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Sample records for alfa darifenacin hydrobromide

  1. Identification and structural elucidation of two process impurities and stress degradants in darifenacin hydrobromide active pharmaceutical ingredient by LC-ESI/MS(n).

    PubMed

    Thomas, Saji; Paul, Saroj Kumar; Shandilya, Sanjeev; Agarwal, Ashutosh; Saxena, Nitesh; Awasthi, Arun Kumar; Matta, Hari babu; Vir, Dharam; Mathela, Chandra S

    2012-08-07

    The present study describes the identification and characterization of two process impurities and major stress degradants in darifenacin hydrobromide using high performance liquid chromatography (HPLC) analysis. Forced degradation studies confirmed that the drug substance was stable under acidic, alkaline, aqueous hydrolysis, thermal and photolytic conditions and susceptible only to oxidative degradation. Impurities were identified using liquid chromatography coupled with ion trap mass spectrometry (LC-MS/MS(n)). Proposed structures were unambiguously confirmed by synthesis followed by characterization using nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR) and elemental analysis (EA). Based on the spectroscopic, spectrometric and elemental analysis data, the unknown impurities were characterized as 2-{1-[2-(2,3-dihydrobenzofuran-5-yl)-2-oxo-ethyl]-pyrrolidin-3-yl}-2,2-diphenylacetamide (Imp-A), 2-[1-(2-benzofuran-5-yl-ethyl)-pyrrolidin-3-yl]-2,2-diphenylacetamide (Imp-B), 2-{1-[2-(2,3-dihydrobenzofuran-5-yl)-ethyl]-1-oxy-pyrrolidin-3-yl}-2,2-diphenylacetamide (Imp-C) and 2-{1-[2-(7-bromo-2,3-dihydrobenzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-2,2-diphenylacetamide (Imp-D). Plausible mechanisms for the formation and control of these impurities have also been proposed. The method was validated as per regulatory guidelines to demonstrate specificity, sensitivity, linearity, precision, accuracy and the stability-indicating nature. Regression analysis showed a correlation coefficient value greater than 0.99 for darifenacin hydrobromide and its impurities. The accuracy of the method was established based on the recovery obtained between 86.6 and 106.7% for all impurities.

  2. Darifenacin

    MedlinePlus

    ... and trimipramine (Surmontil); antihistamines; clarithromycin (Biaxin); flecainide (Tambocor); ipratropium (Atrovent); itraconazole (Sporanox); ketoconazole (Nizoral); medications for irritable ...

  3. Darifenacin in the treatment of overactive bladder.

    PubMed

    Parsons, M; Robinson, D; Cardozo, L

    2005-07-01

    Antimuscarinic drug therapy has been shown to be effective in the management of patients with symptoms of the overactive bladder syndrome (OAB), but the bothersome antimuscarinic adverse effects of dry mouth, constipation, somnolence and blurred vision often affect compliance with medication. The development of bladder selective M3 specific antagonists offers the possibility of increasing efficacy whilst minimising adverse effects. The M3 specific antagonist solifenacin has recently been marketed, and darifenacin will soon be available. The purpose of this article is to review the pharmacology and clinical trial data available for darifenacin, in addition to examining its role in the treatment of the OBS.

  4. Dornase Alfa

    MedlinePlus

    ... and to improve lung function in patients with cystic fibrosis. It breaks down the thick secretions in the ... your doctor.Dornase alfa is used to treat cystic fibrosis but does not cure it. Continue to use ...

  5. Darifenacin: a novel M3 muscarinic selective receptor antagonist for the treatment of overactive bladder.

    PubMed

    Chapple, Christopher R

    2004-11-01

    Darifenacin is a novel M3 muscarinic selective receptor antagonist for once-daily treatment of overactive bladder (OAB), a highly prevalent, chronic and debilitating disease defined by urinary urgency with or without urge incontinence, usually with increased frequency of micturition and nocturia. In vitro, darifenacin is a potent and specific muscarinic receptor antagonist with darifenacin. Subsequent large-scale clinical trials have confirmed that darifenacin (at doses of 7.5 and 15 mg/day) results in central nervous system and cardiac adverse events comparable to placebo, and provides early and meaningful improvement across a range of OAB symptoms including incontinence episodes, urgency and urinary frequency. On the basis of such findings, darifenacin would appear to meet the current need for an effective OAB pharmacotherapy that is efficacious, well-tolerated and, more importantly, minimises the risk of safety-related adverse effects.

  6. 21 CFR 556.308 - Halofuginone hydrobromide.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... halofuginone hydrobromide and the target tissue selected is liver. A tolerance is established in broilers of 0... liver. These marker residue concentrations in liver correspond to total residue concentrations of 0.3 part per million in liver. The safe concentrations for total residues of halofuginone hydrobromide...

  7. 21 CFR 556.308 - Halofuginone hydrobromide.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... halofuginone hydrobromide and the target tissue selected is liver. A tolerance is established in broilers of 0... liver. These marker residue concentrations in liver correspond to total residue concentrations of 0.3 part per million in liver. The safe concentrations for total residues of halofuginone hydrobromide...

  8. 21 CFR 556.308 - Halofuginone hydrobromide.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... halofuginone hydrobromide and the target tissue selected is liver. A tolerance is established in broilers of 0... liver. These marker residue concentrations in liver correspond to total residue concentrations of 0.3 part per million in liver. The safe concentrations for total residues of halofuginone hydrobromide...

  9. 21 CFR 556.308 - Halofuginone hydrobromide.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... halofuginone hydrobromide and the target tissue selected is liver. A tolerance is established in broilers of 0... liver. These marker residue concentrations in liver correspond to total residue concentrations of 0.3 part per million in liver. The safe concentrations for total residues of halofuginone hydrobromide...

  10. 21 CFR 556.308 - Halofuginone hydrobromide.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... halofuginone hydrobromide and the target tissue selected is liver. A tolerance is established in broilers of 0... liver. These marker residue concentrations in liver correspond to total residue concentrations of 0.3 part per million in liver. The safe concentrations for total residues of halofuginone hydrobromide...

  11. Epoetin Alfa Injection

    MedlinePlus

    ... surgery to decrease the chance that blood transfusions (transfer of one person's blood to another person's body) ... wheezing difficulty breathing or swallowing hoarseness lack of energy dizziness fainting Epoetin alfa injection may cause other ...

  12. Drotrecogin alfa Eli Lilly.

    PubMed

    de Jonge, E

    2002-04-01

    Drotrecogin alfa (Xigris, recombinant activated protein C) is an anticoagulant developed and launched by Eli Lilly & Co for the treatment of sepsis [333781], [339372], [430133], [436271]. The FDA and the EMEA accepted the brand name Xigris for drotrecogin alfa in June 2001. This trade name had been proposed by Lilly in place of the previous brand name, Zovant, which was deemed unacceptable by the EMEA due to concerns that the name could be confused with hospital-based drugs [412512]. Filings for sepsis were made in the US, EU and Australia in February 2001 [398514], [447870] and in March 2001, the US FDA assigned drotrecogin alfa Priority Review status [403435]. The FDA extended the action date from July 27 to October 27, 2001 for completion of its review of the biologics license application (BLA) for drotrecogin alfa to assess further supplementary data submitted by Lilly [412512]. At the October 16, 2001 meeting (postponed from September 12), the FDA Advisory Committee on Anti-Infective Drugs split 10 to 10 over whether to recommend approval [425873], [425940]. In late October 2001, Lilly received an approvable letter from the FDA for the treatment of severe sepsis. Approval was contingent upon successful negotiation of labeling, agreement on post-approval clinical trials, and successful completion of manufacturing inspections [427301]. In November 2001, the FDA approved drotrecogin alfa for the reduction of mortality in adult patients with severe sepsis who have a high risk of death [430133]; the product was launched onto the US market days later [436271]. Following the FDA committee's split decision in October 2001, Credit Suisse First Boston, which expected mid-2002 approval but with restrictive labeling, revised its predictions from $1.265 billion in 2004 sharply downwards to $543 million [425929].

  13. Elosulfase alfa: first global approval.

    PubMed

    Sanford, Mark; Lo, Jin Han

    2014-04-01

    Elosulfase alfa (Vimizim™) is a recombinant form of N-acetylgalactosamine-6-sulfatase (GALNS) that was developed by BioMarin Pharmaceutical Inc. as an enzyme replacement therapy for patients with mucopolysaccharidosis type IVA (MPS IVA), also known as Morquio A syndrome. Patients with MPS IVA have a GALNS deficiency, which results in serious musculoskeletal, cardiorespiratory and other system disturbances. Elosulfase alfa was approved by the US FDA on 14 February 2014 for the treatment of MPS IVA. The European Medicines Agency Committee for Medicinal Products for Human Use (CHMP) has recently recommended that elosulfase alfa be approved for use in the EU in the same indication. Within the last year, the manufacturer has also filed applications for approval for the use of elosulfase alfa in MPS IVA in Brazil, Australia, Canada and Mexico. This article summarizes the milestones in the development of elosulfase alfa leading to its first global approval in MPS IVA.

  14. Synthesis of fused indazole ring systems and application to nigeglanine hydrobromide.

    PubMed

    Sather, Aaron C; Berryman, Orion B; Rebek, Julius

    2012-03-16

    The single-step synthesis of fused tricyclic pyridazino[1,2-a]indazolium ring systems is described. Structural details revealed by crystallography explain the unexpected reactivity. The method is applied to the gram scale synthesis of nigeglanine hydrobromide.

  15. Widespread hyoscine hydrobromide toxicity due to contract manufacturer malpractice : the travacalm episode.

    PubMed

    McEwen, John; Thompson, Barry R; Purcell, Patrick M; Kelly, Larry F; Krauss, Adrian S

    2007-01-01

    An outbreak of hyoscine hydrobromide toxicity was detected through the Australian pharmacovigilance system. The unexpectedly wide variation in hyoscine hydrobromide content between individual tablets within single packets created difficulties in initially explaining the clinical experiences. Strict time requirements for review of incoming adverse drug reaction reports and close involvement of the highly skilled national drug regulatory laboratory resulted in early identification of the cause of the outbreak and led in turn to the identification of malpractice by the contract manufacturer.

  16. ALFA: Automated Line Fitting Algorithm

    NASA Astrophysics Data System (ADS)

    Wesson, R.

    2015-12-01

    ALFA fits emission line spectra of arbitrary wavelength coverage and resolution, fully automatically. It uses a catalog of lines which may be present to construct synthetic spectra, the parameters of which are then optimized by means of a genetic algorithm. Uncertainties are estimated using the noise structure of the residuals. An emission line spectrum containing several hundred lines can be fitted in a few seconds using a single processor of a typical contemporary desktop or laptop PC. Data cubes in FITS format can be analysed using multiple processors, and an analysis of tens of thousands of deep spectra obtained with instruments such as MUSE will take a few hours.

  17. [Preparation of scopolamine hydrobromide nanoparticles-in-microsphere system].

    PubMed

    Lü, Wei-ling; Hu, Jin-hong; Zhu, Quan-gang; Li, Feng-qian

    2010-07-01

    This study is to prepare scopolamine hydrobromide nanoparticles-in-microsphere system (SH-NiMS) and evaluate its drug release characteristics in vitro. SH nanoparticles were prepared by ionic crosslinking method with tripolyphosphate (TPP) as crosslinker and chitosan as carrier. Orthogonal design was used to optimize the formulation of SH nanoparticles, which took the property of encapsulation efficiency and drug loading as evaluation parameters. With HPMC as carrier, adjusted the parameters of spray drying technique and sprayed the SH nanoparticles in microspheres encaposulated by HPMC was formed and which is called nanoparticles-in-microsphere system (NiMS). SH-NiMS appearances were observed by SEM, structure was obsearved by FT-IR and the release characteristics in vitro were evaluated. The optimized formulation of SH nanoparticles was TPP/CS 1:3 (w/w), HPMC 0.3%, SH 0.2%. The solution peristaltic speed of the spray drying technique was adjusted to 15%, and the temperature of inlet was 110 degrees C. The encapsulation product yeild, drug loading and particle sizes of SH-NiMS were 94.2%, 20.4%, and 1256.5 nm, respectively. The appearances and the structure of SH-NiMS were good. The preparation method of SH-NiMS is stable and reliable to use, which provide a new way to develop new dosage form.

  18. Thermoreversible nanoethosomal gel for the intranasal delivery of Eletriptan hydrobromide.

    PubMed

    Shelke, Santosh; Shahi, Sadhana; Jadhav, Kiran; Dhamecha, Dinesh; Tiwari, Roshan; Patil, Hemlata

    2016-06-01

    The objective of the current study was to formulate and characterize thermoreversible gel of Eletriptan Hydrobromide for brain targeting via the intranasal route. Ethosomes were prepared by 3(2) factorial design with two independent variables (concentration of soya lecithin and ethanol) and two response variables [percent entrapment efficiency and vesicle size (nm)] using ethanol injection method. Formulated ethosomes were evaluated for preliminary microscopic examination followed by percent drug entrapment efficiency, vesicle size analysis, zeta potential, polydispersibility index and Transmission electron microscopy (TEM). TEM confirms spherical morphology of ethosomes, whereas Malvern zeta sizer confirms that the vesicle size was in the range of 191 ± 6.55-381.3 ± 61.0 nm. Ethosomes were incorporated in gel using poloxamer 407 and carbopol 934 as thermoreversible and mucoadhesive polymers, respectively. Ethosomal gels were evaluated for their pH, viscosity, mucoadhesive strength, in vitro drug release and ex vivo drug permeation through the sheep nasal mucosa. Mucoadhesive strength and pH was found to be 4400 ± 45 to 5500 ± 78.10 dynes/cm(2) and 6.0 ± 0.3 to 6.2 ± 0.1, respectively. In-vitro drug release from the optimized ethosomal gel formulation (G4) was found to be almost 100 % and ex vivo permeation of 4980 µg/ml with a permeability coefficient of 11.94 ± 0.04 × 10(-5) cm/s after 24 h. Histopathological study of the nasal mucosa confirmed non-toxic nature of ethosomal gels. Formulated EH loaded ethosomal thermoreversible gel could serve as the better alternative for the brain targeting via the intranasal route which in turn could subsequently improve its bioavailability.

  19. ALFA: an automated line fitting algorithm

    NASA Astrophysics Data System (ADS)

    Wesson, R.

    2016-03-01

    I present the automated line fitting algorithm, ALFA, a new code which can fit emission line spectra of arbitrary wavelength coverage and resolution, fully automatically. In contrast to traditional emission line fitting methods which require the identification of spectral features suspected to be emission lines, ALFA instead uses a list of lines which are expected to be present to construct a synthetic spectrum. The parameters used to construct the synthetic spectrum are optimized by means of a genetic algorithm. Uncertainties are estimated using the noise structure of the residuals. An emission line spectrum containing several hundred lines can be fitted in a few seconds using a single processor of a typical contemporary desktop or laptop PC. I show that the results are in excellent agreement with those measured manually for a number of spectra. Where discrepancies exist, the manually measured fluxes are found to be less accurate than those returned by ALFA. Together with the code NEAT, ALFA provides a powerful way to rapidly extract physical information from observations, an increasingly vital function in the era of highly multiplexed spectroscopy. The two codes can deliver a reliable and comprehensive analysis of very large data sets in a few hours with little or no user interaction.

  20. Asfotase alfa therapy for children with hypophosphatasia

    PubMed Central

    Madson, Katherine L.; Phillips, Dawn; Reeves, Amy L.; McAlister, William H.; Yakimoski, Amy; Mack, Karen E.; Hamilton, Kim; Kagan, Kori; Fujita, Kenji P.; Thompson, David D.; Moseley, Scott; Odrljin, Tatjana; Rockman-Greenberg, Cheryl

    2016-01-01

    Background. Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) of the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Consequently, cell-surface deficiency of TNSALP phosphohydrolase activity leads to extracellular accumulation of inorganic pyrophosphate, a natural substrate of TNSALP and inhibitor of mineralization. Children with HPP can manifest rickets, skeletal pain, deformity, fracture, muscle weakness, and premature deciduous tooth loss. Asfotase alfa is a recombinant, bone-targeted, human TNSALP injected s.c. to treat HPP. In 2012, we detailed the 1-year efficacy of asfotase alfa therapy for the life-threatening perinatal and infantile forms of HPP. Methods. Here, we evaluated the efficacy and safety of asfotase alfa treatment administered to children 6–12 years of age at baseline who were substantially impaired by HPP. Two radiographic scales quantitated HPP skeletal disease, including comparisons to serial radiographs from similarly affected historical control patients. Results. Twelve children receiving treatment were studied for 5 years. The 6-month primary endpoint was met, showing significant radiographic improvement. Additional significant improvements included patient growth, strength, motor function, agility, and quality of life, which for most patients meant achieving normal values for age- and sex-matched peers that were sustained at 5 years of treatment. For most, pain and disability resolved. Mild to moderate injection-site reactions were common and were sometimes associated with lipohypertrophy. Low anti–asfotase alfa antibody titers were noted in all patients. No evidence emerged for clinically important ectopic calcification or treatment resistance. Conclusions. Asfotase alfa enzyme replacement therapy has substantial and sustained efficacy with a good safety profile for children suffering from HPP. Trial Registration. ClinicalTrials.gov NCT00952484 (https://clinicaltrials.gov/ct2/show

  1. Asfotase alfa therapy for children with hypophosphatasia.

    PubMed

    Whyte, Michael P; Madson, Katherine L; Phillips, Dawn; Reeves, Amy L; McAlister, William H; Yakimoski, Amy; Mack, Karen E; Hamilton, Kim; Kagan, Kori; Fujita, Kenji P; Thompson, David D; Moseley, Scott; Odrljin, Tatjana; Rockman-Greenberg, Cheryl

    2016-06-16

    Background. Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) of the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Consequently, cell-surface deficiency of TNSALP phosphohydrolase activity leads to extracellular accumulation of inorganic pyrophosphate, a natural substrate of TNSALP and inhibitor of mineralization. Children with HPP can manifest rickets, skeletal pain, deformity, fracture, muscle weakness, and premature deciduous tooth loss. Asfotase alfa is a recombinant, bone-targeted, human TNSALP injected s.c. to treat HPP. In 2012, we detailed the 1-year efficacy of asfotase alfa therapy for the life-threatening perinatal and infantile forms of HPP. Methods. Here, we evaluated the efficacy and safety of asfotase alfa treatment administered to children 6-12 years of age at baseline who were substantially impaired by HPP. Two radiographic scales quantitated HPP skeletal disease, including comparisons to serial radiographs from similarly affected historical control patients. Results. Twelve children receiving treatment were studied for 5 years. The 6-month primary endpoint was met, showing significant radiographic improvement. Additional significant improvements included patient growth, strength, motor function, agility, and quality of life, which for most patients meant achieving normal values for age- and sex-matched peers that were sustained at 5 years of treatment. For most, pain and disability resolved. Mild to moderate injection-site reactions were common and were sometimes associated with lipohypertrophy. Low anti-asfotase alfa antibody titers were noted in all patients. No evidence emerged for clinically important ectopic calcification or treatment resistance. Conclusions. Asfotase alfa enzyme replacement therapy has substantial and sustained efficacy with a good safety profile for children suffering from HPP. Trial Registration. ClinicalTrials.gov NCT00952484 (https://clinicaltrials.gov/ct2/show

  2. The ALFA ZOA Deep Survey: First Results

    NASA Astrophysics Data System (ADS)

    McIntyre, T. P.; Henning, P. A.; Minchin, R. F.; Momjian, E.; Butcher, Z.

    2015-07-01

    The Arecibo L-band Feed Array Zone of Avoidance (ALFA ZOA) Deep Survey is the deepest and most sensitive blind H i survey undertaken in the ZOA. ALFA ZOA Deep will cover about 300 square degrees of sky behind the Galactic Plane in both the inner (30^\\circ ≤slant l≤slant 75^\\circ ;b≤slant | 2^\\circ | ) and outer (175^\\circ ≤slant l≤slant 207^\\circ ;-2^\\circ ≤slant b≤slant +1^\\circ ) Galaxy, using the Arecibo Radio Telescope. First results from the survey have found 61 galaxies within a 15 square degree area centered on l=192^\\circ and b = -2°. The survey reached its expected sensitivity of rms = 1 mJy at 9 km s-1 channel resolution, and is shown to be complete above integrated flux, FHi = 0.5 Jy km s-1. The positional accuracy of the survey is 28″ and detections are found out to a recessional velocity of nearly 19,000 km s-1. The survey confirms the extent of the Orion and Abell 539 clusters behind the plane of the Milky Way and discovers expansive voids, at 10,000 and 18,000 km s-1. Twenty-six detections (43%) have a counterpart in the literature, but only two of these have known redshifts. Counterparts are 20% less common beyond vhel = 10,000 km s-1 and 33% less common at extinctions higher than AB = 3.5 mag. The ALFA ZOA Deep survey is able to probe large scale structure beyond redshifts that even the most modern wide-angle surveys have been able to detect in the ZOA at any wavelength.

  3. Epoetin alfa (Eprex) and quality of life.

    PubMed

    Littlewood, Tim

    2005-01-01

    Several recently published clinical trials in anaemic patients with cancer provide convincing evidence that the quality of life of such patients is considerably impaired and that a significant improvement in quality of life can be achieved if their anaemia is corrected by treatment with recombinant erythropoietin (epoetin alfa, Eprex). Findings of some of the major studies are summarised in this issue. These summaries have been prepared to make the findings more accessible to busy clinicians who may not have time to read longer reports in specialist journals but who need to understand the important clinical implications of this research.

  4. Simultaneous determination of pseudoephedrine hydrochloride, chlorpheniramine maleate, and dextromethorphan hydrobromide by second-derivative photodiode array spectroscopy.

    PubMed

    Murtha, J L; Julian, T N; Radebaugh, G W

    1988-08-01

    The simultaneous determination of the active ingredients in multicomponent pharmaceutical products normally requires the use of a separation technique, such as HPLC or GC, followed by quantitation. Presented here is a rapid, validated, analytical method that does not require prior separation for the simultaneous determination of three drugs, pseudoephedrine hydrochloride, chlorpheniramine maleate, and dextromethorphan hydrobromide, in a tablet formulation. A diode array spectrophotometer, capable of multicomponent analysis, was used for the quantitation. The utility of this method was demonstrated in two ways: the analysis of a chewable pediatric tablet (formulation CP) containing 7.5 mg of pseudoephedrine hydrochloride, 0.5 mg of chlorpheniramine maleate, and 2.5 mg of dextromethorphan hydrobromide, and the dissolution analysis of a hydroxypropyl methylcellulose-based sustained-release tablet (formulation SR) containing 120 mg of pseudoephedrine hydrochloride, 8 mg of chlorpheniramine maleate, and 60 mg of dextromethorphan hydrobromide. The sensitivity of this assay is 7.5 micrograms/mL for pseudoephedrine hydrochloride, 1.0 micrograms/mL for chlorpheniramine maleate, and 5.0 micrograms/mL for dextromethorphan hydrobromide, using the second-derivative spectra of the absorbance with respect to wavelength. Determinations were made in 0.1 M sodium acetate buffer at pH 5.0 using a 1-cm quartz cell. Absorbance spectra, and their first and second derivatives, from 240 to 300 nm were used for the determination. The results obtained by this method compared favorably with the results obtained by a validated HPLC method.

  5. An overview of the pharmacokinetic disposition of darbepoetin alfa.

    PubMed

    Zamboni, William C; Stewart, Clinton E

    2002-09-01

    Darbepoetin alfa is a new erythropoiesis-stimulating protein that has five carbohydrate chains compared with three in recombinant human erythropoietin (r-HuEPO, epoetin alfa). Owing to its increased carbohydrate content, the terminal half-life of darbepoetin alfa is 2-3-fold greater than that of r-HuEPO in patients with chronic kidney disease or cancer. This pharmacokinetic property may allow for less frequent administration of darbepoetin alfa compared with r-HuEPO. Although several regimens are still being tested, a predictable increase was observed in serum concentrations of darbepoetin alfa and no clinically relevant accumulation was seen with once-weekly administration for up to 48 weeks. Preliminary data in patients with cancer suggest that concurrent chemotherapy may influence the pharmacokinetics of darbepoetin alfa. Therefore, the timing of dosing relative to chemotherapy may be important. Darbepoetin alfa, through its potential for less frequent dosing, offers a more convenient treatment option than r-HuEPO for patients with anemia secondary to cancer or kidney disease.

  6. Taliglucerase alfa in Gaucher disease: Description of a Brazilian experience.

    PubMed

    Cravo, R; Rotman, V; Oliveira, P M N; Defendi, H G T; Conceição, D A; Xavier, J R; Chertkoff, R; Noronha, T G; Maia, M L S

    2017-01-16

    We evaluated retrospectively, efficacy and safety of taliglucerase alfa for Gaucher disease in a Brazilian population. Thirteen patients were included for efficacy analysis only one of them naïve to enzyme replacement therapy. All the parameters evaluated remained stable throughout treatment (mean duration 3,5years). Only three patients (out of 35) had to discontinue treatment due to a serious adverse event. In conclusion, treatment with taliglucerase alfa was found to be safe and efficient.

  7. Third order nonlinear optical, luminescence and electrical properties of bis glycine hydrobromide single crystals

    NASA Astrophysics Data System (ADS)

    Surekha, R.; Sagayaraj, P.; Ambujam, K.

    2014-03-01

    Optical quality bis glycine hydrobromide (BGHB) single crystal was grown by slow evaporation technique. The third order nonlinear refractive index and nonlinear absorption coefficient of the grown crystal were measured by Z-scan studies. The third order nonlinear susceptibility was found to be 9.612 × 10-4 esu which is fairly higher than the other glycine compounds. The Photoluminescence spectra reveal the emission bands for BGHB crystals. The band gap energy was calculated to be 3.1 eV. The Photoconductivity studies were employed to determine the dependence of photocurrent on the applied electric field. Negative photoconductivity was exhibited by the sample. The d.c. conductivity of the grown crystal was measured by the complex impedance analysis wherein the obtained plot in the form of semicircle finds application in Debye relaxation for materials having large dc conductivity.

  8. The safety profile of drotrecogin alfa (activated)

    PubMed Central

    Fumagalli, Roberto; Mignini, Mariano A

    2007-01-01

    Continued safety assessment is essential for any newly approved therapy. Drotrecogin alfa (activated; DrotAA), which is approved for use in severe sepsis, has undergone clinical trials with corresponding safety analyses since 1995. However, the only comprehensive review of all trials is that reported in 2003 by Bernard and coworkers. This is an important review that focuses on the safety profile of DrotAA in all published studies (six randomized clinical trials and five national registry studies) and in previously unpublished data. DrotAA treatment is associated with an increased risk for bleeding (which in general is manageable). Nevertheless, the available evidence shows that any adverse effects of DrotAA are outweighed by its benefits in patients with severe sepsis who are at high risk for death. So far, more than 9,000 patients have been enrolled in clinical trials involving DrotAA, providing a valuable safety database. It is of note that although DrotAA does increase the risk of bleeding, this has not been associated with an overall increase in the rate of all severe adverse events. PMID:18269693

  9. XM17 Follitropin Alfa (Ovaleap(®)): A Review in Reproductive Endocrine Disorders.

    PubMed

    Hoy, Sheridan M

    2016-08-01

    The subcutaneous recombinant human follicle-stimulating hormone XM17 follitropin alfa (Ovaleap(®)) is approved in the EU as a biosimilar of follitropin alfa (Gonal-f(®)) for use in all indications for which the reference product is approved, including as a multifollicular stimulant in women undergoing superovulation for assisted reproductive technology (ART) treatment. In a nonblind, phase I study in healthy female volunteers, the pharmacokinetic profile of XM17 follitropin alfa was bioequivalent to that of reference follitropin alfa following single dosing. Moreover, in a multinational, phase III study, the efficacy of XM17 follitropin alfa as a multifollicular stimulant was equivalent to that of reference follitropin alfa in terms of the number of retrieved oocytes (primary endpoint) in women undergoing controlled ovarian stimulation for ART treatment. There were no clinically relevant differences in oocyte quality between XM17 follitropin alfa and reference follitropin alfa, with biochemical, clinical and ongoing pregnancy rates and take-home baby rates not significantly differing between the treatment groups. XM17 follitropin alfa was generally well tolerated in this patient population, with its tolerability profile generally similar to that of reference follitropin alfa and with no new unexpected tolerability concerns identified. Thus, XM17 follitropin alfa is an effective treatment option in patients requiring follitropin alfa therapy for various reproductive endocrine disorders, providing a useful alternative to reference follitropin alfa.

  10. Role of elosulfase alfa in mucopolysaccharidosis IVA.

    PubMed

    Regier, Debra S; Tanpaiboon, Pranoot

    2016-01-01

    Mucopolysaccharidosis type IVA (MPS IVA or Morquio A) is an autosomal recessive lysosomal storage disease which results in a striking skeletal phenotype, but does not negatively impact the intellect of the patient. MPS IVA has a phenotypic continuum that ranges from a severe and rapidly progressing form to a slowly progressive form. The clinical diagnosis is often made in the preschool years based on abnormal bone findings on physical examination and dysplasia on radiographic imaging. Supportive care has been the mainstay in caring for patients. Orthopedic physicians often form the core of the care team due to the early and severe skeletal abnormalities; however, systemic disease is common and requires aggressive monitoring and management. Interdisciplinary care teams often consist of medical geneticists, cardiologists, pulmonary specialists, gastroenterologists, otolaryngologists, audiologists, and ophthalmologists. With the US Food and Drug Administration's approval of elosulfase alfa, patients >5 years of age now have access to this medication from the time of diagnosis. The clinical trial with once weekly intravenous dosing (2.0 mg/kg per week) showed improvement in the 6-minute walk test. The composite end point analysis to evaluate the combining changes from baseline in 6-minute walk test, 3-minute stair climb test, and respiratory function showed that at a dose of 2.0 mg/kg per week, subjects performed better when compared to placebo. This indication was clinically meaningful in the treatment group. The treatment was generally well tolerated, and the uncommon infusion reactions responded well to traditional enzyme replacement therapy infusion reaction management algorithms. Currently, clinical trials are underway to determine the efficacy and safety in MPS IVA patients <5 years of age.

  11. Role of elosulfase alfa in mucopolysaccharidosis IVA

    PubMed Central

    Regier, Debra S; Tanpaiboon, Pranoot

    2016-01-01

    Mucopolysaccharidosis type IVA (MPS IVA or Morquio A) is an autosomal recessive lysosomal storage disease which results in a striking skeletal phenotype, but does not negatively impact the intellect of the patient. MPS IVA has a phenotypic continuum that ranges from a severe and rapidly progressing form to a slowly progressive form. The clinical diagnosis is often made in the preschool years based on abnormal bone findings on physical examination and dysplasia on radiographic imaging. Supportive care has been the mainstay in caring for patients. Orthopedic physicians often form the core of the care team due to the early and severe skeletal abnormalities; however, systemic disease is common and requires aggressive monitoring and management. Interdisciplinary care teams often consist of medical geneticists, cardiologists, pulmonary specialists, gastroenterologists, otolaryngologists, audiologists, and ophthalmologists. With the US Food and Drug Administration’s approval of elosulfase alfa, patients >5 years of age now have access to this medication from the time of diagnosis. The clinical trial with once weekly intravenous dosing (2.0 mg/kg per week) showed improvement in the 6-minute walk test. The composite end point analysis to evaluate the combining changes from baseline in 6-minute walk test, 3-minute stair climb test, and respiratory function showed that at a dose of 2.0 mg/kg per week, subjects performed better when compared to placebo. This indication was clinically meaningful in the treatment group. The treatment was generally well tolerated, and the uncommon infusion reactions responded well to traditional enzyme replacement therapy infusion reaction management algorithms. Currently, clinical trials are underway to determine the efficacy and safety in MPS IVA patients <5 years of age. PMID:27366102

  12. Effects of pH and dose on nasal absorption of scopolamine hydrobromide in human subjects

    NASA Technical Reports Server (NTRS)

    Ahmed, S.; Sileno, A. P.; deMeireles, J. C.; Dua, R.; Pimplaskar, H. K.; Xia, W. J.; Marinaro, J.; Langenback, E.; Matos, F. J.; Putcha, L.; Romeo, V. D.; Behl, C. R.

    2000-01-01

    PURPOSE: The present study was conducted to evaluate the effects of formulation pH and dose on nasal absorption of scopolamine hydrobromide, the single most effective drug available for the prevention of nausea and vomiting induced by motion sickness. METHODS: Human subjects received scopolamine nasally at a dose of 0.2 mg/0.05 mL or 0.4 mg/0.10 mL, blood samples were collected at different time points, and plasma scopolamine concentrations were determined by LC-MS/MS. RESULTS: Following administration of a 0.2 mg dose, the average Cmax values were found to be 262+/-118, 419+/-161, and 488+/-331 pg/ mL for pH 4.0, 7.0, and 9.0 formulations, respectively. At the 0.4 mg dose the average Cmax values were found to be 503+/-199, 933+/-449, and 1,308+/-473 pg/mL for pH 4.0, 7.0, and 9.0 formulations, respectively. At a 0.2 mg dose, the AUC values were found to be 23,208+/-6,824, 29,145+/-9,225, and 25,721+/-5,294 pg x min/mL for formulation pH 4.0, 7.0, and 9.0, respectively. At a 0.4 mg dose, the average AUC value was found to be high for pH 9.0 formulation (70,740+/-29,381 pg x min/mL) as compared to those of pH 4.0 (59,573+/-13,700 pg x min/mL) and pH 7.0 (55,298+/-17,305 pg x min/mL) formulations. Both the Cmax and AUC values were almost doubled with doubling the dose. On the other hand, the average Tmax, values decreased linearly with a decrease in formulation pH at both doses. For example, at a 0.4 mg dose, the average Tmax values were 26.7+/-5.8, 15.0+/-10.0, and 8.8+/-2.5 minutes at formulation pH 4.0, 7.0, and 9.0, respectively. CONCLUSIONS: Nasal absorption of scopolamine hydrobromide in human subjects increased substantially with increases in formulation pH and dose.

  13. Growth of poly-DL-lysine hydrobromide single crystal on mica(001) surfaces.

    NASA Astrophysics Data System (ADS)

    Goswami, Dipak; Liu, Xiaogang; Zhang, Yi; Okasinski, John; Salaita, Khalid; Sun, Peng; Bedzyk, Michael; Mirkin, Chad

    2006-03-01

    We present a method for controlling the initiation and kinetics of polymer crystal growth using atomic force microscope tip coated with poly-DL-lysine hydrobromide (PLH). PLH form triangular prisms on freshly cleaved mica(001) surfaces. These prisms grow in a parallel or anti parallel fashion, which indicates epitaxial growth of the crystal with respect to underling mica lattice. Back reflection Laue on mica (001) surface along with optical microscopy measurements guided us to propose a model which showed that two preferred prism orientations exist along [100] direction of the mica lattice. Grazing incidence oscillation x-ray diffraction measurements revealed that the prisms grown on mica are single crystal with a lattice that has an in-plane orientational epitaxy with the underlying mica lattice. We have observed two growth exponents for the growth of the edge length of the PLH prisms. This reveals that in the early stage of the growth, the prisms grow faster and then the growth rate decreases.

  14. Factors affecting the stability and performance of ipratropium bromide; fenoterol hydrobromide pressurized-metered dose inhalers.

    PubMed

    Ninbovorl, Jenjira; Sawatdee, Somchai; Srichana, Teerapol

    2013-12-01

    The aim of the study was to investigate the factors affecting the stability and performance of ipratropium bromide and fenoterol hydrobromide in a pressurized-metered dose inhaler (pMDI). A factorial design was applied to investigate the effects of three parameters (propellant, water, and ethanol) on the performance of 27 designed formulations of a solution-based pMDI. The formulations that contained a hydrofluoroalkane (HFA) propellant lower than 72% v/v and an ethanol concentration higher than 27% v/v remained as clear solutions. Nine formulations that contained the HFA propellant higher than 74% v/v precipitated. The results indicated that it was not only the HFA propellant content of the formulations that was related to the formulation instability but also ethanol content. Only six formulations from the 18 formulations, that did not precipitate, produced drug contents that were within the acceptable range (80-120%). These six formulations generated aerosols with mass median aerodynamic diameters (MMAD) of approximately 2 μm with a fine particle fraction (FPF; particle size, <6.4 μm) between 45% and 52%. The MMAD and FPF did not change significantly after 6 months of storage (P > 0.05).

  15. Evaluation of Arecoline Hydrobromide Toxicity after a 14-Day Repeated Oral Administration in Wistar Rats

    PubMed Central

    Niu, Jianrong; Zhou, Xuzheng; Li, Jianyong; Li, Bing

    2015-01-01

    A subchronic toxicity test was conducted in rats on the basis of a previous acute toxicity test to evaluate the safety of arecoline hydrobromide (Ah), to systematically study its pharmacological effects and to provide experimental support for a safe clinical dose. Eighty rats were randomly divided into four groups: a high-dose group (1000 mg/kg), medium-dose group (200 mg/kg), low-dose group (100mg/kg) and blank control group. The doses were administered daily via gastric lavage for 14 consecutive days. There were no significant differences in the low-dose Ah group compared to the control group (P>0.05) with regard to body weight, organ coefficients, hematological parameters and histopathological changes. The high-dose of Ah influenced some of these parameters, which requires further study. The results of this study indicated that a long-term, continuous high dose of Ah was toxic. However, it is safe to use Ah according to the clinically recommended dosing parameters. The level of Ah at which no adverse effects were observed was 100 mg/kg/day under the present study conditions. PMID:25880067

  16. ALFA: The new ALICE-FAIR software framework

    NASA Astrophysics Data System (ADS)

    Al-Turany, M.; Buncic, P.; Hristov, P.; Kollegger, T.; Kouzinopoulos, C.; Lebedev, A.; Lindenstruth, V.; Manafov, A.; Richter, M.; Rybalchenko, A.; Vande Vyvre, P.; Winckler, N.

    2015-12-01

    The commonalities between the ALICE and FAIR experiments and their computing requirements led to the development of large parts of a common software framework in an experiment independent way. The FairRoot project has already shown the feasibility of such an approach for the FAIR experiments and extending it beyond FAIR to experiments at other facilities[1, 2]. The ALFA framework is a joint development between ALICE Online- Offline (O2) and FairRoot teams. ALFA is designed as a flexible, elastic system, which balances reliability and ease of development with performance using multi-processing and multithreading. A message- based approach has been adopted; such an approach will support the use of the software on different hardware platforms, including heterogeneous systems. Each process in ALFA assumes limited communication and reliance on other processes. Such a design will add horizontal scaling (multiple processes) to vertical scaling provided by multiple threads to meet computing and throughput demands. ALFA does not dictate any application protocols. Potentially, any content-based processor or any source can change the application protocol. The framework supports different serialization standards for data exchange between different hardware and software languages.

  17. Agalsidase alfa and kidney dysfunction in Fabry disease.

    PubMed

    West, Michael; Nicholls, Kathy; Mehta, Atul; Clarke, Joe T R; Steiner, Robert; Beck, Michael; Barshop, Bruce A; Rhead, William; Mensah, Robert; Ries, Markus; Schiffmann, Raphael

    2009-05-01

    In male patients with Fabry disease, an X-linked disorder of glycosphingolipid metabolism caused by deficient activity of the lysosomal enzyme alpha-galactosidase A, kidney dysfunction becomes apparent by the third decade of life and invariably progresses to ESRD without treatment. Here, we summarize the effects of agalsidase alfa on kidney function from three prospective, randomized, placebo-controlled trials and their open-label extension studies involving 108 adult male patients. The mean baseline GFR among 54 nonhyperfiltrating patients (measured GFR <135 ml/min per 1.73 m(2)) treated with placebo was 85.4 +/- 29.6 ml/min per 1.73 m(2); during 6 mo of placebo, the mean annualized rate of change in GFR was -7.0 +/- 32.9 ml/min per 1.73 m(2). Among 85 nonhyperfiltrating patients treated with agalsidase alfa, the annualized rate of change was -2.9 +/- 8.7 ml/min per 1.73 m(2). Treatment with agalsidase alfa did not affect proteinuria. Multivariate analysis revealed that GFR and proteinuria category (< 1 or > or = 1 g/d) at baseline significantly predicted the rate of decline of GFR during treatment. This summary represents the largest group of male patients who had Fabry disease and for whom the effects of enzyme replacement therapy on kidney function have been studied. These data suggest that agalsidase alfa may stabilize kidney function in these patients.

