of risk factors and guide disease-prevention programming. The aims of this study were to (1) identify latent classes based on the clustering of five key biobehavioral risk factors among US adults who reported at least one risk factor and (2) explore the demographic correlates of the identified latent classes. Participants were respondents of the National Epidemiologic Survey of Alcohol and Related Conditions (2004-2005) with at least one of the following disease risk factors in the past year (N = 22,789), which were also the latent class indicators: (1) alcohol abuse/dependence, (2) drug abuse/dependence, (3) nicotine dependence, (4) obesity, and (5) physical inactivity. Housing sample units were selected to match the US National Census in location and demographic characteristics, with young adults oversampled. Participants were administered surveys by trained interviewers. Five latent classes were yielded: 'obese, active non-substance abusers' (23%); 'nicotine-dependent, active, and non-obese' (19%); 'active, non-obese alcohol abusers' (6%); 'inactive, non-substance abusers' (50%); and 'active, polysubstance abusers' (3.7%). Four classes were characterized by a 100% likelihood of having one risk factor coupled with a low or moderate likelihood of having the other four risk factors. The five classes exhibited unique demographic profiles. Risk factors may cluster together in a non-monotonic fashion, with the majority of the at-risk population of US adults expected to have a high likelihood of endorsing only one of these five risk factors. © Royal Society for Public Health 2013.

Targeting molecular networks for drug research

Directory of Open Access Journals (Sweden)

José Pedro Pinto

2014-06-01

Full Text Available The study of molecular networks has recently moved into the limelight of biomedical research. While it has certainly provided us with plenty of new insights into cellular mechanisms, the challenge now is how to modify or even restructure these networks. This is especially true for human diseases, which can be regarded as manifestations of distorted states of molecular networks. Of the possible interventions for altering networks, the use of drugs is presently the most feasible. In this mini-review, we present and discuss some exemplary approaches of how analysis of molecular interaction networks can contribute to pharmacology (e.g., by identifying new drug targets or prediction of drug side effects, as well as listing pointers to relevant resources and software to guide future research. We also outline recent progress in the use of drugs for in vitro reprogramming of cells, which constitutes an example par excellence for altering molecular interaction networks with drugs.

Early cost-utility analysis of general and cerebrospinal fluid-specific Alzheimer's disease biomarkers for hypothetical disease-modifying treatment decision in mild cognitive impairment

NARCIS (Netherlands)

Handels, Ron L. H.; Joore, Manuela A.; Tran-Duy, An; Wimo, Anders; Wolfs, Claire A. G.; Verhey, Frans R. J.; Severens, Johan L.

Introduction: The study aimed to determine the room for improvement of a perfect cerebrospinal fluid (CSF) biomarker and the societal incremental net monetary benefit of CSF in subjects with mild cognitive impairment (MCI) assuming a hypothetical disease-modifying Alzheimer's disease (AD) treatment.

Drug-induced lung disease: High-resolution CT and histological findings

International Nuclear Information System (INIS)

Cleverley, Joanne R.; Screaton, Nicholas J.; Hiorns, Melanie P.; Flint, Julia D.A.; Mueller, Nestor L.

2002-01-01

AIM: To compare the parenchymal high-resolution computed tomography (HRCT) appearances with histological findings in patients with drug-induced lung disease and to determine the prognostic value of HRCT. MATERIALS AND METHODS: Drug history, HRCT features, histological findings and outcome at 3 months in 20 patients with drug induced-lung disease were reviewed retrospectively. The HRCT images were assessed for the pattern and distribution of abnormalities and classified as most suggestive of interstitial pneumonitis/fibrosis, diffuse alveolar damage (DAD), organizing pneumonia (OP) reaction, or a hypersensitivity reaction. RESULTS: On histopathological examination there were eight cases of interstitial pneumonitis/fibrosis, five of DAD, five of OP reactions, one of hypersensitivity reaction and one of pulmonary eosinophilia. The most common abnormalities on HRCT were ground-glass opacities (n = 17), consolidation (n = 14), interlobular septal thickening (n = 15) and centrilobular nodules (n 8). HRCT interpretation and histological diagnosis were concordant in only nine (45%) of 20 patients. The pattern, distribution, and extent of HRCT abnormalities were of limited prognostic value: all eight patients with histological findings of OP, hypersensitivity reaction, or eosinophilic infiltrate improved on follow-up compared to only five of 13 patients with interstitial pneumonitis/fibrosis or DAD. CONCLUSION: In many cases of drug-induced lung injury HRCT is of limited value in determining the histological pattern and prognosis. Cleverly, J.R. et al

The basics of preclinical drug development for neurodegenerative disease indications

Directory of Open Access Journals (Sweden)

Spack Edward G

2009-06-01

Full Text Available Abstract Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA Good Laboratory Practices and international guidelines, including the International Conference on Harmonisation. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s. Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot

Drug repurposing by integrated literature mining and drug–gene–disease triangulation

DEFF Research Database (Denmark)

Sun, Peng; Guo, Jiong; Winnenburg, Rainer

2017-01-01

recent developments in computational drug repositioning and introduce the utilized data sources. Afterwards, we introduce a new data fusion model based on n-cluster editing as a novel multi-source triangulation strategy, which was further combined with semantic literature mining. Our evaluation suggests...... that utilizing drug–gene–disease triangulation coupled to sophisticated text analysis is a robust approach for identifying new drug candidates for repurposing....

Sulfasalazine efficacy and tolerability in rheumatic diseases

Directory of Open Access Journals (Sweden)

V. V. Badokin

2005-01-01

Full Text Available Sulfasalazine is one of the main disease modifying drugs for the treatment of chronic inflammatory joint and spine diseases. The article describes mechanism of action of sulfasalazine and its main metabolites. Detailed information about anti-inflammatory and immunosuppressive action of the drug is presented. Results of many studies of sulfasalazine efficacy in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and reactive arthritis are discussed from the evidence based medicine point of view. Data on sulfasalazine tolerability and safety are presented with separate discussion of hypersensitivity and dose-dependent adverse reactions so as their treatment and prophylaxis.

Orphan drugs: trends and issues in drug development.

Science.gov (United States)

Rana, Proteesh; Chawla, Shalini

2018-04-12

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

The disease modifying osteoarthritis drug (DMOAD)

DEFF Research Database (Denmark)

Qvist, Per; Bay-Jensen, Anne-Christine; Christiansen, Claus

2008-01-01

and with DMOADs in particular, and we advance the need for a new development paradigm for DMOADs. Two central elements in this paradigm are a stronger focus on the biology of the joint and the application of new and more sensitive biomarkers allowing redesign of clinical trials in osteoarthritis....

Reward Prediction Errors in Drug Addiction and Parkinson's Disease: from Neurophysiology to Neuroimaging.

Science.gov (United States)

García-García, Isabel; Zeighami, Yashar; Dagher, Alain

2017-06-01

Surprises are important sources of learning. Cognitive scientists often refer to surprises as "reward prediction errors," a parameter that captures discrepancies between expectations and actual outcomes. Here, we integrate neurophysiological and functional magnetic resonance imaging (fMRI) results addressing the processing of reward prediction errors and how they might be altered in drug addiction and Parkinson's disease. By increasing phasic dopamine responses, drugs might accentuate prediction error signals, causing increases in fMRI activity in mesolimbic areas in response to drugs. Chronic substance dependence, by contrast, has been linked with compromised dopaminergic function, which might be associated with blunted fMRI responses to pleasant non-drug stimuli in mesocorticolimbic areas. In Parkinson's disease, dopamine replacement therapies seem to induce impairments in learning from negative outcomes. The present review provides a holistic overview of reward prediction errors across different pathologies and might inform future clinical strategies targeting impulsive/compulsive disorders.

Genetic engineering in nonhuman primates for human disease modeling.

Science.gov (United States)

Sato, Kenya; Sasaki, Erika

2018-02-01

Nonhuman primate (NHP) experimental models have contributed greatly to human health research by assessing the safety and efficacy of newly developed drugs, due to their physiological and anatomical similarities to humans. To generate NHP disease models, drug-inducible methods, and surgical treatment methods have been employed. Recent developments in genetic and developmental engineering in NHPs offer new options for producing genetically modified disease models. Moreover, in recent years, genome-editing technology has emerged to further promote this trend and the generation of disease model NHPs has entered a new era. In this review, we summarize the generation of conventional disease model NHPs and discuss new solutions to the problem of mosaicism in genome-editing technology.

Chitosan microspheres in novel drug delivery systems.

Science.gov (United States)

Mitra, Analava; Dey, Baishakhi

2011-07-01

The main aim in the drug therapy of any disease is to attain the desired therapeutic concentration of the drug in plasma or at the site of action and maintain it for the entire duration of treatment. A drug on being used in conventional dosage forms leads to unavoidable fluctuations in the drug concentration leading to under medication or overmedication and increased frequency of dose administration as well as poor patient compliance. To minimize drug degradation and loss, to prevent harmful side effects and to increase drug bioavailability various drug delivery and drug targeting systems are currently under development. Handling the treatment of severe disease conditions has necessitated the development of innovative ideas to modify drug delivery techniques. Drug targeting means delivery of the drug-loaded system to the site of interest. Drug carrier systems include polymers, micelles, microcapsules, liposomes and lipoproteins to name some. Different polymer carriers exert different effects on drug delivery. Synthetic polymers are usually non-biocompatible, non-biodegradable and expensive. Natural polymers such as chitin and chitosan are devoid of such problems. Chitosan comes from the deacetylation of chitin, a natural biopolymer originating from crustacean shells. Chitosan is a biocompatible, biodegradable, and nontoxic natural polymer with excellent film-forming ability. Being of cationic character, chitosan is able to react with polyanions giving rise to polyelectrolyte complexes. Hence chitosan has become a promising natural polymer for the preparation of microspheres/nanospheres and microcapsules. The techniques employed to microencapsulate with chitosan include ionotropic gelation, spray drying, emulsion phase separation, simple and complex coacervation. This review focuses on the preparation, characterization of chitosan microspheres and their role in novel drug delivery systems.

Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm.

Science.gov (United States)

Giovannoni, Gavin

2018-06-01

The treatment of multiple sclerosis is evolving rapidly with 11 classes of disease-modifying therapies (DMTs). This article provides an overview of a new classification system for DMTs and treatment paradigm for using these DMTs effectively and safely. A summary of research into the use of more active approaches to early and effective treatment of multiple sclerosis with defined treatment targets of no evident disease activity (NEDA). New insights are discussed that is allowing the field to begin to tackle more advanced multiple sclerosis, including people with multiple sclerosis using wheelchairs. However, the need to modify expectations of what can be achieved in more advanced multiple sclerosis are discussed; in particular, the focus on neuronal systems with reserve capacity, for example, upper limb, bulbar and visual function. The review describes a new more active way of managing multiple sclerosis and concludes with a call to action in solving the problem of slow adoption of innovations and the global problem of untreated, or undertreated, multiple sclerosis.