  18. Astronaut Scott Carpenter practices in the ALFA trainer at Langley

    NASA Technical Reports Server (NTRS)

    1962-01-01

    Project Mercury Astronaut M. Scott Carpenter practices in the Air Lubricated Free Attitude (ALFA) trainer located at NASA's Manned Spacecraft Center at Langley AFB, Virginia. This trainer allows the astronaut to see the image of the earth's surface at his feet while manually controlling the spacecraft.

  19. Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia

    PubMed Central

    Rockman-Greenberg, Cheryl; Ozono, Keiichi; Riese, Richard; Moseley, Scott; Melian, Agustin; Thompson, David D.; Bishop, Nicholas; Hofmann, Christine

    2016-01-01

    Context: Hypophosphatasia (HPP) is an inborn error of metabolism that, in its most severe perinatal and infantile forms, results in 50–100% mortality, typically from respiratory complications. Objectives: Our objective was to better understand the effect of treatment with asfotase alfa, a first-in-class enzyme replacement therapy, on mortality in neonates and infants with severe HPP. Design/Setting: Data from patients with the perinatal and infantile forms of HPP in two ongoing, multicenter, multinational, open-label, phase 2 interventional studies of asfotase alfa treatment were compared with data from similar patients from a retrospective natural history study. Patients: Thirty-seven treated patients (median treatment duration, 2.7 years) and 48 historical controls of similar chronological age and HPP characteristics. Interventions: Treated patients received asfotase alfa as sc injections either 1 mg/kg six times per week or 2 mg/kg thrice weekly. Main Outcome Measures: Survival, skeletal health quantified radiographically on treatment, and ventilatory status were the main outcome measures for this study. Results: Asfotase alfa was associated with improved survival in treated patients vs historical controls: 95% vs 42% at age 1 year and 84% vs 27% at age 5 years, respectively (P < .0001, Kaplan-Meier log-rank test). Whereas 5% (1/20) of the historical controls who required ventilatory assistance survived, 76% (16/21) of the ventilated and treated patients survived, among whom 75% (12/16) were weaned from ventilatory support. This better respiratory outcome accompanied radiographic improvements in skeletal mineralization and health. Conclusions: Asfotase alfa mineralizes the HPP skeleton, including the ribs, and improves respiratory function and survival in life-threatening perinatal and infantile HPP. PMID:26529632

  20. Normal-phase LC method for simultaneous analysis of pseudophedrine hydrochloride, dextromethorphan hydrobromide, chlorpheniramine maleate, and paracetamol in tablet formulations.

    PubMed

    Al-Rimawi, Fuad

    2010-04-01

    A simple, precise, and accurate method is developed and validated for the analysis of pseudophedrine hydrochloride, dextromethorphan hydrobromide, chlorpheniramine maleate, and paracetamol in tablet formulations. The method has shown adequate separation of the four ingredients from each other. Separation was achieved on a silica column (5 μm, 125 × 4.6 mm inner diameter) using a mobile phase consisting of methanol/ammonium dihydrogen phosphate buffer (90:10, v/v) at a flow rate of 1.0 ml/min and UV detection at 220 nm. This new method is validated in accordance with USP requirements for new methods for assay determination, which include accuracy, precision, selectivity, linearity and range, robustness and ruggedness. The current method demonstrates good linearity over the range of 0.15-0.45 mg/ml of pseudophedrine hydrochloride with r (2) of 0.996, and in the range of 0.075-0.225 mg/ml of dextromethorphan hydrobromide with r (2) of 0.992, and in the range of 0.01-0.03 mg/ml of chlorpheniramine maleate with r (2) of 0.994, and in the range of 0.25-0.75 mg/ml of paracetamol with r (2) of 0.991. The average recovery of the method is 99.7%, 98.6%, 98.1%, and 99.2% for pseudophedrine hydrochloride, dextromethorphan hydrobromide, chlorpheniramine maleate, and paracetamol, respectively. The degree of reproducibility of the results obtained as a result of small deliberate variations in the method parameters and by changing analytical operator has proven that the method is robust and rugged.

  1. [Pharmacokinetics of scopolamine hydrobromide oral disintegrative microencapsule tablets in Beagle dogs determined with LC-MS/MS].

    PubMed

    Xia, Tian; Liu, De-Ding; Shi, Li-Fu; Hu, Jin-Hong

    2011-08-01

    The study aims to elucidate the characteristics of pharmacokinetics of scopolamine hydrobromide oral disintegrative microencapsule tablets in healthy Beagle dogs. Chromatographic separation was performed on a C18 column (100 mm x 3.0 mm, 3.5 microm) with methanol - 2 mmol x L(-1) ammonium formate (25 : 75) as the mobile phase. A trip-quadrupole tandem mass spectrum with the electrospray ionization (ESI) source was applied and positive ion multiple reaction monitoring mode was operated. Six Beagle dogs were randomly devided into two groups. They received oral single dose of scopolamine hydrobromide oral disintegrative microencapsule tablets 0.6 mg (test tablet) or scopolamine hydrobromide normal tablets (reference tablet). Plasma samples were collected at designed time. Plasma concentration of scopolamine hydrobromide was determined by LC-MS/MS and pharmacokinetic parameters were calculated. The pharmacokinetic parameters of test tablet vs reference tablet were as follows: C(max): (8.16 +/- 0.67) ng x mL(-1) vs (3.54 +/- 0.64) ng x mL(-1); t1/2: (2.83 +/- 0.45) h vs (3.85 +/- 0.82) h; t(max): (1.25 +/- 0.27) h vs (0.42 +/- 0.09) h; AUC(0-12h): (25.06 +/- 3.75) h x ng x mL(-1) vs (9.59 +/- 1.02) h x ng x mL(-1); AUC(0-infinity): (26.30 +/- 3.92) h x ng x mL(-1) vs (10.80 +/- 1.45) h x ng x mL(-1); MRT(0-12h): (3.38 +/- 0.34) h vs (3.86 +/- 0.26) h; MRT(0-infinity): (3.98 +/- 0.63) h vs (5.37 +/- 1.00) h. The absorption rate and AUC of test tablet is different from that of reference tablet. The bioavailability of test tablet is better than those of reference tablet.

  2. Structure and spectroscopic properties of bis(1-carboxyethyl-3-aminopyridinium) hydrobromide monohydrate

    NASA Astrophysics Data System (ADS)

    Kowalczyk, I.; Katrusiak, A.; Komasa, A.; Szafran, M.

    2011-05-01

    The structure of bis(1-carboxyethyl-3-aminopyridinium) hydrobromide monohydrate, (3-NH 2PB2) 2HBrṡH 2O ( 1), has been studied by X-ray diffraction, B3LYP/6-311G(d,p) calculations, FTIR and NMR spectroscopy and calorimetric measurements. The compound crystallizes in orthorhombic, space group Pbca. The Br anion and water molecules are positionally disordered so that Br(1) and O(1w) are located at the same positions with the same average occupations and they form O(1w)H⋯Br bonded zigzag chains along [1 0 0], with the Br⋯O(1w)⋯Br and O(1w)⋯Br⋯O(1w) angles equal 121.0(3)°. These chains are connected to the O(1)⋯H(1)⋯O(11) bonded cations through NH⋯Br and NH⋯O(1w) bonds. A pair of 3-NH 2PB2 molecules is bridged by a short symmetric O(1)·H·O(11) hydrogen bond of 2.462(6) Ǻ. The FTIR spectrum of ( 1) shows a broad and intense absorption in the 1500-400 cm -1 range, similar to that in the spectra of type A acid salts of carboxylic acids and other 2:1 betaine complexes with mineral acids. The assignment of the anharmonic experimental solid-state vibrational frequencies of the compound investigated is proposed based on the second-derivative spectrum ( d2). Correlations between the experimental 13C and 1H NMR chemical shifts ( δexp) and the GIAO/B3LYP/6-311G(d,p) calculated magnetic isotropic shielding constants ( σcal) in DMSO-d 6, δexp = a + b· σcalc, are reported.

  3. Pharmacokinetics and bioequivalence studies of galantamine hydrobromide dispersible tablet in healthy male Chinese volunteers.

    PubMed

    Zhang, Li-jun; Fang, Xiao-ling; Li, Xue-ning; Wang, Qing-song; Han, Li-mei; Zhang, Zhi-wen; Sha, Xian-yi

    2007-03-01

    A randomized, two-way, crossover study was conducted in 18 healthy male Chinese volunteers to compare pharmacokinetics profiles of galantamine hydrobromide dispersible tablet with that of conventional tablet. A single oral dose of 10 mg galantamine was administrated to each volunteer. Plasma concentrations of galantamine were determined by a validated high-performance liquid chromatography (HPLC) method with fluorescence detection, which allowed 1 ng/mL to be assayed as the lowest quantifiable concentration. From plasma concentrations, AUC(0-->t) (the area under the plasma concentration-time curve from time 0 to the last sampling time, 32 hr), AUC(0-->infinity) (the area under the plasma concentration-time curve from time 0 to infinity), t((1/2)) (elimination of half-life of the terminal log linear phase), C(max) (maximum plasma drug concentration) and T(max) (time to reach C(max)) were evaluated through noncompartmental pharmacokinetic analysis. AUC(0-->t) and AUC(0-->infinity) were calculated by the linear-log trapezoidal rule method. C(max) and T(max) were obtained directly from the plasma concentration-time curve. Analysis of variance was carried out using logarithmically transformed AUC(0-->t), AUC(0-->infinity) and C(max). As far as AUC(0-->t), AUC(0-->infinity) and C(max) were concerned, there was no statistically significant difference between the test and reference formulations. Ninety percent confidence intervals (90% CI) for the ratio of AUC(0-->t), AUC(0-->infinity) and C(max) values for the test and reference formulations were 100.4-107.8%, 99.0-107.2% and 87.5-111.3%, respectively. As the 90% CIs of AUC(0-->t), AUC(0-->infinity) and C(max) were entirely within 80-125%, two formulations were considered bioequivalent.

  4. Environmental Variability at Site Alfa during the Broadband-87 Exercise

    DTIC Science & Technology

    1989-08-01

    temporally sampled XBT data set was taken aboard Lynch during tlie exercise for the purpose of assessing the effects of internal wave activity and...Variability at Site Alfa during tine Broadband-87 Exercise 6. Author(s). Paul J. Bucca and Roger W. Meredith 5. Funding Numbers. Program Element No...Directorate IMaval Ocean Research and Development Activity Stennis Space Center, Mississippi 39529-5004 8. Performing Organization Report Number

  5. Population pharmacokinetics of darbepoetin alfa in healthy subjects

    PubMed Central

    Agoram, Balaji; Sutjandra, Liviawati; Sullivan, John T

    2007-01-01

    Aim To develop and evaluate a population pharmacokinetic (PK) model of the long-acting erythropoiesis-stimulating protein, darbepoetin alfa in healthy subjects. Methods PK profiles were obtained from 140 healthy subjects receiving single intravenous and/or single or multiple subcutaneous doses of darbepoetin alfa (0.75–8.0 µg kg−1, or either 80 or 500 µg). Data were analysed by a nonlinear mixed-effects modelling approach using NONMEM software. Influential covariates were identified by covariate analysis emphasizing parameter estimates and their confidence intervals, rather than stepwise hypothesis testing. The model was evaluated by comparing simulated profiles (obtained using the covariate model) to the observed profiles in a test dataset. Results The population PK model, including first-order absorption, two-compartment disposition and first-order elimination, provided a good description of data. Modelling indicated that for a 70-kg human, the observed nearly twofold disproportionate dose–exposure relationship at the 8.0 µg kg−1-dose relative to the 0.75 µg kg−1-dose may reflect changing relative bioavailability, which increased from ∼48% at 0.75 µg kg−1 to 78% at 8.0 µg kg−1. The covariate analysis showed that increasing body weight may be related to increasing clearance and central compartment volume, and that the absorption rate constant decreased with increasing age. The full covariate model performed adequately in a fixed-effects prediction test against an external dataset. Conclusion The developed population PK model describes the inter- and intraindividual variability in darbepoetin alfa PK. The model is a suitable tool for predicting the PK response of darbepoetin alfa using clinically untested dosing regimens. PMID:16939525

  6. Enhanced antitumor reactivity of tumor-sensitized T cells by interferon alfa

    SciTech Connect

    Vander Woude, D.L.; Wagner, P.D.; Shu, S.; Chang, A.E. )

    1991-03-01

    Tumor-draining lymph node cells from mice bearing the methylcholanthrene-induced MCA 106 tumors can be sensitized in vitro to acquire antitumor reactivity. We examined the effect of interferon alfa on the function of cells that underwent in vitro sensitization in adoptive immunotherapy. Interferon alfa increased the antitumor reactivity of in vitro sensitized cells in the treatment of MCA 106 pulmonary metastases. This effect was evident in irradiated mice, indicating that a host response to the interferon alfa was not required. Interferon alfa treatment increased class I major histocompatibility complex antigen expression on tumor cells and increased their susceptibility to lysis by in vitro sensitized cells. These results suggest that interferon alfa enhancement of adoptive immunotherapy was mediated by its effect on tumor cells. Interferon alfa may be a useful adjunct to the adoptive immunotherapy of human cancer.

  7. Physico-chemical properties and thermal stability of microcrystalline cellulose isolated from Alfa fibres.

    PubMed

    Trache, Djalal; Donnot, André; Khimeche, Kamel; Benelmir, Riad; Brosse, Nicolas

    2014-04-15

    In this study, microcrystalline cellulose (Alfa-MCC) was extracted from Alfa fibres using acid hydrolysis method. The molecular weight of the cellulose samples was determined by gel permeation chromatography. The crystallinities were studied by means of X-ray diffraction and solid state cross polarization magic angle spinning (13)C nuclear magnetic resonance spectroscopy, revealing that Alfa-MCC was more crystalline than the native cellulose isolated from Alfa fibres. The morphology of the celluloses was investigated using scanning electron microscopy, showing a compact structure and a rough surface. Furthermore, a good thermal stability was shown for Alfa-MCC. Based on these analyses, Alfa-MCC showed tremendous potential use as composites reinforcing agent, foods stabilizer and pharmaceutical additive.

  8. Pathophysiology of hypophosphatasia and the potential role of asfotase alfa

    PubMed Central

    Orimo, Hideo

    2016-01-01

    Hypophosphatasia (HPP) is an inherited systemic bone disease that is characterized by bone hypomineralization. HPP is classified into six forms according to the age of onset and severity as perinatal (lethal), perinatal benign, infantile, childhood, adult, and odontohypophosphatasia. The causative gene of the disease is the ALPL gene that encodes tissue-nonspecific alkaline phosphatase (TNAP). TNAP is expressed ubiquitously, and its physiological role is apparent in bone mineralization. A defect in bone mineralization can manifest in several ways, including rickets or osteomalacia in HPP patients. Patients with severe forms suffer from respiratory failure because of hypoplastic chest, which is the main cause of death. They sometimes present with seizures due to a defect in vitamin B6 metabolism resulting from the lack of alkaline phosphatase activity in neuronal cells, which is also lethal. Patients with a mild form of the disease exhibit rickets or osteomalacia and a functional defect of exercise. Odontohypophosphatasia shows only dental manifestations. To date, 302 mutations in the ALPL gene have been reported, mainly single-nucleotide substitutions, and the relationships between phenotype and genotype have been partially elucidated. An established treatment for HPP was not available until the recent development of enzyme replacement therapy. The first successful enzyme replacement therapy in model mice using a modified human TNAP protein (asfotase alfa) was reported in 2008, and subsequently success in patients with severe form of the disease was reported in 2012. In 2015, asfotase alfa was approved in Japan in July, followed by in the EU and Canada in August, and then by the US Food and Drug Administration in the USA in October. It is expected that therapy with asfotase alfa will drastically change treatments and prognosis of HPP. PMID:27274262

  9. Safety and efficacy of velaglucerase alfa in Gaucher disease type 1 patients previously treated with imiglucerase

    PubMed Central

    Zimran, Ari; Pastores, Gregory M.; Tylki-Szymanska, Anna; Hughes, Derralynn A.; Elstein, Deborah; Mardach, Rebecca; Eng, Christine; Smith, Laurie; Heisel-Kurth, Margaret; Charrow, Joel; Harmatz, Paul; Fernhoff, Paul; Rhead, William; Longo, Nicola; Giraldo, Pilar; Ruiz, Juan A.; Zahrieh, David; Crombez, Eric; Grabowski, Gregory A.

    2013-01-01

    Velaglucerase alfa is a glucocerebrosidase produced by gene activation technology in a human fibroblast cell line (HT-1080), and is indicated as an enzyme replacement therapy (ERT) for the treatment of Gaucher disease type 1 (GD1). This multicenter, open-label, 12-month study examined the safety and efficacy of velaglucerase alfa in patients with GD1 previously receiving imiglucerase. Eligible patients, ≥2 years old and clinically stable on imiglucerase therapy, were switched to velaglucerase alfa at a dose equal to their prior imiglucerase dose. Infusion durations were 1 hour every other week. Forty patients received velaglucerase alfa (18 male, 22 female; four previously splenectomized; age range 9–71 years). Velaglucerase alfa was generally well tolerated with most adverse events (AEs) of mild or moderate severity. The three most frequently reported AEs were headache (12 of 40 patients), arthralgia (nine of 40 patients), and nasopharyngitis (eight of 40 patients). No patients developed antibodies to velaglucerase alfa. There was one serious AE considered treatment-related: a Grade 2 anaphylactoid reaction within 30 minutes of the first infusion. The patient withdrew; this was the only AE-related withdrawal. Hemoglobin concentrations, platelet counts, and spleen and liver volumes remained stable through 12 months. In conclusion, adult and pediatric patients with GD1, previously treated with imiglucerase, successfully transitioned to velaglucerase alfa, which was generally well tolerated and demonstrated efficacy over 12-months’ treatment consistent with that observed in the velaglucerase alfa Phase 3 clinical trial program. PMID:23339116

  10. Peginterferon alfa-2a for AIDS-associated Kaposi sarcoma: experience with 10 patients.

    PubMed

    Rokx, Casper; van der Ende, Marchina E; Verbon, Annelies; Rijnders, Bart J A

    2013-11-01

    In this observational cohort study, 10 patients with extensive or treatment-refractory AIDS-associated Kaposi sarcoma were treated with peginterferon alfa-2a. Tumor responses were observed in 9 patients with a median progression-free survival of 645 days. Peginterferon alfa-2a could be an effective therapy for extensive or treatment-resistant Kaposi sarcoma.

  11. Crystal structure of citalopram hydrobromide, C20H22FN2OBr

    SciTech Connect

    Kaduk, James A.; Zhong, Kai; Gindhart, Amy M.; Blanton, Thomas N.

    2016-04-29

    The crystal structure of citalopram hydrobromide has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional theory techniques. Citalopram hydrobromide crystallizes in space group P21/c(#14) with a= 10.766 45(6),b= 33.070 86(16),c= 10.892 85(5) Å,β= 90.8518(3)°,V= 3878.03(4) Å3, andZ= 8. N–H∙∙∙Br hydrogen bonds are important to the structure, but the crystal energy is dominated by van der Waals attraction. The powder pattern was submitted to International Centre for Diffraction Data for inclusion in the Powder Diffraction File™.

  12. Utility of eosin Y as a complexing reagent for the determination of citalopram hydrobromide in commercial dosage forms by fluorescence spectrophotometry.

    PubMed

    Azmi, Syed Najmul Hejaz; Al-Fazari, Ahlam; Al-Badaei, Munira; Al-Mahrazi, Ruqiya

    2015-12-01

    An accurate, selective and sensitive spectrofluorimetric method was developed for the determination of citalopram hydrobromide in commercial dosage forms. The method was based on the formation of a fluorescent ion-pair complex between citalopram hydrobromide and eosin Y in the presence of a disodium hydrogen phosphate/citric acid buffer solution of pH 3.4 that was extractable in dichloromethane. The extracted complex showed fluorescence intensity at λem = 554 nm after excitation at 259 nm. The calibration curve was linear over at concentrations of 2.0-26.0 µg/mL. Under optimized experimental conditions, the proposed method was validated as per ICH guidelines. The effect of common excipients used as additives was tested and the tolerance limit calculated. The limit of detection for the proposed method was 0.121 μg/mL. The proposed method was successfully applied to the determination of citalopram hydrobromide in commercial dosage forms. The results were compared with the reference RP-HPLC method.

  13. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2005-10-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: (-)-Epigallocatechin gallate, (Z)-4-hydroxytamoxifen; Ad.muIFN-beta AD-237, adalimumab, adefovir dipivoxil, agalsidase alfa, alemtuzumab, almotriptan, ALVAC vCP1452, alvimopan hydrate, ambrisentan, anakinra, anti-IFN-gamma MAb; Bimatoprost, BMS-188797, BMS-214662, bortezomib, bosentan, bovine lactoferrin; Caffeine, canertinib dihydrochloride, canfosfamide hydrochloride, cannabidiol, caspofungin acetate, cetuximab, cH36, ChimeriVax-JE, ciclesonide, cilansetron, cinacalcet hydrochloride, clopidogrel, CpG-7909, Cypher; Daptomycin, darbepoetin alfa, darifenacin hydrobromide, decitabine, denufosol tetrasodium, Dexamet, diindolemethane, drotrecogin alfa (activated), duloxetine hydrochloride, DX-9065a; E-7010, edaravone, efalizumab, eicosapentaenoic acid/docosahexaenoic acid, elacridar, eletriptan, emtricitabine, epratuzumab, erlotinib hydrochloride, ertapenem sodium, eszopiclone, everolimus, ezetimibe; Fludarabine, fondaparinux sodium; gamma-Hydroxybutyrate sodium, gavestinel sodium, gefitinib, granisetron-Biochronomer; Human Albumin, human insulin; Imatinib mesylate, indiplon, interleukin-2 XL, isatoribine, ISS-1018, i.v. gamma-globulin, ivabradine hydrochloride, ixabepilone; Lanthanum carbonate, L-arginine hydrochloride, liposomal doxorubicin, LY-450139; Magnesium sulfate, melatonin, motexafin gadolinium, mycophenolic acid sodium salt; Natalizumab, nesiritide, niacin/lovastatin; OGX-011, olmesartan medoxomil, omalizumab, ospemifene; PACAP38, panitumumab, parathyroid hormone (human recombinant), parecoxib sodium, patupilone, pegfilgrastim, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b

  14. Evaluating the transport layer of the ALFA framework for the Intel® Xeon Phi™ Coprocessor

    NASA Astrophysics Data System (ADS)

    Santogidis, Aram; Hirstius, Andreas; Lalis, Spyros

    2015-12-01

    The ALFA framework supports the software development of major High Energy Physics experiments. As part of our research effort to optimize the transport layer of ALFA, we focus on profiling its data transfer performance for inter-node communication on the Intel Xeon Phi Coprocessor. In this article we present the collected performance measurements with the related analysis of the results. The optimization opportunities that are discovered, help us to formulate the future plans of enabling high performance data transfer for ALFA on the Intel Xeon Phi architecture.

  15. Fast radio burst discovered in the Arecibo pulsar ALFA survey

    SciTech Connect

    Spitler, L. G.; Freire, P. C. C.; Lazarus, P.; Lee, K. J.; Cordes, J. M.; Chatterjee, S.; Wharton, R. S.; Brazier, A.; Hessels, J. W. T.; Lorimer, D. R.; McLaughlin, M. A.; Crawford, F.; Deneva, J. S.; Kaspi, V. M.; Karako-Argaman, C.; Allen, B.; Bogdanov, S.; Camilo, F.; Jenet, F. A.; Knispel, B.; and others

    2014-08-01

    Recent work has exploited pulsar survey data to identify temporally isolated, millisecond-duration radio bursts with large dispersion measures (DMs). These bursts have been interpreted as arising from a population of extragalactic sources, in which case they would provide unprecedented opportunities for probing the intergalactic medium; they may also be linked to new source classes. Until now, however, all so-called fast radio bursts (FRBs) have been detected with the Parkes radio telescope and its 13-beam receiver, casting some concern about the astrophysical nature of these signals. Here we present FRB 121102, the first FRB discovery from a geographic location other than Parkes. FRB 121102 was found in the Galactic anti-center region in the 1.4 GHz Pulsar Arecibo L-band Feed Array (ALFA) survey with the Arecibo Observatory with a DM = 557.4 ± 2.0 pc cm{sup –3}, pulse width of 3.0 ± 0.5 ms, and no evidence of interstellar scattering. The observed delay of the signal arrival time with frequency agrees precisely with the expectation of dispersion through an ionized medium. Despite its low Galactic latitude (b = –0.°2), the burst has three times the maximum Galactic DM expected along this particular line of sight, suggesting an extragalactic origin. A peculiar aspect of the signal is an inverted spectrum; we interpret this as a consequence of being detected in a sidelobe of the ALFA receiver. FRB 121102's brightness, duration, and the inferred event rate are all consistent with the properties of the previously detected Parkes bursts.

  16. A novel spray-dried nanoparticles-in-microparticles system for formulating scopolamine hydrobromide into orally disintegrating tablets.

    PubMed

    Li, Feng-Qian; Yan, Cheng; Bi, Juan; Lv, Wei-Lin; Ji, Rui-Rui; Chen, Xu; Su, Jia-Can; Hu, Jin-Hong

    2011-01-01

    Scopolamine hydrobromide (SH)-loaded microparticles were prepared from a colloidal fluid containing ionotropic-gelated chitosan nanoparticles using a spray-drying method. The spray-dried microparticles were then formulated into orally disintegrating tablets (ODTs) using a wet granulation tablet formation process. A drug entrapment efficiency of about 90% (w/w) and loading capacity of 20% (w/w) were achieved for the microparticles, which ranged from 2 μm to 8 μm in diameter. Results of disintegration tests showed that the formulated ODTs could be completely dissolved within 45 seconds. Drug dissolution profiles suggested that SH is released more slowly from tablets made using the microencapsulation process compared with tablets containing SH that is free or in the form of nanoparticles. The time it took for 90% of the drug to be released increased significantly from 3 minutes for conventional ODTs to 90 minutes for ODTs with crosslinked microparticles. Compared with ODTs made with noncrosslinked microparticles, it was thus possible to achieve an even lower drug release rate using tablets with appropriate chitosan crosslinking. Results obtained indicate that the development of new ODTs designed with crosslinked microparticles might be a rational way to overcome the unwanted taste of conventional ODTs and the side effects related to SH's intrinsic characteristics.

  17. Absorption of Cr(VI) onto amino-modified titanate nanotubes using 2-bromoethylamine hydrobromide through SN2 reaction.

    PubMed

    Niu, Guanjun; Liu, Wen; Wang, Ting; Ni, Jinren

    2013-07-01

    Unlike the complex reaction of grafting amino groups using harmful organic solvents, we proposed an environmental friendly method for effective amino grafting on titanate nanotubes (TNTs) with 2-Bromoethylamine hydrobromide (2-Bh) through a two-step SN2 reaction in pure water solution. The amino-modified titanate nanotubes (TNTs-RNH2) were characterized by Transmission electron microscope, X-ray diffraction, X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy. Under optimal conditions, the molar ratio of NaOH/2-Bh was 1.2 for step 1 and 1.3 for step 2 with corresponding reaction time of 12h and 24h, respectively. The adsorption isotherm of Cr(VI) onto TNTs-RNH2 well fits Langmuir model with maximal adsorption capacity of 69.1 mg/g, which is almost five times larger than that of fresh TNTs. The slight decrease in adsorption capacity with NO3(-) concentration was attributed to competition from ions, suppression of electric double layer and changes of Cr(VI) speciation. The wide adsorption pH range was due to much larger point of zero charge (8.2) and electrostatic attraction between positively charged TNTs-RNH2 and Cr(VI) with different speciations. The products could be well reused due to simple desorption at pH 10 with about 20% loss of the adsorption capacity after three recycles without any regeneration treatment.

  18. Pharmacologic Evaluation of Antidepressant Activity and Synthesis of 2-Morpholino-5-phenyl-6H-1,3,4-thiadiazine Hydrobromide

    PubMed Central

    Sarapultsev, Alexey P.; Chupakhin, Oleg N.; Sarapultsev, Petr A.; Sidorova, Larisa P.; Tseitler, Tatiana A.

    2016-01-01

    Substituted thiadiazines exert a reliable therapeutic effect in treating stress, and a schematic description of their ability to influence all aspects of a stress response has been depicted. This study was conducted to pharmacologically evaluate compound L-17, a substituted thiadiazine, (2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide) for possible anti-psychotic/antidepressant activity. Compound L-17 was synthesized by cyclocondensation of α-bromoacetophenone with the original morpholine-4-carbothionic acid hydrazide. Pharmacologic evaluations were conducted using methods described by E.F. Lavretskaya (1985), and in accordance with published guidelines for studying drugs for neuroleptic activity. Compound L-17 was evaluated for various possible mechanisms of action, including its effects on cholinergic system agonists/antagonists, dopaminergic neurotransmission, the adrenergic system, and 5-HT3 serotonin receptors. One or more of these mechanisms may be responsible for the beneficial effects shown by thiadiazine compounds in experiments conducted to evaluate their activity in models of acute stress and acute myocardial infarction. PMID:27213404

  19. Elosulfase Alfa: a review of its use in patients with mucopolysaccharidosis type IVA (Morquio A syndrome).

    PubMed

    Lyseng-Williamson, Katherine A

    2014-10-01

    Elosulfase alfa (Vimizim(®)) is a recombinant form of the human lysosomal enzyme N-acetylgalactosamine-6-sulfatase (GALNS) that is lacking in patients with mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome). It is the first, and currently only, disease-specific treatment option for this very rare, progressively degenerative, autosomal-recessive lysosomal storage disorder. Enzyme replacement therapy with elosulfase alfa aims to restore GALNS activity, thereby preventing the accumulation of keratan sulfate (KS) and chondroitin-6-sulfate in lysosomal compartments of cells that results in the clinical manifestations of MPS IVA. In clinical trials in children and adults with MPS IVA, intravenous elosulfase alfa 2 mg/kg/week provided significant and sustained improvements in urinary levels of KS (a pharmacodynamic biomarker for the disease). In the key placebo-controlled, 24-week, phase 3 trial in patients with MPS IVA aged ≥5 years, elosulfase alfa 2 mg/kg/week significantly improved endurance [least squares mean placebo-adjusted change from baseline in 6-min walk test distance 22.5 m (95 % CI 4.0-40.9)]. Infusion-associated reactions, the primary tolerability issue associated with elosulfase alfa, are generally mild to moderate in severity, self-limiting, and manageable. In the absence of a cure, GALNS enzyme replacement therapy with elosulfase alfa is an important achievement in the treatment of MPS IVA.

  20. Agalsidase alfa: a review of its use in the management of Fabry disease.

    PubMed

    Keating, Gillian M

    2012-10-01

    The enzyme replacement therapy agalsidase alfa (Replagal®) has an amino acid sequence identical to that of native α-galactosidase A; intravenous agalsidase alfa 0.2 mg/kg every other week is indicated for the long-term treatment of patients with confirmed Fabry disease. This article reviews the efficacy and tolerability of agalsidase alfa in patients with Fabry disease, as well as summarizing its pharmacologic properties. Agalsidase alfa had beneficial effects in adult men with Fabry disease, according to the results of two randomized, double-blind, placebo-controlled, 6-month trials (n = 15 and 26). For example, left ventricular mass index was reduced to a significantly greater extent with agalsidase alfa than with placebo. Although the change in myocardial globotriaosylceramide content (primary endpoint in one study) did not significantly differ between agalsidase alfa and placebo recipients, the change in the Brief Pain Inventory (BPI) 'pain at its worst' score (reflecting neuropathic pain while without pain medications; primary endpoint in the second study) was improved to a significantly greater extent with agalsidase alfa than with placebo. In addition, the change in creatinine clearance, but not inulin clearance, significantly favored agalsidase alfa versus placebo recipients. Abnormalities in functional cerebral blood flow and cerebrovascular responses were also reversed with agalsidase alfa therapy. In extensions of these placebo-controlled trials, the reduction in left ventricular mass and improvements in BPI pain scores were maintained after longer-term agalsidase alfa therapy. The significant decline in estimated glomerular filtration rate (eGFR) seen after 48 months' agalsidase alfa treatment was mainly driven by a marked decline in eGFR seen in four patients with stage 3 chronic kidney disease at baseline (although the progression of decline appeared slower than that seen in historic controls); renal function appeared stable in patients with

  1. Charging properties of cassiterite (alfa-SnO2) surfaces

    SciTech Connect

    Rosenqvist, Jorgen K; Machesky, Michael L.; Vlcek, L.; Cummings, Peter T; Wesolowski, David J

    2009-01-01

    The acid-base properties of cassiterite (alfa-SnO2) surfaces at 10 50 C were studied using potentiometric titrations of powder suspensions in aqueous NaCl and RbCl media. The proton sorption isotherms exhibited common intersection points in the pH-range 4.0 to 4.5 at all conditions and the magnitude of charging was similar but not identical in NaCl and RbCl. The hydrogen bonding configuration at the oxide-water interface, obtained from classical Molecular Dynamics (MD) simulations, was analyzed in detail and the results were explicitly incorporated in calculations of protonation constants for the reactive surface sites using the revised MUSIC model. The calculations indicated that the terminal SnOH2 group is more acidic than the bridging Sn2OH group, with protonation constants (log KH) of 3.60 and 5.13 at 25 C, respectively. This is contrary to the situation on the isostructural alfa-TiO2 (rutile), apparently due to the difference in electronegativity between Ti and Sn. MD simulations and speciation calculations indicated considerable differences in the speciation of Na+ and Rb+, despite the similarities in overall charging. Adsorbed sodium ions are almost exclusively found in bidentate surface complexes, while adsorbed rubidium ions form comparable amounts of bidentate and tetradentate complexes. Also, the distribution of adsorbed Na+ between the different complexes shows a considerable dependence on surface charge density (pH), while the distribution of adsorbed Rb+ is almost independent of pH. A Surface Complexation Model (SCM) capable of accurately describing both the measured surface charge and the MD predicted speciation of adsorbed Na+/Rb+ was formulated. According to the SCM, the deprotonated terminal group (SnOH-0.40) and the protonated bridging group (Sn2OH+0.36) dominate the surface speciation over the entire pH-range (2.7 10), illustrating the ability of positively and negatively charged surface groups to coexist. Complexation of the medium cations

  2. Taliglucerase alfa: an enzyme replacement therapy using plant cell expression technology.

    PubMed

    Grabowski, Gregory A; Golembo, Myriam; Shaaltiel, Yoseph

    2014-05-01

    Gaucher disease (GD) is a rare, genetic lysosomal storage disorder caused by functional defects of acid β-glucosidase that results in multiple organ dysfunction. Glycosylation of recombinant acid human β-glucosidase and exposure of terminal mannose residues are critical to the success of enzyme replacement therapy (ERT) for the treatment of visceral and hematologic manifestations in GD. Three commercially available ERT products for treatment of GD type 1 (GD1) include imiglucerase, velaglucerase alfa, and taliglucerase alfa. Imiglucerase and velaglucerase alfa are produced in different mammalian cell systems and require production glycosylation modifications to expose terminal α-mannose residues, which are needed for mannose receptor-mediated uptake by target macrophages. Such modifications add to production costs. Taliglucerase alfa is a plant cell-expressed acid β-glucosidase approved in the United States and other countries for ERT in adults with GD1. A plant-based expression system, using carrot root cell cultures, was developed for production of taliglucerase alfa and does not require additional processing for postproduction glycosidic modifications. Clinical trials have demonstrated that taliglucerase alfa is efficacious, with a well-established safety profile in adult, ERT-naïve patients with symptomatic GD1, and for such patients previously treated with imiglucerase. These included significant improvements in organomegaly and hematologic parameters as early as 6months, and maintenance of achieved therapeutic values in previously treated patients. Ongoing clinical trials will further characterize the long-term efficacy and safety of taliglucerase alfa in more diverse patient populations, and may help to guide clinical decisions for achieving optimal outcomes for patients with GD1.

  3. Interferon Alfa Versus Interferon Alfa Plus Cytarabine Combination Therapy for Chronic Myeloid Leukemia: A Meta-Analysis of Randomized Controlled Trials

    PubMed Central

    Chen, Rui; Ma, Bin; Yang, Kehu; Tian, Jinhui; Liu, Yali; Zhao, Li

    2011-01-01

    Objective This article compares the effect of interferon alfa plus cytarabine (IFN-alfa + Ara-C) versus IFN-alfa alone on the chronic phase of chronic myelogenous leukemia. Methods Electronic searches were performed in the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, Chinese Biomedical Database, China Journal Full-text Database, and Chinese Scientific Journals Database. The languages were limited to Chinese and English. Randomized controlled trials were selected by 2 investigators. Analyses were performed using RevMan 5.0 software. Results A total of 3139 patients in 4 studies met the inclusion criteria. In those patients, complete hematologic response and cytogenetic responses showed significant improvements in favor of IFN-alfa + Ara-C, with complete hematologic response relative risk (RR) of 1.15 (95% CI, 1.09–1.21), complete cytogenetic response RR of 1.87 (95% CI, 1.47–2.38), partial cytogenetic response RR of 1.48 (95% CI, 1.25–1.75), and major cytogenetic response RR of 1.61 (95% CI, 1.42–1.83), respectively. The overall 3-year survival rate in the IFN-alfa + Ara-C group was 86% compared with 79% in the IFN-alfa group (RR = 1.09; 95% CI, 1.03–1.14). In the other 2 studies, 5-year overall survival was 69% compared with 63%, respectively (RR = 1.08; 95% CI, 1.01–1.15). However, IFN-alfa and Ara-C involved higher risk of hematologic toxicity, gastrointestinal adverse events, and severe mucositis compared with IFN-alfa monotherapy (RR = 2.63 [95% CI, 1.94–3.56); RR = 3.38 [95% CI, 2.28–5.00], and RR = 8.84 [95% CI, 3.82–20.46], respectively). Weight loss and skin rash were also observed more frequently in the combination treatment group (RR = 2.00 [95% CI, 1.47–2.73) and RR = 3.75 [95% CI, 2.13–6.59], respectively). Conclusions In patients with chronic myelogenous leukemia in the chronic phase, the combination of IFN-alfa + Ara-C demonstrated improved complete hematologic response, superior cytogenetic responses, and

  4. Influence of Carbopol 71G-NF on the release of dextromethorphan hydrobromide from extended-release matrix tablets.

    PubMed

    Fayed, Mohamed H; Mahrous, Gamal M; Ibrahim, Mohamed A; Sakr, Adel

    2013-01-01

    The objective of this study was to evaluate the potential of Carbopol(®) 71G-NF on the release of dextromethorphan hydrobromide (DM) from matrix tablets in comparison with hydroxypropyl methylcellulose (HPMC(®) K15M) and Eudragit(®) L100-55 polymers. Controlled release DM matrix tablets were prepared using Carbopol 71G-NF, HPMC K15M, and Eudragit L100-55 at different drug to polymer ratios by direct compression technique. The mechanical properties of the tablets as tested by crushing strength and friability tests were improved as the concentration of Carbopol, HPMC, and Eudragit increased. However, Carbopol-based tablets showed a significantly (P<0.05) higher crushing strength and a lower friability than HPMC and Eudragit tablets. No significant differences in weight uniformity and thickness values were observed between the different formulations. It was also found that Carbopol significantly (P<0.05) delayed the release of DM in comparison with HPMC K15M and Eudragit L100-55. A combination of HPMC K15M and Eudragit L100-55 in a 1:1 ratio at 20 and 30% significantly (P<0.05) delayed the release of DM than Eudragit L100-55 alone. Moreover, blends of Carbopol and HPMC at a 1:1 ratio at the 10, 20, and 30% total polymer concentration were investigated. The blend of Carbopol and HPMC at 10% level significantly (P<0.05) slowed the release of DM than Carbopol or HPMC alone, whereas blends at 20 and 30% level significantly (P<0.05) delayed the release of DM compared with HPMC or Carbopol alone. The results with these polymer blends showed that it was possible to reduce the total amount of polymers when used as a combination in formulation.

  5. Radioprotection against biological effects of internal radionuclides in vivo by S-(2-aminoethyl) isothiouronium bromide hydrobromide (AET)

    SciTech Connect

    Narra, V.R.; Harapanhalli, R.S.; Goddu, M.

    1995-02-01

    Radionuclides employed in diagnostic and therapeutic nuclear medicine impart radiation energy to tissue over an extended period of time, which depends on the physical half-life and the biological properties of the radiochemical employed. It is therefore important to examine the capacity of chemical radioprotectors to mitigate damage caused by chronic irradiation by incorporated radionuclides. Spermatogenesis in mouse testis is used as the experimental model, and spermatogonial cell survival as measured by testicular spermhead count is the biological end point. The capacity of S-(2-aminoethyl) isothiouronium bromide hydrobromide (AET) to mitigate radiation damage caused by chronic irradiation by the radiochemicals {sup 125}IUdR, H{sup 125}IPDM and {sup 210}Po-citrate, is investigated. The radioprotection provided by AET is substantial and similar for both of the radioiodinated compounds with dose modification factors (DMF) of 4.0 {plus_minus} 1.2 for {sup 125}IUdR and 3.4 {plus_minus}0.4 for H{sup 125}IPDM. In contrast, the damage caused by {sup 210}Po alpha particles is protected against to a lesser degree (DMF = 2.4 {plus_minus} 005). The present radioprotection data for AET, in conjunction with earlier findings for the chemical protectors cysteamine and vitamin C in the same experimental model, suggest that such compounds may be clinically useful as mitigating agents against biological damage caused by incorporated radionuclides. The observed DMFs for AET also support an earlier premise that the mechanism by which DNA-incorporated Auger emitters impart biological damage is primarily radical mediated, and hence indirect in nature. 43 refs., 7 figs., 2 tabs.

  6. Thermophysical and mechanical characterization of clay bricks reinforced by alfa or straw fibers

    NASA Astrophysics Data System (ADS)

    Elhamdouni, Y.; Khabbazi, A.; Benayad, C.; Mounir, S.; Dadi, A.

    2017-03-01

    This work is part of the valuation of local materials such as clay (earth), alfa fiber and straw fiber. The goal is to use these materials as bricks in rural construction. These materials are abundant, natural, and renewable. The objective of this work is to study the thermal and mechanical behavior of a new material by mixing clay (chosen as the binder) with different mass percentages of alfa fiber (0.5%, 1%, 2%, 3%, 4%), and to compare these results with those of materials often used in the construction of individual houses in rural Morocco (clay + straw). The results obtained prove to us that using straw fibers can reduce the thermal conductivity compared to alfa fiber, which allows to have energy savings of 2% to 7%. By against, alfa fibers can improve the mechanical behavior of clay-based materials when compared to the clay + straw material (an increase of 8% to 17% in the tractive resistance by bending and 6% to 18% for compression resistance). These results also specify the optimal usage conditions of these fibers (alfa and straw) in the clay bricks.

  7. Home infusion program for Fabry disease: experience with agalsidase alfa in Argentina.

    PubMed

    Kisinovsky, Isaac; Cáceres, Guillermo; Coronel, Cristina; Reisin, Ricardo

    2013-01-01

    Fabry disease is an X-linked lysosomal storage disorder caused by inherited deficiency of the enzyme a-galactosidase A. Enzyme replacement treatment using agalsidase alfa significantly reduces pain, improves cardiac function and quality of life, and slows renal deterioration. Nevertheless, it is a life-long treatment which requires regular intravenous infusions and entails a great burden for patients. Our objective was to evaluate retrospectively the safety and tolerability of the home infusion of agalsidase alfa in patients with Fabry disease in Argentina. We evaluated all the patients with Fabry disease who received home infusion with agalsidase alfa 0.2 mg/kg between January 2005 and June 2011. The program included 87 patients; 51 males (mean age: 30 years) and 36 females (mean age: 34 years). A total of 5229 infusions (mean: 59 per patient; range: 1-150) were administered. A total of 5 adverse reactions were seen in 5 patients (5.7% of patients and 0.9% of the total number of infusions). All were mild in severity and resolved by reducing the rate of infusion and by using antihistaminics. All these 5 patients were positive for IgG antibodies, but none of them presented IgE antibodies and none suffered an anaphylactic shock. In our group 18 patients were switched from agalsidase beta to agalsidase alfa without complications. Home infusion with agalsidase alfa is safe, well tolerated and is associated to high compliance.

  8. Treatment of basal cell carcinoma of the nasal pyramid with intralesional interferon alfa-2b.

    PubMed

    Fernández-Vozmediano, José Manuel; Armario-Hita, José Carlos

    2010-04-01

    For patients with basal cell carcinoma (BCC) in whom surgical intervention is not optimal, local treatment with interferon alfa-2b is an alternative. In this study, patients with BCC of the nasal pyramid were treated with intralesional interferon alfa-2b (five million international units three times per week) for four to eight weeks. Cutaneous biopsies were performed before and after treatment for histologic examination. Twelve patients, primarily with the infiltrative histologic form (80%), were treated. Complete clinical and histologic regression was confirmed in all cases, and the aesthetic results were excellent. After four years' follow-up, no tumor persistence was observed in any patient. The most frequent adverse events were transient, mild-to-moderate flu-like symptoms in 95% of patients and asymptomatic leukopenia or neutropenia in 25%. These results suggest that intralesional interferon alfa-2b is a safe and effective nonsurgical alternative approach to treat BCC of the nasal pyramid.

  9. Successful Within-patient Dose Escalation of Olipudase Alfa in Acid Sphingomyelinase Deficiency

    PubMed Central

    Wasserstein, Melissa P.; Jones, Simon A.; Soran, Handrean; Diaz, George A.; Lippa, Natalie; Thurberg, Beth L.; Culm-Merdek, Kerry; Shamiyeh, Elias; Inguilizian, Haig; Cox, Gerald F.; Puga, Ana Cristina

    2015-01-01

    Background Olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is an investigational enzyme replacement therapy (ERT) for patients with ASM deficiency [ASMD; Niemann-Pick Disease (NPD) A and B]. This open-label phase 1b study assessed the safety and tolerability of olipudase alfa using within-patient dose escalation to gradually debulk accumulated sphingomyelin and mitigate the rapid production of metabolites, which can be toxic. Secondary objectives were pharmacokinetics, pharmacodynamics, and exploratory efficacy. Methods Five adults with nonneuronopathic ASMD (NPD B) received escalating doses (0.1 to 3.0 mg/kg) of olipudase alfa intravenously every 2 weeks for 26 weeks. Results All patients successfully reached 3.0 mg/kg without serious or severe adverse events. One patient repeated a dose (2.0 mg/kg) and another had a temporary dose reduction (1.0 to 0.6 mg/kg). Most adverse events (97%) were mild and all resolved without sequelae. The most common adverse events were headache, arthralgia, nausea and abdominal pain. Two patients experienced single acute phase reactions. No patient developed hypersensitivity or anti-olipudase alfa antibodies. The mean circulating half-life of olipudase alfa ranged from 20.9 to 23.4 hours across doses without accumulation. Ceramide, a sphingomyelin catabolite, rose transiently in plasma after each dose, but decreased over time. Reductions in sphingomyelin storage, spleen and liver volumes, and serum chitotriosidase activity, as well as improvements in infiltrative lung disease, lipid profiles, platelet counts, and quality of life assessments, were observed. Conclusions This study provides proof-of-concept for the safety and efficacy of within-patient dose escalation of olipudase alfa in patients with nonneuronopathic ASMD. PMID:26049896

  10. Biological activity of EDQM CRS for Interferon alfa-2a and Interferon alfa-2b - assessment in two in vitro bioassays.

    PubMed

    Silva, M M C G; Gaines-Das, R E; Jones, C; Robinson, C J

    2007-12-01

    The European Directorate for the Quality of Medicines (EDQM) supplies Chemical Reference Substances (CRS) for Interferon (IFN) alfa-2a (CRS I0320300) and for IFN alfa-2b (CRS I0320301) for specified physicochemical tests. However, no information is provided as to their biological activity. In contrast, the World Health Organization (WHO) provides the 2nd International Standards (IS) for IFN alfa-2a (code 95/650) and for IFN alfa-2b (code 95/566), with activity defined in International Units (IU) for calibration of biological activity of preparations of IFN. We have compared the EDQM CRSs with the WHO ISs in two bioassay systems, one measuring the anti-proliferative activity in the Daudi cell line and the other measuring a reporter gene activation in an A549 cell line. In each of these assay systems, the CRSs gave dose - response relations, which were similar to those for the WHO ISs. Estimates of relative activity for each CRS, in terms of the respective IS, showed specific biological activity for the CRSs of the same order as the nominal specific activity for the ISs. However, the estimates of relative activity were not consistent between the two assays systems, emphasizing the need for calibration within each system, if the CRS were to be used as a working standard for bioassays. For structure-activity studies, both physicochemical and biological activity characterisation are required for the same biopharmaceutical preparation. CRS I0320300 and CRS I0320301 may prove useful as working standards for some bioassay systems.

  11. The Synchrony and Diachrony of Bosnian-Croatian-Serbian Adjectival Long-Form Allomorphy (ALFA)

    ERIC Educational Resources Information Center

    Pennington, James Joshua

    2010-01-01

    In Bosnian-Croatian-Serbian (BCS), the gentive (G) and dative/locative (DL) cases exhibit adjectival long-form allomorphy (ALFA). The genitive -"og" -"oga" and the DL -"om" -"ome" -"omu" stand in free variation, inasmuch as when one form is substituted for another the truth value of an utterance…

  12. Interferon alfa-2b and ribavirin: new indication. In children: more risks than in adults.

    PubMed

    2007-04-01

    (1) There is a far lower seroprevalence of hepatitis C virus (HCV) infection in children and adolescents (0.2% to 0.4%) than in adults. In childhood, the principal route of infection is mother-child transmission during pregnancy, while in adolescence transmission is mainly through certain at-risk behaviour (piercing, tattooing and drug injection). In adults with HCV infection, the standard treatment is a combination of peginterferon alfa and ribavirin. (2) 125 children aged 3 to 16 years were treated for 48 weeks in two non comparative trials. HCV RNA was undetectable in plasma in 46% of children six months after treatment cessation (36% for genotype 1 infection, 81% for other genotypes), a proportion similar to that generally seen in adults. It is not known whether the interferon alfa-2b + ribavirin combination slows the progression of histological lesions or prevents clinical complications of HCV infection. (3) Psychological disorders, particularly depression and suicidal tendencies, are the main adverse effects of treatment, especially in children. Growth retardation can also occur, mainly due to gastrointestinal disorders linked to interferon alfa-2b (loss of appetite, nausea and vomiting, diarrhoea). Catch-up growth appears to occur during the six months after treatment cessation. (4) The combination of interferon alfa-2b and ribavirin appears to have similar virological efficacy in children to that seen in adults. Adverse effects, especially those of a psychological nature, remain frequent.

  13. Switch from epoetin to darbepoetin alfa in hemodialysis: dose equivalence and hemoglobin stability

    PubMed Central

    Arrieta, Javier; Moina, Iñigo; Molina, José; Gallardo, Isabel; Muñiz, María Luisa; Robledo, Carmen; García, Oscar; Vidaur, Fernando; Muñoz, Rosa Inés; Iribar, Izaskun; Aguirre, Román; Maza, Antonio

    2014-01-01

    Aim The objective of the study reported here was to describe dose equivalence and hemoglobin (Hb) stability in a cohort of unselected hemodialysis patients who were switched simultaneously from epoetin alfa to darbepoetin alfa. Methods This was a multicenter, observational, retrospective study in patients aged ≥18 years who switched from intravenous (IV) epoetin alfa to IV darbepoetin alfa in October 2007 (Month 0) and continued on hemodialysis for at least 24 months. The dose was adjusted to maintain Hb within 1.0 g/dL of baseline. Results We included 125 patients (59.7% male, mean [standard deviation (SD)] age 70.4 [13.4] years). No significant changes were observed in Hb levels (mean [SD] 11.9 [1.3] g/dL, 12.0 [1.5], 12.0 [1.5], and 12.0 [1.7] at Months −12, 0, 12 and 24, respectively, P=0.409). After conversion, the erythropoiesis-stimulating agent (ESA) dose decreased significantly (P<0.0001), with an annual mean of 174.7 (88.7) international units (IU)/kg/week for epoetin versus 95.7 (43.4) (first year) and 91.4 (42.7) IU/kg/week (second year) for darbepoetin (65% and 64% reduction, respectively). The ESA resistance index decreased from 15.1 (8.5) IU/kg/week/g/dL with epoetin to 8.1 (3.9) (first year) and 7.9 (4.0) (second year) with darbepoetin (P<0.0001). The conversion rate was 354:1 in patients requiring high (>200 IU/kg/week) doses of epoetin and 291:1 in patients requiring low doses. Conclusion In patients on hemodialysis receiving ESAs, conversion from epoetin alfa to darbepoetin alfa was associated with an approximate and persistent reduction of 65% of the required dose. To maintain Hb stability, a conversion rate of 300:1 seems to be appropriate for most patients receiving low doses of epoetin alfa (≤200 IU/kg/week), while 350:1 would be better for patients receiving higher doses. PMID:25336984

  14. Antithrombin alfa in hereditary antithrombin deficient patients: A phase 3 study of prophylactic intravenous administration in high risk situations.

    PubMed

    Tiede, Andreas; Tait, R Campbell; Shaffer, Don W; Baudo, Francesco; Boneu, Bernard; Dempfle, Carl Erik; Horellou, Marie Helene; Klamroth, Robert; Lazarchick, John; Mumford, Andrew D; Schulman, Sam; Shiach, Caroline; Bonfiglio, Laura J; Frieling, Johan T M; Conard, Jacqueline; von Depka, Mario

    2008-03-01

    During surgery and childbirth, patients with hereditary antithrombin (AT) deficiency are at high risk for thrombosis, and heparin prophylaxis may not be sufficiently efficacious. In these patients, exogenous AT may be used in association with heparin. A recombinant human AT (generic name: antithrombin alfa) has been developed. This multi-center study assessed the efficacy and safety of prophylactic intravenous administration of antithrombin alfa to hereditary AT deficient patients in high risk situations, including elective surgery, childbirth, or cesarean section. Antithrombin alfa was administered prior to and during the high risk period for restoration and maintenance of AT activity at 100% of normal. Heparin, low-molecular-weight heparin, and/or vitamin K antagonists were used according to standard of care. The primary efficacy endpoint was the incidence of acute deep vein thrombosis (DVT) from baseline up to day 30 post dosing as assessed by independent central review of duplex ultrasonograms and/or venograms. Safety was assessed based on adverse events (AEs) and laboratory evaluations. Five surgical and nine obstetrical hereditary AT deficiency patients received antithrombin alfa for a mean period of seven days. No clinically overt DVT occurred. Central review of ultrasonograms identified signs of acute DVT in two out of 13 evaluable patients. No antithrombin alfa-related AEs were reported. No patient developed anti-antithrombin alfa antibodies. In conclusion, this study suggests that antithrombin alfa is a safe and effective alternative to human plasma-derived AT for treating hereditary AT deficiency patients at high risk for thromboembolic events.

  15. Safety and efficacy of two dose levels of taliglucerase alfa in pediatric patients with Gaucher disease.

    PubMed

    Zimran, Ari; Gonzalez-Rodriguez, Derlis Emilio; Abrahamov, Aya; Elstein, Deborah; Paz, Alona; Brill-Almon, Einat; Chertkoff, Raul

    2015-01-01

    Taliglucerase alfa is a plant cell-expressed beta-glucocerebrosidase approved in the United States, Israel, Australia, Canada, and other countries for enzyme replacement therapy in adults with Type 1 Gaucher disease (GD), for treatment of pediatric patients in the United States, Australia, and Canada, and for the hematologic manifestations of Type 3 GD in pediatric patients in Canada. This multicenter, randomized, double-blind, parallel-dose, 12-month study assessed efficacy and safety of taliglucerase alfa in pediatric patients with GD. Eleven children were randomized to taliglucerase alfa 30U/kg (n=6) or 60U/kg (n=5) per infusion every other week. From baseline to month 12, the following changes were noted in the taliglucerase alfa 30-U/kg and 60-U/kg dose groups, respectively: median hemoglobin concentrations increased by 12.2% and 14.2%; the interquartile ranges of median percent change in hemoglobin levels from baseline were 20.6 and 10.4, respectively; mean spleen volume decreased from 22.2 to 14.0 multiples of normal (MN) and from 29.4 to 12.9 MN; mean liver volume decreased from 1.8 to 1.5 MN and from 2.2 to 1.7 MN; platelet counts increased by 30.9% and 73.7%; and chitotriosidase activity was reduced by 58.5% and 66.1%. Nearly all adverse events were mild/moderate, unrelated to treatment, and transient. One patient presented with treatment-related gastroenteritis reported as a serious adverse event due to the need for hospitalization for rehydration. No patient discontinued. These data suggest that taliglucerase alfa has the potential to be a therapeutic treatment option for children with GD. This study was registered at www.clinicaltrials.gov as NCT01132690.

  16. Study of forced degradation behavior of eletriptan hydrobromide by LC and LC-MS and development of stability-indicating method.

    PubMed

    Jocić, Biljana; Zecević, Mira; Zivanović, Ljiljana; Protić, Ana; Jadranin, Milka; Vajs, Vlatka

    2009-11-01

    The objective of the present study was to report the stability profile of novel antimigrain drug Eletriptan hydrobromide based on the information obtained from forced degradation studies. The drug was subjected to acid (0.1-1 mol L(-1) HCl), neutral and base (0.1-1 mol L(-1) NaOH) hydrolysis and to oxidative decomposition (3-15% (v/v) H(2)O(2)). Photolysis and thermo degradation at 75 degrees C were carried out in methanol solution and in solid state with both Eletriptan hydrobromide bulk drug and the tablet formulation. The products formed under different stress conditions were investigated by LC and LC-MS. The experimental conditions for LC were chosen by employing experimental design and multicriteria decision making methodology. These powerful tools enabled the accomplishment of satisfactory resolution with the shortest possible analysis time. Analytes were separated on a C(18) column (XTerra, 150 mm x 3.9 mm, 5 microm) with the mobile phase composed of methanol-water solution of TEA (pH 6.52, 1%, v/v) (30:70, v/v) pumped at 1 mL min(-1) flow rate. The column temperature was set at 50 degrees C and the detection at 225 nm using DAD detector. The LC method was suitably modified for LC-MS analysis which was further used to characterize the arisen degradation products. The possible degradation pathway was outlined based on the results. The drug appeared to be instable towards every stress condition but oxidation. The stability was not jeopardized even under more exaggerated conditions such as increased temperature of the solutions to 75 degrees C, increased strength of acid/alkali solutions and prolonged testing period. Validation of the LC-DAD method was carried out in accordance with ICH guideline. The method met all required criteria and was applied when testing the commercially available tablets.

  17. Ovulation induction with minimal dose of follitropin alfa: a case series study

    PubMed Central

    2011-01-01

    Background Gonadotropins are used in ovulation induction (OI) for patients with anovulatory infertility. Pharmacologic OI is associated with risks of ovarian hyperstimulation syndrome and multiple pregnancy. Treatment protocols that minimize these risks by promoting monofollicular development are required. A starting dose of 37.5 IU/day follitropin alfa has been used in OI, particularly among women at high risk of multifollicular development and multiple pregnancy. A retrospective case series study was performed to evaluate rates of monofollicular development and singleton pregnancy following standard treatment with 37.5 IU/day follitropin alfa. Methods Spanish centers that had performed at least five OI cycles during 2008 using 37.5 IU/day follitropin alfa as a starting dose were invited to participate. Data could be provided from any cycle performed in 2008 (up to a maximum of 12 consecutive cycles per site). Case report forms were collected during April-November 2009 and reviewed centrally. Descriptive statistics were obtained from all cases, and follicular development and clinical pregnancy rates assessed. Potential associations of age and body mass index with follicular development and clinical pregnancy were assessed using univariate correlation analyses. Results Thirty centers provided data on 316 cycles of OI using a starting dose of 37.5 IU/day follitropin alfa. Polycystic ovary syndrome was the cause of anovulatory infertility in 217 (68.7%) cases. Follitropin alfa at 37.5 IU/day was sufficient to achieve ovarian stimulation in 230 (72.8%) cycles. A single follicle ≥16 mm in diameter developed in 193 cycles (61.1%; 95% confidence interval [CI] 55.7-66.4%). Seventy-eight women (24.7%; 95% CI 19.9-29.5%) became pregnant: 94.9% singleton and 5.1% twin pregnancies. Fourteen started cycles (4.4%) were cancelled, mainly due to poor response. Univariate correlation analyses detected weak associations. Conclusions Monofollicular growth rate was comparable with

  18. Darbepoietin-alfa has comparable erythropoietic stimulatory effects to recombinant erythropoietin whilst preserving the bone marrow microenvironment.

    PubMed

    Dewamitta, Sita R; Russell, Megan R; Nandurkar, Harshal; Walkley, Carl R

    2013-05-01

    Erythropoiesis stimulating agents are widely used for the treatment of anemia. Recently, we reported erythroid expansion with impaired B lymphopoiesis and loss of trabecular bone in C57BL/6 mice following ten days of treatment with low-dose short acting recombinant human erythropoietin. We have assessed erythropoietin against longer-acting darbepoietin-alfa at a comparable erythroid stimulatory dosage regime. Darbepoietin-alfa and erythropoietin induced similar in vivo erythropoietic expansion. Both agents induced an expansion of the colony-forming unit-erythroid populations. However, unlike erythropoietin, darbepoietin-alfa did not impair bone marrow B lymphopoiesis. Strikingly the bone loss observed with erythropoietin was not apparent following darbepoietin-alfa treatment. This analysis demonstrates that whilst darbepoietin-alfa has similar in vivo erythropoietic potency to erythropoietin, it preserves the bone marrow microenvironment. Thus erythropoietin and darbepoietin-alfa manifest different action showing that erythropoiesis stimulating agents have differential non-erythroid effects dependent on their duration of action.

  19. Use of drotrecogin alfa in necrotizing fasciitis: a case report and pharmacologic review.

    PubMed

    Bland, Christopher M; Frizzi, James D; Reyes, Angel

    2008-01-01

    Necrotizing fasciitis (NF) is a devastating subset of necrotizing soft tissue infections that requires prompt diagnosis and treatment. Although often occurring in patients with impaired host defense mechanisms (diabetes mellitus, systemic immunosuppression, malignancy, etc.), NF may also present in the immunocompetent following a cutaneous lesion or break. Patients with NF often progress to a systemic inflammatory response syndrome or multiorgan system failure that demands advanced critical care practices. We present a case of NF in an immunocompetent patient and the subsequent use of drotrecogin alfa (Xigris). A review of the pharmacologic treatment of streptococcal NF is included. The addition of drotrecogin alfa to operative debridement and penicillin G/clindamycin therapy may be a useful adjunct in the treatment of necrotizing fasciitis due to group A streptococcus.

  20. Human factors engineering and design validation for the redesigned follitropin alfa pen injection device

    PubMed Central

    Mahony, Mary C; Patterson, Patricia; Hayward, Brooke; North, Robert; Green, Dawne

    2015-01-01

    Objectives: To demonstrate, using human factors engineering (HFE), that a redesigned, pre-filled, ready-to-use, pre-asembled follitropin alfa pen can be used to administer prescribed follitropin alfa doses safely and accurately. Methods: A failure modes and effects analysis identified hazards and harms potentially caused by use errors; risk-control measures were implemented to ensure acceptable device use risk management. Participants were women with infertility, their significant others, and fertility nurse (FN) professionals. Preliminary testing included ‘Instructions for Use’ (IFU) and pre-validation studies. Validation studies used simulated injections in a representative use environment; participants received prior training on pen use. Results: User performance in preliminary testing led to IFU revisions and a change to outer needle cap design to mitigate needle stick potential. In the first validation study (49 users, 343 simulated injections), in the FN group, one observed critical use error resulted in a device design modification and another in an IFU change. A second validation study tested the mitigation strategies; previously reported use errors were not repeated. Conclusions: Through an iterative process involving a series of studies, modifications were made to the pen design and IFU. Simulated-use testing demonstrated that the redesigned pen can be used to administer follitropin alfa effectively and safely. PMID:25895897

  1. Efficacy of Alfa EEG wave biofeedback in the management of anxiety

    PubMed Central

    Bhat, Pookala

    2010-01-01

    Background: Biofeedback is a technique in which people are trained to improve their health by learning to control certain internal bodily processes that normally occur involuntarily. Various studies in the past have shown usefulness of Alfa electroencephalographic (EEG) biofeedback in the alleviation of anxiety symptoms. Though most of the psychiatric centers in the armed forces have this facility, not much work has been done in our setup to assess its efficacy in the management of anxiety. Hence this study was undertaken. Materials and Methods: This study was carried out in a multispecialty Command Hospital by enrolling 100 patients with psychiatric diagnosis from both inpatient and outpatient services. The anxiety level was assessed clinically and by using Hamilton Anxiety Scale and Taylor's Manifest Anxiety Scale. One group of 50 patients was treated with Alfa EEG biofeedback sessions only, 5 times in a week for 8 weeks, along with specific pharmacotherapy. The other group was treated with appropriate dose of anxiolytics. The anxiety level was reassessed after 4 weeks and 8 weeks. Results: The response was better for mixed anxiety and depressive disorder with pharmacotherapy than with the biofeedback, but female patients showed better response with EEG biofeedback. Conclusion: In the short term, Alfa EEG biofeedback therapy is almost as efficacious as pharmacological intervention in the management of anxiety symptoms, and relatively more useful in females. PMID:22174533

  2. Velaglucerase alfa (VPRIV) enzyme replacement therapy in patients with Gaucher disease: Long-term data from phase III clinical trials.

    PubMed

    Hughes, Derralynn A; Gonzalez, Derlis E; Lukina, Elena A; Mehta, Atul; Kabra, Madhulika; Elstein, Deborah; Kisinovsky, Isaac; Giraldo, Pilar; Bavdekar, Ashish; Hangartner, Thomas N; Wang, Nan; Crombez, Eric; Zimran, Ari

    2015-07-01

    Type 1 Gaucher disease is an inherited lysosomal enzyme deficiency with variable age of symptom onset. Common presenting signs include thrombocytopenia, anemia, hepatosplenomegaly, bone abnormalities, and, additionally in children, growth failure. Fifty-seven patients aged 3-62 years at the baseline of two phase III trials for velaglucerase alfa treatment were enrolled in the single extension study. In the extension, they received every-other-week velaglucerase alfa intravenous infusions for 1.2-4.8 years at 60 U/kg, although 10 patients experienced dose reduction. No patient experienced a drug-related serious adverse event or withdrew due to an adverse event. One patient died following a convulsion that was reported as unrelated to the study drug. Only one patient tested positive for anti-velaglucerase alfa antibodies. Combining the experience of the initial phase III trials and the extension study, significant improvements were observed in the first 24 months from baseline in hematology variables, organ volumes, plasma biomarkers, and, in adults, the lumbar spine bone mineral density Z-score. Improvements were maintained over longer-term treatment. Velaglucerase alfa had a good long-term safety and tolerability profile, and patients continued to respond clinically, which is consistent with the results of the extension study to the phase I/II trial of velaglucerase alfa. EudraCT number 2008-001965-27; www.clinicaltrials.gov identifier NCT00635427.

  3. Velaglucerase alfa (VPRIV) enzyme replacement therapy in patients with Gaucher disease: Long-term data from phase III clinical trials

    PubMed Central

    Hughes, Derralynn A; Gonzalez, Derlis E; Lukina, Elena A; Mehta, Atul; Kabra, Madhulika; Elstein, Deborah; Kisinovsky, Isaac; Giraldo, Pilar; Bavdekar, Ashish; Hangartner, Thomas N; Wang, Nan; Crombez, Eric; Zimran, Ari

    2015-01-01

    Type 1 Gaucher disease is an inherited lysosomal enzyme deficiency with variable age of symptom onset. Common presenting signs include thrombocytopenia, anemia, hepatosplenomegaly, bone abnormalities, and, additionally in children, growth failure. Fifty-seven patients aged 3–62 years at the baseline of two phase III trials for velaglucerase alfa treatment were enrolled in the single extension study. In the extension, they received every-other-week velaglucerase alfa intravenous infusions for 1.2–4.8 years at 60 U/kg, although 10 patients experienced dose reduction. No patient experienced a drug-related serious adverse event or withdrew due to an adverse event. One patient died following a convulsion that was reported as unrelated to the study drug. Only one patient tested positive for anti-velaglucerase alfa antibodies. Combining the experience of the initial phase III trials and the extension study, significant improvements were observed in the first 24 months from baseline in hematology variables, organ volumes, plasma biomarkers, and, in adults, the lumbar spine bone mineral density Z-score. Improvements were maintained over longer-term treatment. Velaglucerase alfa had a good long-term safety and tolerability profile, and patients continued to respond clinically, which is consistent with the results of the extension study to the phase I/II trial of velaglucerase alfa. EudraCT number 2008-001965-27; http://www.clinicaltrials.gov identifier NCT00635427. Am. J. Hematol. 90:584–591, 2015. © 2015 Wiley Periodicals, Inc. PMID:25801797

  4. Floating matrix dosage form for dextromethorphan hydrobromide based on gas forming technique: in vitro and in vivo evaluation in healthy volunteers.

    PubMed

    Hu, Liandong; Li, Li; Yang, Xun; Liu, Wei; Yang, Jianxue; Jia, Yanhong; Shang, Chuang; Xu, Hongxin

    2011-01-18

    The objective of this study was to develop the dextromethorphan hydrobromide sustained-release (DMB-SR) tablets using floating technique to prolong the gastric residence time and compared their pharmacokinetic behavior with conventional sustained release tablets. DMB-SR floating tablets were prepared employing hydroxypropyl methylcellulose (HPMC) as hydrophilic gel material, sodium bicarbonate as gas-generating agent and hexadecanol as floating assistant agent. An orthogonal experiment design method was used to select the optimized formulation. The floating tablets were evaluated for uniformity of weight, hardness, friability, drug content, floating characteristics, in vitro release and in vivo bioavailability. The optimized tablets were prepared with HPMC K4M 25 mg, sodium bicarbonate 20 mg and hexadecanol 18 mg. The prepared tablets could float within 3 min and maintain for more than 24 h. The data of physical parameters were all lie within the limits. Drug release at 12 h was more than 85%. The comparative pharmacokinetic study was performed by administration of the DMB-SR floating tablets and conventional DMB-SR tablets. The area under curve of plasma concentration-time (AUC) of floating tablets was slightly higher than that of reference tablets, T(max) was prolonged apparently. The results showed the floating tablets are a feasible approach for the sustained-release preparation of drugs, which have limited absorption sites in the stomach.

  5. Lattice potential energy and standard molar enthalpy in the formation of 1—dodecylamine hydrobromide (1-C12H25NH3·Br)(s)

    NASA Astrophysics Data System (ADS)

    Liu, Yu-Pu; Di, You-Ying; Dan, Wen-Yan; He, Dong-Hua; Kong, Yu-Xia; Yang, Wei-Wei

    2011-02-01

    This paper reports that 1-dodecylamine hydrobromide (1-C12H25NH3·Br)(s) has been synthesized using the liquid phase reaction method. The lattice potential energy of the compound 1-C12H25NH3·Br and the ionic volume and radius of the 1-C12H25NH3+ cation are obtained from the crystallographic data and other auxiliary thermodynamic data. The constant-volume energy of combustion of 1-C12H25NH3·Br(s) is measured to be ΔcUmo(1-C12H25NH3·Br, s) = -(7369.03±3.28) kJ·mol-1 by means of an RBC-II precision rotating-bomb combustion calorimeter at T = (298.15±0.001) K. The standard molar enthalpy of combustion of the compound is derived to be ΔcHmo(1-C12H25NH3·Br, s) = -(7384.52±3.28) kJ·mol-1 from the constant-volume energy of combustion. The standard molar enthalpy of formation of the compound is calculated to be ΔfHmo(1-C12H25NH3·Br, s)=-(1317.86±3.67) kJ·mol-1 from the standard molar enthalpy of combustion of the title compound and other auxiliary thermodynamic quantities through a thermochemical cycle.

  6. Cost-effectiveness analysis of treatment with peginterferon-alfa-2a versus peginterferon-alfa-2b for patients with chronic hepatitis C under the public payer perspective in Brazil

    PubMed Central

    2013-01-01

    Background Chronic hepatitis C affects approximately 170 million people worldwide, and thus being one of the main causes of chronic liver disease. About 20% of patients with chronic hepatitis C will develop cirrhosis over 20 years, and present an increased risk of developing hepatic complications. Sustained virological response (SVR) is associated with a better prognosis compared to untreated patients and treatment failures. The objective of this analysis was to compare treatment costs and outcomes of pegylated interferon-alfa-2a versus pegylated interferon-alfa-2b, both associated with ribavirin, in the therapeutic scheme of 24 weeks and 48 week for hepatitis C genotypes 2/3 and genotype 1, respectively, under the Brazilian Public Health System (SUS) scenario. Methods To project disease progression, a Markov model was built based on clinical stages of chronic disease. A Delphi panel was conducted to evaluate medical resources related to each stage, followed by costing of related materials, services, procedures and pharmaceutical products. The evaluation was made from a public payer perspective. The source used for costing was government reimbursement procedures list (SAI/SIH–SUS). Drug acquisition costs were obtained from the Brazilian Official Gazette and “Banco de Preços em Saúde” (government official source). It was assumed a mean patient weight of 70 kg. Costs were reported in 2011 Brazilian Reais (US$1 ≈ $Brz1.80). A systematic review followed by a meta-analysis of the 7 identified randomized controlled trials (RCTs) which compared pegylated interferons, was conducted for obtaining relative efficacy of both drugs: for genotype 2/3, mean rate of SVR was 79.2% for peginterferon-alfa-2a and 73.8% for peginterferon-alfa-2b. For genotype 1, SVR mean rate was 42.09% versus 33.44% (peginterferon-alfa-2a and peginterferon-alfa-2b respectively). Time horizon considered was lifetime. Discount rate for costs and outcomes was 5%, according to Brazilian

  7. Taliglucerase alfa leads to favorable bone marrow responses in patients with type I Gaucher disease.

    PubMed

    van Dussen, L; Zimran, A; Akkerman, E M; Aerts, J M F G; Petakov, M; Elstein, D; Rosenbaum, H; Aviezer, D; Brill-Almon, E; Chertkoff, R; Maas, M; Hollak, C E M

    2013-03-01

    Taliglucerase alfa (Protalix Biotherapeutics, Israel) is a carrot-cell-expressed recombinant human beta-glucocerebrosidase recently approved in the United States for the treatment of type 1 Gaucher disease (GD). As bone disease is one of the most debilitating features of GD, quantification of bone marrow involvement is important for monitoring the response to treatment. Therefore, bone marrow fat fraction (Ff) measured by quantitative chemical shift imaging (QCSI) was included as exploratory parameter to evaluate bone marrow response in treatment naïve GD patients participating in a double-blind, randomized phase III study. Eight GD patients with intact spleens were treated with 30 or 60U/kg biweekly. Ff results were compared to outcomes in 15 untreated Dutch GD patients with a follow-up interval of 1year. Five taliglucerase alfa treated patients had a Ff below the threshold that relates to complication risk (<0.23) at baseline (median (n=8) 0.19, range 0.11-0.35). Ff significantly increased compared to baseline (p=0.012) and compared to untreated patients (p=0.005), already after 1year of follow-up with further improvement up to 36months. In four patients with the lowest Ff, the higher dose resulted in increases above 0.23 within 1year. All patients had sustained improvements in all other parameters. There was no influence of antibodies on response parameters. Treatment with taliglucerase alfa results in significant increases in lumbar spine fat fractions, which indicates clearance of Gaucher cells from the bone marrow.

  8. Prospective surveillance study of haemophilia A patients switching from moroctocog alfa or other factor VIII products to moroctocog alfa albumin-free cell culture (AF-CC) in usual care settings.

    PubMed

    Parra Lopez, Rafael; Nemes, Laszlo; Jimenez-Yuste, Victor; Rusen, Luminita; Cid, Ana R; Charnigo, Robert J; Baumann, James A; Smith, Lynne; Korth-Bradley, Joan M; Rendo, Pablo

    2015-10-01

    This prospective, open-label, postauthorisation safety surveillance study assessed clinically significant inhibitor development in patients with severe haemophilia A transitioning from moroctocog alfa or other factor VIII (FVIII) replacement products to reformulated moroctocog alfa (AF-CC). Males aged ≥ 12 years with severe haemophilia A (FVIII:C) < 1 IU/dl), > 150 exposure days (EDs) to recombinant or plasma-derived FVIII products, and no detectable inhibitor at screening were enrolled. Primary end point was the incidence of clinically significant FVIII inhibitor development. Secondary end points included annualised bleeding rate (ABR), less-than-expected therapeutic effect (LETE), and FVIII recovery. Patients were assigned to one of two cohorts based on whether they were transitioning to moroctocog alfa (AF-CC) from moroctocog alfa (cohort 1; n=146) or from another recombinant or plasma-derived FVIII product (cohort 2; n=62). Mean number of EDs on study was 94 (range, 1-139). Six positive FVIII inhibitor results, as determined by local laboratories, were reported in four patients; none were confirmed by a central laboratory, no inhibitor-related clinical manifestations were reported, and all anti-FVIII antibody assays were negative. Median ABRs were 23.4 and 3.4 in patients categorised at baseline as following on-demand and prophylactic regimens, respectively; 86.5% of bleeding episodes resolved after one infusion. LETE incidence was 0.06% and 0.19% in the on-demand and prophylaxis settings, respectively. FVIII recovery remained constant throughout the study. No new safety concerns were identified. This study found no increased risk of clinically significant FVIII inhibitor development in patients transitioning from moroctocog alfa or other FVIII replacement products to moroctocog alfa (AF-CC).

  9. Alglucosidase alfa enzyme replacement therapy as a therapeutic approach for glycogen storage disease type III.

    PubMed

    Sun, Baodong; Fredrickson, Keri; Austin, Stephanie; Tolun, Adviye A; Thurberg, Beth L; Kraus, William E; Bali, Deeksha; Chen, Yuan-Tsong; Kishnani, Priya S

    2013-02-01

    We investigated the feasibility of using recombinant human acid-α glucosidase (rhGAA, Alglucosidase alfa), an FDA approved therapy for Pompe disease, as a treatment approach for glycogen storage disease type III (GSD III). An in vitro disease model was established by isolating primary myoblasts from skeletal muscle biopsies of patients with GSD IIIa. We demonstrated that rhGAA significantly reduced glycogen levels in the two GSD IIIa patients' muscle cells (by 17% and 48%, respectively) suggesting that rhGAA could be a novel therapy for GSD III. This conclusion needs to be confirmed in other in vivo models.