Exosomes: A Paradigm in Drug Development against Cancer and Infectious Diseases

Directory of Open Access Journals (Sweden)

Mohammad Oves

2018-01-01

Full Text Available Extracellular vesicles are small single lipid membrane entity secreted by eukaryotic and prokaryotic cells and play an important role in intercellular signaling and nutrient transport. The last few decades have witnessed a plethora of research on these vesicles owing to their ability to answer many hidden facts at the supramolecular level. These extracellular vesicles have attracted the researchers because they act as shuttle agents to transfer biomolecules/drugs between cells. Recently, studies have shown the application of exosomes in tumor therapy and infectious disease control. The present review article shows the importance of exosomes in cancer biology and infectious disease diagnoses and therapy and provides comprehensive account of exosomes biogenesis, extraction, molecular profiling, and application in drug delivery.

Uptake mechanism of ApoE-modified nanoparticles on brain capillary endothelial cells as a blood-brain barrier model.

Science.gov (United States)

Wagner, Sylvia; Zensi, Anja; Wien, Sascha L; Tschickardt, Sabrina E; Maier, Wladislaw; Vogel, Tikva; Worek, Franz; Pietrzik, Claus U; Kreuter, Jörg; von Briesen, Hagen

2012-01-01

The blood-brain barrier (BBB) represents an insurmountable obstacle for most drugs thus obstructing an effective treatment of many brain diseases. One solution for overcoming this barrier is a transport by binding of these drugs to surface-modified nanoparticles. Especially apolipoprotein E (ApoE) appears to play a major role in the nanoparticle-mediated drug transport across the BBB. However, at present the underlying mechanism is incompletely understood. In this study, the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells was investigated to differentiate between active and passive uptake mechanism by flow cytometry and confocal laser scanning microscopy. Furthermore, different in vitro co-incubation experiments were performed with competing ligands of the respective receptor. This study confirms an active endocytotic uptake mechanism and shows the involvement of low density lipoprotein receptor family members, notably the low density lipoprotein receptor related protein, on the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells. This knowledge of the uptake mechanism of ApoE-modified nanoparticles enables future developments to rationally create very specific and effective carriers to overcome the blood-brain barrier.

Uptake mechanism of ApoE-modified nanoparticles on brain capillary endothelial cells as a blood-brain barrier model.

Directory of Open Access Journals (Sweden)

Sylvia Wagner

Full Text Available BACKGROUND: The blood-brain barrier (BBB represents an insurmountable obstacle for most drugs thus obstructing an effective treatment of many brain diseases. One solution for overcoming this barrier is a transport by binding of these drugs to surface-modified nanoparticles. Especially apolipoprotein E (ApoE appears to play a major role in the nanoparticle-mediated drug transport across the BBB. However, at present the underlying mechanism is incompletely understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells was investigated to differentiate between active and passive uptake mechanism by flow cytometry and confocal laser scanning microscopy. Furthermore, different in vitro co-incubation experiments were performed with competing ligands of the respective receptor. CONCLUSIONS/SIGNIFICANCE: This study confirms an active endocytotic uptake mechanism and shows the involvement of low density lipoprotein receptor family members, notably the low density lipoprotein receptor related protein, on the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells. This knowledge of the uptake mechanism of ApoE-modified nanoparticles enables future developments to rationally create very specific and effective carriers to overcome the blood-brain barrier.

Drug Hypersensitivity and Anaphylaxis in Cancer and Chronic Inflammatory Diseases: The Role of Desensitizations

Directory of Open Access Journals (Sweden)

Mariana Castells

2017-11-01

Full Text Available Drug allergy is a rising problem in the twenty-first century which affects all populations and races, children, and adults, and for which the recognition, diagnosis, management, and treatment is still not well standardized. Classical and new chemotherapy drugs, monoclonal antibodies (MoAbs, and small molecules to treat cancer and chronic inflammatory diseases are aimed at improving quality of life and life expectancy of patients, but an increasing number of reactions including anaphylaxis precludes their use in targeted populations. Women are more affected by drug allergy and up to 27% of women with ovarian and breast cancer develop carboplatin allergy after multiple cycles of treatment. Carriers of BRCA genes develop drug allergy after fewer exposures and can present with severe reactions, including anaphylaxis. Atopic patients are at increased risk for chemotherapy and MoAbs drug allergy and the current patterns of treatment with recurrent and intermittent drug exposures may favor the development of drug allergies. To overcome drug allergy, desensitization has been developed, a novel approach which provides a unique opportunity to protect against anaphylaxis and to improve clinical outcomes. There is evidence that inhibitory mechanisms blocking IgE/antigen mast cell activation are active during desensitization, enhancing safety. Whether desensitization modulates drug allergic and anaphylactic responses facilitating tolerance is currently being investigated. This review provides insight into the current knowledge of drug allergy and anaphylaxis to cancer and chronic inflammatory diseases drugs, the mechanisms of drug desensitization and its applications to personalized medicine.

M-ficolin levels reflect disease activity and predict remission in early rheumatoid arthritis

DEFF Research Database (Denmark)

Ammitzbøll, Christian Gytz; Thiel, Steffen; Jensenius, Jens Christian

2013-01-01

To assess plasma M-ficolin concentrations in disease-modifying antirheumatic drug (DMARD)-naive patients with early rheumatoid arthritis (RA), to investigate the correlation of M-ficolin concentrations with disease activity markers, and to determine the predictive value of M-ficolin with respect...... to the Disease Activity Score in 28 joints (DAS28)....

Electrochemical and DFT study of an anticancer and active anthelmintic drug at carbon nanostructured modified electrode.

Science.gov (United States)

Ghalkhani, Masoumeh; Beheshtian, Javad; Salehi, Maryam

2016-12-01

The electrochemical response of mebendazole (Meb), an anticancer and effective anthelmintic drug, was investigated using two different carbon nanostructured modified glassy carbon electrodes (GCE). Although, compared to unmodified GCE, both prepared modified electrodes improved the voltammetric response of Meb, the carbon nanotubes (CNTs) modified GCE showed higher sensitivity and stability. Therefore, the CNTs-GCE was chosen as a promising candidate for the further studies. At first, the electrochemical behavior of Meb was studied by cyclic voltammetry and differential pulse and square wave voltammetry. A one step reversible, pH-dependent and adsorption-controlled process was revealed for electro-oxidation of Meb. A possible mechanism for the electrochemical oxidation of Meb was proposed. In addition, electronic structure, adsorption energy, band gap, type of interaction and stable configuration of Meb on the surface of functionalized carbon nanotubes were studied by using density functional theory (DFT). Obtained results revealed that Meb is weakly physisorbed on the CNTs and that the electronic properties of the CNTs are not significantly changed. Notably, CNTs could be considered as a suitable modifier for preparation of the modified electrode for Meb analysis. Then, the experimental parameters affecting the electrochemical response of Meb were optimized. Under optimal conditions, high sensitivity (b(Meb)=dIp,a(Meb)/d[Meb]=19.65μAμM(-1)), a low detection limit (LOD (Meb)=19nM) and a wide linear dynamic range (0.06-3μM) was resulted for the voltammetric quantification of Meb. Copyright © 2016 Elsevier B.V. All rights reserved.

Amyloid-beta immunotherapy: the hope for Alzheimer disease?

Science.gov (United States)

Barrera-Ocampo, Alvaro; Lopera, Francisco

2016-12-30

Alzheimer disease (AD) is the most prevalent form of dementia of adult-onset, characterized by progressive impairment in cognition and memory. There is no cure for the disease and the current treatments are only symptomatic. Drug discovery is an expensive and time-consuming process; in the last decade no new drugs have been found for AD despite the efforts of the scientific community and pharmaceutical companies. The Aβ immunotherapy is one of the most promising approaches to modify the course of AD. This therapeutic strategy uses synthetic peptides or monoclonal antibodies (mAb) to decrease the Aβ load in the brain and slow the progression of the disease. Therefore, this article will discuss the main aspects of AD neuropathogenesis, the classical pharmacologic treatment, as well as the active and passive immunization describing drug prototypes evaluated in different clinical trials.

Tobacco, illicit drugs use and risk of cardiovascular disease in patients living with HIV.

Science.gov (United States)

Raposeiras-Roubín, Sergio; Abu-Assi, Emad; Iñiguez-Romo, Andrés

2017-11-01

There is a strong link between HIV, smoking and illicit drugs. This association could be clinically relevant as it may potentiate the risk of cardiovascular diseases (CVD). The purpose of this review is to bring readers up to date on issues concerning the cardiovascular risk associated with tobacco and illicit drugs in patients living with HIV (PLHIV), examining the studies related to this topic published in the last year. There is a strong association between smoking and atherosclerotic disease in PLHIV, reducing life expectancy secondary to CVD by up to 6 years. Illicit drugs were associated with increased risk of atherosclerotic problems but to a lesser extent than smoking. A significant association of drugs such as cocaine with subclinical coronary atherosclerosis been demonstrated. The relation of marijuana, heroin and amphetamines with atherosclerosis generates more controversy. However, those drugs are associated with cardiovascular morbidity, independently of smoking and other traditional risk factors. Tobacco and illicit drugs are linked to CVD in HIV patients. This leads to the need to create special programs to address the addiction to smoking and illicit drugs, in order to mitigate their consequences and reduce cardiovascular risk.

Fast Removal of Citalopram Drug from Waste Water Using Magnetic Nanoparticles Modified with Sodium Dodecyl Sulfate Followed by UV-Spectrometry

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M. Khoeini Sharifabadi

2014-02-01

Full Text Available A simple and sensitive, solid-phase extraction method for the removal of Citalopram drug from waste water has been developed by using magnetic nanoparticles modified with surfactant sodium dodecyl sulfate. These magnetic nanoparticles have shown great adsorptive tendency towards Citalopram drug. The effect of different parameters influencing the extraction efficiency of this drug were investigated and optimized including the pH, amount of the surfactant, contact time and temperature. The extracts were analyzed by ultraviolet spectrophotometry at 239nm. Under these conditions, the related standard deviation (RSD % of the method at two concentrations (5 and 50µg.mL-1 was in the range of (3.14–3.75 % (n = 8. The calibration curve was linear in the range of 2-100 µg.mL-1 of Citalopram drug with a correlation coefficient of >0.99.

Fast Removal of Citalopram Drug from Waste Water Using Magnetic Nanoparticles Modified with Sodium Dodecyl Sulfate Followed by UV-Spectrometry

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M. Khoeini Sharifabadi

2013-04-01

Full Text Available A simple and sensitive, solid-phase extraction method for the removal of Citalopram drug from waste water has been developed by using magnetic nanoparticles modified with surfactant sodium dodecyl sulfate. These magnetic nanoparticles have shown great adsorptive tendency towards Citalopram drug. The effect of different parameters influencing the extraction efficiency of this drug were investigated and optimized including the pH, amount of the surfactant, contact time and temperature. The extracts were analyzed by ultraviolet spectrophotometry at 239nm. Under these conditions, the related standard deviation (RSD % of the method at two concentrations (5 and 50µg.mL-1 was in the range of (3.14–3.75 % (n = 8. The calibration curve was linear in the range of 2-100 µg.mL-1 of Citalopram drug with a correlation coefficient of >0.99.