  10. Effectiveness of corifollitropin alfa used for ovarian stimulation of poor responder patients

    PubMed Central

    Selman, Helmy; Rinaldi, Leonardo

    2016-01-01

    Purpose To evaluate the efficiency and efficacy of corifollitropin alfa (follicle-stimulating hormone–carboxy terminal peptide) in the treatment of poor responder patients. Methods A total of 85 poor responder patients with a mean age 40.2±3.9 years entered our assisted fertilization program. The patients were prospectively randomized into two groups based on the ovarian stimulation regimen used: group A (study group) (n=42) received clomiphene citrate and corifollitropin alfa for the first 7 days of stimulation followed by recombinant follicle stimulating hormone (rFSH) in a gonadotropin-releasing hormone antagonist protocol, and group B (control group) (n=43) received clomiphene citrate and a daily injection of rFSH in a gonadotropin-releasing hormone antagonist protocol. We analyzed the stimulation outcome, the number of retrieved oocytes, cleaving embryos, and pregnancy and implantation rates as well. Results Comparable results were observed between the two groups in terms of demographic data, stimulation outcome, and the number of canceled cycles. There were no differences evident between groups A and B with respect to the number of retrieved oocytes (3.0±0.8 and 2.7±0.7, respectively) and the number of cleaving embryos (1.8±0.6 and 1.7±0.7, respectively). Higher, though not statistically significant, differences were observed in favor of group A compared to group B in terms of pregnancy rate per cycle (19% and 16.3%, respectively), pregnancy rate per transfer (21.6% and 17.9%, respectively), and implantation rate (14.7% and 13.4%, respectively). Also, miscarriage rate was similar between patients treated with corifollitropin alfa and those treated with daily rFSH injection (12.5% and 14.2%, respectively). Conclusion The results show that ovarian stimulation with corifollitropin alfa appears to be as efficacious and efficient as daily injection rFSH regimen to treat patients with poor ovarian response. PMID:27799826

  11. Interferon alfa-2a versus combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil in patients with untreated metastatic renal cell carcinoma (MRC RE04/EORTC GU 30012): an open-label randomised trial

    PubMed Central

    Gore, Martin E; Griffin, Clare L; Hancock, Barry; Patel, Poulam M; Pyle, Lynda; Aitchison, Michael; James, Nicholas; Oliver, Roderick TD; Mardiak, Jozef; Hussain, Tahera; Sylvester, Richard; Parmar, Mahesh KB; Royston, Patrick; Mulders, Peter FA

    2010-01-01

    Summary Background In metastatic renal cell carcinoma combinations of interferon alfa-2a, interleukin-2, and fluorouracil produce higher response rates and longer progression-free survival than do single agents. We aimed to compare overall survival in patients receiving combination treatment or interferon alfa-2a. Methods RE04/30012 was an open-label randomised trial undertaken in 50 centres across eight countries. 1006 treatment-naive patients diagnosed with advanced metastatic renal cell carcinoma were randomly allocated (1 to 1) by minimisation to receive interferon alfa-2a alone or combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil. Treatment was not masked. The primary endpoint was overall survival. Treatment groups were compared with a non-stratified log-rank test. Analysis was by intention to treat. This study is registered, number ISRCTN 46518965. Findings 502 patients were randomly assigned to receive interferon alfa-2a and 504 to receive combined treatment. Median follow-up was 37·2 months (24·8–52·3). Median overall survival was 18·8 months (17·0–23·2) for patients receiving interferon alfa-2a versus 18·6 months (16·5–20·6) for those receiving combination therapy. Overall survival did not differ between the two groups (hazard ratio 1·05 [95% CI 0·90–1·21], p=0·55; absolute difference 0·3% (−5·1 to 5·6) at 1 year and 2·7% (−8·2 to 2·9) at 3 years). Serious adverse events were reported in 113 (23%) patients receiving interferon alfa-2a and 131 (26%) of those receiving combined treatment. Interpretation Although combination therapy does not improve overall or progression-free survival compared with interferon alfa-2a alone, immunotherapy might still have a role because it can produce remissions that are of clinically relevant length in some patients. Identification of patients who will benefit from immunotherapy is crucial. Funding UK Medical Research Council. PMID:20153039

  12. Epoetin alfa improves survival after chemoradiation for Stage III esophageal cancer: Final results of a prospective observational study

    SciTech Connect

    Rades, Dirk . E-mail: Rades.Dirk@gmx.net; Tribius, Silke; Yekebas, Emre F.; Bahrehmand, Roia; Wildfang, Ingeborg; Kilic, Ergin; Muellerleile, Ulrich; Gross, Eberhard; Schild, Steven E.; Alberti, Winfried

    2006-06-01

    Purpose: This prospective, nonrandomized study evaluates the effectiveness of epoetin alfa to maintain the hemoglobin levels at 12 to14 g/dL (optimal range for tumor oxygenation) during chemoradiation for Stage III esophageal cancer and its impact on overall survival (OS), metastatic-free survival (MFS), and locoregional control (LC). Methods and Materials: Ninety-six patients were included. Forty-two patients received epoetin alfa (150 IU/kg, 3 times a week) during radiotherapy, which was started at hemoglobin less than 13 g/dL and stopped at 14 g/dL or higher. Hemoglobin levels were measured weekly during RT. Results: Both groups were balanced for age, sex, performance status, tumor length/location, histology, grading, T-stage/N-stage, chemotherapy, treatment schedule, and hemoglobin before RT. Median change of hemoglobin was +0.3 g/dL/wk with epoetin alfa and -0.5 g/dL/wk without epoetin alfa. At least 60% of hemoglobin levels were 12 to 14 g/dL in 64% and 17% of the patients, respectively (p < 0.001). Patients who received epoetin alfa had better OS (32% vs. 8% at 2 years, p = 0.009) and LC (67% vs. 15% at 2 years, p = 0.001). MFS was not significantly different (42% vs. 18% at 2 years, p = 0.09). Conclusions: The findings suggest that epoetin alfa when used to maintain the hemoglobin levels at 12 to 14 g/dL can improve OS and LC of Stage III esophageal cancer patients.

  13. Drotrecogin alfa (activated)...a sad final fizzle to a roller-coaster party.

    PubMed

    Angus, Derek C

    2012-02-06

    Following the failure of PROWESS-SHOCK to demonstrate efficacy, Eli Lilly and Company withdrew drotrecogin alfa (activated) from the worldwide market. Drotrecogin was initially approved after the original trial, PROWESS, was stopped early for overwhelming efficacy. These events prompt consideration of both the initial approval decision and the later decision to withdraw. It is regrettable that the initial decision was made largely on a single trial that was stopped early. However, the decision to approve was within the bounds of normal regulatory practice and was made by many approval bodies around the world. Furthermore, the overall withdrawal rate of approved drugs remains very low. The decision to withdraw was a voluntary decision by Eli Lilly and Company and likely reflected key business considerations. Drotrecogin does have important biologic effects, and it is probable that we do not know how best to select patients who would benefit. Overall, there may still be a small advantage to drotrecogin alfa, even used non-selectively, but the costs of determining such an effect with adequate certainty are likely prohibitive, and the point is now moot. In the future, we should consider ways to make clinical trials easier and quicker so that more information can be available in a timely manner when considering regulatory approval. At the same time, more sophisticated selection of patients seems key if we are to most wisely test agents designed to manipulate the septic host response.

  14. ARECIBO PULSAR SURVEY USING ALFA: PROBING RADIO PULSAR INTERMITTENCY AND TRANSIENTS

    SciTech Connect

    Deneva, J. S.; Cordes, J. M.; McLaughlin, M. A.; Lorimer, D. R.; Edel, S.; Kondratiev, V. I.; Nice, D. J.; Crawford, F.; Bhat, N. D. R.; Camilo, F.; Champion, D. J.; Freire, P. C. C.; Hessels, J. W. T.; Jenet, F. A.; Kasian, L.; Kaspi, V. M.; Lazarus, P.; Stairs, I. H.; Kramer, M.; Ransom, S. M.

    2009-10-01

    We present radio transient search algorithms, results, and statistics from the ongoing Arecibo Pulsar ALFA (PALFA) survey of the Galactic plane. We have discovered seven objects through a search for isolated dispersed pulses. All of these objects are Galactic and have measured periods between 0.4 and 4.7 s. One of the new discoveries has a duty cycle of 0.01%, smaller than that of any other radio pulsar. We discuss the impact of selection effects on the detectability and classification of intermittent sources, and compare the efficiencies of periodicity and single-pulse (SP) searches for various pulsar classes. For some cases we find that the apparent intermittency is likely to be caused by off-axis detection or a short time window that selects only a few bright pulses and favors detection with our SP algorithm. In other cases, the intermittency appears to be intrinsic to the source. No transients were found with DMs large enough to require that they originate from sources outside our Galaxy. Accounting for the on-axis gain of the ALFA system, as well as the low gain but large solid-angle coverage of far-out sidelobes, we use the results of the survey so far to place limits on the amplitudes and event rates of transients of arbitrary origin.

  15. Novel treatment options for lysosomal acid lipase deficiency: critical appraisal of sebelipase alfa

    PubMed Central

    Su, Kim; Donaldson, Emma; Sharma, Reena

    2016-01-01

    Lysosomal acid lipase deficiency (LAL-D) is a rare disorder of cholesterol metabolism with an autosomal recessive mode of inheritance. The absence or deficiency of the LAL enzyme gives rise to pathological accumulation of cholesterol esters in various tissues. A severe LAL-D phenotype manifesting in infancy is associated with adrenal calcification and liver and gastrointestinal involvement with characteristic early mortality. LAL-D presenting in childhood and adulthood is associated with hepatomegaly, liver fibrosis, cirrhosis, and premature atherosclerosis. There are currently no curative pharmacological treatments for this life-threatening condition. Supportive management with lipid-modifying agents does not ameliorate disease progression. Hematopoietic stem cell transplantation as a curative measure in infantile disease has mixed success and is associated with inherent risks and complications. Sebelipase alfa (Kanuma) is a recombinant human LAL protein and the first enzyme replacement therapy for the treatment of LAL-D. Clinical trials have been undertaken in infants with rapidly progressive LAL-D and in children and adults with later-onset LAL-D. Initial data have shown significant survival benefits in the infant group and improvements in biochemical parameters in the latter. Sebelipase alfa has received marketing authorization in the United States and Europe as long-term therapy for all affected individuals. The availability of enzyme replacement therapy for this rare and progressive disorder warrants greater recognition and awareness by physicians. PMID:27799810

  16. Macroscale production of crystalline interferon alfa-2b in microgravity on STS-52

    NASA Astrophysics Data System (ADS)

    Nagabhushan, Tattanahalli L.; Reichert, Paul; Long, Marianna M.; DeLucas, Lawrence J.; Bugg, Charles E.

    1995-01-01

    Macroscale crystallization of zinc interferon alfa-2b was achieved on STS-52 in October 1992 in the Protein Crystallization Facility. Conditions for crystallization were established by adapting a microscale vapor diffusion method to a macroscale temperature induction method. A series of earth based pilot experiments established conditions to reproducibly crystallize zinc interferon alfa-2b in high yield and under cleanroom conditions. As a control for the STS-52 mission, a ground experiment was run simultaneously and in the same configuration as the flight experiment. Greater than 95% of the available protein crystallized in both the ground and flight experiments. Using a battery of physical, biochemical and biological characterization assays, demonstrated that sample processing, polysulfone bottle confinement and the conditions used for crystallization did not have a negative effect on protein integrity. Redissolved crystals from the flight and ground experiments showed full biological activity in a cytopathic effect inhibition assay as compared to an interferon control standard. Morphometric analysis comparing the overall length and width of the derived crystals showed a 2.4 fold increase in the length and width of the space grown crystals as compared to earth grown crystals. Space grown crystals have remained a stable free flowing suspension for over 2 years. Based on these results, further experiments are envisioned to investigate macroscale crystallization of biologically active macromolecules in microgravity.

  17. Darbepoetin alfa 300 or 500 μg once every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia.

    PubMed

    Auerbach, Michael; Silberstein, Peter T; Webb, R Timothy; Averyanova, Svetlana; Ciuleanu, Tudor-Eliade; Shao, James; Bridges, Kenneth

    2010-09-01

    This study evaluated efficacy and safety of darbepoetin alfa administered every 3 weeks (Q3W) at fixed doses of 300 or 500 μg with or without intravenous (IV) iron in treating anemia in patients receiving multicycle chemotherapy. This Phase 2, double-blind, 2 × 2 factorial study randomized patients to one of four treatment arms; darbepoetin alfa 300 μg (n = 62), darbepoetin alfa 300 μg plus IV iron (n = 60), darbepoetin alfa 500 μg (n = 60), or darbepoetin alfa 500 μg plus IV iron (n = 60). Patients had nonmyeloid malignancies, hemoglobin levels ≤10 g dL(-1), and no iron deficiency. Primary endpoint was achievement of target hemoglobin (≥11 g dL(-1)). Secondary endpoints included incidence of transfusions and change in Functional Assessment of Cancer Therapy Fatigue (FACT-F) score from baseline to end of study. Safety was evaluated by incidence of adverse events. No evidence of a statistically significant interaction between darbepoetin alfa dose received and IV iron usage was observed, therefore, results are provided separately comparing darbepoetin alfa doses and comparing IV iron usage groups. Similar proportions of patients receiving darbepoetin alfa 300 or 500 μg achieved target hemoglobin (75 and 78%, respectively); Kaplan-Meier median time to target hemoglobin was 10 and 8 weeks, respectively. More patients receiving IV iron (82%) than not receiving IV iron (72%) achieved hemoglobin target. Adverse events profiles were similar for darbepoetin alfa treatment groups. Transient anaphylactoid reactions were reported in two patients receiving IV iron. Darbepoetin alfa at 300 μg Q3W and 500 μg Q3W showed similar benefit, while added IV iron improved treatment response in these patients.

  18. A novel approach using a minimal number of injections during the IVF/ICSI cycle: Luteal half-dose depot GnRH agonist following corifollitropin alfa versus the corifollitropin alfa with a GnRH-antagonist cycle

    PubMed Central

    Haydardedeoğlu, Bülent; Kılıçdağ, Esra Bulgan

    2016-01-01

    Objective Corifollitropin alfa is a good choice for assisted reproductive technology (ART) cycles because fewer injections are needed than with other agents. In this retrospective cohort, we analyzed luteal injected half-dose depot gonadotropin hormone-releasing hormone (GnRH) agonist cycles in women who received corifollitropin alfa and those who underwent a conventional corifollitropin alfa cycle with a GnRH antagonist. Material and Methods In this retrospective cohort, we analyzed luteal injected half-dose depot GnRH agonist cycles in women who received corifollitropin alfa and those who underwent a conventional corifollitropin alfa cycle with a GnRH antagonist at the Division of Reproductive Endocrinology and IVF Unit, Obstetrics and Gynecology Department, Başkent University School of Medicine, Adana, Turkey, from March 2014 to August 2015. The patient’s baseline characteristics were similar between the two groups. Forty-five patients underwent the long protocol, in which a half-dose of depot GnRH agonist was administered on day 21 of the preceding cycle. Forty-nine patients underwent the GnRH-antagonist protocol. Corifollitropin alfa was administered on the menstrual cycle day 3. Results The mean ages of the two groups were similar (32.77±5.55 vs. 34.2±4.51 years [“for the long- and antagonist-protocol groups, respectively”]). The total number of retrieved oocytes, the fertilization rate, and the number of transferred embryos were similar between the two groups. The only significant difference between the two protocols was the number of injections during the controlled ovarian stimulation (COH) cycle, which included the depot-agonist injection in the long-protocol group (4.46±1.64 vs. 5.71±2.51, p=0.006). The clinical pregnancy and implantation rates were similar in the two protocols (16/45 [35.6%] vs. 16/49 [32.7%] for the intention to treat and 32.5±6.82% vs. 36.25±8.58%, respectively). Conclusion Our results show that ART cycles could be

  19. Accurate Learning with Few Atlases (ALFA): an algorithm for MRI neonatal brain extraction and comparison with 11 publicly available methods

    NASA Astrophysics Data System (ADS)

    Serag, Ahmed; Blesa, Manuel; Moore, Emma J.; Pataky, Rozalia; Sparrow, Sarah A.; Wilkinson, A. G.; MacNaught, Gillian; Semple, Scott I.; Boardman, James P.

    2016-03-01

    Accurate whole-brain segmentation, or brain extraction, of magnetic resonance imaging (MRI) is a critical first step in most neuroimage analysis pipelines. The majority of brain extraction algorithms have been developed and evaluated for adult data and their validity for neonatal brain extraction, which presents age-specific challenges for this task, has not been established. We developed a novel method for brain extraction of multi-modal neonatal brain MR images, named ALFA (Accurate Learning with Few Atlases). The method uses a new sparsity-based atlas selection strategy that requires a very limited number of atlases ‘uniformly’ distributed in the low-dimensional data space, combined with a machine learning based label fusion technique. The performance of the method for brain extraction from multi-modal data of 50 newborns is evaluated and compared with results obtained using eleven publicly available brain extraction methods. ALFA outperformed the eleven compared methods providing robust and accurate brain extraction results across different modalities. As ALFA can learn from partially labelled datasets, it can be used to segment large-scale datasets efficiently. ALFA could also be applied to other imaging modalities and other stages across the life course.

  20. Accurate Learning with Few Atlases (ALFA): an algorithm for MRI neonatal brain extraction and comparison with 11 publicly available methods.

    PubMed

    Serag, Ahmed; Blesa, Manuel; Moore, Emma J; Pataky, Rozalia; Sparrow, Sarah A; Wilkinson, A G; Macnaught, Gillian; Semple, Scott I; Boardman, James P

    2016-03-24

    Accurate whole-brain segmentation, or brain extraction, of magnetic resonance imaging (MRI) is a critical first step in most neuroimage analysis pipelines. The majority of brain extraction algorithms have been developed and evaluated for adult data and their validity for neonatal brain extraction, which presents age-specific challenges for this task, has not been established. We developed a novel method for brain extraction of multi-modal neonatal brain MR images, named ALFA (Accurate Learning with Few Atlases). The method uses a new sparsity-based atlas selection strategy that requires a very limited number of atlases 'uniformly' distributed in the low-dimensional data space, combined with a machine learning based label fusion technique. The performance of the method for brain extraction from multi-modal data of 50 newborns is evaluated and compared with results obtained using eleven publicly available brain extraction methods. ALFA outperformed the eleven compared methods providing robust and accurate brain extraction results across different modalities. As ALFA can learn from partially labelled datasets, it can be used to segment large-scale datasets efficiently. ALFA could also be applied to other imaging modalities and other stages across the life course.

  1. Home infusion of intravenous velaglucerase alfa: Experience from pooled clinical studies in 104 patients with type 1 Gaucher disease.

    PubMed

    Elstein, Deborah; Burrow, T Andrew; Charrow, Joel; Giraldo, Pilar; Mehta, Atul; Pastores, Gregory M; Lee, Hak-Myung; Mellgard, Björn; Zimran, Ari

    The introduction of a home therapy option during clinical trials of velaglucerase alfa in patients with type 1 Gaucher disease marked the first time that home infusions have been permitted during a clinical trial for an investigational drug for Gaucher disease. Home infusions were an available option in 4 open-label velaglucerase alfa clinical studies to eligible patients who received their initial infusions at a clinic. Patients who participated in the home therapy option and received at least 10% of their infusions at home (n=100) received a range of 11.6%-100% of their scheduled infusions at home (median 87.5%), excluding infusions received at the clinic during protocol-mandated visits. The length of time over which individual patients received home therapy ranged from 13days to 4.56years (median 0.57years). During the time that home therapy was available, 2904 of 3572 (81.3%) infusions were administered at home. Ten patients experienced 62 infusion-related adverse events (IRAEs) during 38 home infusions, with malaise, pain, hypertension, fatigue, and headache being reported most frequently. No notable differences were found between the type and severity of IRAEs experienced at home and those experienced at the clinic. Home infusions administered by trained and qualified medical personnel were successfully introduced into the velaglucerase alfa clinical development program, and fewer than 10% of patients experienced IRAEs in the home setting. Local labeling and practice guidelines should be consulted for administration of velaglucerase alfa infusions at home.

  2. Characterization of IXINITY® (Trenonacog Alfa), a Recombinant Factor IX with Primary Sequence Corresponding to the Threonine-148 Polymorph

    PubMed Central

    Monroe, Dougald M.; Jenny, Richard J.; Van Cott, Kevin E.; Saward, Laura L.

    2016-01-01

    The goal of these studies was to extensively characterize the first recombinant FIX therapeutic corresponding to the threonine-148 (Thr-148) polymorph, IXINITY (trenonacog alfa [coagulation factor IX (recombinant)]). Gel electrophoresis, circular dichroism, and gel filtration were used to determine purity and confirm structure. Chromatographic and mass spectrometry techniques were used to identify and quantify posttranslational modifications. Activity was assessed as the ability to activate factor X (FX) both with and without factor VIIIa (FVIIIa) and in a standard clotting assay. All results were consistent across multiple lots. Trenonacog alfa migrated as a single band on Coomassie-stained gels; activity assays were normal and showed <0.002 IU of activated factor IX (FIXa) per IU of FIX. The molecule has >97%  γ-carboxylation and underwent the appropriate structural change upon binding calcium ions. Trenonacog alfa was activated normally with factor XIa (FXIa); once activated it bound to FVIIIa and FXa. When activated to FIXa, it was inhibited efficiently by antithrombin. Glycosylation patterns were similar to plasma-derived FIX with sialic acid content consistent with the literature reports of good pharmacokinetic performance. These studies have shown that trenonacog alfa is a highly pure product with a primary sequence and posttranslational modifications consistent with the common Thr-148 polymorphism of plasma-derived FIX. PMID:26997955

  3. Arecibo Pulsar Survey Using ALFA. I. Survey Strategy and First Discoveries

    NASA Astrophysics Data System (ADS)

    Cordes, J. M.; Freire, P. C. C.; Lorimer, D. R.; Camilo, F.; Champion, D. J.; Nice, D. J.; Ramachandran, R.; Hessels, J. W. T.; Vlemmings, W.; van Leeuwen, J.; Ransom, S. M.; Bhat, N. D. R.; Arzoumanian, Z.; McLaughlin, M. A.; Kaspi, V. M.; Kasian, L.; Deneva, J. S.; Reid, B.; Chatterjee, S.; Han, J. L.; Backer, D. C.; Stairs, I. H.; Deshpande, A. A.; Faucher-Giguère, C.-A.

    2006-01-01

    We report results from the initial stage of a long-term pulsar survey of the Galactic plane using the Arecibo L-band Feed Array (ALFA), a seven-beam receiver operating at 1.4 GHz with 0.3 GHz bandwidth, and fast-dump digital spectrometers. The search targets low Galactic latitudes, |b|<~5deg, in the accessible longitude ranges 32deg<~l<~77deg and 168deg<~l<~214deg. The instrumentation, data processing, initial survey observations, sensitivity, and database management are described. Data discussed here were collected over a 100 MHz passband centered on 1.42 GHz using a spectrometer that recorded 256 channels every 64 μs. Analysis of the data with their full time and frequency resolutions is ongoing. Here we report the results of a preliminary, low-resolution analysis for which the data were decimated to speed up the processing. We have detected 29 previously known pulsars and discovered 11 new ones. One of these, PSR J1928+1746, with a period of 69 ms and a relatively low characteristic age of 82 kyr, is a plausible candidate for association with the unidentified EGRET source 3EG J1928+1733. Another, PSR J1906+07, is a nonrecycled pulsar in a relativistic binary with an orbital period of 3.98 hr. In parallel with the periodicity analysis, we also search the data for isolated dispersed pulses. This technique has resulted in the discovery of PSR J0628+09, an extremely sporadic radio emitter with a spin period of 1.2 s. Simulations we have carried out indicate that ~1000 new pulsars will be found in our ALFA survey. In addition to providing a large sample for use in population analyses and for probing the magnetoionic interstellar medium, the survey maximizes the chances of finding rapidly spinning millisecond pulsars and pulsars in compact binary systems. Our search algorithms exploit the multiple data streams from ALFA to discriminate between radio frequency interference and celestial signals, including pulsars and possibly new classes of transient radio sources.

  4. A multicenter open-label treatment protocol (HGT-GCB-058) of velaglucerase alfa enzyme replacement therapy in patients with Gaucher disease type 1: safety and tolerability

    PubMed Central

    Pastores, Gregory M.; Rosenbloom, Barry; Weinreb, Neal; Goker-Alpan, Ozlem; Grabowski, Gregory; Cohn, Gabriel M.; Zahrieh, David

    2014-01-01

    Purpose: To evaluate the safety of velaglucerase alfa in patients with type 1 Gaucher disease who received velaglucerase alfa in the US treatment protocol HGT-GCB-058 (ClinicalTrials.gov identifier NCT00954460) during a global supply shortage of imiglucerase. Methods: This multicenter open-label treatment protocol enrolled patients who were either treatment naïve or had been receiving imiglucerase. Patients received intravenous velaglucerase alfa every other week at a dose of 60 U/kg (treatment naïve) or 15–60 U/kg (previously treated). Results: A total of 211 (including six treatment-naïve) patients were enrolled. Among the 205 previously treated patients, 35 (17.1%) experienced an adverse event considered related to study drug. Among the six treatment-naïve patients, one had an adverse event considered related to study drug. Infusion-related adverse events occurred in 28 (13.3%) of the 211 patients and usually occurred during the first three infusions. De novo, nonneutralizing, anti–velaglucerase alfa antibodies developed during treatment in one (<1.0%) previously treated patient and none of the treatment-naïve patients. Conclusion: The currently observed safety profile was consistent with those previously reported for imiglucerase and velaglucerase alfa phase III clinical trials. These results support the safety of initiating treatment with velaglucerase alfa or transitioning patients from imiglucerase therapy to velaglucerase alfa therapy. PMID:24263462

  5. [Topical interferon alfa-2b for primary treatment of conjunctiva-cornea intraepithelial neoplasia].

    PubMed

    Pérez de Arcelus, M; Aranguren, M; Andonegui, J

    2012-01-01

    We describe two cases of conjunctival-cornea intraepithelial neoplasia (CIN), treated with topical IFN alfa 2b. The traditional treatment for CIN is surgical excision usually with adjunctive cryotherapy. However, residual tumour may remain, which can lead to recurrence rates of more than 50%. 5-Fluorouracil, mitomicyn C and interferon α 2b are new pharmacological agents that have proved their efficacy in the treatment of CIN. As side effects are common, we present IFN α 2b as a single therapeutic agent as an effective and optimal treatment for presumed recurrent corneal and conjunctival intraepithelial neoplasia. It offers the benefits of topical therapy and avoids the risks of surgical or other interventions - specifically, ocular surface toxicity, cicatricial conjunctival changes, and limbal stem cell deficiency.

  6. Interferon alfa-2b in the management of recurrent conjunctival papillomatosis.

    PubMed

    Singh, Manpreet; Gautam, Natasha; Gupta, Adit; Kaur, Manpreet

    2016-10-01

    A 2-year-old boy presented with a recurrent strawberry-like reddish mass arising from the left caruncular region for 8 months. An incisional biopsy was performed elsewhere 2 months earlier, followed by an increase in size of mass, significant epiphora, and intermittent bleeding. On examination, exuberant exophytic gelatinous mass with multifocal origin was observed arising from inferior forniceal conjunctiva and caruncle. Clinical differential of multifocal conjunctival papilloma was kept, and topical interferon alfa-2b (INFα-2b) was started. No clinical reduction in mass or symptomatology was observed over 6 weeks. Excision biopsy with cryotherapy and subconjunctival injection of INFα-2b was performed over all foci. Conjunctival papilloma was confirmed on histopathology, and topical INFα-2b was continued in postoperative period for 3 months. At 14 months of follow-up, no recurrence, epiphora, or bleeding was noticed. We advocate a possible role of local INF therapy in managing and preventing recurrences of conjunctival papillomatosis.

  7. Peginterferon alfa-2b and ribavirin in thalassaemia/chronic hepatitis C virus-co-infected non-responder to standard interferon-based.

    PubMed

    Hamidah, A; Thambidorai, C R; Jamal, R

    2005-10-01

    We describe a patient with HbE-beta thalassaemia and chronic hepatitis C virus infection (genotype 1a) who was treated successfully with peginterferon alfa-2b and ribavirin, following failure to respond to standard interferon and ribavirin therapy. She had sustained virological response for nearly 24 months after completing peginterferon alfa-2b and ribavirin therapy. Transfusion requirements were significantly increased during combination therapy due to ribavirin-induced haemolysis. The adverse effects of interferon were well tolerated. Combination therapy with peginterferon alfa-2b and ribavirin maybe a feasible treatment option for a subset of thalassaemia/HCV infected non-responders to standard interferon-based therapy.

  8. Properties of Cold HI Emission Clouds in the Inner-Galaxy ALFA Survey

    NASA Astrophysics Data System (ADS)

    Hughes, James Marcus; Gibson, Steven J.; Noriega-Crespo, Alberto; Newton, Jonathan; Koo, Bon-Chul; Douglas, Kevin A.; Peek, Joshua Eli Goldston; Park, Geumsook; Kang, Ji-hyun; Korpela, Eric J.; Heiles, Carl E.; Dame, Thomas M.

    2017-01-01

    Star formation, a critical process within galaxies, occurs in the coldest, densest interstellar clouds, whose gas and dust content are observed primarily at radio and infrared wavelengths. The formation of molecular hydrogen (H2) from neutral atomic hydrogen (HI) is an essential early step in the condensation of these clouds from the ambient interstellar medium, but it is not yet completely understood, e.g., what is the predominant trigger? Even more troubling, the abundance of H2 may be severely underestimated by standard tracers like CO, implying significant "dark" H2, and the quantity of HI may also be in error if opacity effects are neglected. We have developed an automated method to account for both HI and H2 in cold, diffuse clouds traced by narrow-line HI 21-cm emission in the Arecibo Inner-Galaxy ALFA (I-GALFA) survey. Our algorithm fits narrow (2-5 km/s), isolated HI line profiles to determine their spin temperature, optical depth, and true column density. We then estimate the "visible" H2 column in the same clouds with CfA and Planck CO data and the total gas column from dust emission measured by Planck, IRAS, and other surveys. Together, these provide constraints on the dark H2 abundance, which we examine in relation to other cloud properties and stages of development. Our aim is to build a database of H2-forming regions with significant dark gas to aid future analyses of coalescing interstellar clouds. We acknowledge support from NSF, NASA, Western Kentucky University, and Williams College. I-GALFA is a GALFA-HI survey observed with the 7-beam ALFA receiver on the 305-meter William E. Gordon Telescope. The Arecibo Observatory is a U.S. National Science Foundation facility operated under sequential cooperative agreements with Cornell University and SRI International, the latter in alliance with the Ana G. Mendez-Universidad Metropolitana and the Universities Space Research Association.

  9. A review of ipratropium bromide/fenoterol hydrobromide (Berodual) delivered via Respimat Soft Mist Inhaler in patients with asthma and chronic obstructive pulmonary disease.

    PubMed

    Kässner, Frank; Hodder, Rick; Bateman, Eric D

    2004-01-01

    Asthma and chronic obstructive pulmonary disease (COPD) can be effectively treated by the use of bronchodilator therapies delivered by inhalation. Berodual is a fixed combination of the anticholinergic agent ipratropium bromide (IB) and the beta2-adrenergic agonist fenoterol hydrobromide (FEN). IB/FEN has been available for the treatment of asthma and COPD in a pressurised metered dose inhaler (MDI) [pMDI] formulation for many years. The pMDI is the most widely used device for the delivery of inhaled medications, such as IB/FEN. However, most conventional pMDIs contain chlorofluorocarbon (CFC) propellants, which are currently being withdrawn because of their detrimental effects on the environment. This has resulted in alternative methods of drug delivery being developed. Respimat Soft Mist Inhaler (SMI) is a new generation, propellant-free inhaler that generates a fine, slow-moving cloud (the Soft Mist) which can be easily inhaled. Scintigraphic studies have shown that this improves deposition of drugs in the lung and results in less oropharyngeal deposition than the CFC-MDI. A clinical development programme has been conducted to compare the efficacy and safety of IB/FEN delivered via Respimat SMI with that of IB/FEN via CFC-MDI in the treatment of patients with asthma or COPD. Five clinical studies (two phase II and three phase III) investigated dosages of IB/FEN 5/12.5 microg to 320/800 microg via Respimat SMI in single and multiple dose administration regimens. Four of the trials were conducted in patients with asthma (three in adults and one in children), while one phase III trial was conducted in patients with COPD. In phase III, 2058 patients participated, with a total of 1112 patients treated with IB/FEN via Respimat SMI. In the phase III studies, each dose from Respimat SMI was given in one actuation compared with two actuations with the CFC-MDI. In the paediatric asthma phase III study, all CFC-MDI doses were delivered via a spacer device. The results of

  10. Long-term safety and efficacy of taliglucerase alfa in pediatric Gaucher disease patients who were treatment-naïve or previously treated with imiglucerase.

    PubMed

    Zimran, Ari; Gonzalez-Rodriguez, Derlis Emilio; Abrahamov, Aya; Cooper, Peter A; Varughese, Sheeba; Giraldo, Pilar; Petakov, Milan; Tan, Ee Shien; Chertkoff, Raul

    2016-10-20

    Taliglucerase alfa is an enzyme replacement therapy approved for treatment of Gaucher disease (GD) in children and adults in several countries. This multicenter extension study assessed the efficacy and safety of taliglucerase alfa in pediatric patients with GD who were treatment-naïve (n=10) or switched from imiglucerase (n=5). Patients received taliglucerase alfa 30 or 60U/kg (treatment-naïve) or the same dose as previously treated with imiglucerase every other week. In treatment-naïve patients, taliglucerase alfa 30 and 60U/kg, respectively, reduced mean spleen volume (-18.6 multiples of normal [MN] and -26.0MN), liver volume (-0.8MN and -0.9MN), and chitotriosidase activity (-72.7% and -84.4%), and increased mean Hb concentration (+2.0g/dL and +2.3g/dL) and mean platelet count (+38,200/mm(3) and +138,250/mm(3)) from baseline through 36 total months of treatment. In patients previously treated with imiglucerase, these disease parameters remained stable through 33 total months of treatment with taliglucerase alfa. Most adverse events were mild/moderate; treatment was well tolerated. These findings extend the taliglucerase alfa safety and efficacy profile and demonstrate long-term clinical improvement in treatment-naïve children receiving taliglucerase alfa and maintenance of disease stability in children switched to taliglucerase alfa. Treatment was well-tolerated, with no new safety signals. This study is registered at www.clinicaltrials.gov as NCT01411228.

  11. Maintenance treatment of renal anaemia in haemodialysis patients with methoxy polyethylene glycol-epoetin beta versus darbepoetin alfa administered monthly: a randomized comparative trial

    PubMed Central

    Carrera, Fernando; Lok, Charmaine E.; de Francisco, Angel; Locatelli, Francesco; Mann, Johannes F.E.; Canaud, Bernard; Kerr, Peter G.; Macdougall, Iain C.; Besarab, Anatole; Villa, Giuseppe; Kazes, Isabelle; Van Vlem, Bruno; Jolly, Shivinder; Beyer, Ulrich; Dougherty, Frank C.

    2010-01-01

    Background. Several studies with erythropoiesis-stimulating agents claim that maintenance therapy of renal anaemia may be possible at extended dosing intervals; however, few studies were randomized, results varied, and comparisons between agents were absent. We report results of a multi-national, randomized, prospective trial comparing haemoglobin maintenance with methoxy polyethylene glycol-epoetin beta and darbepoetin alfa administered once monthly. Methods. Haemodialysis patients (n = 490) on stable once-weekly intravenous darbepoetin alfa were randomized to methoxy polyethylene glycol-epoetin beta once monthly or darbepoetin alfa every 2 weeks for 26 weeks, with dose adjustment for individual haemoglobin target (11–13 g/dL; maximum decrease from baseline 1 g/dL). Subsequently, patients entered a second 26-week period of once-monthly methoxy polyethylene glycol-epoetin beta and darbepoetin alfa. The primary endpoint was the proportion of patients who maintained average haemoglobin ≥10.5 g/dL, with a decrease from baseline ≤1 g/dL, in Weeks 50–53; the secondary endpoint was dose change over time. The trial is registered at www.ClinicalTrials.gov, number NCT00394953. Results. Baseline characteristics were similar between groups. One hundred and fifty-seven of 245 patients treated with methoxy polyethylene glycol-epoetin beta and 99 of 245 patients with darbepoetin alfa met the response definition (64.1% and 40.4%; P < 0.0001). Doses increased by 6.8% with methoxy polyethylene glycol-epoetin beta and 58.8% with darbepoetin alfa during once-monthly treatment. Death rates were equal between treatments (5.7%). Most common adverse events included hypertension, procedural hypotension, nasopharyngitis and muscle spasms, with no differences between groups. Conclusions. Methoxy polyethylene glycol-epoetin beta maintained target haemoglobin more successfully than darbepoetin alfa at once-monthly dosing intervals despite dose increases with darbepoetin alfa

  12. Long-term efficacy and safety results of taliglucerase alfa up to 36 months in adult treatment-naïve patients with Gaucher disease.

    PubMed

    Zimran, Ari; Durán, Gloria; Mehta, Atul; Giraldo, Pilar; Rosenbaum, Hanna; Giona, Fiorina; Amato, Dominick J; Petakov, Milan; Muñoz, Eduardo Terreros; Solorio-Meza, Sergio Eduardo; Cooper, Peter A; Varughese, Sheeba; Chertkoff, Raul; Brill-Almon, Einat

    2016-07-01

    Taliglucerase alfa is an intravenous enzyme replacement therapy approved for treatment of type 1 Gaucher disease (GD), and is the first available plant cell-expressed recombinant therapeutic protein. Herein, we report long-term safety and efficacy results of taliglucerase alfa in treatment-naïve adult patients with GD. Patients were randomized to receive taliglucerase alfa 30 or 60 U/kg every other week, and 23 patients completed 36 months of treatment. Taliglucerase alfa (30 U/kg; 60 U/kg, respectively) resulted in mean decreases in spleen volume (50.1%; 64.6%) and liver volume (25.6%; 24.4%) with mean increases in hemoglobin concentration (16.0%; 35.8%) and platelet count (45.7%; 114.0%), and mean decreases in chitotriosidase activity (71.5%; 82.2%). All treatment-related adverse events were mild to moderate in intensity and transient. The most common adverse events were nasopharyngitis, arthralgia, upper respiratory tract infection, headache, pain in extremity, and hypertension. These 36-month results of taliglucerase alfa in treatment-naïve adult patients with GD demonstrate continued improvement in disease parameters with no new safety concerns. These findings extend the taliglucerase alfa clinical safety and efficacy dataset. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:656-660, 2016. © 2016 Wiley Periodicals, Inc.

  13. Long‐term efficacy and safety results of taliglucerase alfa up to 36 months in adult treatment‐naïve patients with Gaucher disease

    PubMed Central

    Durán, Gloria; Mehta, Atul; Giraldo, Pilar; Rosenbaum, Hanna; Giona, Fiorina; Amato, Dominick J.; Petakov, Milan; Muñoz, Eduardo Terreros; Solorio‐Meza, Sergio Eduardo; Cooper, Peter A.; Varughese, Sheeba; Chertkoff, Raul; Brill‐Almon, Einat

    2016-01-01

    Taliglucerase alfa is an intravenous enzyme replacement therapy approved for treatment of type 1 Gaucher disease (GD), and is the first available plant cell–expressed recombinant therapeutic protein. Herein, we report long‐term safety and efficacy results of taliglucerase alfa in treatment‐naïve adult patients with GD. Patients were randomized to receive taliglucerase alfa 30 or 60 U/kg every other week, and 23 patients completed 36 months of treatment. Taliglucerase alfa (30 U/kg; 60 U/kg, respectively) resulted in mean decreases in spleen volume (50.1%; 64.6%) and liver volume (25.6%; 24.4%) with mean increases in hemoglobin concentration (16.0%; 35.8%) and platelet count (45.7%; 114.0%), and mean decreases in chitotriosidase activity (71.5%; 82.2%). All treatment‐related adverse events were mild to moderate in intensity and transient. The most common adverse events were nasopharyngitis, arthralgia, upper respiratory tract infection, headache, pain in extremity, and hypertension. These 36‐month results of taliglucerase alfa in treatment‐naïve adult patients with GD demonstrate continued improvement in disease parameters with no new safety concerns. These findings extend the taliglucerase alfa clinical safety and efficacy dataset. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:656–660, 2016. © 2016 Wiley Periodicals, Inc. PMID:27174694

  14. Evaluation of results obtained with corifollitropin alfa after poor ovarian response in previous cycle using recombinant follicular stimulating hormone in the long-term protocol

    PubMed Central

    Salgueiro, Lister L.; Rolim, Juliana R.; Moura, Bernardo R. L.; Machado, Suelen P. P.; Haddad, Carolina

    2016-01-01

    Objective This study evaluated the use of Corifollitropin alfa in patients with previous poor response to recombinant follicle stimulating hormone in long-term protocols using gonadotropin-releasing hormone. Methods Twenty-seven poor responders to previous treatment with the long term protocol using the recombinant follicle stimulating hormone (Group 1) were selected and then submitted to a second attempt using the same long term protocol with Corifollitropin alfa instead of the recombinant follicle stimulating hormone (Group 2). Ovarian down-regulation was achieved using subcutaneous administration of Leuprolide Acetate. Ovarian stimulation was performed with recombinant follicle stimulating hormone until the administration of human chorionic gonadotropin, followed by follicular aspiration (Group 1). Group 2 was submitted to this same protocol using Corifollitropin alfa instead of recombinant follicle stimulating hormone. Results There were significant differences in the number of aspirated oocytes, percentage of mature oocytes, amount of injected oocytes and transferred embryos - with all of these parameters being increased in the Corifollitropin alfa group. In addition, the rates of pregnancy and ongoing pregnancy were also significantly higher in the Corifollitropin alfa group. Conclusion The present study demonstrated that the use of Corifollitropin alfa in the long-term protocol could be a highly effective alternative for patients with poor ovarian response, who were unsuccessful in a previous treatment with In Vitro Fertilization - Intracytoplasmic Sperm Injection. PMID:27584604

  15. Tongue hyperpigmentation resulting from peginterferon alfa-2b and ribavirin treatment in a patient with chronic hepatitis C.

    PubMed

    Ghosh, Souvik; Duseja, Ajay; Dhiman, Radha Krishan; Chawla, Yogesh Kumar

    2012-03-01

    Hepatitis C virus (HCV) infection has been associated with several cutaneous diseases such as lichen planus, porphyria cutanea tarda, chronic pruritus, and cutaneous necrotizing vasculitis (Doutre, Arch Dermatol 135:1401-1403, 1999). The antiviral treatment for chronic HCV with interferon alfa (INF) or peginterferon alfa (PEG-INF) combined with rivabirin also leads to many skin side effects including injection site reaction, generalized skin rashes, pruritus, dry skin, alopecia, and exacerbation of autoimmune processes, particularly psoriasis, lichen planus or vitiligo (Dalekos et al., Eur J Gastroenterol Hepatol 10:933-939, 1998; Sookoian et al., Arch Dermatol 135:1000-1000, 1999). There are case reports of tongue hyperpigmentation during combination therapy of PEG IFN and RBV in chronic hepatitis C both in dark-skined as well as Caucasian. We report the first case of tongue hyperpigmentation associated with PEG-INF-2b plus ribavirin administration in a non-Caucasian patient with genotype 4.

  16. Safety and efficacy results of switch from imiglucerase to velaglucerase alfa treatment in patients with type 1 Gaucher disease.

    PubMed

    Elstein, Deborah; Mehta, Atul; Hughes, Derralynn A; Giraldo, Pilar; Charrow, Joel; Smith, Laurie; Shankar, Suma P; Hangartner, Thomas N; Kunes, Yune; Wang, Nan; Crombez, Eric; Zimran, Ari

    2015-07-01

    Gaucher disease (GD) is a lysosomal storage disorder; symptomatic patients with type 1 GD need long-term disease-specific therapy of which the standard of care has been enzyme replacement therapy (ERT). Thirty-eight of 40 patients (aged 9-71 years) clinically stable on ERT with imiglucerase, safely switched to a comparable dose of velaglucerase alfa (units/kg) during TKT034, a 12-month, open-label clinical study, and for 10-50 months in an extension study. The most common adverse events (AEs) judged to be drug-related in the extension were fatigue and bone pain. No drug-related serious AEs were reported. No AEs led to study withdrawal. At 24 months from baseline (baseline being TKT034 week 0), patients had generally stable hemoglobin, platelet, spleen, liver, and bone density parameters. Nevertheless, dose adjustment based on the achievement of therapeutic goals was permitted, and 10 patients, including seven patients who had platelet counts <100 × 10(9) /L at baseline, were given at least one 15 U/kg-dose increase during the extension. Trends indicative of improvement in platelet count and spleen volume, and decreasing levels of GD biomarkers, chitotriosidase and CCL18, were observed. Immunogenicity was seen in one patient positive for anti-imiglucerase antibodies at baseline. This patient tested positive for anti-velaglucerase alfa antibodies in TKT034, with low antibody concentrations, and throughout the extension study; however, the patient continued to receive velaglucerase alfa without clinical deterioration. In conclusion, clinically stable patients can be switched from imiglucerase to velaglucerase alfa ERT and maintain or achieve good therapeutic outcomes.

  17. Clinical improvement of diffuse lymphangiomatosis with pegylated interferon alfa-2b therapy: case report and review of the literature.

    PubMed

    Ozeki, Michio; Funato, Michinori; Kanda, Kaori; Ito, Masahumi; Teramoto, Takahide; Kaneko, Hideo; Fukao, Toshiyuki; Kondo, Naomi

    2007-01-01

    Diffuse lymphangiomatosis is a very rare congenital disease, characterized by diffuse or multifocal lymphangioma in the skeletal tissue, spleen, liver, mediastinum, and/or lung. The prognosis is usually poor, especially for children with thoracic lesion, and treatments for the disease are controversial. The authors report a 9-year-old boy with diffuse lymphangiomatosis involving the thorax with pleural effusions, the spleen, and systemic bone. The patient was treated with pegylated interferon alfa-2b, and achieved good clinical and radiological improvement.

  18. The oxidation of methionine-54 of epoetinum alfa does not affect molecular structure or stability, but does decrease biological activity.

    PubMed

    Labrenz, Steven R; Calmann, Melissa A; Heavner, George A; Tolman, Glen

    2008-01-01

    Erythropoietin therapy is used to treat severe anemia in renal failure and chemotherapy patients. One of these therapies based on recombinant human erythropoietin is marketed under the trade name of EPREX and utilizes epoetinum alfa as the active pharmaceutical ingredient. The effect of oxidation of methionine-54 on the structure and stability of the erythropoietin molecule has not been directly tested. We have observed partial and full chemical oxidation of methionine-54 to methionine-54 sulfoxide, accomplished using tert-Butylhydroperoxide and hydrogen peroxide, respectively. A blue shift in the fluorescence center of spectral mass wavelength was observed as a linear response to the level of methionine sulfoxide in the epoetinum alfa molecule, presumably arising from a local change in the environment near tryptophan-51, as supported by potassium iodide quenching studies. Circular dichroism studies demonstrated no change in the folded structure of the molecule with methionine oxidation. The thermal unfolding profiles of partial and completely oxidized epoetinum alfa overlap, with a T(m) of 49.5 degrees C across all levels of methionine sulfoxide content. When the protein was tested for activity, a decrease in biological activity was observed, correlating with methionine sulfoxide levels. An allosteric effect between Met54, Trp51, and residues involved in receptor binding is proposed. These results indicate that methionine oxidation has no effect on the folded structure and global thermodynamic stability of the recombinant human erythropoietin molecule. Oxidation can affect potency, but only at levels significantly in excess of those seen in EPREX.

  19. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2006-03-01

    Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 131I-labetuzumab; Abacavir sulfate, abatacept, adalimumab, ademetionine, adjuvanted influenza vaccine, alefacept, alemtuzumab, amlodipine, amphotericin B, anakinra, aripiprazole, aspirin, axitinib; Betamethasone dipropionate, bevacizumab, biphasic insulin aspart, bortezomib, bosentan, botulinum toxin type B, BQ-123; Calcium folinate, canertinib dihydrochloride, carboplatin, carmustine, cetirizine hydrochloride, cetuximab, cholecalciferol, ciclesonide, ciclosporin, cinacalcet hydrochloride, cisplatin, clarithromycin, clofazimine, cold-adapted influenza vaccine trivalent, CpG-7909; Darbepoetin alfa, darifenacin hydrobromide, DB-289, desloratadine, Dexamet, dicycloverine hydrochloride, dimethyl fumarate, docetaxel, dolastatin 10, drospirenone, drospirenone/estradiol, duloxetine hydrochloride; Ecogramostim, edotecarin, efaproxiral sodium, enalapril maleate, epoetin beta, epoprostenol sodium, epratuzumab, erlotinib hydrochloride, escitalopram oxalate, estradiol, etanercept; Fluconazole, fludarabine phosphate, fluorouracil; Gefitinib, gemcitabine, Ghrelin (human), glibenclamide, glimepiride, GTI-2040; Haloperidol, human insulin, hydrocortisone probutate; Imatinib mesylate, indisulam, influenza vaccine, inhaled insulin, insulin aspart, insulin glulisine, insulin lispro, irinotecan, ispronicline; Lamivudine, lamivudine/zidovudine/abacavir sulfate, lapatinib, letrozole, levocetirizine, lomustine, lonafarnib, lumiracoxib;Magnesium sulfate, MD-1100, melphalan, metformin hydrochloride, methotrexate, metoclopramide hydrochloride, mitiglinide calcium hydrate, monophosphoryl lipid A, montelukast sodium, motexafin gadolinium

  20. [Good virological response to pegylated interferon alfa monotherapy of chronic hepatitis C infection in hemodialysis patient].

    PubMed

    Caro, P; Núñez, A; Delgado, R; Dapena, F; Amann, R

    2007-01-01

    Liver disease caused by hepatitis C virus infection is associated to significant morbidity and mortality among patient with end stage renal disease on maintenance hemodialysis (HD). Therapy in these patients consists of Interferon, preferably pegylated Interferon (pIFN), thus Ribavirin (RBV) is not recommended for patients with impaired renal function, outside its use in controlled trials. We report a case of 35 years young woman on HD treatment, renal transplantation candidate with chronic hepatitis C virus infection, HCV RNA positive (by PCR), genotype 3a, moderate viral load, light increase of aminotransferases. Pegylated Interferon alfa-2a (135 mcg/weekly/SC) was initiated. She achieved HVC RNA negative within 12 weeks, following with pINF as monotherapy to complete 24 weeks (6 months). Sustained virologic response persisted to 24 and 48 weeks. Most important side effects were light detriment of anemia, moderate neutropenia and thombocytopenia, transitory elevation of transaminases and "flu-like" syndrome. Adverse events were well tolerated with total compliance with pIFN dose, no requiring reduce or stop the treatment. These findings confirm that hemodialysis patients with chronic hepatitis C respond well to pegylated IFN monotherapy and a long-term sustained virologic response is achieved, appears to be better tolerated with less side effects, so combination therapy with pINF plus ribavirin is not necessary in all cases.

  1. Pharmacokinetics of Novel Plant Cell-Expressed Taliglucerase Alfa in Adult and Pediatric Patients with Gaucher Disease

    PubMed Central

    Abbas, Richat; Park, Glen; Damle, Bharat; Chertkoff, Raul; Alon, Sari

    2015-01-01

    Taliglucerase alfa is a beta-glucocerebrosidase enzyme replacement therapy approved in the United States, Israel, and other countries for treatment of Type 1 Gaucher disease in adults, and is the first approved plant cell—expressed recombinant protein. In this report, taliglucerase alfa pharmacokinetics were assessed in adult and pediatric patients with Gaucher disease from separate multicenter trials of 30 Units/kg and 60 Units/kg doses infused every 2 weeks. Serial blood samples were obtained from adult patients following single-dose administration on day 1 (n = 26) and multiple doses at week 38 (n = 29), and from pediatric patients following administration of multiple doses of taliglucerase alfa for 10–27 months (n = 10). In both adult and pediatric patients, maximum plasma concentration (Cmax), area under the plasma concentration-time curve from time zero to last measureable concentration (AUC0-t), and from time zero to infinity (AUC0-∞) were higher after 60 Units/kg dose than 30 Units/kg dose. No tendency for accumulation or change in taliglucerase alfa pharmacokinetic parameters over time from day 1 to week 38 was observed with repeated doses of 30 or 60 Units/kg in adults. After multiple doses, mean (range) dose-normalized pharmacokinetic parameters were similar for adult versus pediatric patients receiving 60 Units/kg: Cmax expressed in ng/mL/mg was 42.4 (14.5–95.4) in adults and 46.6 (34.4–68.4) in pediatric patients, AUC0 t expressed in ng•h/mL/mg was 63.4 (26.3–156) in adults and 63.9 (39.8–85.1) in pediatric patients, t1/2 expressed in minutes was 34.8 (11.3–104) in adults and 31.5 (18.0–42.9) in pediatric patients and total body clearance expressed in L/h was 19.9 (6.25–37.9) in adults and 17.0 (11.7–24.9) in pediatric patients. These pharmacokinetic data extend the findings of taliglucerase alfa in adult and pediatric patients. Trial Registration ClinicalTrials.gov. NCT00376168 (in adults); NCT01411228 (in children) PMID

  2. Enzyme replacement therapy with taliglucerase alfa: 36-month safety and efficacy results in adult patients with Gaucher disease previously treated with imiglucerase.

    PubMed

    Pastores, Gregory M; Shankar, Suma P; Petakov, Milan; Giraldo, Pilar; Rosenbaum, Hanna; Amato, Dominick J; Szer, Jeffrey; Chertkoff, Raul; Brill-Almon, Einat; Zimran, Ari

    2016-07-01

    Taliglucerase alfa is the first available plant cell-expressed human recombinant therapeutic protein. It is indicated for treatment of patients with type 1 Gaucher disease (GD) in adult and pediatric patients in several countries. Study PB-06-002 examined the safety and efficacy of taliglucerase alfa for 9 months in patients who previously received imiglucerase. The results of adult patients from Study PB-06-002 who continued receiving taliglucerase alfa in extension Study PB-06-003 for up to 36 months are reported here. Eighteen patients received at least one dose of taliglucerase alfa in Study PB-06-003; 10 patients completed 36 total months of therapy, and four patients who transitioned to commercial drug completed 30-33 months of treatment. In patients who completed 36 total months of treatment, mean percent (±standard error) changes from baseline/time of switch to taliglucerase alfa to 36 months were as follows: hemoglobin concentration, -1.0% (±1.9%; n = 10); platelet count, +9.3% (±9.8%; n = 10); spleen volume measured in multiples of normal (MN), -19.8% (±9.9%; n = 7); liver volume measured in MN, +0.9% (±5.4%; n = 8); chitotriosidase activity, -51.5% (±8.1%; n = 10); and CCL18 concentration, -36.5 (±8.0%; n = 10). Four patients developed antidrug antibodies, including one with evidence of neutralizing activity in vitro. All treatment-related adverse events were mild or moderate and transient. The 36-month results of switching from imiglucerase to taliglucerase alfa treatment in adults with GD provide further data on the clinical safety and efficacy of taliglucerase alfa beyond the initial 9 months of the original study. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:661-665, 2016. © 2016 Wiley Periodicals, Inc.

  3. Peginesatide for Maintenance Treatment of Anemia in Hemodialysis and Nondialysis Patients Previously Treated with Darbepoetin Alfa

    PubMed Central

    Roger, Simon D.; Martin, Edouard; Runyan, Grant; O’Neil, Janet; Qiu, Ping; Locatelli, Francesco

    2013-01-01

    Summary Background and objectives Peginesatide (Omontys) is a novel, synthetic, PEGylated, peptide-based erythropoiesis-stimulating agent (ESA) that is designed to specifically stimulate the erythropoietin receptor. This study evaluated maintenance of hemoglobin levels in patients after conversion from darbepoetin alfa to once-monthly peginesatide. Design, setting, participants, & measurements This open-label, multicenter study included 101 CKD patients, 52 of whom were receiving dialysis. The duration of the study was 24 weeks. The primary endpoint was the mean change in hemoglobin from baseline to the evaluation period (weeks 19–24). The study was conducted during the period from September 22, 2008 to December 24, 2009. Results The mean change among hemodialysis patients was –0.42 g/dl (95% confidence interval, –0.65 to –0.19) and the mean change among CKD nondialysis patients was 0.49 g/dl (95% confidence interval, 0.26–0.71). The percentages of patients who maintained hemoglobin levels within ±1.0 g/dl of baseline values were as follows: 80.0% for hemodialysis and 68.1% for nondialysis, and73.3% for hemodialysis and 68.1% for nondialysis within the target range of 10.0–12.0 g/dl. Few patients received red blood cell transfusions (hemodialysis, 5.8%; nondialysis, 2.0%). Seventy-nine patients experienced adverse events, the majority of which were mild or moderate in severity. There were 40 serious adverse events and 2 deaths reported. Conclusions In this study, once-monthly peginesatide resulted in a slight decrease in mean hemoglobin levels in individuals on hemodialysis and a small increase in individuals with CKD who were not on dialysis. PMID:23243269

  4. Clearance of Hepatic Sphingomyelin by Olipudase Alfa Is Associated With Improvement in Lipid Profiles in Acid Sphingomyelinase Deficiency

    PubMed Central

    Wasserstein, Melissa P.; Jones, Simon A.; Schiano, Thomas D.; Cox, Gerald F.; Puga, Ana Cristina

    2016-01-01

    Acid sphingomyelinase deficiency (ASMD; Niemann-Pick disease type A and B) is a lysosomal storage disorder characterized by abnormal intracellular sphingomyelin (SM) accumulation. Prominent liver involvement results in hepatomegaly, fibrosis/cirrhosis, abnormal liver chemistries, and a proatherogenic lipid profile. Olipudase alfa (recombinant human ASM) is in clinical development as an investigational enzyme replacement therapy for the non-neurological manifestations of ASMD. In a phase 1b study conducted to evaluate the safety and tolerability of within-patient dose escalation with olipudase alfa, measurement of SM levels in liver biopsies was used as a pharmacodynamic biomarker of substrate burden. Five adult patients with non neuronopathic ASMD received escalating doses of olipudase alfa every 2 weeks for 26 weeks. Liver biopsies obtained at baseline and 26 weeks after treatment were evaluated for SM storage by histomorphometric analysis, biochemistry, and electron microscopy. Biopsies were also assessed for inflammation and fibrosis, and for the association of SM levels with liver volume, liver function tests, and lipid profiles. At baseline, SM storage present in Kupffer cells and hepatocytes ranged from 9.8% to 53.8% of the microscopic field. After 26 weeks of treatment, statistically significant reductions in SM (P<0.0001) measured by morphometry were seen in 4 patients with evaluable liver biopsies. The 26-week biopsy of the fifth patient was insufficient for morphometric quantitation. Posttreatment SM levels ranged from 1.2% to 9.5% of the microscopic field, corresponding to an 84% to 92% relative reduction from baseline. Improvements in liver volume, liver function tests, and lipid profiles were also observed. This study illustrates the utility of SM assessment by liver biopsy as a pharmacodynamic biomarker of disease burden in these patients. PMID:27340749

  5. Safety and clinical activity of elosulfase alfa in pediatric patients with Morquio A syndrome (mucopolysaccharidosis IVA) less than 5 y

    PubMed Central

    Jones, Simon A.; Bialer, Martin; Parini, Rossella; Martin, Ken; Wang, Hui; Yang, Ke; Shaywitz, Adam J.; Harmatz, Paul

    2015-01-01

    Background: Previous studies have shown that elosulfase alfa has a favorable efficacy/safety profile in Morquio A patients aged ≥5 y. This study evaluated safety and impact on urine keratan sulfate (uKS) levels and growth velocity in younger patients. Methods: Fifteen Morquio A patients aged <5 y received elosulfase alfa 2.0 mg/kg/week for 52 wk during the primary treatment phase of a phase II, open-label, multinational study. Primary endpoint was safety and tolerability; secondary endpoints were change in uKS and growth velocity over 52 wk. Results: All 15 patients completed the primary treatment phase. Six of 743 infusions (0.8%) administered led to adverse events (AEs) requiring infusion interruption and medical intervention. Eleven patients (73.3%) had ≥1 study drug-related AE, mostly infusion-associated reactions. Mean z-score growth rate per year numerically improved from −0.6 at baseline to −0.4 at week 52. Comparison to untreated subjects of similar age in the Morquio A Clinical Assessment Program study showed a smaller decrease in height z-scores for treated than for untreated patients. Mean percent change from baseline in uKS was −30.2% at 2 wk and −43.5% at 52 wk. Conclusion: Early intervention with elosulfase alfa is well-tolerated and produces a decrease in uKS and a trend toward improvement in growth. PMID:26331768

  6. Biochemical surrogate markers of liver fibrosis and activity in a randomized trial of peginterferon alfa-2b and ribavirin.

    PubMed

    Poynard, Thierry; McHutchison, John; Manns, Michael; Myers, Rob P; Albrecht, Janice

    2003-08-01

    Liver fibrosis and activity indexes were validated in patients infected by hepatitis C virus (HCV) nontreated and treated by interferon. The aim was to validate their usefulness as surrogate markers of histologic features using the data of a randomized trial of combination peginterferon alfa-2b and ribavirin. Three hundred fifty-two patients who had had 2 interpretable liver biopsies and stored serum sample before and after treatment were selected. Two hundred eight patients received peginterferon alfa-2b 1.5 mcg per kg and ribavirin and 144 patients interferon alfa-2b 3 MU three times a week and ribavirin for 48 weeks. A fibrosis and an activity index combining 5 and 6 biochemical markers were assessed at baseline and at end of follow-up (24 weeks after treatment). The biochemical markers have significant predictive values both for the diagnosis of fibrosis and for activity. For the diagnosis of bridging fibrosis and/or moderate necroinflammatory activity, the area under the receiver operating characteristics curve of the activity index was 0.76 +/- 0.03 at baseline and 0.82 +/- 0.02 at end of follow-up. A cutoff of activity index at 0.30 (range, 0.00-1.00) had 90% sensitivity and 88% positive predictive value for the diagnosis of bridging fibrosis or moderate necroinflammatory activity. Sensitivity analyses with biopsy specimens of size greater than 15 mm suggest that a part of discordances between biochemical markers and histology were due to biopsy specimen sampling error. In conclusion, these biochemical markers of fibrosis and activity could be used as surrogate markers for liver biopsy in patients with chronic hepatitis C, both for the initial evaluation and for follow-up.

  7. Is there a need for recombinant human luteinizing hormone (lutropin alfa) supplementation in ovarian stimulation for assisted reproduction?

    PubMed

    Nawroth, Frank; Ludwig, Michael

    2006-05-01

    Luteinizing hormone is now available as the recombinant product, lutropin alfa for the treatment of female infertility. It is necessary in the natural process of follicular growth and maturation. It is not yet clear which patients really benefit from the addition of this medication to conventional gonadotropin stimulation procedures in infertility treatment. Certainly, it has a proven benefit in patients suffering from hypogonadotropic hypogonadism (WHO I). Others may be older patients, patients with a profound gonadotropin suppression stimulated in long gonadotropin-releasing hormone agonist protocols, or patients with poor ovarian response to conventional stimulation strategies. The available data are reviewed herein.

  8. Extensive Psoriasis Induced by Pegylated Interferon Alfa-2a and Ribavirin in the Treatment of Chronic Hepatitis C

    PubMed Central

    Kim, Gun-Wook; Jwa, Seung-Wook; Song, Margaret; Kim, Hoon-Soo; Kim, Byung-Soo; Kim, Moon-Bum

    2013-01-01

    A 56-year-old man with chronic hepatitis C was treated with pegylated interferon alfa-2a in combination with ribavirin. However, psoriatic lesions appeared and worsened dramatically during therapy. Because of the extensive skin eruptions, he stopped therapy for chronic hepatitis C and subsequently started narrow-band ultraviolet B phototherapy and topical calcipotriol/betamethasone dipropionate ointment. After this, the psoriasis improved in a slow but comprehensive manner. Our case suggests that physicians should keep in mind the possibility of psoriasis as a side effect of interferon treatment for chronic hepatitis C. PMID:24371397

  9. Antibody-mediated pure red cell aplasia (PRCA) on switching from darbepoetin alfa to epoetin beta: what are the implications?

    PubMed Central

    Assunção, José; Vinhas, José

    2008-01-01

    We report the development of antibody-mediated pure red cell aplasia (PRCA) in a 63-year-old man with end-stage renal disease following a switch from darbepoetin alfa to epoetin beta. Haemoglobin levels began to decrease 6 months after the switch. Increasing the epoetin beta dose produced no response and regular blood transfusions were required; PRCA was confirmed and epoetin beta was discontinued. The patient responded positively to immunosuppression; after 2 months on prednisone and cyclophosphamide, haemoglobin levels stabilized and no further transfusions were required. This case highlights the difficulty in establishing a cause-effect relationship where more than one erythropoiesis-stimulating agent is involved. PMID:25983889

  10. Antibody-mediated pure red cell aplasia (PRCA) on switching from darbepoetin alfa to epoetin beta: what are the implications?

    PubMed

    Assunção, José; Vinhas, José

    2008-08-01

    We report the development of antibody-mediated pure red cell aplasia (PRCA) in a 63-year-old man with end-stage renal disease following a switch from darbepoetin alfa to epoetin beta. Haemoglobin levels began to decrease 6 months after the switch. Increasing the epoetin beta dose produced no response and regular blood transfusions were required; PRCA was confirmed and epoetin beta was discontinued. The patient responded positively to immunosuppression; after 2 months on prednisone and cyclophosphamide, haemoglobin levels stabilized and no further transfusions were required. This case highlights the difficulty in establishing a cause-effect relationship where more than one erythropoiesis-stimulating agent is involved.

  11. Consensus interferon and ribavirin in patients with chronic hepatitis C who were nonresponders to pegylated interferon alfa-2b and ribavirin.

    PubMed

    Leevy, Carroll B

    2008-07-01

    Recent studies suggest that consensus interferon and ribavirin is effective in retreating patients with chronic hepatitis C who failed therapy with interferon alfa and ribavirin. The objective of the present study was to assess the efficacy, safety, and tolerability of consensus interferon and ribavirin in patients who did not respond to pegylated interferon alfa-2b and ribavirin. We retrospectively identified 137 consecutive nonresponders to pegylated interferon alfa-2b and ribavirin and initiated patients on daily treatment with consensus interferon 15 mug subcutaneously and weight-based ribavirin for 48 weeks. If patients were HCV RNA negative at 12 weeks, the dose was reduced to 15 mug three times weekly for the remaining 36 weeks. The sustained virologic response rate was 37%. Daily consensus interferon therapy was safe and well tolerated in all patients. No dose reductions were required, and no patient discontinued therapy. Further studies of consensus interferon and ribavirin in nonresponders are warranted.

  12. Gateways to clinical trials.

    PubMed

    Moral, M A; Tomillero, A

    2008-03-01

    Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 131-I-Chlorotoxin, 423557; Abatacept, Ad.Egr.TNF.11D, Adalimumab, AE-941, Ambrisentan, AMR-001, Anacetrapib, Anakinra, Aripiprazole, Atazanavir sulfate; BAY-639044, Bazedoxifene acetate, Belimumab, Bevacizumab, Bortezomib, Botulinum toxin type B, Brivaracetam, Bucindolol hydrochloride; Carfilzomib, Carisbamate, CCX-282, CD20Bi, Ceftobiprole, Certolizumab pegol, CF-101, Cinacalcet hydrochloride, Cypher; Darifenacin hydrobromide, Degarelix acetate, Denosumab, Desvenlafaxine succinate, Dexlansoprazole, Dexverapamil, Drotrecogin alfa (activated), Duloxetine hydrochloride, Dutasteride; Efalizumab, EPs-7630, Escitalopram oxalate, Etoricoxib; Fluticasone furoate, Fondaparinux sodium, Fospropofol disodium; Hexadecyloxypropyl-cidofovir, HIV gp120/NefTat/AS02A, HPV-6/11/16/18; INCB-18424, Incyclinide, Inhalable human insulin, Insulin detemir; KNS-760704, KW-0761; Lacosamide, Lenalidomide, Levetiracetam, Licofelone, Lidocaine/prilocaine; mAb 216, MEDI-528, Men ACWY, Meningococcal C-CRM197 vaccine, Methylnaltrexone bromide; Nemifitide ditriflutate, Nicotine conjugate vaccine, Nilotinib hydrochloride monohydrate; Octaparin; Parathyroid hormone (human recombinant), Pegaptanib octasodium, Pitrakinra, Prasterone, Pregabalin; Ranelic acid distrontium salt, Rasagiline mesilate, Retigabine, Rimonabant, RTS,S/AS02D; Sarcosine, Sitaxentan sodium, Solifenacin succinate, Sunitinib malate; Taranabant, Taxus, Teduglutide, Teriparatide, Ticagrelor, Travoprost, TRU-015; USlipristal acetate, Urocortin 2; Vardenafil hydrochloride hydrate; YM-155, Yttrium 90 (90Y) ibritumomab tiuxetan; Zanolimumab, Zoledronic acid monohydrate, Zotarolimus

  13. Arecibo pulsar survey using ALFA. III. Precursor survey and population synthesis

    SciTech Connect

    Swiggum, J. K.; Lorimer, D. R.; McLaughlin, M. A.; Bates, S. D.; Senty, T. R.; Champion, D. J.; Lazarus, P.; Ransom, S. M.; Brazier, A.; Chatterjee, S.; Cordes, J. M.; Hessels, J. W. T.; Nice, D. J.; Ellis, J.; Allen, B.; Bhat, N. D. R.; Bogdanov, S.; Camilo, F.; Crawford, F.; Deneva, J. S.; and others

    2014-06-01

    The Pulsar Arecibo L-band Feed Array (PALFA) Survey uses the ALFA 7-beam receiver to search both inner and outer Galactic sectors visible from Arecibo (32° ≲ ℓ ≲ 77° and 168° ≲ ℓ ≲ 214°) close to the Galactic plane (|b| ≲ 5°) for pulsars. The PALFA survey is sensitive to sources fainter and more distant than have previously been seen because of Arecibo's unrivaled sensitivity. In this paper we detail a precursor survey of this region with PALFA, which observed a subset of the full region (slightly more restrictive in ℓ and |b| ≲ 1°) and detected 45 pulsars. Detections included 1 known millisecond pulsar and 11 previously unknown, long-period pulsars. In the surveyed part of the sky that overlaps with the Parkes Multibeam Pulsar Survey (36° ≲ ℓ ≲ 50°), PALFA is probing deeper than the Parkes survey, with four discoveries in this region. For both Galactic millisecond and normal pulsar populations, we compare the survey's detections with simulations to model these populations and, in particular, to estimate the number of observable pulsars in the Galaxy. We place 95% confidence intervals of 82,000 to 143,000 on the number of detectable normal pulsars and 9000 to 100,000 on the number of detectable millisecond pulsars in the Galactic disk. These are consistent with previous estimates. Given the most likely population size in each case (107,000 and 15,000 for normal and millisecond pulsars, respectively), we extend survey detection simulations to predict that, when complete, the full PALFA survey should have detected 1000{sub −230}{sup +330} normal pulsars and 30{sub −20}{sup +200} millisecond pulsars. Identical estimation techniques predict that 490{sub −115}{sup +160} normal pulsars and 12{sub −5}{sup +70} millisecond pulsars would be detected by the beginning of 2014; at the time, the PALFA survey had detected 283 normal pulsars and 31 millisecond pulsars, respectively. We attribute the deficiency in normal pulsar detections

  14. Pivotal trial with plant cell-expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease.

    PubMed

    Zimran, Ari; Brill-Almon, Einat; Chertkoff, Raul; Petakov, Milan; Blanco-Favela, Francisco; Muñoz, Eduardo Terreros; Solorio-Meza, Sergio E; Amato, Dominick; Duran, Gloria; Giona, Fiorina; Heitner, Rene; Rosenbaum, Hanna; Giraldo, Pilar; Mehta, Atul; Park, Glen; Phillips, Mici; Elstein, Deborah; Altarescu, Gheona; Szleifer, Mali; Hashmueli, Sharon; Aviezer, David

    2011-11-24

    Taliglucerase alfa (Protalix Biotherapeutics, Carmiel, Israel) is a novel plant cell-derived recombinant human β-glucocerebrosidase for Gaucher disease. A phase 3, double-blind, randomized, parallel-group, comparison-dose (30 vs 60 U/kg body weight/infusion) multinational clinical trial was undertaken. Institutional review board approvals were received. A 9-month, 20-infusion trial used inclusion/exclusion criteria in treatment-naive adult patients with splenomegaly and thrombocytopenia. Safety end points were drug-related adverse events: Ab formation and hypersensitivity reactions. Primary efficacy end point was reduction in splenic volume measured by magnetic resonance imaging. Secondary end points were: changes in hemoglobin, hepatic volume, and platelet counts. Exploratory parameters included biomarkers and bone imaging. Twenty-nine patients (11 centers) completed the protocol. There were no serious adverse events; drug-related adverse events were mild/moderate and transient. Two patients (6%) developed non-neutralizing IgG Abs; 2 other patients (6%) developed hypersensitivity reactions. Statistically significant spleen reduction was achieved at 9 months: 26.9% (95% confidence interval [CI]: -31.9, -21.8) in the 30-unit dose group and 38.0% (95% CI: -43.4, -32.8) in the 60-unit dose group (both P < .0001); and in all secondary efficacy end point measures, except platelet counts at the lower dose. These results support safety and efficacy of taliglucerase alfa for Gaucher disease.

  15. Transient low-dose methotrexate generates B regulatory cells that mediate antigen-specific tolerance to alglucosidase alfa.

    PubMed

    Joly, Marguerite S; Martin, Roderick P; Mitra-Kaushik, Shibani; Phillips, Lucy; D'Angona, Alida; Richards, Susan M; Joseph, Alexandra M

    2014-10-15

    Biologic drugs, including enzyme-replacement therapies, can elicit anti-drug Abs (ADA) that may interfere with drug efficacy and impact patient safety. In an effort to control ADA, we focused on identifying regimens of immune tolerance induction that may be readily available for clinical use. Data generated in both wild-type mice and a Pompe disease mouse model demonstrate that single-cycle, low-dose methotrexate can be as effective as three cycles of methotrexate in providing a long-lived reduction in alglucosidase alfa-specific ADA. In addition, we show that methotrexate induces Ag-specific tolerance as mice generate similar Ab responses to an irrelevant Ag regardless of prior methotrexate treatment. Methotrexate-induced immune tolerance does not seem to involve cell depletion, but rather a specific expansion of IL-10- and TGF-β-secreting B cells that express Foxp3, suggesting an induction of regulatory B cells. The mechanism of immune tolerance induction appears to be IL-10 dependent, as methotrexate does not induce immune tolerance in IL-10 knockout mice. Splenic B cells from animals that have been tolerized to alglucosidase alfa with methotrexate can transfer tolerance to naive hosts. We hypothesize that methotrexate induction treatment concomitant with initial exposure to the biotherapeutic can induce Ag-specific immune tolerance in mice through a mechanism that appears to involve the induction of regulatory B cells.

  16. Baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF)

    PubMed Central

    McMurray, John J.V.; Anand, Inder S.; Diaz, Rafael; Maggioni, Aldo P.; O'Connor, Christopher; Pfeffer, Marc A.; Solomon, Scott D.; Tendera, Michal; van Veldhuisen, Dirk J.; Albizem, Moetaz; Cheng, Sunfa; Scarlata, Debra; Swedberg, Karl; Young, James B.; Amuchastegui, M.; Belziti, C.; Bluguermann, J.; Caccavo, M.; Cartasegna, L.; Colque, R.; Cuneo, C.; Fernandez, A.; Gabito, A.; Goicochea, R.; Gonzalez, M.; Gorosito, V.; Grinfeld, L.; Hominal, M.; Kevorkian, R.; Litvak Bruno, M.; Llanos, J.; Mackinnon, I.; Manuale, O.; Marzetti, E.; Nul, D.; Perna, E.; Riccitelli, M.; Sanchez, A.; Santos, D.; Schygiel, P.; Toblli, J.; Vogel, D.; Aggarwal, A.; Amerena, J.; De Looze, F.; Fletcher, P.; Hare, D.; Ireland, M.; Krum, H.; Lattimore, J.; Marwick, T.; Sindone, A.; Thompson, P.; Waites, J.; Altenberger, J.; Ebner, C.; Lenz, K.; Pacher, R.; Poelzl, G.; Charlier, F.; de Ceuninck, M.; De Keulenaer, G.; Dendale, P.; Maréchal, P.; Mullens, W.; Thoeng, J.; Vanderheyden, M.; Vanhaecke, J.; Weytjens, C.; Wollaert, B.; Albuquerque, D.; Almeida, D.; Aspe y Rosas, J.; Bocchi, E.; Bordignon, S.; Clausell, N.; Kaiser, S.; Leaes, P.; Martins Alves, S.; Montera, M.; Moura, L.; Pereira de Castro, R.; Rassi, S.; Reis, A.; Saraiva, J.; Simões, M.; Souza Neto, J.; Teixeira, M.; Benov, H.; Chompalova, B.; Donova, T.; Georgiev, P.; Gotchev, D.; Goudev, A.; Grigorov, M.; Guenova, D.; Hergeldjieva, V.; Ivanov, D.; Kostova, E.; Manolova, A.; Marchev, S.; Nikolov, F.; Popov, A.; Raev, D.; Tzekova, M.; Czarnecki, W.; Giannetti, N.; Haddad, H.; Heath, J.; Huynh, T.; Lepage, S.; Liu, P.; Lonn, E.; Ma, P.; Manyari, D.; Moe, G.; Parker, J.; Pesant, Y.; Rajda, M.; Ricci, J.; Roth, S.; Sestier, F.; Sluzar, V.; Sussex, B.; Vizel, S.; Antezana, G.; Bugueno, C.; Castro, P.; Conejeros, C.; Manriquez, L.; Martinez, D.; Potthoff, S.; Stockins, B.; Vukasovic, J.; Gregor, P.; Herold, M.; Jerabek, O.; Jirmar, R.; Kuchar, R.; Linhart, A.; Podzemska, B.; Soucek, M.; Spac, J.; Spacek, R.; Vodnansky, P.; Bronnum-Schou, J.; Clemmensen, K.; Egstrup, K.; Jensen, G.; Kjoller-Hansen, L.; Kober, L.; Markenvard, J.; Rokkedal, J.; Skagen, K.; Torp-Pedersen, C.; Tuxen, C.; Videbak, L.; Laks, T.; Vahula, V.; Harjola, V.; Kettunen, R.; Kotila, M.; Bauer, F.; Cohen Solal, A.; Coisne, D.; Davy, J.; De Groote, P.; Dos Santos, P.; Funck, F.; Galinier, M.; Gibelin, P.; Isnard, R.; Neuder, Y.; Roul, G.; Sabatier, R.; Trochu, J.; Anker, S.; Denny, S.; Dreykluft, T.; Flesch, M.; Genth-Zotz, S.; Hambrecht, R.; Hein, J.; Jeserich, M.; John, M.; Kreider-Stempfle, H.; Laufs, U.; Muellerleile, K.; Natour, M.; Sandri, M.; Schäufele, T.; von Hodenberg, E.; Weyland, K.; Winkelmann, B.; Tse, H.; Yan, B.; Barsi, B.; Csikasz, J.; Dezsi, C.; Edes, I.; Forster, T.; Karpati, P.; Kerekes, C.; Kis, E.; Kosa, I.; Lupkovics, G.; Nagy, A.; Preda, I.; Ronaszeki, A.; Tomcsanyi, J.; Zamolyi, K.; Agarwal, D.; Bahl, V.; Bordoloi, A.; Chockalingam, K.; Chopda, M.; Chopra, V.; Dugal, J.; Ghaisas, N.; Ghosh, S.; Grant, P.; Hiremath, S.; Iyengar, S.; Jagadeesa Subramania, B.; Jain, P.; Joshi, A.; Khan, A.; Mullasari, A.; Naik, S.; Oomman, A.; Pai, V.; Pareppally Gopal, R.; Parikh, K.; Patel, T.; Prakash, V.; Sastry, B.; Sathe, S.; Sinha, N.; Srikanthan, V.; Subburamakrishnan, P.; Thacker, H.; Wander, G.; Admon, D.; Katz, A.; Klainman, E.; Lewis, B.; Marmor, A.; Moriel, M.; Mosseri, M.; Shotan, A.; Weinstein, J.; Zimlichman, R.; Agostoni, P.; Albanese, M.; Alunni, G.; Bini, R.; Boccanelli, A.; Bolognese, L.; Campana, C.; Carbonieri, E.; Carpino, C.; Checco, L.; Cosmi, F.; D'Angelo, G.; De Cristofaro, M.; Floresta, A.; Fucili, A.; Galvani, M.; Ivleva, A.; Marra, S.; Musca, G.; Peccerillo, N.; Perrone Filardi, P.; Picchio, E.; Russo, T.; Scelsi, L.; Senni, M.; Tavazzi, L.; Erglis, A.; Jasinkevica, I.; Kakurina, N.; Veze, I.; Volans, E.; Bagdonas, A.; Berukstis, E.; Celutkiene, J.; Dambrauskaite, A.; Jarasuniene, D.; Luksiene, D.; Rudys, A.; Sakalyte, G.; Sliaziene, S.; Aguilar-Romero, R.; Cardona-Muñoz, E.; Castro-Jimenez, J.; Chavez-Herrera, J.; Chuquiure Valenzuela, E.; De la Pena, G.; Herrera, E.; Leiva-Pons, J.; Lopez Alvarado, A.; Mendez Machado, G.; Ramos-Lopez, G.; Basart, D.; Buijs, E.; Cornel, J.; de Leeuw, M.; Dijkgraaf, R.; Dunselman, P.; Freericks, M.; Hamraoui, K.; Lenderlink, T.; Linssen, G.; Lodewick, P.; Lodewijks, C.; Lok, D.; Nierop, P.; Ronner, E.; Somsen, A.; van Dantzig, J.; van der Burgh, P.; van Kempen, L.; van Vlies, B.; Voors, A.; Wardeh, A.; Willems, F.; Dickstein, K.; Gundersen, T.; Hole, T.; Thalamus, J.; Westheim, A.; Dabrowski, M.; Gorski, J.; Korewicki, J.; Kuc, K.; Miekus, P.; Musial, W.; Niegowska, J.; Piotrowski, W.; Podolec, P.; Polonski, L.; Ponikowski, P.; Rynkiewicz, A.; Szelemej, R.; Trusz-Gluza, M.; Ujda, M.; Wojciechowski, D; Wysokinski, A.; Camacho, A.; Fonseca, C.; Monteiro, P.; Apetrei, E.; Bruckner, I.; Carasca, E.; Coman, I.; Datcu, M.; Dragulescu, S.; Ionescu, P.; Iordachescu-Petica, D.; Manitiu, I.; Popa, V.; Pop-Moldovan, A.; Radoi, M.; Stamate, S.; Tomescu, M.; Vita, I.; Aroutiounov, G.; Ballyuzek, M.; Bart, B.; Churina, S.; Glezer, M.; Goloshchekin, B.; Ivleva, A.; Kobalava, Z.; Kostenko, V.; Lopatin, Y.; Martynov, A.; Orlov, V.; Semernin, E.; Shogenov, Z.; Sidorenko, B.; Skvortsov, A.; Storzhakov, G.; Sulimov, V.; Talibov, O.; Tereshenko, S.; Tsyrline, V.; Zadionchenko, V.; Zateyshchikov, D.; Dzupina, A.; Hranai, M.; Kmec, J.; Micko, K.; Murin, J.; Pella, D.; Sojka, G.; Spisak, V.; Vahala, P.; Vinanska, D.; Badat, A.; Bayat, J.; Dawood, S.; Delport, E.; Ellis, G.; Garda, R.; Klug, E.; Mabin, T.; Naidoo, D.; Pretorius, M.; Ranjith, N.; Van Zyl, L.; Weich, H.; Anguita, M.; Berrazueta, J.; Bruguera i Cortada, J.; de Teresa, E.; Gómez Sánchez, M.; González Juanatey, J.; Gonzalez-Maqueda, I.; Jordana, R.; Lupon, J.; Manzano, L.; Pascual Figal, D.; Pulpón, L.; Recio, J.; Ridocci Soriano, F.; Rodríguez Lambert, J.; Roig Minguell, E.; Roig Minguell, E.; Romero, J.; Valdovinos, P.; Klintberg, L.; Kronvall, T.; Lycksell, M.; Morner, S.; Rydberg, E.; Swedberg, K.; Timberg, I.; Wikstrom, G.; Moccetti, T.4; Ashok, J.; Banerjee, P.; Carr-White, G.; Cleland, J.; Connolly, E.; Francis, M.; Greenbaum, R.; Kadr, H.; Lindsay, S.; McMurray, J.; Megarry, S.; Memon, A.; Murdoch, D.; Senior, R.; Squire, I.; Tan, L.; Witte, K.; Adams, K.; Adamson, P.; Adler, A.; Altschul, L.; Altschuller, A.; Amirani, H.; Anand, I.; Andreou, C.; Ansari, M.; Antonishen, M.; Banchs, H.; Banerjee, S.; Banish, D.; Bank, A.; Barbagelata, A.; Barnard, D.; Bellinger, R.; Benn, A.; Berk, M.; Berry, B.; Bethala, V.; Bilazarian, S.; Bisognano, J.; Bleyer, F.; Blum, M.; Boehmer, J.; Bouchard, A.; Boyle, A.; Bozkurt, B.; Brown, C.; Burlew, B.; Burnham, K.; Butler, J.; Call, J.; Cambier, P.; Cappola, T.; Carlson, R.; Chandler, B.; Chandra, R.; Chandraratna, P.; Chernick, R.; Colan, D.; Colfer, H.; Colucci, W.; Connelly, T.; Costantini, O.; Dadkhah, S.; Dauber, I.; Davis, J.; Davis, S.; Denning, S.; Drazner, M.; Dunlap, S.; Egbujiobi, L.; Elkayam, U.; Elliott, J.; El-Shahawy, M.; Essandoh, L.; Ewald, G.; Fang, J.; Farhoud, H.; Felker, G.; Fernandez, J.; Festin, R.; Fishbein, G.; Florea, V.; Flores, E.; Floro, J.; Gabris, M.; Garg, M.; Gatewood, R.; Geller, M.; Ghali, J.; Ghumman, W.; Gibbs, G.; Gillespie, E.; Gilmore, R.; Gogia, H.; Goldberg, L.; Gradus-Pizlo, I.; Grainger, T.; Gudmundsson, G.; Gunawardena, D.; Gupta, D.; Hack, T.; Hall, S.; Hamroff, G.; Hankins, S.; Hanna, M.; Hargrove, J.; Haught, W.; Hauptman, P.; Hazelrigg, M.; Herzog, C.; Heywood, J.; Hill, T.; Hilton, T.; Hirsch, H.; Hunter, J.; Ibrahim, H.; Imburgia, M.; Iteld, B.; Jackson, B.; Jaffrani, N.; Jain, D.; Jain, A.; James, M.; Jimenez, J.; Johnson, E.; Kale, P.; Kaneshige, A.; Kapadia, S.; Karia, D.; Karlsberg, R.; Katholi, R.; Kerut, E.; Khoury, W.; Kipperman, R.; Klapholz, M.; Kosinski, E.; Kozinn, M.; Kraus, D.; Krueger, S.; Krum, H.; Kumar, S.; Lader, E.; Lee, C.; Levy, W.; Lewis, E.; Light-McGroary, K.; Loh, I.; Lombardi, W.; Machado, C.; Maislos, F.; Mancini, D.; Markus, T.; Mather, P.; McCants, K.; McGrew, F.; McLaurin, B.; McMillan, E.; McNamara, D.; Meyer, T.; Meymandi, S.; Miller, A.; Minami, E.; Modi, M.; Mody, F.; Mohanty, P.; Moscoso, R.; Moskowitz, R.; Moustafa, M.; Mullen, M.; Naz, T.; Noonan, T.; O'Brien, T.; Oellerich, W.; Oren, R.; Pamboukian, S.; Pereira, N.; Pitt, W.; Porter, C.; Prabhu, S.; Promisloff, S.; Ratkovec, R.; Richardson, R.; Ross, A.; Saleh, N.; Saltzberg, M.; Sarkar, S.; Schmedtje, J.; Schneider, R.; Schuyler, G.; Shanes, J.; Sharma, A.; Siegel, C.; Siegel, R.; Silber, D.; Singh, V.; Singh, N.; Singh, J.; Sklar, J.; Small, R.; Smith, A.; Smith, E.; Smith, E.; Smull, D.; Sotolongo, R.; Staniloae, C.; Stapleton, D.; Steele, P.; Stehlik, J.; Stein, M.; Tang, W.; Thadani, U.; Torre-Amoine, G.; Trichon, B.; Tsai, C.; Tummala, R.; Van Bakel, A.; Vicari, R.; Vijay, N.; Vijayaraghavan, K.; Vittorio, T.; Vossler, M.; Wagoner, L.; Wallis, D.; Ward, N.; Widmer, M.; Wight, J.; Wilkins, C.; Williams, C.; Williams, G.; Winchester, M.; Winkel, E.; Wittmer, B.; Wood, D.; Wormer, D.; Wright, R.; Xu, Z.; Yasin, M.; Zolty, R.