Induced pluripotent stem cell-derived cardiomyocytes for cardiovascular disease modeling and drug screening.

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Sharma, Arun; Wu, Joseph C; Wu, Sean M

2013-12-24

Human induced pluripotent stem cells (hiPSCs) have emerged as a novel tool for drug discovery and therapy in cardiovascular medicine. hiPSCs are functionally similar to human embryonic stem cells (hESCs) and can be derived autologously without the ethical challenges associated with hESCs. Given the limited regenerative capacity of the human heart following myocardial injury, cardiomyocytes derived from hiPSCs (hiPSC-CMs) have garnered significant attention from basic and translational scientists as a promising cell source for replacement therapy. However, ongoing issues such as cell immaturity, scale of production, inter-line variability, and cell purity will need to be resolved before human clinical trials can begin. Meanwhile, the use of hiPSCs to explore cellular mechanisms of cardiovascular diseases in vitro has proven to be extremely valuable. For example, hiPSC-CMs have been shown to recapitulate disease phenotypes from patients with monogenic cardiovascular disorders. Furthermore, patient-derived hiPSC-CMs are now providing new insights regarding drug efficacy and toxicity. This review will highlight recent advances in utilizing hiPSC-CMs for cardiac disease modeling in vitro and as a platform for drug validation. The advantages and disadvantages of using hiPSC-CMs for drug screening purposes will be explored as well.

Tofacitinib in Combination With Conventional Disease-Modifying Antirheumatic Drugs in Patients With Active Rheumatoid Arthritis: Patient-Reported Outcomes From a Phase III Randomized Controlled Trial.

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Strand, Vibeke; Kremer, Joel M; Gruben, David; Krishnaswami, Sriram; Zwillich, Samuel H; Wallenstein, Gene V

2017-04-01

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We compared patient-reported outcomes (PROs) in patients with RA treated with tofacitinib or placebo in combination with conventional disease-modifying antirheumatic drugs (DMARDs). In a 12-month, phase III randomized controlled trial (ORAL Sync), patients (n = 795) with active RA and previous inadequate response to therapy with ≥1 conventional or biologic DMARD were randomized 4:4:1:1 to tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID, placebo advanced to 5 mg BID, or placebo to 10 mg BID, in combination with stable background DMARD therapy. PROs included patient global assessment of arthritis (PtGA), patient assessment of arthritis pain (Pain), physical function (Health Assessment Questionnaire disability index [HAQ DI]), health-related quality of life (Short Form 36 health survey [SF-36]), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F]), and sleep (Medical Outcomes Study Sleep [MOS Sleep]). At month 3, statistically significant improvements from baseline versus placebo were reported in PtGA, Pain, HAQ DI, all 8 SF-36 domains, FACIT-F, and MOS Sleep with tofacitinib 10 mg BID, and in PtGA, Pain, HAQ DI, 7 SF-36 domains, FACIT-F, and MOS Sleep with tofacitinib 5 mg BID. Improvements were sustained to month 12. Significantly more tofacitinib-treated patients reported improvements of greater than or equal to the minimum clinically important differences at month 3 versus placebo in all PROs, except the SF-36 role-emotional domain (significant for tofacitinib 10 mg BID). Patients with active RA treated with tofacitinib combined with background conventional DMARD therapy reported sustained, significant, and clinically meaningful improvements in PROs versus placebo. © 2016, The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.

Increased baseline RUNX2, caspase 3 and p21 gene expressions in the peripheral blood of disease-modifying anti-rheumatic drug-naïve rheumatoid arthritis patients are associated with improved clinical response to methotrexate therapy.

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Tchetina, Elena V; Demidova, Natalia V; Markova, Galina A; Taskina, Elena A; Glukhova, Svetlana I; Karateev, Dmitry E

2017-10-01

To investigate the potential of the baseline gene expression in the whole blood of disease-modifying anti-rheumatic drug-naïve rheumatoid arthritis (RA) patients for predicting the response to methotrexate (MTX) treatment. Twenty-six control subjects and 40 RA patients were examined. Clinical, immunological and radiographic parameters were assessed before and after 24 months of follow-up. The gene expressions in the whole blood were measured using real-time reverse transcription polymerase chain reaction. The protein concentrations in peripheral blood mononuclear cells were quantified using enzyme-linked immunosorbent assay. Receiver operating characteristic curve analyses were used to suggest thresholds that were associated with the prediction of the response. Decreases in the disease activity at the end of the study were accompanied by significant increases in joint space narrowing score (JSN). Positive correlations between the expressions of the Unc-51-like kinase 1 (ULK1) and matrix metalloproteinase 9 (MMP-9) genes with the level of C-reactive protein and MMP-9 expression with Disease Activity Score of 28 joints (DAS28) and swollen joint count were noted at baseline. The baseline tumor necrosis factor (TNF)α gene expression was positively correlated with JSN at the end of the follow-up, whereas p21, caspase 3, and runt-related transcription factor (RUNX)2 were correlated with the ΔDAS28 values. Our results suggest that the expressions of MMP-9 and ULK1 might be associated with disease activity. Increased baseline gene expressions of RUNX2, p21 and caspase 3 in the peripheral blood might predict better responses to MTX therapy. © 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

Association between use of disease-modifying antirheumatic drugs and diabetes in patients with ankylosing spondylitis, rheumatoid arthritis, or psoriasis/psoriatic arthritis: a nationwide, population-based cohort study of 84,989 patients

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Chen HH

2017-05-01

Full Text Available Hsin-Hua Chen,1–7 Der-Yuan Chen,1–6 Chi-Chen Lin,1,2 Yi-Ming Chen,1–4 Kuo-Lung Lai,3,4 Ching-Heng Lin1 1Department of Medical Research, Taichung Veterans General Hospital, 2Institute of Biomedical Science and Rong Hsing Research Center for Translational Medicine, Chung-Hsing University, Taichung, 3School of Medicine, National Yang-Ming University, Taipei, 4Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taichung Veterans General Hospital, 5School of Medicine, Chung-Shan Medical University, 6Department of Medical Education, Taichung Veterans General Hospital, Taichung, 7Institute of Public Health and Community Medicine Research Center, National Yang-Ming University, Taipei, Taiwan Purpose: The aim of this study is to investigate the association between the use of disease-modifying antirheumatic drugs (DMARDs and diabetes mellitus (DM in patients with ankylosing spondylitis (AS, rheumatoid arthritis (RA, or psoriasis/psoriatic arthritis (PS/PSA.Patients and methods: This retrospective cohort study used a nationwide, population-based administrative database to enroll 84,989 cases with AS, RA, or PS/PSA who initiated treatment with anti-tumor necrosis factor (anti-TNF drugs or nonbiologic DMARDs. Multivariable analysis was used to estimate the effect of different therapies on the risk of DM.Results: The incidence rates of DM per 1,000 person-years were 8.3 for users of anti-TNF drugs, 13.3 for users of cyclosporine (CSA, 8.4 for users of hydroxychloroquine (HCQ, and 8.1 for users of other nonbiologic DMARDs. Compared with the users of nonbiologic DMARDs, the multivariate-adjusted hazard ratios (aHRs for DM were significantly lower for those who used anti-TNF drugs with HCQ (aHR: 0.49, 95% confidence interval [CI]: 0.36–0.66 and those who used HCQ alone (aHR: 0.70, 95% CI: 0.63–0.78, but not for those who used anti-TNFs without HCQ (aHR: 1.23, 95% CI: 0.94–1.60 or CSA (aHR: 1.14, 95% CI: 0.77–1

Definition of drug resistance of Mycobacterium tuberculosis to antituberculosis drugs in patients with multidrugresistant tuberculosis and TB with extremely drug resistant depending on the case of the disease

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Kryzhanovsky D.G.

2014-11-01

Full Text Available There was studied the profile of drug resistance to the main (I line and reserve (II line antituberculosis drugs in patients with MDR and XDR tuberculosis, depending of the case of the disease. According to the randomized retrospective research 200 patients with MDR and XDR tuberculosis, who received treatment in the clinic of hospital Municipal institution «Dnipropetrovsk rigional clinical association «Phthisiology» Dnipropetrovsk regional Council» during the period 2010 – 2012 were involved. Data about patients contained the data on a case of the disease and the results of the test of drug sensitivity to MBT. XDR – TB was revealed in 7.5% of patients with MDR tuberculosis. In patients with MDR tuberculosis as compared with patients with XDR tuberculosis «new cases» were diagnosed in 19.5% against 18.5% (p <0.05. In patients with MDR tuberculosis and with XDR tuberculosis resistance to the antituberculosis drug more commonly developed to S - 88.5%, E - 55% and Z - 24%. The presence of MDR-TB and XDR-TB prevails in patients, who underwent previous courses of treatment with anti-TB drugs in case history as compared with patients with «new cases» of treatment. The development of resistance to anti-TB drugs depends on the availability of these drugs in the previous treatment regimens.

Adverse event management in mass drug administration for neglected tropical diseases.

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Caplan, Arthur; Zink, Amanda

2014-03-01

The ethical challenges of reporting and managing adverse events (AEs) and serious AEs (SAEs) in the context of mass drug administration (MDA) for the treatment of neglected tropical diseases (NTDs) require reassessment of domestic and international policies on a global scale. Although the World Health Organization has set forth AE/SAE guidelines specifically for NTD MDA that incorporate suspected causality, and recommends that only SAEs get reported in this setting, most regulatory agencies continue to require the reporting of all SAEs exhibiting even a merely temporal relationship to activities associated with an MDA program. This greatly increases the potential for excess "noise" and undue risk aversion and is not only impractical but arguably unethical where huge proportions of populations are being treated for devastating diseases, and no good baseline exists against which to compare possible AE/SAE reports. Other population-specific variables that might change the way drug safety ought to be assessed include differing efficacy rates of a drug, background morbidity/mortality rates of the target disease in question, the growth rate of the incidence of disease, the availability of rescue or salvage therapies, and the willingness of local populations to take risks that other populations might not. The fact that NTDs are controllable and potentially eradicable with well-tolerated, effective, existing drugs might further alter our assessment of MDA safety and AE/SAE tolerability. At the same time, diffuseness of population, communication barriers, lack of resources, and other difficult surveillance challenges may present in NTD-affected settings. These limitations could impair the ability to monitor an MDA program's success, as well as hinder efforts to obtain informed consent or provide rescue therapy. Denying beneficial research interventions and MDA programs intended to benefit millions requires sound ethical justification based on more than the identification of

Modifiable Coronary Heart Disease Risk Factors in the Population Aged 20-49 Years

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Francisco Carlos Valladares Mas

2014-04-01

Full Text Available Background: evidence provided by the Framingham Heart Study established the critical role of risk factors in the development of coronary heart disease. Over half a century later, current detection and control are still inadequate. Objective: to identify modifiable risk factors of coronary heart disease in individuals aged 20 to 49 years. Methods: a descriptive, cross-sectional study was conducted in 276 individuals from the doctor’s office No. 1 of the Fabio di Celmo Community Teaching Polyclinic in Cienfuegos. Patients were examined in the clinic visit and/or whole family visit. The studied variables included age, sex, skin color, risk factors (excess weight/obesity, physical inactivity, smoking, hypertension, diabetes, dyslipidemia and psychosocial factors, which were obtained from the medical interview, physical examination, laboratory tests (total cholesterol and triglycerides and review of individual medical records and family history. Results: risk factors most frequently identified were excess weight/obesity (42.4 %, physical inactivity (34.4 % and smoking (20.3 %. Presence of these risk factors increased with age, showing differences in the distribution by sex and was associated with psychosocial factors. Their coexistence and progress with age was significant. Conclusion: prevalence of modifiable risk factors for coronary heart disease in a young population was high, with frequent association, predominating factors related to unhealthy lifestyles.