    2013-01-01

    Aims This report describes the baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) which is testing the hypothesis that anaemia correction with darbepoetin alfa will reduce the composite endpoint of death from any cause or hospital admission for worsening heart failure, and improve other outcomes. Methods and results Key demographic, clinical, and laboratory findings, along with baseline treatment, are reported and compared with those of patients in other recent clinical trials in heart failure. Compared with other recent trials, RED-HF enrolled more elderly [mean age 70 (SD 11.4) years], female (41%), and black (9%) patients. RED-HF patients more often had diabetes (46%) and renal impairment (72% had an estimated glomerular filtration rate <60 mL/min/1.73 m2). Patients in RED-HF had heart failure of longer duration [5.3 (5.4) years], worse NYHA class (35% II, 63% III, and 2% IV), and more signs of congestion. Mean EF was 30% (6.8%). RED-HF patients were well treated at randomization, and pharmacological therapy at baseline was broadly similar to that of other recent trials, taking account of study-specific inclusion/exclusion criteria. Median (interquartile range) haemoglobin at baseline was 112 (106–117) g/L. Conclusion The anaemic patients enrolled in RED-HF were older, moderately to markedly symptomatic, and had extensive co-morbidity. PMID:23329651

  17. Ropeginterferon alfa-2b, a novel IFNα-2b, induces high response rates with low toxicity in patients with polycythemia vera.

    PubMed

    Gisslinger, Heinz; Zagrijtschuk, Oleh; Buxhofer-Ausch, Veronika; Thaler, Josef; Schloegl, Ernst; Gastl, Guenther A; Wolf, Dominik; Kralovics, Robert; Gisslinger, Bettina; Strecker, Karin; Egle, Alexander; Melchardt, Thomas; Burgstaller, Sonja; Willenbacher, Ella; Schalling, Martin; Them, Nicole C; Kadlecova, Pavla; Klade, Christoph; Greil, Richard

    2015-10-08

    In this prospective, open-label, multicenter phase 1/2 dose escalation study, we used a next-generation, mono-pegylated interferon (IFN) α-2b isoform, ropeginterferon alfa-2b. The unique feature of ropeginterferon alfa-2b is a longer elimination half-life, which allows administration every 2 weeks. We present data from 51 polycythemia vera patients. The main goal was to define the maximum tolerated dose and to assess safety and efficacy. A dose range of 50 to 540 µg was tested without the appearance of dose-limiting toxicities. All drug-related adverse events were known toxicities associated with IFN-α. The cumulative overall response rate was 90%, comprising complete response in 47% and partial response in 43% of patients; the best individual molecular response level was a complete response in 21% of patients and partial response in 47%. Notably, we did not observe any correlation between the dose level and the response rate or response duration, suggesting that already low levels of ropeginterferon alfa-2b are sufficient to induce significant hematologic and molecular responses. These data suggest promising efficacy and safety of ropeginterferon alfa-2b and support the development of the drug in a randomized phase 3 clinical trial. The study was disclosed at www.clinicaltrials.gov as #NCT01193699 before including the first patient.

  18. Enzyme replacement therapy with taliglucerase alfa: 36‐month safety and efficacy results in adult patients with Gaucher disease previously treated with imiglucerase

    PubMed Central

    Shankar, Suma P.; Petakov, Milan; Giraldo, Pilar; Rosenbaum, Hanna; Amato, Dominick J.; Szer, Jeffrey; Chertkoff, Raul; Brill‐Almon, Einat; Zimran, Ari

    2016-01-01

    Taliglucerase alfa is the first available plant cell‐expressed human recombinant therapeutic protein. It is indicated for treatment of patients with type 1 Gaucher disease (GD) in adult and pediatric patients in several countries. Study PB‐06‐002 examined the safety and efficacy of taliglucerase alfa for 9 months in patients who previously received imiglucerase. The results of adult patients from Study PB‐06‐002 who continued receiving taliglucerase alfa in extension Study PB‐06‐003 for up to 36 months are reported here. Eighteen patients received at least one dose of taliglucerase alfa in Study PB‐06‐003; 10 patients completed 36 total months of therapy, and four patients who transitioned to commercial drug completed 30–33 months of treatment. In patients who completed 36 total months of treatment, mean percent (±standard error) changes from baseline/time of switch to taliglucerase alfa to 36 months were as follows: hemoglobin concentration, −1.0% (±1.9%; n = 10); platelet count, +9.3% (±9.8%; n = 10); spleen volume measured in multiples of normal (MN), −19.8% (±9.9%; n = 7); liver volume measured in MN, +0.9% (±5.4%; n = 8); chitotriosidase activity, −51.5% (±8.1%; n = 10); and CCL18 concentration, −36.5 (±8.0%; n = 10). Four patients developed antidrug antibodies, including one with evidence of neutralizing activity in vitro. All treatment‐related adverse events were mild or moderate and transient. The 36‐month results of switching from imiglucerase to taliglucerase alfa treatment in adults with GD provide further data on the clinical safety and efficacy of taliglucerase alfa beyond the initial 9 months of the original study. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:661–665, 2016. © 2016 Wiley Periodicals, Inc. PMID:27102949

  19. Long-term effectiveness of agalsidase alfa enzyme replacement in Fabry disease: A Fabry Outcome Survey analysis

    PubMed Central

    Beck, Michael; Hughes, Derralynn; Kampmann, Christoph; Larroque, Sylvain; Mehta, Atul; Pintos-Morell, Guillem; Ramaswami, Uma; West, Michael; Wijatyk, Anna; Giugliani, Roberto

    2015-01-01

    Outcomes from 5 years of treatment with agalsidase alfa enzyme replacement therapy (ERT) for Fabry disease in patients enrolled in the Fabry Outcome Survey (FOS) were compared with published findings for untreated patients with Fabry disease. Data were extracted from FOS, a Shire-sponsored database, for comparison with data from three published studies. Outcomes evaluated were the annualized rate of change in estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI) as well as time to and ages at a composite morbidity endpoint and at death. FOS data were extracted for 740 treated patients who were followed for a median of ~ 5 years. Compared with no treatment, patients treated with agalsidase alfa demonstrated slower decline in renal function and slower progression of left ventricular hypertrophy. Treated male patients with baseline eGFR < 60 mL/min/1.73 m2 had a mean (standard error of the mean [SEM]) annualized change in eGFR of − 2.86 (0.53) mL/min/1.73 m2/y compared with − 6.8 (1.5) in the published untreated cohort. The mean (SEM) rate of LVMI increase with treatment was 0.33 (0.10) g/m2.7/y in males and 0.48 (0.09) in females, compared with 4.07 (1.03) in untreated males and 2.31 (0.81) in untreated females. Morbidity occurred later in treated patients, with ~ 16% risk of a composite morbidity event (26% in males) after 24 months with ERT versus ~ 45% without treatment, with first events and deaths also occurring at older ages in patients administered ERT (e.g., estimated median survival in treated males was 77.5 years versus 60 years in untreated males). Findings from these retrospective comparisons of observational data and published literature support the long-term benefits of ERT with agalsidase alfa for Fabry disease in slowing the progression of renal impairment and cardiomyopathy. Treatment also appeared to delay the onset of morbidity and mortality. Interpretation of these findings should take into

  20. Long-term effectiveness of agalsidase alfa enzyme replacement in Fabry disease: A Fabry Outcome Survey analysis.

    PubMed

    Beck, Michael; Hughes, Derralynn; Kampmann, Christoph; Larroque, Sylvain; Mehta, Atul; Pintos-Morell, Guillem; Ramaswami, Uma; West, Michael; Wijatyk, Anna; Giugliani, Roberto

    2015-06-01

    Outcomes from 5 years of treatment with agalsidase alfa enzyme replacement therapy (ERT) for Fabry disease in patients enrolled in the Fabry Outcome Survey (FOS) were compared with published findings for untreated patients with Fabry disease. Data were extracted from FOS, a Shire-sponsored database, for comparison with data from three published studies. Outcomes evaluated were the annualized rate of change in estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI) as well as time to and ages at a composite morbidity endpoint and at death. FOS data were extracted for 740 treated patients who were followed for a median of ~ 5 years. Compared with no treatment, patients treated with agalsidase alfa demonstrated slower decline in renal function and slower progression of left ventricular hypertrophy. Treated male patients with baseline eGFR < 60 mL/min/1.73 m(2) had a mean (standard error of the mean [SEM]) annualized change in eGFR of - 2.86 (0.53) mL/min/1.73 m(2)/y compared with - 6.8 (1.5) in the published untreated cohort. The mean (SEM) rate of LVMI increase with treatment was 0.33 (0.10) g/m(2.7)/y in males and 0.48 (0.09) in females, compared with 4.07 (1.03) in untreated males and 2.31 (0.81) in untreated females. Morbidity occurred later in treated patients, with ~ 16% risk of a composite morbidity event (26% in males) after 24 months with ERT versus ~ 45% without treatment, with first events and deaths also occurring at older ages in patients administered ERT (e.g., estimated median survival in treated males was 77.5 years versus 60 years in untreated males). Findings from these retrospective comparisons of observational data and published literature support the long-term benefits of ERT with agalsidase alfa for Fabry disease in slowing the progression of renal impairment and cardiomyopathy. Treatment also appeared to delay the onset of morbidity and mortality. Interpretation of these findings should take

  1. Long-term efficacy and safety results of taliglucerase alfa through 5years in adult treatment-naïve patients with Gaucher disease.

    PubMed

    Zimran, Ari; Durán, Gloria; Giraldo, Pilar; Rosenbaum, Hanna; Giona, Fiorina; Petakov, Milan; Terreros Muñoz, Eduardo; Solorio-Meza, Sergio Eduardo; Cooper, Peter A; Varughese, Sheeba; Alon, Sari; Chertkoff, Raul

    2016-07-18

    Taliglucerase alfa, the first available plant cell-expressed recombinant therapeutic protein, is an enzyme replacement therapy approved for Gaucher disease (GD). PB-06-001, a pivotal phase 3, multicenter, randomized, double-blind, parallel-dose study investigated taliglucerase alfa 30 or 60U/kg every other week through 9months in treatment-naïve adults with GD; 30-month extension study PB-06-003 followed. Patients completing PB-06-001 and PB-06-003 could continue treatment in PB-06-007. Nineteen patients enrolled in PB-06-007 (30U/kg, n=8; 60U/kg, n=9; dose adjusted, n=2); 17 completed 5 total years of treatment. In these 3 groups, respectively, taliglucerase alfa resulted in mean decreases in spleen volume (-8.7, -6.9, -12.4 multiples of normal), liver volume (-0.6, -0.4, -0.5 multiples of normal), chitotriosidase activity (-83.1%, -93.4%, -87.9%), and chemokine (CC motif) ligand 18 concentration (-66.7%, -83.3%, -78.9%), as well as mean increases in hemoglobin concentration (+2.1, +2.1, +1.8mg/dL) and platelet count (+31,871, +106,800, +34,000/mm(3)). The most common adverse events were nasopharyngitis and arthralgia. Most adverse events were mild/moderate; no serious adverse events were considered treatment-related. These results demonstrate continued improvement of disease parameters during 5years of taliglucerase alfa therapy in 17 treatment-naive patients with no new safety concerns, extending the taliglucerase alfa clinical efficacy and safety dataset. This study was registered at www.clinicaltrials.gov as NCT01422187.

  2. Balapiravir plus peginterferon alfa-2a (40KD)/ribavirin in a randomized trial of hepatitis C genotype 1 patients(◆)

    PubMed Central

    Nelson, David R.; Zeuzem, Stefan; Andreone, Pietro; Ferenci, Peter; Herring, Robert; Jensen, Donald M.; Marcellin, Patrick; Pockros, Paul J.; Rodríguez-Torres, Maribel; Rossaro, Lorenzo; Rustgi, Vinod K.; Sepe, Thomas; Sulkowski, Mark; Thomason, Isaac R.; Yoshida, Eric M.; Chan, Anna; Hill, George

    2013-01-01

    Introduction Balapiravir (R1626, RG1626) is the prodrug of a nucleoside analogue inhibitor of the hepatitis C virus (HCV) RNA-dependent RNA polymerase (R1479, RG1479). This phase 2, double-blind international trial evaluated the optimal treatment regimen of balapiravir plus peginterferon alfa-2a (40KD)/ribavirin. Material and methods Treatment-naive genotype 1 patients (N = 516) were randomized to one of seven treatment groups in which they received balapiravir 500, 1,000, or 1,500 mg twice daily, peginterferon alfa-2a (40KD) 180 or 90 μg/week and ribavirin 1,000/1,200 mg/day or peginterferon alfa-2a (40KD)/ribavirin. The planned treatment duration with balapiravir was reduced from 24 to 12 weeks due to safety concerns. Results The percentage of patients with undetectable HCV RNA was consistently higher in all balapiravir groups from week 2 to 12. However, high rates of dose modifications and discontinuations of one/all study drugs compromised the efficacy assessment and resulted in similar sustained virological response rates in the balapiravir groups (range 32-50%) and the peginterferon alfa-2a (40KD)/ribavirin group (43%). Balapiravir was discontinued for safety reasons in 28-36% of patients (most often for lymphopenia) and the percentage of patients with serious adverse events (especially hematological, infection, ocular events) was dose related. Serious hematological adverse events (particularly neutropenia, lymphopenia) were more common in balapiravir recipients. Two deaths in the balapiravir/peginterferon alfa-2a/ribavirin combination groups were considered possibly related to study medication. Conclusion Further development of balapiravir for the treatment of chronic hepatitis C has been halted because of the unacceptable benefit to risk ratio revealed in this study (www.ClinicalTrials.gov NCT 00517439). PMID:22166557

  3. [A case of Bell's palsy associated with peginterferon Alfa-2a and ribavirin therapy for chronic hepatitis C virus infection].

    PubMed

    Lee, Moo Yeol; Cho, Hoon; Kim, Yeong Muk; Lee, Joon Sang

    2006-09-01

    Pegylated interferon alfa-2a (PEG-IFN) and ribavirin combination therapy is the first line treatment for chronic HCV infection. There are four reports of Bell's palsy associated with interferon-alpha (IFN-alpha) and ribavirin therapy. We report here a case of Bell's palsy that occurred in a patient with chronic HCV infection during combination PEG-IFN and ribavirin therapy. The patient was 49-year-old man with chronic hepatitis C for 2 years. The liver biopsy showed grade 1 and stage 1. Therapy with PEG-IFN (Pegasys) 180 microgram/week and ribavirin 1200 mg/day was initiated. After 3 weeks of treatment, the patient showed a loss of muscular tone on the left side of his face. A diagnosis of Bell's palsy was made, and the PEG-IFN and ribavirin therapy was stopped. Prednisolone 45 mg/d was given and then tapered for 8 weeks. His palsy improved over 6 weeks.

  4. Daclatasvir vs telaprevir plus peginterferon alfa/ribavirin for hepatitis C virus genotype 1

    PubMed Central

    Jacobson, Ira; Zeuzem, Stefan; Flisiak, Robert; Knysz, Brygida; Lueth, Stefan; Zarebska-Michaluk, Dorota; Janczewska, Ewa; Ferenci, Peter; Diago, Moises; Zignego, Anna Linda; Safadi, Rifaat; Baruch, Yaacov; Abdurakhmanov, Dzhamal; Shafran, Stephen; Thabut, Dominique; Bruck, Rafael; Gadano, Adrian; Thompson, Alexander James; Kopit, Justin; McPhee, Fiona; Michener, Tracy; Hughes, Eric A; Yin, Philip D; Noviello, Stephanie

    2016-01-01

    AIM: To evaluate daclatasvir vs telaprevir, each combined with peginterferon alfa-2a/ribavirin (pegIFN/RBV), in treatment-naive hepatitis C virus (HCV) genotype (GT) 1-infected patients. METHODS: In this phase 3, randomized, open-label, noninferiority study, 602 patients were randomly assigned (2:1) to daclatasvir vs telaprevir, stratified by IL28B rs12979860 host genotype (CC vs non-CC), cirrhosis status (compensated cirrhosis vs no cirrhosis), and HCV GT1 subtype (GT1a vs GT1b). Patients were selected by study inclusion criteria from a total of 793 enrolled patients. Patients received daclatasvir 60 mg once daily or telaprevir 750 mg 3 times daily plus pegIFN/RBV. Daclatasvir recipients received 24 wk of daclatasvir plus pegIFN/RBV; those without an extended rapid virologic response (eRVR; undetectable HCV-RNA at weeks 4 and 12) received an additional 24 wk of pegIFN/RBV. Telaprevir-treated patients received 12 wk of telaprevir plus pegIFN/RBV followed by 12 (with eRVR) or 36 (no eRVR) wk of pegIFN/RBV. The primary objective was to compare for noninferiority of sustained virologic response rates at posttreatment week 12 (SVR12) in GT1b-infected patients. Key secondary objectives were to demonstrate that the rates of anemia (hemoglobin < 10 g/dL) and rash-related events, through week 12, were lower with daclatasvir + pegIFN/RBV than with telaprevir + pegIFN/RBV among GT1b-infected patients. Resistance testing was performed using population-based sequencing of the NS5A region for all patients at baseline, and for patients with virologic failure or relapse and HCV-RNA ≥ 1000 IU/mL, to investigate any link between NS5A polymorphisms associated with daclatasvir resistance and virologic outcome. RESULTS: Patient demographics and disease characteristics were generally balanced across treatment arms; however, there was a higher proportion of black/African Americans in the daclatasvir groups (6.0% and 8.2% in the GT1b and GT1a groups, respectively) than in the

  5. Impact of elosulfase alfa in patients with morquio A syndrome who have limited ambulation: An open‐label, phase 2 study

    PubMed Central

    Mengel, Eugen; Geberhiwot, Tarekegn; Muschol, Nicole; Hendriksz, Christian J.; Burton, Barbara K.; Jameson, Elisabeth; Berger, Kenneth I.; Jester, Andrea; Treadwell, Marsha; Sisic, Zlatko; Decker, Celeste

    2016-01-01

    Efficacy and safety of elosulfase alfa enzyme replacement therapy (ERT) were assessed in an open‐label, phase 2, multi‐national study in Morquio A patients aged ≥5 years unable to walk ≥30 meters in the 6‐min walk test. Patients received elosulfase alfa 2.0 mg/kg/week intravenously for 48 weeks. Efficacy measures were functional dexterity, pinch/grip strength, mobility in a modified timed 25‐foot walk, pain, quality of life, respiratory function, and urine keratan sulfate (KS). Safety/tolerability was also assessed. Fifteen patients received elosulfase alfa, three patients discontinued ERT due to adverse events (two were grade 3 drug‐related adverse events, the other was not drug‐related), and two patients missed >20% of planned infusions; 10 completed treatment through 48 weeks and received ≥80% of planned infusions (Modified Per Protocol [MPP] population). The study population had more advanced disease than that enrolled in other trials. From baseline to week 48, MPP data showed biochemical efficacy (urine KS decreased 52.4%). The remaining efficacy results were highly variable due to challenges in test execution because of severe skeletal and joint abnormalities, small sample sizes, and clinical heterogeneity among patients. Eight patients showed improvements in one or more outcome measures; several patients indicated improvements not captured by the study assessments (e.g., increased energy, functional ability). The nature of adverse events was similar to other elosulfase alfa studies. This study illustrates the considerable challenges in objectively measuring impact of ERT in very disabled Morquio A patients and highlights the need to examine results on an individual basis. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc. PMID:27774754

  6. A Saudi Gastroenterology Association Position Statement on the Use of Tumor Necrosis Factor-alfa Antagonists for the Treatment of Inflammatory Bowel Disease

    PubMed Central

    Mosli, Mahmoud H.; Al-Harbi, Othman; Feagan, Brian G.; Almadi, Majid A.

    2015-01-01

    The objective of this position statement from the Saudi Gastroenterology Association is to guide gastroenterologists on the use of tumor necrosis factor-alfa (TNF-α) antagonists for the treatment of the idiopathic inflammatory bowel diseases, Crohn's disease, and ulcerative colitis. In this article, we summarize the relevant literature regarding the safety and efficacy of TNF-α antagonists, highlight relevant safety concerns specific to the environment in Saudi Arabia, and provide specific recommendations for the use of these agents. PMID:26228361

  7. Health management program: factors influencing completion of therapy with high-dose interferon alfa-2b for high-risk melanoma

    PubMed Central

    Levesque, N.; Mitchinson, K.; Lawrie, D.; Fedorak, L.; MacDonald, D.; Normand, C.; Pouliot, J.F.

    2008-01-01

    The goal of the 1-year observational, multicentre, open-label study reported here was to identify factors influencing adherence to high-dose interferon alfa-2b adjuvant therapy in patients at high risk of recurrence following surgical excision of malignant melanoma. The study was carried out in 23 tertiary-care centres across Canada. The 225 patients enrolled in the study all had malignant melanoma that was surgically excised and that required adjuvant treatment with interferon alfa-2b. Of these patients, 64% were men. Mean age was 51.7 years. All patients received interferon alfa-2b treatment during a 4-week induction phase (20 MU/m2 intravenously 5 days per week) followed by a 48-week maintenance phase (10 MU/m2 subcutaneously 3 days per week). Oncology nurses reviewed side-effect management with the patients before the induction and maintenance phases. Patients were provided with daily diaries, comprehensive educational materials, and ongoing nursing support. Data on side effects and discontinuations were obtained from patient interviews and diaries. The main outcome measurements were related to treatment discontinuation: rate, timing, reason, and prevention. Of the 225 patients, 75 (33.3%) discontinued interferon during the induction phase, and 58 (25.8%) discontinued during the maintenance phase. The main reasons for discontinuation were adverse events (58%) and disease progression (26%). Patients with a daily fluid intake greater than 1.5 L were more likely to complete therapy than were those with an intake less than 1.5 L (64% vs. 36%, p < 0.0001). Of 225 patients enrolled in the interferon alfa-2b health management program, 41% completed the 1-year treatment course. Higher fluid intake (>1.5 L daily) was associated with increased adherence to therapy. PMID:18317583

  8. Impact of elosulfase alfa in patients with morquio A syndrome who have limited ambulation: An open-label, phase 2 study.

    PubMed

    Harmatz, Paul R; Mengel, Eugen; Geberhiwot, Tarekegn; Muschol, Nicole; Hendriksz, Christian J; Burton, Barbara K; Jameson, Elisabeth; Berger, Kenneth I; Jester, Andrea; Treadwell, Marsha; Sisic, Zlatko; Decker, Celeste

    2017-02-01

    Efficacy and safety of elosulfase alfa enzyme replacement therapy (ERT) were assessed in an open-label, phase 2, multi-national study in Morquio A patients aged ≥5 years unable to walk ≥30 meters in the 6-min walk test. Patients received elosulfase alfa 2.0 mg/kg/week intravenously for 48 weeks. Efficacy measures were functional dexterity, pinch/grip strength, mobility in a modified timed 25-foot walk, pain, quality of life, respiratory function, and urine keratan sulfate (KS). Safety/tolerability was also assessed. Fifteen patients received elosulfase alfa, three patients discontinued ERT due to adverse events (two were grade 3 drug-related adverse events, the other was not drug-related), and two patients missed >20% of planned infusions; 10 completed treatment through 48 weeks and received ≥80% of planned infusions (Modified Per Protocol [MPP] population). The study population had more advanced disease than that enrolled in other trials. From baseline to week 48, MPP data showed biochemical efficacy (urine KS decreased 52.4%). The remaining efficacy results were highly variable due to challenges in test execution because of severe skeletal and joint abnormalities, small sample sizes, and clinical heterogeneity among patients. Eight patients showed improvements in one or more outcome measures; several patients indicated improvements not captured by the study assessments (e.g., increased energy, functional ability). The nature of adverse events was similar to other elosulfase alfa studies. This study illustrates the considerable challenges in objectively measuring impact of ERT in very disabled Morquio A patients and highlights the need to examine results on an individual basis. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

  9. Pegylated Interferon Alfa-2a Monotherapy Results in Suppression of HIV Type 1 Replication and Decreased Cell-Associated HIV DNA Integration

    PubMed Central

    Azzoni, Livio; Foulkes, Andrea S.; Papasavvas, Emmanouil; Mexas, Angela M.; Lynn, Kenneth M.; Mounzer, Karam; Tebas, Pablo; Jacobson, Jeffrey M.; Frank, Ian; Busch, Michael P.; Deeks, Steven G.; Carrington, Mary; O'Doherty, Una; Kostman, Jay; Montaner, Luis J.

    2013-01-01

    Background. Antiretroviral therapy (ART)–mediated immune reconstitution fails to restore the capacity of the immune system to spontaneously control human immunodeficiency virus (HIV) replication. Methods. A total of 23 HIV type 1 (HIV-1)–infected, virologically suppressed subjects receiving ART (CD4+ T-cell count, >450 cells/μL) were randomly assigned to have 180 μg/week (for arm A) or 90 μg/week (for arm B) of pegylated (Peg) interferon alfa-2a added to their current ART regimen. After 5 weeks, ART was interrupted, and Peg–interferon alfa-2a was continued for up to 12 weeks (the primary end point), with an option to continue to 24 weeks. End points included virologic failure (viral load, ≥400 copies/mL) and adverse events. Residual viral load and HIV-1 DNA integration were also assessed. Results. At week 12 of Peg–interferon alfa-2a monotherapy, viral suppression was observed in 9 of 20 subjects (45%), a significantly greater proportion than expected (arm A, P = .0088; arm B, P = .0010; combined arms, P < .0001). Over 24 weeks, both arms had lower proportions of subjects who had viral load, compared with the proportion of subjects in a historical control group (arm A, P = .0046; arm B, P = .0011). Subjects who had a sustained viral load of <400 copies/mL had decreased levels of integrated HIV DNA (P = .0313) but increased residual viral loads (P = .0078), compared with subjects who experienced end-point failure. Conclusions. Peg–interferon alfa-2a immunotherapy resulted in control of HIV replication and decreased HIV-1 integration, supporting a role for immunomediated approaches in HIV suppression and/or eradication. Clinical Trials Registration. NCT00594880. PMID:23105144

  10. Influence of wool and thermo-binder fibers relative fractions on the adhesion of non-woven Alfa fibers reinforced unsaturated polyester hybrid composites

    NASA Astrophysics Data System (ADS)

    Amin Omri, Med; Triki, A.; Ben Hassen, Med; Arous, M.; Bulou, A.

    2016-10-01

    Alfa/wool/thermo-binder fibers hybrid composites were investigated in order to analyze adhesion state. Bearing in mind the chemical structure of wool and thermo-binder fibers, this study revealed a good compatibility between the reinforcement and the matrix. Dielectric measurements revealed the presence of two dielectric relaxations in the composite. The first relaxation was attributed to the α mode relaxation and the second one was associated with the conductivity noted for high temperature. This study allowed the analysis of the interfacial polarization effect using the Havrilliak-Negami model in the electric modulus formalism. The lowness of this relaxation intensity revealed a good adhesion of the fibers in the matrix. Differential Scanning Calorimetry (DSC) showed a slow decrease of the Tg glass transition temperature compared to the matrix, which could be explained by the existence of interactions between the fibers and the matrix. Vibrational analysis, based on FTIR measurements, showed a less hydrophilic character of Alfa fibers owing to a basic dissociation that occurs between the wool fibers and the water molecules associated with Alfa fibers. Furthermore, adhesion mechanism in the composite material was established by covalent and hydrogen bonds. Tensile testing performed on this composite confirmed that such adhesion was improved by increasing the thermo-binder fibers relative fraction.

  11. Darbepoetin alfa (Aranesp) improves recognition memory in adult rats that have sustained bilateral ventral hippocampal lesions as neonates or young adults.

    PubMed

    Hori, S E; Powell, K J; Robertson, G S

    2007-01-05

    Recognition memory was assessed in adult rats that received bilateral injections of saline (sham lesions) or ibotenic acid (lesioned) in the ventral hippocampus as neonates (postnatal day 7, PD7) or young adult (42 days of age, PD42) using the Novel Object Recognition Test (NORT). Normal or sham-lesioned rats were able to distinguish novel from familiar objects over a 0.5 and 2 h delay between the sample and choice phases. Adult rats (PD70) lesioned as neonates performed progressively worse than sham-lesioned animals at delays of 0.5 and 2 h. A single injection of darbepoetin alfa (500 or 5000 U/kg, i.p.), given 1 h before the sample phase restored performance 0.5 or 2 h later in the choice phase to same levels as sham-lesioned rats. Adults lesioned on PD42 displayed deficits in NORT performance with a 2 h delay between the choice and sample phases that were completely reversed by administration of darbepoetin alfa (5000 U/kg, i.p.) 1 h before the sample phase. These results suggest that darbepoetin alfa may have utility in treating memory deficits associated with brain dysfunction related to developmental disorders such as schizophrenia.

  12. Darbepoetin-alfa and intravenous iron administration after autologous hematopoietic stem cell transplantation: a prospective multicenter randomized trial.

    PubMed

    Beguin, Yves; Maertens, Johan; De Prijck, Bernard; Schots, Rik; Seidel, Laurence; Bonnet, Christophe; Hafraoui, Kaoutar; Willems, Evelyne; Vanstraelen, Gaetan; Servais, Sophie; Jaspers, Aurélie; Fillet, Georges; Baron, Frederic

    2013-12-01

    We conducted a randomized study analyzing the impact of darbepoetin alfa (DA) administration with or without intravenous (i.v.) iron on erythroid recovery after autologous hematopoietic cell transplantation (HCT). Patients were randomized between no DA (Arm 1), DA 300 μg every 2 weeks starting on Day 28 after HCT (Arm 2), or DA plus i.v. iron 200 mg on Days 28, 42, and 56 (Arm 3). The proportion achieving complete hemoglobin (Hb) response within 18 weeks (primary end point) was 21% in Arm 1 (n = 24), 79% in Arm 2 (n = 25), and 100% in Arm 3 (n = 23; P < 0.0001). Erythropoietic response was shown to be significantly higher in Arm 3 (n = 46) than in Arm 2 (n = 50; P = 0.008), resulting in lower DA use, reduced drug costs, and improved quality of life scores, but the effect on transfusions was not significant. In multivariate analysis, DA administration (P < 0.0001), i.v. iron administration (P = 0.0010), high baseline Hb (P < 0.0001), and low baseline creatinine (P = 0.0458) were independently associated with faster achievement of complete Hb response. In conclusion, DA is highly effective to ensure full erythroid reconstitution after autologous HCT when started on Day 28 post-transplant. I.v. iron sucrose further improves erythroid recovery.

  13. The Budget of the Atmosphere-Soil Exchange: A Long-term Fluxes Analysis (BASE:ALFA) project.

    NASA Astrophysics Data System (ADS)

    Caporaso, L.; di Giuseppe, F.; Bonafè, G.

    2010-09-01

    A long term measurements of parameters characterizing the energy and water cycle in the Po Valley (Italy) has been carried out between summers 2009 and 2010 to create a data pool of micro-meteorological/soil data to test and validate Surface Vegetation Atmosphere Transfer Scheme (SVATS) and Regional Numerical weather prediction R-NWP with respect to the representation of near-surface processes. The BASE:ALFA project organized in the middle of the Po valley was thought as a prototype experience which tried to fulfill the need highlighted in recent SRNWP program for a network of surface stations which should soon appear in Europe as a spontaneous cooperation of national weather services. We report on our experimental campaigns and on some modeling outcomes. In particular, we will present one targeted application of the collected dataset, which we found of special interest for the area. That is how the wrong PBL mixing height modeling can impact air quality assessment. Most air quality models for pollutant concentrations estimations, in fact, uses R-NWP predicted and or analyzed PBL mixing height to estimate air quality indices, as for example PM10 concentrations.

  14. Impact of epoetin alfa on left ventricular structure, function, and pressure volume relations as assessed by cardiac magnetic resonance: the heart failure preserved ejection fraction (HFPEF) anemia trial.

    PubMed

    Green, Philip; Babu, Benson A; Teruya, Sergio; Helmke, Stephen; Prince, Martin; Maurer, Mathew S

    2013-01-01

    Anemia, a common comorbidity in older adults with heart failure and a preserved ejection fraction (HFPEF), is associated with worse outcomes. The authors quantified the effect of anemia treatment on left ventricular (LV) structure and function as measured by cardiac magnetic resonance (CMR) imaging. A prospective, randomized single-blind clinical trial (NCT NCT00286182) comparing the safety and efficacy of epoetin alfa vs placebo for 24 weeks in which a subgroup (n=22) had cardiac magnetic resonance imaging (MRI) at baseline and after 3 and 6 months to evaluate changes in cardiac structure and function. Pressure volume (PV) indices were derived from MRI measures of ventricular volume coupled with sphygmomanometer-measured pressure and Doppler estimates of filling pressure. The end-systolic and end-diastolic PV relations and the area between them as a function of end-diastolic pressure, the isovolumic PV area (PVAiso), were calculated. Patients (75±10 years, 64% women) with HFPEF (EF=63%±15%) with an average hemoglobin of 10.3±1.1 gm/dL were treated with epoetin alfa using a dose-adjusted algorithm that increased hemoglobin compared with placebo (P<.0001). As compared with baseline, there were no significant changes in end-diastolic (-7±8 mL vs -3±8 mL, P=.81) or end-systolic (-0.4±2 mL vs -0.7±5 mL, P=.96) volumes at 6-month follow-up between epoetin alfa compared with placebo. LV function as measured based on EF (-1.5%±1.6% vs -2.6%±3.3%, P=.91) and pressure volume indices (PVAiso-EDP at 30 mm Hg, -5071±4308 vs -1662±4140, P=.58) did not differ between epoetin alfa and placebo. Administration of epoetin alfa to older adult patients with HFPEF resulted in a significant increase in hemoglobin, without evident change in LV structure, function, or pressure volume relationships as measured quantitatively using CMR imaging.

  15. Prospective randomized multicenter adjuvant dermatologic cooperative oncology group trial of low-dose interferon alfa-2b with or without a modified high-dose interferon alfa-2b induction phase in patients with lymph node-negative melanoma.

    PubMed

    Hauschild, Axel; Weichenthal, Michael; Rass, Knuth; Linse, Ruthild; Ulrich, Jens; Stadler, Rudolf; Volkenandt, Matthias; Grabbe, Stephan; Proske, Ulrike; Schadendorf, Dirk; Brockmeyer, Norbert; Vogt, Thomas; Rompel, Rainer; Kaufmann, Roland; Kaatz, Martin; Näher, Helmut; Mohr, Peter; Eigentler, Thomas; Livingstone, Elisabeth; Garbe, Claus

    2009-07-20

    PURPOSE Interferon alfa (IFN-alpha) has shown clinical efficacy in the adjuvant treatment of patients with high-risk melanoma in several clinical trials, but optimal dosing and duration of treatment are still under discussion. It has been argued that in high-dose IFN-alpha (HDI), the intravenous (IV) induction phase might be critical for the clinical benefit of the regimen. PATIENTS AND METHODS In an attempt to investigate the potential role of a modified high-dose induction phase, lymph node-negative patients with resected primary malignant melanoma of more than 1.5-mm tumor thickness were included in this prospective randomized multicenter Dermatologic Cooperative Oncology Group trial. Six hundred seventy-four patients were randomly assigned to receive 4 weeks of a modified HDI scheme. This schedule consisted of 5 times weekly 10 MU/m(2) IFN-alpha-2b IV for 2 weeks and 5 times weekly 10 MU/m(2) IFN-alpha-2b administered subcutaneously (SC) for another 2 weeks followed by 23 months of low-dose IFN-alpha-2b (LDI) 3 MU SC three times a week (arm A). LDI 3 MU three times a week was given for 24 months in arm B. Results Of 650 assessable patients, there were 92 relapses among the 321 patients receiving high-dose induction as compared with 95 relapses among the 329 patients receiving LDI only. Five-year relapse-free survival rates were 68.0% (arm A) and 67.1% (arm B), respectively. Likewise, melanoma-related fatalities were similar between both groups, resulting in 5-year overall survival rates of 80.2% (arm A) and 82.9% (arm B). CONCLUSION The addition of a 4-week modified HDI induction phase to a 2-year low-dose adjuvant IFN-alpha-2b treatment schedule did not improve the clinical outcome.

  16. Clinical Experience of Interferon Alfa-2a Treatment for Refractory Uveitis in Behçet's Disease.

    PubMed

    Park, Ji-Youn; Chung, Yoo-Ri; Lee, Kihwang; Song, Ji Hun; Lee, Eun-So

    2015-07-01

    Behçet's disease (BD) involves multisystem vasculitis of unknown origin. Ocular manifestations of BD mostly include bilateral panuveitis and retinal vasculitis, which are very challenging to treat. Interferon alfa-2a (IFN) has been recently introduced for treating refractory Behçet uveitis, mainly in Germany and Turkey. Nonetheless, there is so far no consensus about the ideal treatment regimen of IFN for Behçet uveitis. We report our experience of IFN treatment in five Korean BD patients with refractory uveitis. All patients complained of oral ulcers; one patient had a positive pathergy test and 2 showed the presence of HLA-B51. Immunosuppressive agents used prior to IFN treatment included cyclosporine and methotrexate. The IFN treatment was commenced with a dose of 6-9 MIU/day for 7 days, adjusted according to individual ocular manifestations, tapered down to 3 MIU three times in a week, and then discontinued. All patients showed positive response to IFN treatment; 50% of them showed complete response without additional major ocular inflammation during the follow-up period. Other BD symptoms also improved after IFN treatment in most cases. After treatment, the relapse rate and the required dose of oral corticosteroid were decreased in most cases, showing a significant steroid-sparing effect. However, the visual acuity was not improved in most cases due to irreversible macular sequelae. Despite the small sample size of this study, we suggest that, in Korean patients, IFN is an effective treatment modality for BD uveitis as was observed in German and Turkish patients.

  17. Therapeutic and routine prophylactic properties of rFactor VIII Fc (efraloctocog alfa, Eloctate®) in hemophilia A

    PubMed Central

    Chowdary, Pratima; Fosbury, Emma; Riddell, Anne; Mathias, Mary

    2016-01-01

    rFVIIIFc (efraloctocog alfa, Eloctate®) is an extended half-life (EHL) factor VIII licensed for use in patients with hemophilia A for prophylaxis and treatment of bleeding and surgical episodes. Pharmacokinetic studies in adults have shown a mean 1.5-fold increase in half-life compared to full-length factor VIII. When compared to adults, the half-life is decreased by 8% in adolescents between 12 and 17 years, by 18% in children 6 to <12 years, and by 33% in children between the ages of 2 and <6 years. There is a considerable interindividual variation in the prolongation of the half-life particularly in children and across the age groups, the range extending from no increase to a 2.5-fold increase. In addition to age, von willebrand factor (VWF) antigen level has demonstrated a significant impact on rFVIIIFc half-life, with higher VWF levels associated with greater prolongation of half-life. The pivotal and pediatric clinical trials have demonstrated the efficacy and safety of rFVIIIFc for use in regular prophylaxis and in management of bleeds and surgery. In these studies, just under half the participants showed a zero annualized bleed rate (ABR), and the median ABR (1.6 in the pivotal study for the individualized prophylaxis arm) showed a further decrease in the extension study. On average, the patients required fewer infusions (reduced by at least a third), and the mean weekly consumption seems to be in keeping with standard recombinant factor VIII. EHL rFVIIIFc has made decreased infusion frequency a possibility. However, the interindividual variability in dose and infusion frequency highlights the need for a personalized approach based on individual patient’s half-life and/or response to treatment. PMID:27695377

  18. TSAT is a better predictor than ferritin of hemoglobin response to Epoetin alfa in US dialysis patients.

    PubMed

    Gaweda, Adam E; Bhat, Premila; Maglinte, Gregory A; Chang, Chun-Lan; Hill, Jerrold; Park, Grace S; Ashfaq, Akhtar; Gitlin, Matthew

    2014-01-01

    Clinical guidelines recommend concurrent treatment of anemia in end-stage renal disease with erythropoiesis-stimulating agents (ESAs) and iron. However, there are mixed data about optimal iron supplementation. To help address this gap, the relationship between iron markers and hemoglobin (Hb) response to ESA (Epoetin alfa) dose was examined. Electronic medical records of 1902 US chronic hemodialysis patients were analyzed over a 12-month period between June 2009 and June 2010. The analysis included patients who had at least one Hb value during each 4-week interval for four consecutive intervals (k - 2, k - 1, k, and k + 1; k is the index interval), received at least one ESA dose during intervals k - 1 or k, had at least one transferrin saturation (TSAT) value at interval k, and at least one ferritin value during intervals k - 2, k - 1, or k. Effect modification by TSAT and ferritin on Hb response was evaluated using the generalized estimating equations approach. Patients had a mean (standard deviation) age of 62 (15) years; 41% were Caucasian, 34% African American, 65% had hypertension, and 39% diabetes. Transferrin saturation, but not ferritin, had a statistically significant (P < 0.05) modifying effect on Hb response. Maximum Hb response was achieved when TSAT was 34%, with minimal incremental effect beyond these levels. Of the two standard clinical iron markers, TSAT should be used as the primary marker of the modifying effect of iron on Hb response to ESA. Long-term safety of iron use to improve Hb response to ESA warrants further study.

  19. Management of anaemia in oncohaematological patients treated with biosimilar epoetin alfa: results of an Italian observational, retrospective study

    PubMed Central

    Rosti, Giovanni; Petrini, Mario; Bosi, Alberto; Galieni, Piero; Bernardi, Daniele; Giglio, Gianfranco; Dorotea, Laura; Falini, Brunangelo; Scelzi, Elvira; Veltri, Enzo; Castelli, Roberto; Longagnani, Chiara; Raggi, Tommaso; Simonetti, Federico

    2016-01-01

    Background: Many patients with solid tumours or nonmyeloid haematopoietic tumours develop symptomatic anaemia, which has a major impact on quality of life (QoL). The efficacy of erythropoiesis-stimulating agents (ESAs) in improving QoL and reducing blood transfusions has been widely demonstrated. Binocrit® (biosimilar epoetin alfa) is an ESA indicated in the European Union for treating chemotherapy-induced anaemia. The aim of this study was to investigate the effect of Binocrit® on haemoglobin (Hb) levels in anaemic cancer patients in Italian clinical practice. Methods: The ANEMONE study was a national, longitudinal, retrospective, multicentre observational study. Patients had to be 18 years or older, with a solid tumour or non-Hodgkin’s lymphoma, Hodgkin’s disease or multiple myeloma, receiving chemotherapy, and treated with Binocrit® to manage chemotherapy-induced anaemia. The primary outcomes were the proportion of patients with a Hb increase ⩾1 g/dl during the first 4 weeks and with a Hb increase ⩾2 g/dl during the first 12 weeks. Results: A total of 245 patients were enrolled and 215 patients were evaluable for statistical analysis. In the first 4 weeks, 49.3% of patients showed an increase in Hb of ⩾1 g/dl: 45.5% in patients with solid tumours and 52.1% in patients with haematological malignancies. In the first 12 weeks, 51.6% of patients showed an increase in Hb of ⩾2 g/dl (48.4% solid tumours, 54.2% haematological diseases). Treatment with Binocrit® was well tolerated. Conclusions: These results confirm the effectiveness and safety of Binocrit® for chemotherapy-induced anaemia in routine practice in patients with solid tumours, lymphoma and myeloma. PMID:28203295

  20. A cost-effectiveness evaluation comparing originator follitropin alfa to the biosimilar for the treatment of infertility

    PubMed Central

    Gizzo, Salvatore; Garcia-Velasco, Juan A; Heiman, Franca; Ripellino, Claudio; Bühler, Klaus

    2016-01-01

    Objectives To perform a cost-effectiveness evaluation comparing the originator follitropin alfa (Gonal-f®) to the biosimilar (Bemfola®) in the Italian and Spanish contexts, with an assessment of the German and UK backgrounds. Methods Starting from the study by Rettenbacher et al, a cost-effectiveness model was developed in the Italian and Spanish contexts. Clinical data on subjects, doses of gonadotropin, pregnancies, live-born children, and ovarian hyperstimulation syndrome were used to feed the model. Costs related to drugs, hospitalizations, specialist visits, and examinations were retrieved from Italian and Spanish tariffs. Gonadotropin acquisition costs for Germany and the UK were also taken into account to expand the economical assessment to the other countries. The evaluation was done based on the National Health Service perspective. Sensitivity analyses, both univariate and probabilistic, as long as scenario analyses, tested the robustness of the model. Results Originator follicle-stimulating hormone (FSH) costs were €3,663 and €6,387 in Italy and Spain, respectively, whereas biosimilar FSH costs were €3,483 and €6,342. The efficacy was found to be 0.52 for the originator and 0.47 for the biosimilar. The average cost per live birth was estimated to be €7,044 and €12,283 for the originator FSH and €7,411 and €13,494 for the biosimilar for Italy and Spain, respectively. Furthermore, the originator FSH generated an incremental cost-effectiveness ratio of €3,600 for Italy and €900 for Spain compared to the biosimilar. Sensitivity analyses confirmed the results of the base case model. Conclusion This analysis indicated that the originator FSH is a cost-efficient treatment strategy for Italian and Spanish health services compared to the biosimilar and it would be worthwhile extending this evaluation to other countries. PMID:27994486

  1. Arecibo Pulsar Survey Using ALFA. IV. Mock Spectrometer Data Analysis, Survey Sensitivity, and the Discovery of 40 Pulsars

    NASA Astrophysics Data System (ADS)

    Lazarus, P.; Brazier, A.; Hessels, J. W. T.; Karako-Argaman, C.; Kaspi, V. M.; Lynch, R.; Madsen, E.; Patel, C.; Ransom, S. M.; Scholz, P.; Swiggum, J.; Zhu, W. W.; Allen, B.; Bogdanov, S.; Camilo, F.; Cardoso, F.; Chatterjee, S.; Cordes, J. M.; Crawford, F.; Deneva, J. S.; Ferdman, R.; Freire, P. C. C.; Jenet, F. A.; Knispel, B.; Lee, K. J.; van Leeuwen, J.; Lorimer, D. R.; Lyne, A. G.; McLaughlin, M. A.; Siemens, X.; Spitler, L. G.; Stairs, I. H.; Stovall, K.; Venkataraman, A.

    2015-10-01

    The on-going Arecibo Pulsar-ALFA (PALFA) survey began in 2004 and is searching for radio pulsars in the Galactic plane at 1.4 GHz. Here we present a comprehensive description of one of its main data reduction pipelines that is based on the PRESTO software and includes new interference-excision algorithms and candidate selection heuristics. This pipeline has been used to discover 40 pulsars, bringing the survey’s discovery total to 144 pulsars. Of the new discoveries, eight are millisecond pulsars (MSPs; P\\lt 10 ms) and one is a Fast Radio Burst (FRB). This pipeline has also re-detected 188 previously known pulsars, 60 of them previously discovered by the other PALFA pipelines. We present a novel method for determining the survey sensitivity that accurately takes into account the effects of interference and red noise: we inject synthetic pulsar signals with various parameters into real survey observations and then attempt to recover them with our pipeline. We find that the PALFA survey achieves the sensitivity to MSPs predicted by theoretical models but suffers a degradation for P≳ 100 ms that gradually becomes up to ˜10 times worse for P\\gt 4 {{s}} at {DM}\\lt 150 pc cm-3. We estimate 33 ± 3% of the slower pulsars are missed, largely due to red noise. A population synthesis analysis using the sensitivity limits we measured suggests the PALFA survey should have found 224 ± 16 un-recycled pulsars in the data set analyzed, in agreement with the 241 actually detected. The reduced sensitivity could have implications on estimates of the number of long-period pulsars in the Galaxy.

  2. A comparison of menotropin, highly-purified menotropin and follitropin alfa in cycles of intracytoplasmic sperm injection

    PubMed Central

    Esteves, Sandro C; Schertz, Joan C; Verza, Sidney; Schneider, Danielle T; Zabaglia, Silval FC

    2009-01-01

    Background Over the last several decades, as a result of an evolution in manufacturing processes, a marked development has been made in the field of gonadotropins for ovarian stimulation. Initially, therapeutic gonadotropins were produced from a simple process of urine extraction and purification; now they are produced via a complex system involving recombinant technology, which yields gonadotropins with high levels of purity, quality, and consistency. Methods A retrospective analysis of 865 consecutive intracytoplasmic sperm injection (ICSI) cycles of controlled ovarian hyperstimulation (COH) compared the clinical efficacy of three gonadotropins (menotropin [hMG; n = 299], highly-purified hMG [HP-hMG; n = 330] and follitropin alfa [r-hFSH; n = 236]) for ovarian stimulation after pituitary down-regulation. The endpoints were live birth rates and total doses of gonadotropin per cycle and per pregnancy. Results Laboratory and clinical protocols remained unchanged over time, except for the type of gonadotropin used, which was introduced sequentially (hMG, then HP-hMG, and finally r-hFSH). Live birth rates were not significantly different for hMG (24.4%), HP-hMG (32.4%) and r-hFSH (30.1%; p = 0.09) groups. Total dose of gonadotropin per cycle was significantly higher in the hMG (2685 +/- 720 IU) and HP-hMG (2903 +/- 867 IU) groups compared with the r-hFSH-group (2268 +/- 747 IU; p < 0.001). Total dose of gonadotropin required to achieve clinical pregnancy was 15.7% and 11.0% higher for the hMG and HP-hMG groups, respectively, compared with the r-hFSH group, and for live births, the differences observed were 45.3% and 19.8%, respectively. Conclusion Although similar live birth rates were achieved, markedly lower doses of r-hFSH were required compared with hMG or HP-hMG. PMID:19828024

  3. Enzyme replacement therapy with alglucosidase alfa in 44 patients with late-onset glycogen storage disease type 2: 12-month results of an observational clinical trial.

    PubMed

    Strothotte, S; Strigl-Pill, N; Grunert, B; Kornblum, C; Eger, K; Wessig, C; Deschauer, M; Breunig, F; Glocker, F X; Vielhaber, S; Brejova, A; Hilz, M; Reiners, K; Müller-Felber, W; Mengel, E; Spranger, M; Schoser, Benedikt

    2010-01-01

    Late-onset glycogen storage disease type 2 (GSD2)/Pompe disease is a progressive multi-system disease evoked by a deficiency of lysosomal acid alpha-glucosidase (GAA) activity. GSD2 is characterized by respiratory and skeletal muscle weakness and atrophy, resulting in functional disability and reduced life span. Since 2006 alglucosidase alfa has been licensed as a treatment in all types of GSD2/Pompe disease. We here present an open-label, investigator-initiated observational study of alglucosidase alfa enzyme replacement therapy (ERT) in 44 late-onset GSD2 patients with various stages of disease severity. Alglucosidase alfa was given i.v. at the standard dose of 20 mg/kg every other week. Assessments included serial arm function tests (AFT), Walton Gardner Medwin scale (WGMS), timed 10-m walk tests, four-stair climb tests, modified Gowers' maneuvers, 6-min walk tests, MRC sum score, forced vital capacities (FVC), creatine kinase (CK) levels and SF-36 self-reporting questionnaires. All tests were performed at baseline and every 3 months for 12 months of ERT. We found significant changes from baseline in the modified Gowers' test, the CK levels and the 6-min walk test (341 +/- 149.49 m, median 342.25 m at baseline; 393 +/- 156.98 m; median 411.50 m at endpoint; p = 0.026), while all other tests were unchanged. ERT over 12 months revealed minor allergic reactions in 10% of the patients. No serious adverse events occurred. None of the patients died or required de novo ventilation. Our clinical outcome data imply stabilization of neuromuscular deficits over 1 year with mild functional improvement.

  4. Seven‐year safety and efficacy with velaglucerase alfa for treatment‐naïve adult patients with type 1 Gaucher disease

    PubMed Central

    Wang, Nan; Ogg, Carol; Crombez, Eric; Cohn, Gabriel M.; Elstein, Deborah

    2015-01-01

    Velaglucerase alfa is a human β‐glucocerebrosidase approved for Gaucher disease type 1 (GD1) treatment. This report summarizes the 7‐year experience of the now‐completed phase I/II and extension studies of adult GD1 patients who received velaglucerase alfa. Ten patients who completed the 9‐month, phase I/II study entered the extension trial TKT025EXT, of which eight completed this study. Doses were reduced after a cumulative treatment period of 15 to 18 months. Although all patients experienced ≥1 adverse event, no patient withdrew due to a drug‐related adverse event or required premedication. No patient developed anti‐drug antibodies, compliance remained high (median 98%), and seven of eight eligible patients transitioned to home infusions under supervision by healthcare professionals. Statistically significant improvements were observed for efficacy parameters: mean percentage changes from baseline (95% confidence intervals) were 18% (12%, 24%) for hemoglobin concentration, 115% (66%, 164%) for platelet counts, and −42% (−53%, −31%) and −78% (−94%, −62%) for liver and spleen volumes, respectively. Improvements were also observed for secondary endpoints chitotriosidase and CCL18 levels and exploratory endpoints (bone mineral density [BMD], bone marrow burden [BMB] scores). Normalization to near‐normalization of individuals' hemoglobin concentrations, platelet counts, liver volumes, and BMB scores was observed, and there were marked improvements in spleen volumes, biomarkers, and BMD. TKT025EXT represents the longest, prospective clinical trial for GD1 treatment to date and suggests that, despite dose reduction within 18 months of initiating therapy, velaglucerase alfa was generally well tolerated and was associated with marked improvement, including near normalization and/or normalization of key GD1 disease parameters. Am. J. Hematol. 90:577–583, 2015. © 2015 The Authors. American Journal of Hematology published by Wiley Periodicals

  5. Impact of Switching From Darbepoetin Alfa to Epoetin Beta Pegol on Iron Utilization and Blood Pressure in Peritoneal Dialysis Patients.

    PubMed

    Washida, Naoki; Inoue, Shuji; Kasai, Takahiro; Shinozuka, Keisuke; Hosoya, Koji; Morimoto, Kohkichi; Wakino, Shu; Hayashi, Koichi; Itoh, Hiroshi

    2015-10-01

    New erythropoiesis-stimulating agents with a longer half-life have been developed for the treatment of anemia in patients with end-stage renal disease. This study evaluated the efficacy of darbepoetin alfa (DA) and long-acting epoetin beta pegol (continuous erythropoietin receptor activator, CERA) in patients on peritoneal dialysis (PD). Twenty-nine patients who had undergone PD for at least 6 months and were iron replacement-naïve and negative for inflammatory parameters were enrolled. Hemoglobin (Hgb) levels and blood pressure were evaluated before and after switching from DA to CERA. Percent transferrin saturation (TSAT), serum ferritin levels and blood pressure were also assessed. Twenty-eight patients were subject to the analysis, excluding one patient with a decrease in Hgb by ≥10%. Switching from DA to CERA did not alter Hgb levels. The doses of DA and CERA after 12 month treatment of each agent were 118.48 ± 79.63 and 89.88 ± 47.50 μg/4 weeks, respectively (conversion ratio, 1:0.76). The CERA dose administered during the final 6 months was abated, compared with that given during the initial 6 months (P = 0.035). The frequency of CERA injection over a 12-month period was less than that of DA (10.0 ± 3.0 vs. 16.4 ± 5.0, P < 0.01). The conversion from DA to CERA did not alter TSAT, but decreased serum ferritin levels (from 202.69 ± 132.57 to 150.15 ± 110.07 ng/mL, P = 0.012) and systolic blood pressure (from 133.8 ± 17.3 to 129.5 ± 11.3 mm Hg, P = 0.024). In PD patients, lower doses and less frequent injection of CERA are sufficient to maintain Hgb at levels similar to those achieved by DA therapy, with improved iron utilization and reduced blood pressure.

  6. Sustained Virologic Response to a Dual Peginterferon alfa-2a and Ribavirin in Treating Chronic hepatitis C Infection

    PubMed Central

    Naing, Cho; Sitt, Than; Aung, Aye TD; Aung, Kyan

    2015-01-01

    Abstract In Myanmar, hepatitis C virus (HCV) infection prevalence is 2%. A combination therapy of pegylated interferon alfa-2a and ribavirin (PEG-IFNa/RBV) is a standard treatment, but the effect of this antiviral therapy needs evaluation as to determine the efficacy and safety of dual PEG-IFNa/RBV therapy in treating patients infected with HCV in Myanmar. This was a retrospective analysis of data from a single clinic exclusively for gastrointestinal diseases in Yangon, Myanmar. We assessed treatment responses at the defined time points and stratified by genotypes of HCV. We also determined incidences of adverse events (AEs). We investigated independent predictors of sustained virologic response (SVR) in the participants. A total of 362 HCV-infected cases were included in this study. The majority were females (51.7%) with mean age of 47.12 years (±11.6) and noncirrhosis patients (82%). Rapid virologic response (RVR), early virologic response (EVR), end of treatment response (ETR), and SVR 24 weeks after completion of the dual treatment were 50.3% (178/362), 88% (314/357), 80.1% (286/357), and 85.6% (167/195), respectively. The most frequently reported AEs were nausea/anorexia (72.8%) and flu-like symptoms (62.4%). In multivariate analysis, 4 factors were independently associated with SVR; SVR to genotype 3 (odds ratio [OR] 2.4, 95% CI: 1.24–4.62), EVR (OR 0.54, 95% CI: 0.3–0.95), and duration of treatment (OR 1.52, 95% CI: 1.18–1.98). Study limitations were acknowledged. The efficacy and safety of the dual therapy in treating HCV-infected patient in Myanmar was acceptable. We recommend a prospective randomized control trial looking at duration of therapy and rates of achieving SVR, which could significantly impact the care of HCV-infected patients in Myanmar and perhaps other countries as well. PMID:26222859

  7. Benefit of adjuvant interferon alfa-2b (IFN-α) therapy in melanoma patients with high serum MMP-8 levels.

    PubMed

    Vihinen, Pia; Tervahartiala, Taina; Sorsa, Timo; Hansson, Johan; Bastholt, Lars; Aamdal, Steinar; Stierner, Ulrika; Pyrhönen, Seppo; Syrjänen, Kari; Lundin, Johan; Hernberg, Micaela

    2015-02-01

    Matrix metalloproteinases (MMPs) are important enzymes in tissue turnover and various inflammatory processes. In this study, it was evaluated whether serum MMP-8 can predict the response to adjuvant interferon alfa-2b (IFN-α) therapy in patients with operated high-risk cutaneous melanoma. Pre-treatment sera from 460 patients with stage IIB-IIIC melanoma were analyzed for MMP-8. The patients were randomized after surgery to adjuvant IFN-α for 12 or 24 months (n = 313) or observation only (n = 147). The median serum MMP-8 level was used to classify the patients into a low MMP-8 (n = 232) and a high MMP-8 (n = 228) group. In the high MMP-8 subgroup, IFN-α therapy significantly improved relapse-free survival (RFS). RFS was 36.8 months in patients with high MMP-8 levels receiving IFN-α therapy, whereas RFS for those with high MMP-8 levels with observation only was 10.6 months (P = 0.027). Median overall survival for patients with high MMP-8 and observation only was 36.7 versus 71.7 months in those receiving IFN-α (P = 0.13). In a multivariate model, IFN-α therapy was a significant predictor of favorable RFS (HR 0.74; 95 % CI 0.55-0.99; P = 0.048), after adjustment for pre-treatment MMP-8 (HR 1.17; 95 % CI 0.88-1.55; P = 0.28), gender (HR 1.16; 95 % CI 0.86-1.56; P = 0.32), age (HR 1.00; 95 % CI 1.00-1.02; P = 0.12), ulceration (HR 1.09; 95 % CI 0.81-1.46; P = 0.58), and the presence of node metastases (HR 1.36; 95 % CI 1.17-1.58; P < 0.0001). In conclusion, patients with high serum MMP-8 levels may benefit from adjuvant IFN-α therapy, but this observation should be further investigated.

  8. HBcrAg Identifies Patients Failing to Achieve HBeAg Seroconversion Treated with Pegylated Interferon Alfa-2b

    PubMed Central

    Ma, Hui; Yang, Rui-Feng; Li, Xiao-He; Jin, Qian; Wei, Lai

    2016-01-01

    Background: We aimed to evaluate the usefulness of serum hepatitis B virus core-related antigens (HBcrAg) for predicting hepatitis B e antigen (HBeAg) seroconversion in HBeAg-positive chronic hepatitis B patients treated with conventional interferon (IFN) alfa-2b or pegylated IFN. Methods: Fifty-eight patients were enrolled: 29 for the training group and 29 for the validating group. HBcrAg was measured at baseline, week 12, end of the treatment, and 12- and 24-week follow-ups. Sixteen patients in the training group were enrolled in the long-term follow-up (LTFU), during which time the dynamics of the HBcrAg was monitored. Results: The serum HBcrAg level gradually declined during treatment among the HBeAg seroconversion patients of the training group (from baseline, week 12, end of the treatment, 12-week follow-up to 24-week follow-up were 110,245 kU/ml, 3760 kU/ml, 7410 kU/ml, 715 kU/ml, 200 kU/ml, respectively). HBcrAg <19,565 kU/ml at week 24, HBcrAg <34,225 kU/ml at 12-week follow-up, and HBcrAg decrease ≥0.565 log10 kU/ml from the baseline to the end of treatment (EOT) had negative predictive values (NPVs) of 100% for HBeAg seroconversion at the end of follow-up, whereas the positive predictive values (PPVs) were 30.77%, 26.67%, and 25.00%, respectively. The patients with HBeAg seroconversion at the end of 24-week follow-up remained in seroconversion during the LTFU, during which time their serum HBcrAg levels steadily declined or even became undetectable, ranging from 0 to 2.1 kU/ml. Conclusions: Effective antiviral treatment can decrease HBcrAg levels in the serum. The NPVs of HBcrAg for predicting HBeAg seroconversion at 24-week follow-up was 100%, but the PPVs were not satisfactory (all <31%). The serum HBcrAg levels of the patients with HBeAg seroconversion at the end of the 24-week follow-up steadily declined or even became undetectable during the LTFU. PMID:27625094

  9. Pegylated interferon alfa-2b (peg-intron) plus ribavirin (rebetol) in the treatment of chronic hepatitis C: a local experience.

    PubMed

    Seow, E L; Robert Ding, P H

    2005-12-01

    This was an open-label, uncontrolled study with the aim of assessing the efficacy and safety of pegylated interferon alfa-2b plus ribavirin in the treatment of chronic hepatitis C. The study was conducted in Island Hospital, Penang beween January 2002 and December 2003. Thirty-three patients were enrolled in this study with ten defaulters. The overall sustained virological response (SVR) (Intention-To-Treat analysis) in naïve patients was 39.10%. However, when the study was adjusted to only include those who completed treatment and follow-up, overall SVR as 52.9%. Side-effects were tolerable in most patients with anaemia occurring in 22 patients (66.7%), leukopenia 23 patients (69.7%) and thrombocytopenia in 15 patients (45.5%). This study showed that pegylated interferon alfa-2b 1.5 mcg/kg/week plus ribavirin > 10.6 mg/kg/day is efficacious and safe to be used in the treatment of: chronic hepatitis C.

  10. Epoetin alfa 40000 U once weekly and intravenous iron supply in solid tumor patients: early increase of hemoglobin level during chemotherapy.

    PubMed

    Lalle, M; Pistillucci, G; Antimi, M; D'Aprile, M

    2005-06-01

    The objective of this observational study was the early evaluation of the impact, a week after the first administration of epoetin alfa 40000 U once weekly and i.v. dose of 62.5 mg sodium ferric gluconate for seven days in improving hemoglobin levels in cancer patients affected by mild/moderate or severe anemia during chemotherapy. Twenty patients affected by solid tumors who received epoetin alfa 40000 U once weekly and daily i.v. sodium ferric gluconate for one week were evaluated: 90% of the patients showed hemoglobin increase, with a median level of hemoglobin increase of 0.73 g/L from baseline, and 50% of them showing a hemoglobin increase > 1 gr/L. The treatment was well tolerated and no adverse event was observed. The early increase of hemoglobin level from baseline is interesting and suggestive for the possibility of achieving an adequate hemoglobin level with a short-term treatment. It is still necessary to further explore the real need of iron supplementation to maintain adequate erythropoiesis prior and during epoetin therapy.

  11. Darbepoetin Alfa Injection

    MedlinePlus

    ... with the grey cover and that the yellow plastic sleeve has not been pulled over the needle. ... to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in ...

  12. 21 CFR 558.265 - Halofuginone hydrobromide.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...) Indications for use. For the prevention of coccidiosis caused by Eimeria tenella, E. necatrix, E. acervulina... bambermycins 1 to 2 grams. (A) Indications for use. For the prevention of coccidiosis caused by Eimeria tenella... Eimeria tenella, E. necatrix, E. acervulina, E. brunetti, E. mivati, and E. maxima; for increased rate...

  13. 21 CFR 558.265 - Halofuginone hydrobromide.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...) Indications for use. For the prevention of coccidiosis caused by Eimeria tenella, E. necatrix, E. acervulina... bambermycins 1 to 2 grams. (A) Indications for use. For the prevention of coccidiosis caused by Eimeria tenella... Eimeria tenella, E. necatrix, E. acervulina, E. brunetti, E. mivati, and E. maxima; for increased rate...

  14. 21 CFR 558.265 - Halofuginone hydrobromide.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...) Indications for use. For the prevention of coccidiosis caused by Eimeria tenella, E. necatrix, E. acervulina... bambermycins 1 to 2 grams. (A) Indications for use. For the prevention of coccidiosis caused by Eimeria tenella... Eimeria tenella, E. necatrix, E. acervulina, E. brunetti, E. mivati, and E. maxima; for increased rate...

  15. 21 CFR 558.265 - Halofuginone hydrobromide.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...) Indications for use. For the prevention of coccidiosis caused by Eimeria tenella, E. necatrix, E. acervulina... bambermycins 1 to 2 grams. (A) Indications for use. For the prevention of coccidiosis caused by Eimeria tenella... Eimeria tenella, E. necatrix, E. acervulina, E. brunetti, E. mivati, and E. maxima; for increased rate...

  16. A Phase 3, multicenter, open-label, switchover trial to assess the safety and efficacy of taliglucerase alfa, a plant cell-expressed recombinant human glucocerebrosidase, in adult and pediatric patients with Gaucher disease previously treated with imiglucerase.

    PubMed

    Pastores, Gregory M; Petakov, Milan; Giraldo, Pilar; Rosenbaum, Hanna; Szer, Jeffrey; Deegan, Patrick B; Amato, Dominick J; Mengel, Eugen; Tan, Ee Shien; Chertkoff, Raul; Brill-Almon, Einat; Zimran, Ari

    2014-12-01

    Taliglucerase alfa is a β-glucosidase enzyme replacement therapy (ERT) approved in the US and other countries for the treatment of Gaucher disease (GD) in adults and is approved in pediatric and adult patients in Australia and Canada. It is the first approved plant cell-expressed recombinant human protein. A Phase 3, multicenter, open-label, 9-month study assessed safety and efficacy of switching to taliglucerase alfa in adult and pediatric patients with GD treated with imiglucerase for at least the previous 2years. Patients with stable disease were offered taliglucerase alfa treatment using the same dose (9-60U/kg body weight) and regimen of administration (every 2weeks) as imiglucerase. This report summarizes results from 26 adult and 5 pediatric patients who participated in the trial. Disease parameters (spleen and liver volumes, hemoglobin concentration, platelet count, and biomarker levels) remained stable through 9months of treatment in adults and children following the switch from imiglucerase. All treatment-related adverse events were mild or moderate in severity and transient in nature. Exploratory parameters of linear growth and development showed positive outcomes in pediatric patients. These findings provide evidence of the efficacy and safety profile of taliglucerase alfa as an ERT for GD in patients previously treated with imiglucerase. This trial was registered at www.clinicaltrials.gov as # NCT00712348.

  17. Reduction of circulating regulatory T cells by intravenous high-dose interferon alfa-2b treatment in melanoma patients.

    PubMed

    Mozzillo, Nicola; Ascierto, Paolo

    2012-10-01

    High-dose interferon alfa-2b (IFNα-2b) is the only approved adjuvant systemic therapy for resected, high risk melanoma in the United States (Fecher and Flaherty, in Natl Compr Cancer Netw 7:295-304, 2009). Recently, two important meta-analyses of randomized trials (Wheatley et al., in J Clin Oncol, 2007; Mocellin et al. in J Natl Cancer Inst, 2010) investigating IFNα-2b versus observation in high risk melanoma patients, showed that adjuvant IFNα-2b has an impact both on relapse-free survival (RFS) and overall survival (OS) independently by dosage, duration and route compared with observation in high risk melanoma patients. Despite of an absolute benefits of 3 % (Wheatley et al., in J Clin Oncol, 2007), this treatment is associated with significant toxicity, which impacts on patient quality of life. A better understanding of the mechanism of action may help to potentiate the clinical efficacy and reduce the toxicity of IFNα-2b/Peg-IFNα-2b. Numerous studies suggest that interferon's mechanism of action in melanoma is primarily immunomodulatory (Table 1) (de La Salmoniere, in Clin Cancer Res 6:4713-4718, 2000; Stuckert, in J Clin Oncol 25:8506, 2007; Gogas et al., in N Engl J Med 354:709-718, 2006; Moschos et al., in J Clin Oncol 24:3164-3171, 2006; Ascierto and Kirkwood, in J Transl Med 6:62, 2008) Recent efforts to elucidate the mechanism of action for interferon have focused upon signal transducers and activators of transcription (STAT) (Simons et al., in J Transl Med 9:52, 2011) signaling and immunoregulatory responses mediated by regulatory T cells (Tregs) (Wang et al., in Clin Cancer Res 13:1523-1531, 2007; Clin Cancer Res 14:8314-8320, 2008). Tregs are a suppressive CD4+ T cell population that is present, along with primed effector T cells, in tumor and tumor-draining lymph nodes (Hiura et al. in J Immunol 175:5058-5066, 2005). Tregs express high levels of surface antigens such as CD25, cytotoxic T lymphocyte associated antigen 4 (CTLA-4), and

  18. A first-year dornase alfa treatment impact on clinical parameters of patients with cystic fibrosis: the Brazilian cystic fibrosis multicenter study

    PubMed Central

    Rozov, Tatiana; Silva, Fernando Antônio A. e; Santana, Maria Angélica; Adde, Fabíola Villac; Mendes, Rita Heloisa

    2013-01-01

    OBJECTIVE: To describe the clinical impact of the first year treatment with dornase alfa, according to age groups, in a cohort of Brazilian Cystic Fibrosis (CF) patients. METHODS: The data on 152 eligible patients, from 16 CF reference centers, that answered the medical questionnaires and performed laboratory tests at baseline (T0), and at six (T2) and 12 (T4) months after dornase alfa initiation, were analyzed. Three age groups were assessed: six to 11, 12 to 13, and >14 years. Pulmonary tests, airway microbiology, emergency room visits, hospitalizations, emergency and routine treatments were evaluated. Student's t-test, chi-square test and analysis of variance were used when appropriated. RESULTS: Routine treatments were based on respiratory physical therapy, regular exercises, pancreatic enzymes, vitamins, bronchodilators, corticosteroids, and antibiotics. In the six months prior the study (T0 phase), hospitalizations for pulmonary exacerbations occurred in 38.0, 10.0 and 61.4% in the three age groups, respectively. After one year of intervention, there was a significant reduction in the number of emergency room visits in the six to 11 years group. There were no significant changes in forced expiratory volume in one second (VEF1), in forced vital capacity (FVC), in oxygen saturation (SpO2), and in Tiffenau index for all age groups. A significant improvement in Shwachman-Kulczychi score was observed in the older group. In the last six months of therapy, chronic or intermittent colonization by P. aeruginosa was detected in 75.0, 71.4 and 62.5% of the studied groups, respectively, while S. aureus colonization was identified in 68.6, 66.6 and 41.9% of the cases. CONCLUSIONS: The treatment with dornase alfa promoted the maintenance of pulmonary function parameters and was associated with a significant reduction of emergency room visits due to pulmonary exacerbations in the six to 11 years age group, with better clinical scores in the >14 age group, one year after the

  19. Evaluation of the efficacy and safety of three dosing regimens of agalsidase alfa enzyme replacement therapy in adults with Fabry disease

    PubMed Central

    Goláň, Lubor; Goker-Alpan, Ozlem; Holida, Myrl; Kantola, Ikka; Klopotowski, Mariusz; Kuusisto, Johanna; Linhart, Aleš; Musial, Jacek; Nicholls, Kathleen; Gonzalez-Rodriguez, Derlis; Sharma, Reena; Vujkovac, Bojan; Chang, Peter; Wijatyk, Anna

    2015-01-01

    Purpose Efficacy and safety of agalsidase alfa at 0.2 mg/kg weekly were compared with 0.2 mg/kg every other week (EOW). Exploratory analyses were performed for 0.4 mg/kg weekly. Patients and methods This was a 53-week, Phase III/IV, multicenter, open-label study (NCT01124643) in treatment-naïve adults (≥18 years) with Fabry disease. Inclusion criteria were left ventricular hypertrophy at baseline, defined as left ventricular mass indexed to height >50 g/m2.7 for males and >47 g/m2.7 for females. Primary endpoint was reduction of left ventricular mass indexed to height as assessed by echocardiography. Secondary endpoints included cardiac (peak oxygen consumption, 6-minute walk test, Minnesota Living with Heart Failure Questionnaire, New York Heart Association classification), renal (Modification of Diet in Renal Disease, estimated glomerular filtration rate), and biomarker (plasma globotriaosylceramide) assessments. Safety endpoints were adverse events and anti–agalsidase alfa antibodies. Results Twenty patients were randomized to 0.2 mg/kg EOW (mean age, 50.3 years; 70% male), 19 to 0.2 mg/kg weekly (51.8 years; 53% male), and 5 to 0.4 mg/kg weekly (49.4 years; 40% male). The mean change in left ventricular mass indexed to height by Week 53 in the 0.2-mg/kg EOW and weekly groups was 3.2 g/m2.7 and 0.5 g/m2.7, with no significant difference between groups. No clinically meaningful changes by Week 53 were found within or between the 0.2-mg/kg groups for peak oxygen consumption, 6-minute walk test, or Minnesota Living with Heart Failure Questionnaire. Two patients in each group improved by ≥1 New York Heart Association classification. No significant differences were found between 0.2 mg/kg EOW and weekly for mean change in estimated glomerular filtration rate (−1.21 mL/min/1.73 m2 vs −3.32 mL/min/1.73 m2) or plasma globotriaosylceramide (−1.05 nmol/mL vs −2.13 nmol/mL), respectively. Infusion-related adverse events were experienced by 25% and 21% in the

  20. HCV quasispecies evolution during treatment with interferon alfa-2b and ribavirin in two children coinfected with HCV and HIV-1.