Epidemiology, classification, and modifiable risk factors of peripheral arterial disease

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Nicolas W Shammas

2007-05-01

Full Text Available Nicolas W ShammasMidwest Cardiovascular Research Foundation, Cardiovascular Medicine, PC, Davenport, IA, USAAbstract: Peripheral arterial disease (PAD is part of a global vascular problem of diffuse atherosclerosis. PAD patients die mostly of cardiac and cerebrovascular-related events and much less frequently due to obstructive disease of the lower extremities. Aggressive risk factors modification is needed to reduce cardiac mortality in PAD patients. These include smoking cessation, reduction of blood pressure to current guidelines, aggressive low density lipoprotein lowering, losing weight, controlling diabetes and the use of oral antiplatelet drugs such as aspirin or clopidogrel. In addition to quitting smoking and exercise, cilostazol and statins have been shown to reduce claudication in patients with PAD. Patients with critical rest limb ischemia or severe progressive claudication need to be treated with revascularization to minimize the chance of limb loss, reduce symptoms, and improve quality of life.Keywords: peripheral arterial disease, epidemiology, risk factors, classification

Endothelin 1 gene is not a major modifier of chronic kidney disease advancement among the autosomal dominant polycystic kidney disease patients

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Annapareddy Shiva Nagendra Reddy

2016-01-01

Full Text Available Introduction: Autosomal dominant polycystic kidney disease (ADPKD is characterized by the presence of numerous cysts in the kidney and manifest with various renal and extra-renal complications leading to ESRD. Endothelin may contribute to various renal and extra-renal manifestations pointing to genetic and environmental modifying factors that alter the risk of developing chronic kidney disease (CKD in ADPKD. In the present study we investigated six genes coding for endothelin 1 (EDN1 tagging-single nucleotide polymorphisms (tag-SNPs to unravel the EDN1 gene modifier effect for renal disease progression in ADPKD. Materials and Methods: The tag-SNPs were genotyped using FRET-based KASPar method in 108 ADPKD patients and 119 healthy subjects. Cochran-Armitage trend test was used to determine the association between ADPKD and EDN1 tag-SNPs. Multivariate logistic regression analysis was performed to assess the effect of tag-SNPs on CKD progression. The relationship between different CKD stages and hypertension and their interaction Mantel-Haenszel stratified analysis was performed. Results: All loci are polymorphic and followed Hardy-Weinberg equilibrium. Distribution of EDN1 genotypes and haplotypes in control and ADPKD is not statistically significant. Five SNPs covering 3.4 kb forming single LD block, but the LD was not strong between SNPs. The EDN1 genotypes are not contributing to the CKD advancement among the ADPKD patients. Conclusion: These results suggest that the EDN1 gene is not a major modifier of CKD advancement among ADPKD patients.

Stem cells as a novel tool for drug screening and treatment of degenerative diseases.

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Zuba-Surma, Ewa K; Wojakowski, Wojciech; Madeja, Zbigniew; Ratajczak, Mariusz Z

2012-01-01

Degenerative diseases similarly as acute tissue injuries lead to massive cell loss and may cause organ failure of vital organs (e.g., heart, central nervous system). Therefore, they belong to a group of disorders that may significantly benefit from stem cells (SCs)-based therapies. Several stem and progenitor cell populations have already been described as valuable tools for developing therapeutic strategies in regenerative medicine. In particular, pluripotent stem cells (PSCs), including adult-tissue-derived PSCs, neonatal-tissue-derived SCs, embryonic stem cells (ESCs), and recently described induced pluripotent stem cells (iPSCs), are the focus of particular attention because of their capacity to differentiate into all the cell lineages. Although PSCs are predominantly envisioned to be applied for organ regeneration, they may be also successfully employed in drug screening and disease modeling. In particular, adult PSCs and iPSCs derived from patient tissues may not only be a source of cells for autologous therapies but also for individual customized in vitro drug testing and studies on the molecular mechanisms of disease. In this review, we will focus on the potential applications of SCs, especially PSCs i) in regenerative medicine therapies, ii) in studying mechanisms of disease, as well as iii) in drug screening and toxicology tests that are crucial in new drug development. In particular, we will discuss the application of SCs in developing new therapeutic approaches to treat degenerative diseases of the neural system and heart. The advantage of adult PSCs in all the above-mentioned settings is that they can be directly harvested from patient tissues and used not only as a safe non-immunogenic source of cells for therapy but also as tools for personalized drug screening and pharmacological therapies.

Applications of patient-specific induced pluripotent stem cells; focused on disease modeling, drug screening and therapeutic potentials for liver disease.

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Chun, Yong Soon; Chaudhari, Pooja; Jang, Yoon-Young

2010-12-14

The recent advances in the induced pluripotent stem cell (iPSC) research have significantly changed our perspectives on regenerative medicine by providing researchers with a unique tool to derive disease-specific stem cells for study. In this review, we describe the human iPSC generation from developmentally diverse origins (i.e. endoderm-, mesoderm-, and ectoderm- tissue derived human iPSCs) and multistage hepatic differentiation protocols, and discuss both basic and clinical applications of these cells including disease modeling, drug toxicity screening/drug discovery, gene therapy and cell replacement therapy.

The clinical implication of drug dependency in children and adults with inflammatory bowel disease: a review

DEFF Research Database (Denmark)

Duricova, Dana; Pedersen, Natalia; Lenicek, Martin

2011-01-01

Drug dependency in adult and paediatric patients with inflammatory bowel disease (IBD) is described and the significance of this response pattern in clinical practice discussed in this review. Dependent patients maintain remission while on the treatment, but they relapse shortly after drug...... corticosteroid dependency. Infliximab dependency was described in 42-66% of children and 29% of adults with Crohn's disease. The risk of surgery 50 and 40 months after treatment start was 10% and 23% in infliximab dependent children and adults, respectively. Maintenance of infliximab in dependent patients...... was suggested to postpone if not avoid the need of surgery. Lastly, mesalazine dependency was identified in 23% of adults with Crohn's disease. These patients were characterized by mild disease course and lower surgical risk compared to non-responders to mesalazine (32 vs. 61%). Identification of drug...

The Impact of Disease and Drugs on Hip Fracture Risk

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Leavy, Breiffni; Michaëlsson, Karl; Åberg, Anna Cristina; Melhus, Håkan; Byberg, Liisa

2017-01-01

We report the risks of a comprehensive range of disease and drug categories on hip fracture occurrence using a strict population-based cohort design. Participants included the source population of a Swedish county, aged ?50?years (n?=?117,494) including all incident hip fractures during 1?year (n?=?477). The outcome was hospitalization for hip fracture (ICD-10 codes S72.0?S72.2) during 1?year (2009?2010). Exposures included: prevalence of (1) inpatient diseases [International Classification o...

Clinical benefits of drug-eluting stent implantation in septuagenarians with coronary artery disease

International Nuclear Information System (INIS)

Fang Yuehua; Shen Weifeng; Zhang Ruiyan; Zhang Jiansheng; Hu Jian; Zhang Xian; Zheng Aifang

2005-01-01

Objective: This study evaluated the safety and long-term outcomes of drug-eluting stents in septuagenarians with coronary artery disease. Methods: Two hundred and thirty-nine consecutive patients with coronary artery disease underwent drug-eluting stenting, including 88 patients aged ≥70 years (group A) and 151 aged <70 years (group B). Baseline clinical characteristics, procedural success rate, occurrence of cardiac events during follow-up were recorded and compared between the two groups. Results: Procedural success rate and complications were similar for the two groups. During follow-up, group A had higher recurrence rate of chest pain than group B (23.9% vs. 7.3%, P<0.001), and occurrence of cardiac events was higher in group A than in group B (5.7% vs. 2.7%, P<0.296). There was no significant difference in the frequency of restenosis between the two groups. Conclusions: Drug-eluting stent implantation for septuagenarians with coronary artery disease is safe but may have more recurrence of angina than younger ones during long-term follow-up. (authors)

Diabetes and modifiable risk factors for cardiovascular disease: the prospective Million Women Study

International Nuclear Information System (INIS)

Spencer, Elizabeth A.; Pirie, Kirstin L.; Stevens, Richard J.; Beral, Valerie; Brown, Anna; Liu, Bette; Green, Jane; Reeves, Gillian K.

2008-01-01

To compare the effect of potentially modifiable lifestyle factors on the incidence of vascular disease in women with and without diabetes. In 1996-2001 over one million middle-aged women in the UK joined a prospective study, providing medical history, lifestyle and socio-demographic information. All participants were followed for hospital admissions and deaths using electronic record-linkage. Adjusted relative risks (RRs) and incidence rates were calculated to compare the incidence of coronary heart disease and stroke in women with and without diabetes and by lifestyle factors. At recruitment 25,915 women (2.1% of 1,242,338) reported current treatment for diabetes. During a mean follow-up of 6.1 years per woman, 21,928 had a first hospital admission or death from coronary heart disease (RR for women with versus without diabetes = 3.30, 95% CI 3.14-3.47) and 7,087 had a first stroke (RR = 2.47, 95% CI 2.24-2.74). Adjusted incidence rates of these conditions in women with diabetes increased with duration of diabetes, obesity, inactivity and smoking. The 5-year adjusted incidence rates for cardiovascular disease were 4.6 (95% CI 4.4-4.9) per 100 women aged 50-69 in non-smokers with diabetes, 5.9 (95% CI 4.6-7.6) in smokers with diabetes not using insulin and 11.0 (95% CI 8.3-14.7) in smokers with diabetes using insulin. Non-smoking women with diabetes who were not overweight or inactive still had threefold increased rate for coronary disease or stroke compared with women without diabetes. Of the modifiable factors examined in middle aged women with diabetes, smoking causes the greatest increase in cardiovascular disease, especially in those with insulin treated diabetes

Rethinking the Food and Drug Administration's 2013 guidance on developing drugs for early-stage Alzheimer's disease.

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Schneider, Lon S

2014-03-01

The February 2013 Food and Drug Administration (FDA) draft guidance for developing drugs for early-stage Alzheimer's disease (AD) creates certain challenges as they guide toward the use of one cognitive outcome to gain accelerated marketing approval for preclinical AD drugs, and a composite clinical scale - the Clinical Dementia Rating Scale in particular - for the primary outcome for prodromal AD clinical trials. In light of the developing knowledge regarding early stage diagnoses and clinical trials outcomes, we recommend that FDA describe its requirements for validating preclinical AD diagnoses for drug development purposes, maintain the principle for requiring coprimary outcomes, and encourage the advancement of outcomes for early stage AD trials. The principles for drug development for early stage AD should not differ from those for clinical AD, especially as the diagnoses of prodromal and early AD impinge on each other. The FDA should not recommend that a composite scale be used as a sole primary efficacy outcome to support a marketing claim unless it requires that the cognitive and functional components of such a scale are demonstrated to be individually meaningful. The current draft guidelines may inadvertently constrain efforts to better assess the clinical effects of new drugs and inhibit innovation in an area where evidence-based clinical research practices are still evolving. Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Crowdfunding drug development: the state of play in oncology and rare diseases.

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Dragojlovic, Nick; Lynd, Larry D

2014-11-01

In this article, we present descriptive data on 125 crowdfunding campaigns aimed at financing research in oncology (including basic research, drug discovery, and clinical trials). We also describe five campaigns that have succeeded in raising substantial funds to support the development of treatments for ultrarare diseases. The data suggest that crowdfunding is a viable approach to supporting early proof-of-concept research that could allow researchers in oncology and rare diseases to succeed in traditional grant competitions or to attract private investment. The data also suggest that such an approach could become a valuable additional source of funding for early-stage innovators in the drug development arena. Copyright © 2014 Elsevier Ltd. All rights reserved.

Acute fulminant drug induced necrotizing pancreatitis in a patient with ankylosing spondylitis

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Pablo Miramontes

2015-03-01

Full Text Available Drug-induced acute necrotizing pancreatitis is a rare adverse event, although it has been reported in association with different drugs, including non-steroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, and analgesic agents commonly used in rheumatology. In different reviews of the pancreotoxicity of drugs, infliximab and etanercept are mentioned among all medications implicated in drug-induced pancreatitis, but clinical cases of acute pancreatitis complicating treatment with these anti-TNF-α agents have been exceptionally reported. We describe a patient with ankylosing spondylitis treated with etanercept, who developed an acute fulminant necrotizing pancreatitis that resulted in death. Doctors should pay close attention to patients taking biologic drugs in which a complaint of abdominal pain lasting for several days with no apparent cause may require a prompt referral for medical consultation.

Nanotechnology in dentistry: drug delivery systems for the control of biofilm-dependent oral diseases.

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de Sousa, Francisco Fabio Oliveira; Ferraz, Camila; Rodrigues, Lidiany K Arla de Azevedo; Nojosa, Jacqueline de Santiago; Yamauti, Monica

2014-01-01

Dental disorders, such as caries, periodontal and endodontic diseases are major public health issues worldwide. In common, they are biofilm-dependent oral diseases, and the specific conditions of oral cavity may develop infectious foci that could affect other physiological systems. Efforts have been made to develop new treatment routes for the treatment of oral diseases, and therefore, for the prevention of some systemic illnesses. New drugs and materials have been challenged to prevent and treat these conditions, especially by means of bacteria elimination. "Recent progresses in understanding the etiology, epidemiology and microbiology of the microbial flora in those circumstances have given insight and motivated the innovation on new therapeutic approaches for the management of the oral diseases progression". Some of the greatest advances in the medical field have been based in nanosized systems, ranging from the drug release with designed nanoparticles to tissue scaffolds based on nanotechnology. These systems offer new possibilities for specific and efficient therapies, been assayed successfully in preventive/curative therapies to the oral cavity, opening new challenges and opportunities to overcome common diseases based on bacterial biofilm development. The aim of this review is to summarize the recent nanotechnological developments in the drug delivery field related to the prevention and treatment of the major biofilm-dependent oral diseases and to identify those systems, which may have higher potential for clinical use.

Infections and treatment of patients with rheumatic diseases

DEFF Research Database (Denmark)

Atzeni, F; Bendtzen, K; Bobbio-Pallavicini, F

2008-01-01

, and for the shortest possible time should therefore greatly reduce the risk of infections. Infection is a major co-morbidity in rheumatoid arthritis (RA), and conventional disease-modifying anti-rheumatic drugs (DMARDs) can increase the risk of their occurrence, including tuberculosis. TNF-alpha plays a key role...

Sustainable rare diseases business and drug access: no time for misconceptions.

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Rollet, Pierrick; Lemoine, Adrien; Dunoyer, Marc

2013-07-23

Legislative incentives enacted in Europe through the Regulation (EC) No. 141/2000 to incentivize orphan drug development have over the last 12 years constituted a powerful impetus toward R&D directed at the rare diseases population. However, despite therapeutic promises contained in these projects and significant economic impact linked to burgeoning R&D expenditures, the affordability and value of OMPs has become a topic of health policy debate in Europe fueled by the perception that OMPs have high acquisition costs, and by misconceptions around pricing dynamics and rare-diseases business models. In order to maintain sustainable patient access to new and innovative therapies, it is essential to address these misconceptions, and to ensure the successful continuation of a dynamic OMPs R&D within rare-diseases public health policy. Misconceptions abound regarding the pricing of rare diseases drugs and reflect a poor appreciation of the R&D model and the affordability and value of OMPs. Simulation of potential financial returns of small medium sized rare diseases companies focusing on high priced drugs show that their economic returns are likely to be close to their cost of capital. Research in rare diseases is a challenging endeavour characterised by high fixed costs in which companies accrue substantial costs for several years before potentially generating returns from the fruits of their investments. Although heavily dependent upon R&D capabilities of each individual company or R&D organization, continuous flow of R&D financial investment should allow industry to increasingly include efficiencies in research and development in cost considerations to its customers. Industry should also pro-actively work on facilitating development of a specific value based pricing approach to help understanding what constitute value in rare diseases. Policy makers must reward innovation based upon unmet need and patient outcome. Broader understanding by clinicians, the public, and

A comparison of machine learning techniques for detection of drug target articles.

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Danger, Roxana; Segura-Bedmar, Isabel; Martínez, Paloma; Rosso, Paolo

2010-12-01

Important progress in treating diseases has been possible thanks to the identification of drug targets. Drug targets are the molecular structures whose abnormal activity, associated to a disease, can be modified by drugs, improving the health of patients. Pharmaceutical industry needs to give priority to their identification and validation in order to reduce the long and costly drug development times. In the last two decades, our knowledge about drugs, their mechanisms of action and drug targets has rapidly increased. Nevertheless, most of this knowledge is hidden in millions of medical articles and textbooks. Extracting knowledge from this large amount of unstructured information is a laborious job, even for human experts. Drug target articles identification, a crucial first step toward the automatic extraction of information from texts, constitutes the aim of this paper. A comparison of several machine learning techniques has been performed in order to obtain a satisfactory classifier for detecting drug target articles using semantic information from biomedical resources such as the Unified Medical Language System. The best result has been achieved by a Fuzzy Lattice Reasoning classifier, which reaches 98% of ROC area measure. Copyright © 2010 Elsevier Inc. All rights reserved.

Nanotechnology-based drug delivery systems for Alzheimer's disease management: Technical, industrial, and clinical challenges.

Science.gov (United States)

Wen, Ming Ming; El-Salamouni, Noha S; El-Refaie, Wessam M; Hazzah, Heba A; Ali, Mai M; Tosi, Giovanni; Farid, Ragwa M; Blanco-Prieto, Maria J; Billa, Nashiru; Hanafy, Amira S

2017-01-10

Alzheimer's disease (AD) is a neurodegenerative disease with high prevalence in the rapidly growing elderly population in the developing world. The currently FDA approved drugs for the management of symptomatology of AD are marketed mainly as conventional oral medications. Due to their gastrointestinal side effects and lack of brain targeting, these drugs and dosage regiments hinder patient compliance and lead to treatment discontinuation. Nanotechnology-based drug delivery systems (NTDDS) administered by different routes can be considered as promising tools to improve patient compliance and achieve better therapeutic outcomes. Despite extensive research, literature screening revealed that clinical activities involving NTDDS application in research for AD are lagging compared to NTDDS for other diseases such as cancers. The industrial perspectives, processability, and cost/benefit ratio of using NTDDS for AD treatment are usually overlooked. Moreover, active and passive immunization against AD are by far the mostly studied alternative AD therapies because conventional oral drug therapy is not yielding satisfactorily results. NTDDS of approved drugs appear promising to transform this research from 'paper to clinic' and raise hope for AD sufferers and their caretakers. This review summarizes the recent studies conducted on NTDDS for AD treatment, with a primary focus on the industrial perspectives and processability. Additionally, it highlights the ongoing clinical trials for AD management. Copyright © 2016 Elsevier B.V. All rights reserved.

Multifunctional Amine Mesoporous Silica Spheres Modified with Multiple Amine as Carriers for Drug Release

Directory of Open Access Journals (Sweden)

Yan Li

2018-01-01

Full Text Available Mesoporous silica spheres were synthesized by using Stöber theory (MSN-40. Calcination of the mesostructured phase resulted in the starting solid. Organic modification with aminopropyl groups resulted in two MSN-40 materials: named MSN-NH2 and MSN-DQ-40, respectively. These two kinds of samples with different pore sizes (obtained from 3-[2-(2-aminoethylaminoethylamino]propyl-trimethox-ysilane (NQ-62 and modified NQ-62 showed control of the delivery rate of ibuprofen (IBU from the siliceous matrix. The obtained sample from modified NQ-62 has an increased loading rate and shows better control of the delivery rate of IBU than the obtained sample from NQ-62. These three solids were characterized using standard solid state procedures. During tests of in vitro drug release, an interesting phenomenon was observed: at high pH (pH 7.45, IBU in all carriers was released slowly; at low pH (pH 4.5, only a part of the IBU was slowly released from this carrier within 25 hours; most IBU was effectively confined in mesoporous material, but the remaining IBU was released rapidly and completely after 25 hours.

[Guideline for the treatment of Graves' disease with antithyroid drug].

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Nakamura, Hirotoshi

2006-12-01

We have published "Guideline for the Treatment of Graves' Disease with Antithyroid Drug in Japan 2006" in the middle of May from the Japan Thyroid Association. The background, working process, composition, aim and significance of this guideline are described. The most remarkable feature of this guideline is "evidence based".

The Protective Effect of Minocycline in a Paraquat-Induced Parkinson's Disease Model in Drosophila is Modified in Altered Genetic Backgrounds

Directory of Open Access Journals (Sweden)

Arati A. Inamdar

2012-01-01

Full Text Available Epidemiological studies link the herbicide paraquat to increased incidence of Parkinson's disease (PD. We previously reported that Drosophila exposed to paraquat recapitulate PD symptoms, including region-specific degeneration of dopaminergic neurons. Minocycline, a tetracycline derivative, exerts ameliorative effects in neurodegenerative disease models, including Drosophila. We investigated whether our environmental toxin-based PD model could contribute to an understanding of cellular and genetic mechanisms of minocycline action and whether we could assess potential interference with these drug effects in altered genetic backgrounds. Cofeeding of minocycline with paraquat prolonged survival, rescued mobility defects, blocked generation of reactive oxygen species, and extended dopaminergic neuron survival, as has been reported previously for a genetic model of PD in Drosophila. We then extended this study to identify potential interactions of minocycline with genes regulating dopamine homeostasis that might modify protection against paraquat and found that deficits in GTP cyclohydrolase adversely affect minocycline rescue. We further performed genetic studies to identify signaling pathways that are necessary for minocycline protection against paraquat toxicity and found that mutations in the Drosophila genes that encode c-Jun N-terminal kinase (JNK and Akt/Protein kinase B block minocycline rescue.

Drug targets in the cytokine universe for autoimmune disease.

Science.gov (United States)

Liu, Xuebin; Fang, Lei; Guo, Taylor B; Mei, Hongkang; Zhang, Jingwu Z

2013-03-01

In autoimmune disease, a network of diverse cytokines is produced in association with disease susceptibility to constitute the 'cytokine milieu' that drives chronic inflammation. It remains elusive how cytokines interact in such a complex network to sustain inflammation in autoimmune disease. This has presented huge challenges for successful drug discovery because it has been difficult to predict how individual cytokine-targeted therapy would work. Here, we combine the principles of Chinese Taoism philosophy and modern bioinformatics tools to dissect multiple layers of arbitrary cytokine interactions into discernible interfaces and connectivity maps to predict movements in the cytokine network. The key principles presented here have important implications in our understanding of cytokine interactions and development of effective cytokine-targeted therapies for autoimmune disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.

MANAGEMENT OF ENDOCRINE DISEASE: Arguments for the prolonged use of antithyroid drugs in children with Graves' disease.

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Léger, Juliane; Carel, Jean-Claude

2017-08-01

Graves' disease is an autoimmune disorder. It is the leading cause of hyperthyroidism, but is rare in children. Patients are initially managed with antithyroid drugs (ATDs), such as methimazole/carbimazole. A major disadvantage of treatment with ATD is the high risk of relapse, exceeding 70% of children treated for duration of 2 years, and the potential major side effects of the drug reported in exceptional cases. The major advantage of ATD treatment is that normal homeostasis of the hypothalamus-pituitary-thyroid axis may be restored, with periods of drug treatment followed by freedom from medical intervention achieved in approximately 40-50% of cases after prolonged treatment with ATD, for several years, in recent studies. Alternative ablative treatments such as radioactive iodine and, less frequently and mostly in cases of very high volume goiters or in children under the age of 5 years, thyroidectomy, performed by pediatric surgeons with extensive experience should be proposed in cases of non-compliance, intolerance to medical treatment or relapse after prolonged medical treatment. Ablative treatments are effective against hyperthyroidism, but they require the subsequent administration of levothyroxine throughout the patient's life. This review considers data relating to the prognosis for Graves' disease remission in children and explores the limitations of study designs and results; and the emerging proposal for management through the prolonged use of ATD drugs. © 2017 European Society of Endocrinology.

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

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

2017-11-27

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

Comparative in silico profiling of epigenetic modifiers in human tissues.

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Son, Mi-Young; Jung, Cho-Rok; Kim, Dae-Soo; Cho, Hyun-Soo

2018-04-06

The technology of tissue differentiation from human pluripotent stem cells has attracted attention as a useful resource for regenerative medicine, disease modeling and drug development. Recent studies have suggested various key factors and specific culture methods to improve the successful tissue differentiation and efficient generation of human induced pluripotent stem cells. Among these methods, epigenetic regulation and epigenetic signatures are regarded as an important hurdle to overcome during reprogramming and differentiation. Thus, in this study, we developed an in silico epigenetic panel and performed a comparative analysis of epigenetic modifiers in the RNA-seq results of 32 human tissues. We demonstrated that an in silico epigenetic panel can identify epigenetic modifiers in order to overcome epigenetic barriers to tissue-specific differentiation.

Antiepileptic drugs in pregnancy and hemorrhagic disease of the newborn: An update

OpenAIRE

Kazmin, Aleksey; Wong, Renee C.; Sermer, Mathew; Koren, Gideon

2010-01-01

QUESTION What is the current evidence regarding the association between hemorrhagic disease of the newborn and maternal use of hepatic enzyme-inducing antiepileptic drugs (eg, carbamazepine, phenobarbitone, topiramate)?

Hit and lead criteria in drug discovery for infectious diseases of the developing world.

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Katsuno, Kei; Burrows, Jeremy N; Duncan, Ken; Hooft van Huijsduijnen, Rob; Kaneko, Takushi; Kita, Kiyoshi; Mowbray, Charles E; Schmatz, Dennis; Warner, Peter; Slingsby, B T

2015-11-01

Reducing the burden of infectious diseases that affect people in the developing world requires sustained collaborative drug discovery efforts. The quality of the chemical starting points for such projects is a key factor in improving the likelihood of clinical success, and so it is important to set clear go/no-go criteria for the progression of hit and lead compounds. With this in mind, the Japanese Global Health Innovative Technology (GHIT) Fund convened with experts from the Medicines for Malaria Venture, the Drugs for Neglected Diseases initiative and the TB Alliance, together with representatives from the Bill &Melinda Gates Foundation, to set disease-specific criteria for hits and leads for malaria, tuberculosis, visceral leishmaniasis and Chagas disease. Here, we present the agreed criteria and discuss the underlying rationale.

A magnetic nanoparticle stabilized gas containing emulsion for multimodal imaging and triggered drug release.

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Guo, Wei; Li, Diancheng; Zhu, Jia-an; Wei, Xiaohui; Men, Weiwei; Yin, Dazhi; Fan, Mingxia; Xu, Yuhong

2014-06-01

To develop a multimodal imaging guided and triggered drug delivery system based on a novel emulsion formulation composed of iron oxide nanoparticles, nanoscopic bubbles, and oil containing drugs. Iron oxide paramagnetic nanoparticles were synthesized and modified with surface conjugation of polyethylenimide (PEI) or Bovine Serum Albumin (BSA). Both particles were used to disperse and stabilize oil in water emulsions containing coumarin-6 as the model drug. Sulfur hexafluoride was introduced into the oil phase to form nanoscopic bubbles inside the emulsions. The resulted gas containing emulsions were evaluated for their magnetic resonance (MR) and ultrasound (US) imaging properties. The drug release profile triggered by ultrasound was also examined. We have successfully prepared the highly integrated multi-component emulsion system using the surface modified iron oxide nanoparticles to stabilize the interfaces. The resulted structure had distinctive MR and US imaging properties. Upon application of ultrasound waves, the gas containing emulsion would burst and encapsulated drug could be released. The integrated emulsion formulation was multifunctional with paramagnetic, sono-responsive and drug-carrying characteristics, which may have potential applications for disease diagnosis and imaging guided drug release.

[Technological and pharmacotherapeutic properties of selected drugs with modified release of diclofenac sodium].

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Kołodziejczyk, Michał Krzysztof; Kołodziejska, Justyna; Zgoda, Marian Mikołaj

2012-01-01

Diclofenac and its sodium salt is one of the best-known and popular therapeutic agents from the group of NSAIDs used in medicine in many various pharmaceutical forms. Therapeutic products containing diclofenac sodium salt in doses of 100 mg and 75 mg with a qualitatively and quantitatively diversified share of excipients and a variable dosage form of the drug (solid capsules, tablets with modified release) were subjected to technological and pharmaceutical analysis. The effect of solid formulation components of polymer character making the core and the coating of the pharmaceutical form of therapeutic products on the disintegration time and pharmaceutical availability in pharmacopoeial receptor fluids was estimated. Market therapeutic products with diclofenac sodium in doses of 75 mg and 100 mg, technological analysis of the drug dosage form was conducted, disintegration time of solid oral dosage forms of the drug with diclofenac sodium salt was examined and research on pharmaceutical availability of diclofenac sodium salt from tested therapeutic products was conducted using the acid phase and the buffer phase according to the FP standards for delayed release enteral dosage forms. The experimental data was supplemented with the statistical analysis. There are three formulations in the form of solid capsules and one formulation in the form of a coated tablet. All therapeutic products bear features of a dosage form of modified release of diclofenac sodium salt, frequently of a delayed release formula in the duodenum or the small intestine with regard to the limitation of typical undesirable effects after taking NSAIDs. Considerable diversity between solid capsules and the tablet with modified release during disintegration or hydration and swelling has been observed. In the environment of a receptor fluid--purified water (pH = 7) the capsule Dicloberl retard disintegrates at the fastest rate in 5,49 minutes, and then in the order: DicloDuo 75 mg--8,13 minutes and

Protecting Bone Health in Pediatric Rheumatic Diseases: Pharmacological Considerations.

Science.gov (United States)

Zhang, Yujuan; Milojevic, Diana

2017-06-01

Bone health in children with rheumatic conditions may be compromised due to several factors related to the inflammatory disease state, delayed puberty, altered life style, including decreased physical activities, sun avoidance, suboptimal calcium and vitamin D intake, and medical treatments, mainly glucocorticoids and possibly some disease-modifying anti-rheumatic drugs. Low bone density or even fragility fractures could be asymptomatic; therefore, children with diseases of high inflammatory load, such as systemic onset juvenile idiopathic arthritis, juvenile dermatomyositis, systemic lupus erythematosus, and those requiring chronic glucocorticoids may benefit from routine screening of bone health. Most commonly used assessment tools are laboratory testing including serum 25-OH-vitamin D measurement and bone mineral density measurement by a variety of methods, dual-energy X-ray absorptiometry as the most widely used. Early disease control, use of steroid-sparing medications such as disease-modifying anti-rheumatic drugs and biologics, supplemental vitamin D and calcium, and promotion of weight-bearing physical activities can help optimize bone health. Additional treatment options for osteoporosis such as bisphosphonates are still controversial in children with chronic rheumatic diseases, especially those with decreased bone density without fragility fractures. This article reviews common risk factors leading to compromised bone health in children with chronic rheumatic diseases and discusses the general approach to prevention and treatment of bone fragility.

MARKETING STUDIES OF LOCAL MARKET OF DRUGS WHICH ARE APPLIED FOR PREVENTION AND TREATMENT OF ORAL CAVITY DISEASES

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O. A. Tsarakhov

2015-01-01

Full Text Available Stomatological market has actively developed recent years. Domestic experts received an access to contemporary technologies of dental diseases treatment in the world. This conditioned the appearance of new drugs and parapharmaceutical products applied in dental practice on the pharmaceutical market. In this connection, study of these drugs market, their price policy, demand and supply. Assortment of parapharmaceutical products applied in dental practice for oral cavity hygiene is represented mainly by liquid forms, such as mouth rinse, balms, elixirs, and a special place is occupied by toothpastes. Their assortment amounts to more than 700 types. Drugs, applied in dental practice are represented by the following groups: anti-inflammatory, antimicrobial, antiallergenic, anesthetics, drugs which stimulate tissues regeneration, fluoric drugs. The purpose of this study was the analysis of regional pharmaceutical market assortment, which offers parapharmaceutical goods and drugs for prevention and treatment of oral cavity diseases to the stomatological establishments. Pharmaceutical market of the Republic of North Ossetia – Alania is represented by a wide range of drugs for dental diseases treatment. This group is represented in the assortment of practically all distributors. The drugs for dental diseases treatment is not only supplied by domestic producers but also go from pharmaceutical companies of 29 foreign countries, which influences positively on the state of drug therapy of paradontum in the region.

Drug-induced interstitial lung diseases. Often forgotten

International Nuclear Information System (INIS)

Poschenrieder, F.; Stroszczynski, C.; Hamer, O.W.

2014-01-01

Drug-induced interstitial lung diseases (DILD) are probably more common than diagnosed. Due to their potential reversibility, increased vigilance towards DILD is appropriate also from the radiologist's point of view, particularly as these diseases regularly exhibit radiological correlates in high-resolution computed tomography (HRCT) of the lungs. Based on personal experience typical relatively common manifestations of DILD are diffuse alveolar damage (DAD), eosinophilic pneumonia (EP), hypersensitivity pneumonitis (HP), organizing pneumonia (OP), non-specific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP). These patterns are presented based on case studies, whereby emphasis is placed on the clinical context. This is to highlight the relevance of interdisciplinary communication and discussion in the diagnostic field of DILD as it is a diagnosis of exclusion or of probability in most cases. Helpful differential diagnostic indications for the presence of DILD, such as an accompanying eosinophilia or increased attenuation of pulmonary consolidations in amiodarone-induced pneumopathy are mentioned and the freely available online database http://www.pneumotox.com is presented. (orig.) [de

A kernel for open source drug discovery in tropical diseases.

Science.gov (United States)

Ortí, Leticia; Carbajo, Rodrigo J; Pieper, Ursula; Eswar, Narayanan; Maurer, Stephen M; Rai, Arti K; Taylor, Ginger; Todd, Matthew H; Pineda-Lucena, Antonio; Sali, Andrej; Marti-Renom, Marc A

2009-01-01

Conventional patent-based drug development incentives work badly for the developing world, where commercial markets are usually small to non-existent. For this reason, the past decade has seen extensive experimentation with alternative R&D institutions ranging from private-public partnerships to development prizes. Despite extensive discussion, however, one of the most promising avenues-open source drug discovery-has remained elusive. We argue that the stumbling block has been the absence of a critical mass of preexisting work that volunteers can improve through a series of granular contributions. Historically, open source software collaborations have almost never succeeded without such "kernels". HERE, WE USE A COMPUTATIONAL PIPELINE FOR: (i) comparative structure modeling of target proteins, (ii) predicting the localization of ligand binding sites on their surfaces, and (iii) assessing the similarity of the predicted ligands to known drugs. Our kernel currently contains 143 and 297 protein targets from ten pathogen genomes that are predicted to bind a known drug or a molecule similar to a known drug, respectively. The kernel provides a source of potential drug targets and drug candidates around which an online open source community can nucleate. Using NMR spectroscopy, we have experimentally tested our predictions for two of these targets, confirming one and invalidating the other. The TDI kernel, which is being offered under the Creative Commons attribution share-alike license for free and unrestricted use, can be accessed on the World Wide Web at http://www.tropicaldisease.org. We hope that the kernel will facilitate collaborative efforts towards the discovery of new drugs against parasites that cause tropical diseases.

Organoclays for drug delivery Systems

OpenAIRE

Canovas Creus, Alba

2008-01-01

Modified clays can be used as carriers of drugs due to their suitable properties and structure in order to achieve improvements in drug delivery. The study of this thesis starts with an introduction to mineral clays and its classification, properties and characterization, then deepens into modified clays (properties, comparison with mineral clays, applications and procedure of modification). Another chapter is focused in drug delivery: definition, its difficulties nowadays and the different w...

RGD peptide-modified multifunctional dendrimer platform for drug encapsulation and targeted inhibition of cancer cells.

Science.gov (United States)

He, Xuedan; Alves, Carla S; Oliveira, Nilsa; Rodrigues, João; Zhu, Jingyi; Bányai, István; Tomás, Helena; Shi, Xiangyang

2015-01-01

Development of multifunctional nanoscale drug-delivery systems for targeted cancer therapy still remains a great challenge. Here, we report the synthesis of cyclic arginine-glycine-aspartic acid (RGD) peptide-conjugated generation 5 (G5) poly(amidoamine) dendrimers for anticancer drug encapsulation and targeted therapy of cancer cells overexpressing αvβ3 integrins. In this study, amine-terminated G5 dendrimers were used as a platform to be sequentially modified with fluorescein isothiocyanate (FI) via a thiourea linkage and RGD peptide via a polyethylene glycol (PEG) spacer, followed by acetylation of the remaining dendrimer terminal amines. The developed multifunctional dendrimer platform (G5.NHAc-FI-PEG-RGD) was then used to encapsulate an anticancer drug doxorubicin (DOX). We show that approximately six DOX molecules are able to be encapsulated within each dendrimer platform. The formed complexes are water-soluble, stable, and able to release DOX in a sustained manner. One- and two-dimensional NMR techniques were applied to investigate the interaction between dendrimers and DOX, and the impact of the environmental pH on the release rate of DOX from the dendrimer/DOX complexes was also explored. Furthermore, cell biological studies demonstrate that the encapsulation of DOX within the G5.NHAc-FI-PEG-RGD dendrimers does not compromise the anticancer activity of DOX and that the therapeutic efficacy of the dendrimer/DOX complexes is solely related to the encapsulated DOX drug. Importantly, thanks to the role played by RGD-mediated targeting, the developed dendrimer/drug complexes are able to specifically target αvβ3 integrin-overexpressing cancer cells and display specific therapeutic efficacy to the target cells. The developed RGD peptide-targeted multifunctional dendrimers may thus be used as a versatile platform for targeted therapy of different types of αvβ3 integrin-overexpressing cancer cells. Copyright © 2014 Elsevier B.V. All rights reserved.

Chemotext: A Publicly Available Web Server for Mining Drug-Target-Disease Relationships in PubMed.

Science.gov (United States)

Capuzzi, Stephen J; Thornton, Thomas E; Liu, Kammy; Baker, Nancy; Lam, Wai In; O'Banion, Colin P; Muratov, Eugene N; Pozefsky, Diane; Tropsha, Alexander

2018-02-26

Elucidation of the mechanistic relationships between drugs, their targets, and diseases is at the core of modern drug discovery research. Thousands of studies relevant to the drug-target-disease (DTD) triangle have been published and annotated in the Medline/PubMed database. Mining this database affords rapid identification of all published studies that confirm connections between vertices of this triangle or enable new inferences of such connections. To this end, we describe the development of Chemotext, a publicly available Web server that mines the entire compendium of published literature in PubMed annotated by Medline Subject Heading (MeSH) terms. The goal of Chemotext is to identify all known DTD relationships and infer missing links between vertices of the DTD triangle. As a proof-of-concept, we show that Chemotext could be instrumental in generating new drug repurposing hypotheses or annotating clinical outcomes pathways for known drugs. The Chemotext Web server is freely available at http://chemotext.mml.unc.edu .

Automatic extraction of drug indications from FDA drug labels.

Science.gov (United States)

Khare, Ritu; Wei, Chih-Hsuan; Lu, Zhiyong

2014-01-01

Extracting computable indications, i.e. drug-disease treatment relationships, from narrative drug resources is the key for building a gold standard drug indication repository. The two steps to the extraction problem are disease named-entity recognition (NER) to identify disease mentions from a free-text description and disease classification to distinguish indications from other disease mentions in the description. While there exist many tools for disease NER, disease classification is mostly achieved through human annotations. For example, we recently resorted to human annotations to prepare a corpus, LabeledIn, capturing structured indications from the drug labels submitted to FDA by pharmaceutical companies. In this study, we present an automatic end-to-end framework to extract structured and normalized indications from FDA drug labels. In addition to automatic disease NER, a key component of our framework is a machine learning method that is trained on the LabeledIn corpus to classify the NER-computed disease mentions as "indication vs. non-indication." Through experiments with 500 drug labels, our end-to-end system delivered 86.3% F1-measure in drug indication extraction, with 17% improvement over baseline. Further analysis shows that the indication classifier delivers a performance comparable to human experts and that the remaining errors are mostly due to disease NER (more than 50%). Given its performance, we conclude that our end-to-end approach has the potential to significantly reduce human annotation costs.

Creating New Economic Incentives for Repurposing Generic Drugs for Unsolved Diseases Using Social Finance.

Science.gov (United States)

Bloom, Bruce E

2015-12-01

Repurposing research improves patient lives by taking drugs approved for one disease and clinically testing them to create a treatment for a different disease. Repurposing drugs that are generic, inexpensive, and widely available and that can be taken in their current dosage and formulation in the new indication provide a quick, affordable, and effective way to create "new" treatments. However, generic drug repurposing often provides no profit potential, and so there is no economic incentive for industry to pursue this, and philanthropy and government funds are often insufficient. One way to create new economic incentive for the repurposing of generic drugs is through social finance. This perspective describes how social finance can create a new economic incentive by using a social impact bond, or similar financial structure, to repay for-profit investors who fund the repurposing research from the proceeds of healthcare cost reductions generated when these affordable, effective, and widely available repurposed therapies improve healthcare outcomes.

Open-source approaches for the repurposing of existing or failed candidate drugs: learning from and applying the lessons across diseases.

Science.gov (United States)

Allarakhia, Minna

2013-01-01

Repurposing has the objective of targeting existing drugs and failed, abandoned, or yet-to-be-pursued clinical candidates to new disease areas. The open-source model permits for the sharing of data, resources, compounds, clinical molecules, small libraries, and screening platforms to cost-effectively advance old drugs and/or candidates into clinical re-development. Clearly, at the core of drug-repurposing activities is collaboration, in many cases progressing beyond the open sharing of resources, technology, and intellectual property, to the sharing of facilities and joint program development to foster drug-repurposing human-capacity development. A variety of initiatives under way for drug repurposing, including those targeting rare and neglected diseases, are discussed in this review and provide insight into the stakeholders engaged in drug-repurposing discovery, the models of collaboration used, the intellectual property-management policies crafted, and human capacity developed. In the case of neglected tropical diseases, it is suggested that the development of human capital be a central aspect of drug-repurposing programs. Open-source models can support human-capital development through collaborative data generation, open compound access, open and collaborative screening, preclinical and possibly clinical studies. Given the urgency of drug development for neglected tropical diseases, the review suggests elements from current repurposing programs be extended to the neglected tropical diseases arena.

A searchable cross-platform gene expression database reveals connections between drug treatments and disease

Directory of Open Access Journals (Sweden)

Williams Gareth

2012-01-01

Full Text Available Abstract Background Transcriptional data covering multiple platforms and species is collected and processed into a searchable platform independent expression database (SPIED. SPIED consists of over 100,000 expression fold profiles defined independently of control/treatment assignment and mapped to non-redundant gene lists. The database is thus searchable with query profiles defined over genes alone. The motivation behind SPIED is that transcriptional profiles can be quantitatively compared and ranked and thus serve as effective surrogates for comparing the underlying biological states across multiple experiments. Results Drug perturbation, cancer and neurodegenerative disease derived transcriptional profiles are shown to be effective descriptors of the underlying biology as they return related drugs and pathologies from SPIED. In the case of Alzheimer's disease there is high transcriptional overlap with other neurodegenerative conditions and rodent models of neurodegeneration and nerve injury. Combining the query signature with correlating profiles allows for the definition of a tight neurodegeneration signature that successfully highlights many neuroprotective drugs in the Broad connectivity map. Conclusions Quantitative querying of expression data from across the totality of deposited experiments is an effective way of discovering connections between different biological systems and in particular that between drug action and biological disease state. Examples in cancer and neurodegenerative conditions validate the utility of SPIED.

Polymeric materials and formulation technologies for modified-release tablet development.

Science.gov (United States)

Zarate, J; Igartua, M; Hernández, R M; Pedraz, J L

2009-11-01

Over the last years significant advances have been made in the area of drug delivery with the development of modified-release (MR) dosage forms. The present review is divided into two parts, one dealing with technologies for the design of modified-release drug delivery tablets and the other with the use of synthetic and natural polymers that are capable of controlling drug release.

Pathogen infection distribution and drug resistance analysis of patients with severe liver disease

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Xi CHEN

2018-04-01

Full Text Available Objective　To explore the infection distribution and drug resistance of pathogens in patients with severe liver disease, and provide reference for clinical medication. Methods　Retrospective analysis of the microbiological specimens from patients with severe liver disease in Department of Infection of our hospital from August 2014 to November 2016 and the drug susceptibility testing were carried out by means of K-B disc diffusion method after bacterial culturing, and the distribution and drug resistance of pathogens were analyzed. Results　Totally 17 of 73 patients with severe liver disease developed hospital infection (23.3%. 104 strains of bacteria were isolated and 78 strains out of them were multidrug-resistant bacteria (75.0%. Among them, 28(26.9% strains were gram-positive coccus, mainly consisting of Staphylococcus aureus and Staphylococcus epidermidis, and 58(55.8% were gram-negative coccus, mainly composed of Escherichia coli, Klebsiella pneumonia and Acinetobacter baumannii, and 18(17.3% strains fungi. S.aureus and enterococci were resistant to penicillin, erythromycin and levofloxacin, the resistance rates were above 80.0%, but had low resistance rates to vancomycin, teicoplanin and tigecycline. The resistance rates of E.coli and K.pneumoniae to piperacillin, cefazolin and cefuroxime sodium were above 85.0%, but they had lower resistance rates to tigecycline and amikacin. Acinetobacter baumannii was 100% resistant to piperacillin and tazobactam, ceftazidime, imipenem and amikacin, but had low resistance to tigecycline and minocycline. Conclusions　Multi-drug resistant bacteria are the main bacterial pathogens in patients with severe liver disease and have a high resistance rate to commonly used antibiotics, empirical treatment in the population at high risk of multidrug-resistant bacteria infections requires the use of broad-spectrum or high-grade antibiotics (e.g. carbapenems or tigecycline and drugs against specific pathogenic

Modified biomolecule as potential vehicle for buccal delivery of doxepin.

Science.gov (United States)

Laffleur, Flavia; Zilio, Martina; Shuwisitkul, Duangratana

2016-10-01

Doxepin is a traditional tricyclic antidepressant with analgesic and anesthetic properties when applied topically to the mucosa. Doxepin is one approach in treating insomnia and depression in Parkinson's disease. Patients with Parkinson's disease suffer difficulties in swallowing. Therefore, it was the aim of this study to develop a buccal-adhesive delivery system. Pectin was modified with cysteine. Stability assays in form of disintegration assay according to the Ph.Eur were performed. Furthermore, bioadhesiveness on buccal mucosa was investigated incorporating the drug doxepin. The adhesiveness was improved 1.4-fold and revealed a sustained release over 3 h. Taking these findings into account, the modifications render this designed excipient fruitful for buccal delivery.

Humanized mouse models: Application to human diseases.

Science.gov (United States)

Ito, Ryoji; Takahashi, Takeshi; Ito, Mamoru

2018-05-01

Humanized mice are superior to rodents for preclinical evaluation of the efficacy and safety of drug candidates using human cells or tissues. During the past decade, humanized mouse technology has been greatly advanced by the establishment of novel platforms of genetically modified immunodeficient mice. Several human diseases can be recapitulated using humanized mice due to the improved engraftment and differentiation capacity of human cells or tissues. In this review, we discuss current advanced humanized mouse models that recapitulate human diseases including cancer, allergy, and graft-versus-host disease. © 2017 Wiley Periodicals, Inc.

Surface Modified Multifunctional and Stimuli Responsive Nanoparticles for Drug Targeting: Current Status and Uses

Directory of Open Access Journals (Sweden)

Panoraia I. Siafaka

2016-08-01

Full Text Available Nanocarriers, due to their unique features, are of increased interest among researchers working with pharmaceutical formulations. Polymeric nanoparticles and nanocapsules, involving non-toxic biodegradable polymers, liposomes, solid lipid nanoparticles, and inorganic–organic nanomaterials, are among the most used carriers for drugs for a broad spectrum of targeted diseases. In fact, oral, injectable, transdermal-dermal and ocular formulations mainly consist of the aforementioned nanomaterials demonstrating promising characteristics such as long circulation, specific targeting, high drug loading capacity, enhanced intracellular penetration, and so on. Over the last decade, huge advances in the development of novel, safer and less toxic nanocarriers with amended properties have been made. In addition, multifunctional nanocarriers combining chemical substances, vitamins and peptides via coupling chemistry, inorganic particles coated by biocompatible materials seem to play a key role considering that functionalization can enhance characteristics such as biocompatibility, targetability, environmental friendliness, and intracellular penetration while also have limited side effects. This review aims to summarize the “state of the art” of drug delivery carriers in nanosize, paying attention to their surface functionalization with ligands and other small or polymeric compounds so as to upgrade active and passive targeting, different release patterns as well as cell targeting and stimuli responsibility. Lastly, future aspects and potential uses of nanoparticulated drug systems are outlined.

Modeling the modified drug release from curved shape drug delivery systems - Dome Matrix®.

Science.gov (United States)

Caccavo, D; Barba, A A; d'Amore, M; De Piano, R; Lamberti, G; Rossi, A; Colombo, P

2017-12-01

The controlled drug release from hydrogel-based drug delivery systems is a topic of large interest for research in pharmacology. The mathematical modeling of the behavior of these systems is a tool of emerging relevance, since the simulations can be of use in the design of novel systems, in particular for complex shaped tablets. In this work a model, previously developed, was applied to complex-shaped oral drug delivery systems based on hydrogels (Dome Matrix®). Furthermore, the model was successfully adopted in the description of drug release from partially accessible Dome Matrix® systems (systems with some surfaces coated). In these simulations, the erosion rate was used asa fitting parameter, and its dependence upon the surface area/volume ratio and upon the local fluid dynamics was discussed. The model parameters were determined by comparison with the drug release profile from a cylindrical tablet, then the model was successfully used for the prediction of the drug release from a Dome Matrix® system, for simple module configuration and for module assembled (void and piled) configurations. It was also demonstrated that, given the same initial S/V ratio, the drug release is independent upon the shape of the tablets but it is only influenced by the S/V evolution. The model reveals itself able to describe the observed phenomena, and thus it can be of use for the design of oral drug delivery systems, even if complex shaped. Copyright © 2017 Elsevier B.V. All rights reserved.

Drugs meeting the molecular basis of diabetic kidney disease: bridging from molecular mechanism to personalized medicine.

Science.gov (United States)

Lambers Heerspink, Hiddo J; Oberbauer, Rainer; Perco, Paul; Heinzel, Andreas; Heinze, Georg; Mayer, Gert; Mayer, Bernd

2015-08-01

Diabetic kidney disease (DKD) is a complex, multifactorial disease and is associated with a high risk of renal and cardiovascular morbidity and mortality. Clinical practice guidelines for diabetes recommend essentially identical treatments for all patients without taking into account how the individual responds to the instituted therapy. Yet, individuals vary widely in how they respond to medications and therefore optimal therapy differs between individuals. Understanding the underlying molecular mechanisms of variability in drug response will help tailor optimal therapy. Polymorphisms in genes related to drug pharmacokinetics have been used to explore mechanisms of response variability in DKD, but with limited success. The complex interaction between genetic make-up and environmental factors on the abundance of proteins and metabolites renders pharmacogenomics alone insufficient to fully capture response variability. A complementary approach is to attribute drug response variability to individual variability in underlying molecular mechanisms involved in the progression of disease. The interplay of different processes (e.g. inflammation, fibrosis, angiogenesis, oxidative stress) appears to drive disease progression, but the individual contribution of each process varies. Drugs at the other hand address specific targets and thereby interfere in certain disease-associated processes. At this level, biomarkers may help to gain insight into which specific pathophysiological processes are involved in an individual followed by a rational assessment whether a specific drug's mode of action indeed targets the relevant process at hand. This article describes the conceptual background and data-driven workflow developed by the SysKid consortium aimed at improving characterization of the molecular mechanisms underlying DKD at the interference of the molecular impact of individual drugs in order to tailor optimal therapy to individual patients. © The Author 2015. Published by

Micro RNA, A Review: Pharmacogenomic drug targets for complex diseases

Directory of Open Access Journals (Sweden)

Sandhya Bawa

2010-01-01

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