    PubMed

    Quesnel-Vallières, Mathieu; Lemay, Mireille; Lapointe, Normand; Martin, Steven R; Soudeyns, Hugo

    2008-10-01

    Two children who acquired hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) infection by mother-to-child transmission were monitored during interferon alfa-2b and ribavirin treatment. In Patient C1, CD4(+) T cell counts were within normal range and HIV-1 viral load was undetectable. HCV viral load declined slightly following treatment initiation while novel variants rapidly emerged, indicative of quasispecies diversification. In Patient C2, CD4(+) T cell counts were low and HIV-1 replication was not fully controlled by antiretroviral therapy. HCV viral load rose during treatment and a striking conservation of the variant spectrum was observed. In both cases, there was no decline in quasispecies complexity following treatment initiation and sustained virological response was not achieved. These results suggest that reduction in quasispecies complexity, which is observed in adult responders following interferon treatment, may be mechanistically unrelated with evolution of the variant profile and/or selective pressure exerted on HCV.

  1. Rare Form of Erdheim-Chester Disease Presenting with Isolated Central Skeletal Lesions Treated with a Combination of Alfa-Interferon and Zoledronic Acid

    PubMed Central

    Bulycheva, E. N.; Baykov, V. V.; Zaraĭskiĭ, M. I.; Salogub, G. N.

    2015-01-01

    Erdheim-Chester disease (ECD) represents a clonal non-Langerhans histiocytosis, which manifests under an extensive variety of clinical symptoms. This creates a challenge for the physician, who is required to recognize and diagnose the disease in the early stages. Despite this considerable challenge, in the last decade there has been a dramatic increase in ECD diagnoses, in most part due to an increasing awareness of this rare disorder. Involvement of the axial skeleton is exclusively uncommon with no official recommendations for the treatment of the bone lesions. Here, we present a case report of a young male patient with isolated lesions of the spine, ribs, and pelvis, who was successfully treated with a combination therapy of alfa-interferon and zoledronic acid. PMID:25949835

  2. A Pharmacoeconomic Analysis of In-Hospital Costs Resulting from Reintubation in Preterm Infants Treated with Lucinactant, Beractant, or Poractant Alfa

    PubMed Central

    Guardia, Carlos G.; Moya, Fernando R.; Sinha, Sunil; Simmons, Phillip D.; Segal, Robert; Greenspan, Jay S.

    2012-01-01

    OBJECTIVES Reintubation and subsequent mechanical ventilation (MV) in preterm infants after surfactant replacement therapy are associated with excess morbidity and mortality and likely increase in-hospital costs. Specific surfactant therapy selection for prevention of respiratory distress syndrome (RDS) in preterm infants receiving conventional MV may impact not only clinical outcomes but also pharmacoeconomic outcomes. METHODS We conducted a pharmacoeconomic analysis of the impact of surfactant selection and reintubation and subsequent MV of preterm infants on health care resource utilization. Rates of reintubation and duration of MV after reintubation were determined from 1546 preterm infants enrolled in two surfactant trials comparing lucinactant to beractant and poractant alfa. Hospital costs were obtained from a 2010 US database from 1564 preterm infants with RDS, with a direct cost of $2637 per day for MV in the neonatal intensive care unit. Cost of reintubation by study and treatment was estimated as the incidence of reintubation multiplied by days on MV therapy after reintubation multiplied by cost per day for direct MV costs, standardized per 100 surfactant-treated infants. RESULTS There were no differences between studies or treatment groups in the overall extubation rate. Average MV duration following reintubation was similar between groups in both trials; however, reintubation rates were significantly lower (p<0 05) for infants treated with lucinactant than for those receiving beractant or poractant alfa. The observed differences in reintubation rates resulted in a projected cost saving of $160,013 to $252,203 per 100 infants treated with lucinactant versus animal-derived surfactants. CONCLUSIONS In this analysis, higher reintubation rates following successful extubation in preterm infants receiving animal-derived surfactant preparations significantly increased estimated in-hospital costs, primarily due to excess costs associated with MV. This analysis

  3. An open-label clinical trial of agalsidase alfa enzyme replacement therapy in children with Fabry disease who are naïve to enzyme replacement therapy

    PubMed Central

    Goker-Alpan, Ozlem; Longo, Nicola; McDonald, Marie; Shankar, Suma P; Schiffmann, Raphael; Chang, Peter; Shen, Yinghua; Pano, Arian

    2016-01-01

    Background Following a drug manufacturing process change, safety/efficacy of agalsidase alfa were evaluated in enzyme replacement therapy (ERT)-naïve children with Fabry disease. Methods In an open-label, multicenter, Phase II study (HGT-REP-084; Shire), 14 children aged ≥7 years received 0.2 mg/kg agalsidase alfa every other week for 55 weeks. Primary endpoints: safety, changes in autonomic function (2-hour Holter monitoring). Secondary endpoints: estimated glomerular filtration rate, left ventricular mass index (LVMI), midwall fractional shortening, pharmacodynamic parameters, and patient-reported quality-of-life. Results Among five boys (median 10.2 [range 6.7, 14.4] years) and nine girls (14.8 [10.1, 15.9] years), eight patients experienced infusion-related adverse events (vomiting, n=4; nausea, n=3; dyspnea, n=3; chest discomfort, n=2; chills, n=2; dizziness, n=2; headache, n=2). One of these had several hypersensitivity episodes. However, no patient discontinued for safety reasons and no serious adverse events occurred. One boy developed immunoglobulin G (IgG) and neutralizing antidrug antibodies. Overall, no deterioration in cardiac function was observed in seven patients with low/abnormal SDNN (standard deviation of all filtered RR intervals; <100 ms) and no left ventricular hypertrophy: mean (SD) baseline SDNN, 81.6 (20.9) ms; mean (95% confidence interval [CI]) change from baseline to week 55, 17.4 (2.9, 31.9) ms. Changes in SDNN correlated with changes in LVMI (r=−0.975). No change occurred in secondary efficacy endpoints: mean (95% CI) change from baseline at week 55 in LVMI, 0.16 (−3.3, 3.7) g/m2.7; midwall fractional shortening, −0.62% (−2.7%, 1.5%); estimated glomerular filtration rate, 0.15 (−11.4, 11.7) mL/min/1.73 m2; urine protein, −1.8 (−6.0, 2.4) mg/dL; urine microalbumin, 0.6 (−0.5, 1.7) mg/dL; plasma globotriaosylceramide (Gb3), −5.71 (−10.8, −0.6) nmol/mL; urinary Gb3, −1,403.3 (−3,714.0, 907.4) nmol/g creatinine

  4. Durability of sustained response shown in paediatric patients with chronic hepatitis C who were treated with interferon alfa-2b plus ribavirin.

    PubMed

    Kelly, D A; Haber, B; González-Peralta, R P; Murray, K F; Jonas, M M; Molleston, J P; Narkewicz, M R; Sinatra, F R; Lang, T; Lachaux, A; Wirth, S; Shelton, M; Te, H S; Pollack, H; Deng, W; Noviello, S; Albrecht, J K

    2012-04-01

    Long-term studies in adults indicate that sustained virologic response (SVR) after combination treatment for chronic hepatitis C (CHC) predicts long-term clearance. Although peginterferon plus ribavirin is now standard care for children with CHC, long-term follow-up studies are not yet available. This study evaluated durability of virologic response over 5 years in children previously treated with interferon alfa-2b plus ribavirin (IFN/R). Ninety-seven of 147 children with CHC, who were treated with IFN/R and completed the 6-month follow-up in two previous clinical trials, participated in this long-term follow-up study. All were assessed annually for up to 5 years; patients with SVR were assessed for durability of virologic response. Children with SVR (n = 56) and those with detectable hepatitis C virus (HCV) RNA 24-week post-treatment (n = 41) were followed for a median of 284 weeks. Overall, 70% (68/97) of patients completed the 5-year follow-up. One patient with genotype 1a CHC had SVR and relapsed at year 1 of follow-up with the same genotype. Kaplan-Meier estimate for sustained response at 5 years was 98% (95% CI: 95%, 100%). Six patients with low-positive HCV RNA levels (n = 4) or missing HCV RNA at the 24-week follow-up visit (n = 2) in the initial treatment studies had virologic response during this long-term follow-up study. Linear growth rate was impaired during treatment with rapid increases in the immediate 6 months post-treatment. Mean height percentile at the end of the 5-year follow-up was slightly less than the mean pretreatment height percentile. Five patients experienced serious adverse events; none related to study drug exposure. SVR after IFN/R predicts long-term clearance of HCV in paediatric patients; growth normalized in the majority of children during the long-term follow-up. Similar long-term results could be expected after peginterferon alfa-2b plus ribavirin treatment.

  5. Development of a high performance size exclusion chromatography method to determine the stability of Human Serum Albumin in a lyophilized formulation of Interferon alfa-2b.

    PubMed

    Qian, Jin; Tang, Qinglin; Cronin, Bart; Markovich, Robert; Rustum, Abu

    2008-06-13

    Intron Powder for Injection is a lyophilized formulation of Interferon alfa-2b marketed for treatment of Hepatitis C and some cancer indications. Human Serum Albumin (HSA) is used as a lyoprotectant and cryoprotectant at 1.0 mg/mL in the product formulation. No stability-indicating method, which can quantitate HSA and its dimer or oligomer aggregates in the formulated product, has been published to date. This paper describes the development and validation of a stability-indicating high performance size exclusion chromatography (HPSEC) method for the assay of HSA and estimation of HSA related compounds in lyophilized Intron Powder for Injection. The method employs a YMC-Pack Diol-200 column (7.8 mm x 30 cm, 5 microm porous particles with 250 A pore size), UV detection at 214 nm, and a mobile phase of 0.1 M phosphate buffer at pH 7.0 with 0.1 M sodium sulfate. The mobiles phase runs in an isocratic mode at 1.0 mL/min and the total chromatographic run time is 30 min. The method was validated for specific, linearity, accuracy, sensitivity, and robustness. It was shown to be specific for HSA and HSA aggregates (dimer and oligomers) with a limit of quantitation of 0.0005 mg/mL or 0.05% of HSA label claim in the presence of active therapeutic protein, Interferon alfa-2b, and the other pharmaceutical excipients, glycine, sodium phosphate dibasic, sodium phosphate monobasic. The method is stability indicating and is suitable for assay of HSA from 0.0005 mg/mL to 1.5mg/mL. (0.05-150% of HSA label claim) and for estimation of HSA related aggregates (dimer, and oligomer) from 0.0005 mg/mL to 0.15 mg/mL (0.05-15% of HSA label claim). The method is robust for routine use in product quality control. The method was applied to the analysis of batches of lyophilized Intron Powder for Injection of low, middle and high strength from the beginning, middle and end of shelf-life. The results indicated that HSA is stable in the product through out its shelf-life.

  6. Clinical trials update from the European Society of Cardiology heart failure meeting: TNT subgroup analysis, darbepoetin alfa, FERRIC-HF and KW-3902.

    PubMed

    Coletta, Alison P; Tin, Lwin; Loh, P Huan; Clark, Andrew L; Cleland, John G F

    2006-08-01

    This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure, presented at the European Society of Cardiology heart failure meeting held in June 2006. All reports should be considered as preliminary data, as analyses may change in the final publication. In a sub-group analysis of the TNT study, intensive treatment with high-dose atorvastatin significantly reduced hospitalisations for heart failure in patients with stable coronary heart disease, compared with low-dose atorvastatin; this benefit was most evident in patients with a history of heart failure at baseline. In a combined analysis of two studies of darbepoetin alfa, which included 475 patients, treatment increased and maintained haemoglobin levels and produced non-significant improvements in symptoms and morbidity in anaemic heart failure patients compared to placebo. In the FERRIC-HF study (n=35), intravenous iron sucrose therapy improved exercise capacity and symptom status in iron-deficient heart failure patients. In a combined analysis of two studies (n=186), the adenosine A(1) receptor antagonist KW-3902 showed diuretic properties and appeared to enhance response to loop diuretics in heart failure patients hospitalised with fluid overload.

  7. Mutations selected in the hepatitis C virus NS3 protease domain during sequential treatment with boceprevir with and without pegylated interferon alfa-2b.

    PubMed

    Vermehren, J; Susser, S; Lange, C M; Forestier, N; Karey, U; Hughes, E; Ralston, R; Tong, X; Zeuzem, S; Sarrazin, C

    2012-02-01

    Treatment with hepatitis C virus (HCV)-NS3-protease inhibitors lead to the selection of resistant variants. Viral kinetics and resistance profiles in patients who are re-treated with the same protease inhibitor are unknown. Viral kinetics and NS3-resistance mutations obtained by clonal sequencing of the NS3-protease were analyzed in nine HCV-genotype-1-infected nonresponder patients who were sequentially treated with boceprevir (400 mg t.i.d.) for 1 week, peginterferon-alfa-2b for 2 weeks and combination of the two for 2 weeks in varying order. In addition to predominant wild-type isolates, previously described boceprevir-resistant mutations (V36, T54, R155, A156, V170) were observed. Furthermore, two resistant mutations (Q41, F43) were detected for the first time in vivo. In three patients, mutations selected after initial treatment with boceprevir were re-selected during subsequent boceprevir exposure. However, mutational patterns after the first and second exposure to boceprevir were different in five patients. In one patient, a viral variant (V55A) known to reduce susceptibility to boceprevir was the predominant variant observed at baseline and throughout treatment and was associated with a shallow viral decline. Different resistance mutations were selected during treatment with boceprevir ± peginterferon. Sequential short-term dosing of boceprevir was not associated with accumulation of resistant variants but pre-existing variants may impair virologic response.

  8. THE ARECIBO LEGACY FAST ALFA SURVEY. VIII. H I SOURCE CATALOG OF THE ANTI-VIRGO REGION AT {delta} = +25 DEG

    SciTech Connect

    Martin, Ann M.; Giovanelli, Riccardo; Haynes, Martha P.; Stierwalt, Sabrina; Saintonge, Amelie; Hoffman, G. Lyle; Kent, Brian R. E-mail: riccardo@astro.cornell.edu E-mail: sabrina@astro.cornell.edu E-mail: hoffmang@lafayette.edu

    2009-08-01

    We present a fourth catalog of H I sources from the Arecibo Legacy Fast ALFA (ALFALFA) Survey. We report 541 detections over 136 deg{sup 2}, within the region of the sky having 22{sup h} < {alpha} < 03{sup h} and 24 deg. < {delta} < 26 deg. This complements a previous catalog in the region 26 deg. < {delta} < 28 deg. We present here the detections falling into three classes: (1) extragalactic sources with signal-to-noise ratio (S/N)>6.5, where the reliability of the catalog is better than 95%; (2) extragalactic sources 5.0 < S/N < 6.5 and a previously measured optical redshift that corroborates our detection; or (3) High Velocity Clouds (HVCs), or subcomponents of such clouds, in the periphery of the Milky Way. Of the 541 objects presented here, 90 are associated with HVCs, while the remaining 451 are identified as extragalactic objects. Optical counterparts have been matched with all but one of the extragalactic objects.

  9. Treatment-naïve Gaucher disease patients achieve therapeutic goals and normalization with velaglucerase alfa by 4years in phase 3 trials.

    PubMed

    Zimran, Ari; Elstein, Deborah; Gonzalez, Derlis E; Lukina, Elena A; Qin, Yulin; Dinh, Quinn; Turkia, Hadhami Ben

    2016-10-21

    Gaucher disease is an inherited metabolic disease characterized by β-glucocerebrosidase deficiency and commonly treated with enzyme replacement therapy (ERT). The efficacy of ERT with velaglucerase alfa was assessed based on the achievement of published therapeutic goals and the normalization of disease parameters in 39 treatment-naïve patients with type 1 Gaucher disease, 6 to 62years of age, enrolled in phase 3 clinical trials. After 4years of ERT, therapeutic goals for thrombocytopenia and splenomegaly had been achieved in 100% of patients; goals for anemia and hepatomegaly had been achieved in 95% and 94% of patients, respectively. Consistent with the goal for bone mineral density, lumbar spine bone density improved in 87% of patients ≥18years of age. At year 4, compared with clinical ranges for healthy individuals, 86% of patients with a low baseline hemoglobin concentration had normalized, 60% with a low baseline platelet count had normalized, 67% with baseline splenomegaly had normalized, 58% with hepatomegaly had normalized, and lumbar spine bone density had normalized in 53% of adults. The decade-old therapeutic goals do not reflect the potential for normalization of clinical parameters in ERT-treated patients. Goals consistent with normalization or near-normalization should be considered. ClinicalTrials.gov identifiers: NCT00430625, NCT00553631, NCT00635427.

  10. Biosimilar epoetin alfa increases haemoglobin levels and brings cognitive and socio-relational benefits to elderly transfusion-dependent multiple myeloma patients: results from a pilot study.

    PubMed

    Castelli, Roberto; Sciara, Simona; Lambertenghi Deliliers, Giorgio; Pantaleo, Giuseppe

    2017-05-01

    Anaemia is a complication reported in up to 70% of the multiple myeloma patients (MM), with remarkable clinical, cognitive and socio-relational consequences. Anaemia relates to the course of MM, normalizing in patients during remission and reappearing in relapsing/non-responding patients. In a pilot study with 31 patients with MM and transfusion-dependent anaemia, we evaluated the effects of Binocrit (biosimilar epoetin alfa) on transfusions, haemoglobin levels, mental status (mini-mental state evaluation) and the patients' social-relational functioning and quality of life (QoL). Within a 12-week interval, patients received 40.000 U Binocrit once a week. Binocrit significantly decreased the incidence of transfusion, regardless of the patients' transfusion history, and significantly increased haemoglobin levels (before-and-after-treatment median haemoglobin values = 8.20 vs. 9.40 g/dl, respectively; Wilcoxon Z test, p < .001). A comparatively greater increment in haemoglobin levels among patients who responded to first vs. additional lines of chemotherapy was also observed. Importantly, we additionally found moderate-to-strong positive associations between increments in haemoglobin levels and corresponding increments both in psychological well-being and QoL (FACT-An scores) and the patients' cognitive status (mini-mental state evaluation scores). After statistically controlling for possible concurrent benefits of anti-myeloma therapy, increments in haemoglobin levels clearly predicted both increments in socio-relational FACT-An scores (Spearman's rho = 0.60, p < .001) and in cognitive functioning scores (Spearman's rho = 0.49, p < .006). Binocrit thus appears as an effective, well-tolerated agent for the management of myeloma anaemia, whose documented benefits include amelioration of anaemia, reduction in transfusion, and improvements in the patients' social-relational functioning and cognitive well-being.

  11. Impact of severe haemophilia A on patients' health status: results from the guardian(™) 1 clinical trial of turoctocog alfa (NovoEight(®) ).

    PubMed

    Ozelo, M; Chowdary, P; Regnault, A; Busk, A K

    2015-07-01

    Haemophilia and its treatment interfere with patients' life and may affect adherence to treatment. This study explored the impact of severe haemophilia A on patients' health status, especially in young adults (YA), using data from guardian(™) 1, a multinational, open-label, non-controlled phase 3 trial investigating safety and efficacy of turoctocog alfa (NovoEight(®) ) in previously treated patients aged 12 years and older with severe haemophilia A (FVIII ≤ 1%). Health status was assessed using the EuroQoL-5 dimensions (EQ-5D-3L), covering 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort and anxiety/depression), and a visual analogue scale (VAS) measuring self-rated overall health status. EQ-5D was administered pretreatment (screening/baseline) and posttreatment (end-of-trial). Baseline responses to the EQ-5D dimensions and VAS were described overall and by age and compared to reference values from UK general population. Guardian(™) 1 included 150 patients (16 adolescents, 83 YA aged 16-29 and 51 adults aged 30+). All five dimensions of patients' health status were impacted at baseline. The percentage of haemophilia patients reporting problems was consistently significantly greater than age-matched general population reference values. Likewise, for all age groups mean baseline EQ-5D VAS score was significantly lower for haemophilia patients (YA: 78.0) than for the general population (YA aged 18-29: 87.3). The health status of patients with severe haemophilia A entering guardian(™) 1 was markedly poorer than that of the general population, particularly regarding mobility and pain. YA patients reported better health status than older patients, but considerably lower than that of the general YA population.

  12. THE ARECIBO LEGACY FAST ALFA SURVEY. V. THE H I SOURCE CATALOG OF THE ANTI-VIRGO REGION AT {delta} = +27{sup 0}

    SciTech Connect

    Saintonge, Amelie; Giovanelli, Riccardo; Haynes, Martha P.; Kent, Brian R.; Martin, Ann M.; Stierwalt, Sabrina E-mail: bkentastro@cornell.edu E-mail: sabrina@astro.cornell.edu E-mail: haynes@astro.cornell.edu

    2008-02-15

    We present a second catalog of H I sources detected in the Arecibo Legacy Fast ALFA Survey. We report 488 detections over 135 deg{sup 2}, within the region of the sky having 22 h < {alpha} < 03 h and +26{sup 0} < {delta} < +28{sup 0}. We present here the detections that have either (a) S/N>6.5, where the reliability of the catalog is better than 95% or (b) 5.0 < S/N < 6.5 and a previously measured redshift that corroborates our detection. Of the 488 objects presented here, 49 are high-velocity clouds or clumps thereof with negative heliocentric recession velocities. These clouds are mostly very compact and isolated, while some of them are associated with large features such as Wright's Cloud or the northern extension of the Magellanic Stream. The remaining 439 candidate detections are identified as extragalactic objects and have all been matched with optical counterparts. Five of the six galaxies detected with M{sub Hi}<10{sup 7.5} M{sub sun} are satellites of either the NGC672/IC1727 nearby galaxy pair or their neighboring dwarf irregular galaxy NGC784. The data of this catalog release include a slice through the Pisces-Perseus foreground void, a large nearby underdensity of galaxies. We report no detections within the void, where our catalog is complete for systems with H i masses of 10{sup 8} M{sub sun}. Gas-rich, optically-dark galaxies do not seem to constitute an important void population, and therefore do not suffice for producing a viable solution to the void phenomenon.

  13. THE ARECIBO LEGACY FAST ALFA SURVEY. IX. THE LEO REGION H I CATALOG, GROUP MEMBERSHIP, AND THE H I MASS FUNCTION FOR THE LEO I GROUP

    SciTech Connect

    Stierwalt, Sabrina; Haynes, Martha P.; Giovanelli, Riccardo; Martin, Ann M.; Kent, Brian R.; Saintonge, Amelie; Karachentsev, Igor D.; Karachentseva, Valentina E. E-mail: haynes@astro.cornell.edu E-mail: amartin@astro.cornell.edu E-mail: amelie@physik.uzh.ch E-mail: vkarach@observ.univ.kiev.ua

    2009-08-15

    We present the catalog of H I sources extracted from the ongoing Arecibo Legacy Fast ALFA (ALFALFA) extragalactic H I line survey, found within the sky region bounded by 9{sup h}36{sup m} < {alpha} < 11{sup h}36{sup m} and +08{sup 0} < {delta} < +12{sup 0}. The H I catalog presented here for this 118 deg{sup 2} region is combined with the ones derived from surrounding regions also covered by the ALFALFA survey to examine the large-scale structure in the complex Leo region. Because of the combination of wide sky coverage and superior sensitivity, spatial and spectral resolution, the ALFALFA H I catalog of the Leo region improves significantly on the numbers of low H I mass sources as compared with those found in previous H I surveys. The H I mass function of the Leo I group presented here is dominated by low-mass objects: 45 of the 65 Leo I members have M{sub H{sub l}}<10{sup 8} M-odot, yielding tight constraints on the low-mass slope of the Leo I H I mass function. The best-fit slope is {alpha} {approx_equal} -1.41 + 0.2 - 0.1. A direct comparison between the ALFALFA H I line detections and an optical search of the Leo I region proves the advantage of the ALFALFA strategy in finding low-mass, gas-rich dwarfs. These results suggest the existence of a significant population of low surface brightness, gas-rich, yet still very low H I mass galaxies, and may reflect the same type of morphological segregation as is seen in the Local Group. While the low-mass end slope of the Leo I H I mass function is steeper than that determined for luminosity functions of the group, the slope still falls short of the values predicted by simulations of structure formation in the lambda cold dark matter paradigm.

  14. EFFECT OF HCV RNA SUPPRESSION DURING PEGINTERFERON ALFA-2A MAINTENANCE THERAPY ON CLINICAL OUTCOMES IN THE HALT-C TRIAL

    PubMed Central

    Shiffman, Mitchell L; Morishima, Chihiro; Dienstag, Jules L; Lindsay, Karen L; Hoefs, John C; Lee, William M; Wright, Elizabeth C.; Naishadham, Deepa; Everson, Gregory T; Lok, Anna S; Di Bisceglie, Adrian M; Bonkovsky, Herbert L; Ghany, Marc G

    2013-01-01

    Background and Aims The HALT-C trial demonstrated that low-dose peginterferon maintenance therapy was ineffective in preventing clinical outcomes in patients with chronic hepatitis C, advanced fibrosis and failure to achieve a sustained virologic response during lead-in phase treatment with standard dose peginterferon/ribavirin. This analysis was performed to determine if suppressing HCV RNA during the trial was associated with a reduction in clinical outcomes. Methods 764 patients treated during the lead-in phase of HALT-C were randomized to either peginterferon alfa-2a (90 mcg/week) maintenance therapy or no treatment (control) for 3.5 years. Clinical outcomes included an increase in Child-Turcotte-Pugh score, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, variceal hemorrhage, hepatocellular carcinoma and mortality. Results During the lead-in, ≥4 log10 decline in serum HCV RNA occurred in 178 patients; 82% of whom lost detectable HCV RNA and later broke through or relapsed. These patients had significantly (p=0.003) fewer clinical outcomes whether randomized to maintenance therapy or control. Following randomization serum HCV RNA increased significantly in all 90 control patients and 58/88 receiving maintenance therapy. Only 30 patients had persistent suppression of HCV RNA by ≥4 log10 during maintenance therapy. No significant reduction in clinical outcomes was observed in these patients. Conclusions Viral suppression by ≥4 log10 with full dose peginterferon/ribavirin is associated with a significant reduction in clinical outcomes. Continuing low dose peginterferon maintenance therapy, even in patients with persistent viral suppression, does not lead to a further decline in clinical outcomes. PMID:19747918

  15. Peginterferon alfa-2a plus Weight-Based or Flat-Dose Ribavirin for Treatment-Naïve Hepatitis C Virus Genotype 2 Rapid Responders: A Randomized Trial

    PubMed Central

    Liu, Chen-Hua; Huang, Chung-Feng; Liu, Chun-Jen; Dai, Chia-Yen; Huang, Jee-Fu; Lin, Jou-Wei; Liang, Cheng-Chao; Yang, Sheng-Shun; Lin, Chih-Lin; Su, Tung-Hung; Yang, Hung-Chih; Chen, Pei-Jer; Chen, Ding-Shinn; Chuang, Wan-Long; Kao, Jia-Horng; Yu, Ming-Lung

    2015-01-01

    The impact of ribavirin (RBV) dosage on sustained virologic response (SVR) rates remains elusive in hepatitis C virus genotype 2 (HCV-2) rapid responders receiving 16 weeks of peginterferon (Peg-IFN) plus RBV. Treatment-naïve HCV-2 patients with rapid virologic response (RVR) received Peg-IFN alfa-2a 180 μg/week plus weight-based RBV (1,000 or 1,200 mg/day; cut-off body weight: 75 kg) for 6 weeks, and then randomly received Peg-IFN alfa-2a 180 μg/week plus weight-based (1,000 or 1,200 mg/day; n = 247) or flat-dose (800 mg/day; n = 246) RBV for additional 10 weeks. The primary endpoint was SVR24. Patients receiving weight-based and flat-dose RBV therapies had comparable SVR24 rates (93.5% versus 91.9%, P = 0.49). The risk differences (RDs) of SVR24 receiving weight-based and flat-dose RBV arms were 7.1% [95% CI: 0.7% to 13.6%] in males, and −5.8% [95% CI: −12.1% to 0.5%] in females (interaction P = 0.01). The SVR24 rate was higher in males receiving ≥13 mg/kg/day than those receiving <13 mg/kg/day (96.3% versus 85.1%, P = 0.001). In conclusion, Peg-IFN alfa-2a plus weight-based or flat-dose RBV for 16 weeks provides comparable SVR24 rates in treatment-naïve HCV-2 rapid responders. However, males should receive weight-based RBV to achieve a high SVR24 rate. PMID:26469083

  16. The effectiveness of retreatment with peginterferon alfa and ribavirin in patients with chronic viral hepatitis C genotype 2 and 3: a prospective cohort study in Brazil

    PubMed Central

    2012-01-01

    Background More than 50% of patients infected with chronic hepatitis C virus (HCV) do not respond to treatment with conventional interferon (IFN) combined with ribavirin (RBV). The aim of our study was to evaluate the effectiveness of retreatment with peginterferon alfa-2a or 2b (PEG-IFN 2a or 2b) concomitantly with RBV in patients with HCV genotype 2 and 3, which were non-responders or relapsers to initial treatment with IFN / RBV and to identify possible predictors of sustained virological response (SVR). Methods From September 2003 to March 2009 a cohort of 216 patients who had previously failed therapy with a regimen of standard interferon and ribavirin, were followed in a specialized service implemented in the Brazilian Unified Health System, Rio Grande do Sul. All patients were retreated with PEG-IFN 2a or 2b per week, associated with RBV, through oral route, with doses determined according to weight (1,000 mg if weight ≤ 75 Kg and 1,250 mg if ≥ 75 Kg) per day for 48 weeks. The HCV-RNA was tested by Polymerase Chain Reaction (PCR). Virological Response (VR) within 48 weeks and SVR in the 72 weeks was considered for evaluation of treatment efficacy. Analyses were performed in patients who received at least one dose of PEG-IFN. Results The SVR rate for non-responders to previous treatment was 34.4% and for relapsers was 50% (p = 0.031). As predictive factors that contribute to improve SVR, were identified the age (p = 0.005), to be relapsers to previous treatment (p = 0.023) and present liver biopsy examination Metavir F0-F2 (p = 0.004). In assessing the safety profile, 51 patients (23.6%) discontinued treatment prematurely. Conclusions This alternative retreatment for patients who have failed prior therapies for anti-HCV, has demonstrated promising SVR rate, provided that it includes a careful selection of patients with predictors of response and adverse events monitored. PMID:23270376

  17. THE ARECIBO LEGACY FAST ALFA SURVEY. X. THE H I MASS FUNCTION AND {Omega}{sub H{sub i}} FROM THE 40% ALFALFA SURVEY

    SciTech Connect

    Martin, Ann M.; Papastergis, Emmanouil; Giovanelli, Riccardo; Haynes, Martha P.; Springob, Christopher M.; Stierwalt, Sabrina E-mail: papastergis@astro.cornell.ed E-mail: haynes@astro.cornell.ed E-mail: sabrina@ipac.caltech.ed

    2010-11-10

    The Arecibo Legacy Fast ALFA (ALFALFA) survey has completed source extraction for 40% of its total sky area, resulting in the largest sample of H I-selected galaxies to date. We measure the H I mass function from a sample of 10,119 galaxies with 6.2 < log (M{sub H{sub i}}/M{sub sun}) < 11.0 and with well-described mass errors that accurately reflect our knowledge of low-mass systems. We characterize the survey sensitivity and its dependence on profile velocity width, the effect of large-scale structure, and the impact of radio frequency interference in order to calculate the H I mass function with both the 1/V{sub max} and 2DSWML methods. We also assess a flux-limited sample to test the robustness of the methods applied to the full sample. These measurements are in excellent agreement with one another; the derived Schechter function parameters are {phi}{sub *} (h {sup 3}{sub 70} Mpc{sup -3} dex{sup -1}) = 4.8 {+-} 0.3 x 10{sup -3}, log (M{sub *}/M{sub sun}) + 2 log h{sub 70} = 9.96 {+-} 0.02, and {alpha} = -1.33 {+-} 0.02. We find {Omega}{sub H{sub i}}= 4.3 {+-} 0.3 x10{sup -4} h {sup -1}{sub 70}, 16% larger than the 2005 HIPASS result, and our Schechter function fit extrapolated to log (M{sub H{sub i}}/M{sub sun}) = 11.0 predicts an order of magnitude more galaxies than HIPASS. The larger values of {Omega}{sub H{sub i}} and of M{sub *} imply an upward adjustment for estimates of the detection rate of future large-scale H I line surveys with, e.g., the Square Kilometer Array. A comparison with simulated galaxies from the Millennium Run and a treatment of photoheating as a method of baryon removal from H I-selected halos indicate that the disagreement between dark matter mass functions and baryonic mass functions may soon be resolved.

  18. Quantification of hepatitis C virus in patients treated with peginterferon-alfa 2a plus ribavirin treatment by COBAS TaqMan HCV test.

    PubMed

    Kanda, T; Imazeki, F; Yonemitsu, Y; Mikami, S; Takada, N; Nishino, T; Takashi, M; Tsubota, A; Kato, K; Sugiura, N; Tawada, A; Wu, S; Tanaka, T; Nakamoto, S; Mikata, R; Tada, M; Chiba, T; Kurihara, T; Arai, M; Fujiwara, K; Kanai, F; Yokosuka, O

    2011-07-01

    Extremely low levels of serum hepatitis C virus (HCV) RNA can be detected by COBAS TaqMan HCV test. To investigate whether the COBAS TaqMan HCV test is useful for measuring rapid virological response (RVR) and early virological response (EVR) to predict sustained virological response (SVR), we compared the virological response to PEG-IFN-alfa 2a plus RBV in 76 patients infected with HCV genotype 1 when undetectable HCV RNA by the COBAS TaqMan HCV test was used, with those when below 1.7 log IU/mL HCV RNA by COBAS TaqMan HCV test was used, which corresponded to the use of traditional methods. Among the 76 patients, 28 (36.8%) had SVR, 13 (17.1%) relapsed, 19 (25.0%) did not respond, and 16 (21.0%) discontinued the treatment due to side effects. The positive predictive values for SVR based on undetectable HCV RNA by COBAS TaqMan HCV test at 24 weeks after the end of treatment [10/10 (100%) at week 4, 21/23 (91.3%) at week 8 and 26/33 (78.7%) at week 12] were superior to those based on <1.7 log IU/mL HCV RNA [17/19 (89.4%) at week 4, 27/38 (71.0%) at week 8, and 27/43 (62.7%) at week 12]. The negative predictive values for SVR based on <1.7 log IU/mL HCV RNA by COBAS TaqMan HCV test [46/57 (80.7%) at week 4, 37/38 (97.3%) at week 8, and 32/33 (96.9%) at week 12] were superior to those based on undetectable HCV RNA [48/66 (72.7%) at week 4, 46/53 (86.7%) at week 8, and 41/43 (95.3%) at week 12]. The utilization of both undetectable RNA and <1.7 log IU/mL HCV RNA by COBAS TaqMan HCV test is useful and could predict SVR and non-SVR patients with greater accuracy.

  19. Recombinant follitropin alfa/lutropin alfa in fertility treatment

    PubMed Central

    Gibreel, Ahmed; Bhattacharya, Siladitya

    2010-01-01

    Recombinant human follicle stimulating hormone (rFSH) and luteinizing hormone (LH), also known as follitropin alpha and lutropin alpha, are manufactured by genetic engineering techniques which ensure high quality and batch to batch consistency. Follitropin alpha can be used for controlled ovarian hyperstimulation in assisted reproduction, ovulation induction for WHO group I and II anovulatory infertility and in men with hypogonadotrophic hypogonadism (HH) or idiopathic oligo-asthenospermia. Current evidence suggests superiority of urinary human menopausal gonadotropin (HMG) over follitropin alpha in controlled ovarian hyperstimulation for IVF in terms of live birth rate per couple. Addition of lutropin to follitropin alpha in an unselected IVF population does not appear to confer any benefit; however, it may have a role in ovulation induction in women with hypothalamic hypogonadism. Urinary HMG preparations (especially currently available highly purified preparations) are more cost effective than rFSH in terms of cost per ongoing pregnancy. However, women using rFSH injection pen devices have higher levels of satisfaction as compared to those using urinary HMG by means of conventional syringes. PMID:20161981

  20. Interferon Alfa-2b Injection

    MedlinePlus

    ... medication either subcutaneously or intramuscularly three times a week. HBV, inject the medication either subcutaneously or intramuscularly three times a week usually for 16 weeks. hairy cell leukemia, inject ...

  1. Peginterferon Alfa-2a Injection

    MedlinePlus

    ... interferons. Peginterferon is a combination of interferon and polyethylene glycol, which helps the interferon stay active in ... alpha interferons, any other medications, benzyl alcohol, or polyethylene glycol (PEG). Ask your doctor if you are ...

  2. Tolerability of intensified intravenous interferon alfa-2b versus the ECOG 1684 schedule as adjuvant therapy for stage III melanoma: a randomized phase III Italian Melanoma Inter-group trial (IMI – Mel.A.) [ISRCTN75125874

    PubMed Central

    Chiarion-Sileni, Vanna; Del Bianco, Paola; Romanini, Antonella; Guida, Michele; Paccagnella, Adriano; Dalla Palma, Maurizio; Naglieri, Emanuele; Ridolfi, Ruggero; Silvestri, Barbara; Michiara, Maria; De Salvo, Gian Luca

    2006-01-01

    Background High-dose interferon alfa-2b (IFNalfa-2b), according to the ECOG 1684 schedule, is the only approved adjuvant treatment for stage III melanoma patients by the FDA and EMEA. However, the risk/benefit profile has been questioned limiting its world-wide use. In the late nineties, the Italian Melanoma Inter-group started a spontaneous randomized clinical trial (RCT) to verify if a more intense, but shorter than the ECOG 1684 regimen, could improve survival without increasing the toxicity profile. The safety analysis in the first 169 patients who completed the treatment is here described. Methods Stage III melanoma patients were randomized to receive IFNalfa-2b 20 MU/m2/d intravenously (IV) 5 days/week × 4 weeks, repeated for three times on weeks 9 to 12, 17 to 20, 25 to 28 (Dose-Dense/Dose-Intense, DD/DI, arm), or IFNalfa-2b 20 MU/m2/d IV 5 days/week × 4 weeks followed by 10 MU/m2 subcutaneously (SC) three times per week × 48 weeks (High Dose Interferon, HDI, arm). Toxicity was recorded and graded, according to the WHO criteria, as the worst grade that occurred during each cycle. Results The most common toxicities in both arms were flu-like and gastrointestinal symptoms, leukopenia, liver and neuro-psichiatric morbidities; with regard to severe toxicity, only leukopenia was statistically more frequent in DD/DI arm than in HDI arm (24% vs 9%) (p = 0.0074), yet, this did not cause an increase in the infection risk. Discontinuation of treatment, due to toxicity, was observed in 13 and 17% of the patients in the DD/DI and HDI arm, respectively. The median actual dose intensity delivered in the DD/DI arm (36.4 MU/m2/week) was statistically higher than that delivered in the HDI arm (30.7 MU/m2/week) (p = 0.003). Conclusion Four cycles of intravenous high-dose IFNalfa-2b can be safely delivered with an increase in the median dose intensity. Efficacy results from this trial are eagerly awaited. PMID:16504154

  3. The ALFA Roman Pot detectors of ATLAS

    NASA Astrophysics Data System (ADS)

    Abdel Khalek, S.; Allongue, B.; Anghinolfi, F.; Barrillon, P.; Blanchot, G.; Blin-Bondil, S.; Braem, A.; Chytka, L.; Conde Muíño, P.; Düren, M.; Fassnacht, P.; Franz, S.; Gurriana, L.; Grafström, P.; Heller, M.; Haguenauer, M.; Hain, W.; Hamal, P.; Hiller, K.; Iwanski, W.; Jakobsen, S.; Joram, C.; Kötz, U.; Korcyl, K.; Kreutzfeldt, K.; Lohse, T.; Maio, A.; Maneira, M. J. P.; Mapelli, A.; Notz, D.; Nozka, L.; Palma, A.; Petschull, D.; Pons, X.; Puzo, P.; Ravat, S.; Schneider, T.; Seabra, L.; Sykora, T.; Staszewski, R.; Stenzel, H.; Trzebinski, M.; Valkar, S.; Viti, M.; Vorobel, V.; Wemans, A.

    2016-11-01

    The ATLAS Roman Pot system is designed to determine the total proton-proton cross section as well as the luminosity at the Large Hadron Collider (LHC) by measuring elastic proton scattering at very small angles. The system is made of four Roman Pot stations, located in the LHC tunnel in a distance of about 240 m at both sides of the ATLAS interaction point. Each station is equipped with tracking detectors, inserted in Roman Pots which approach the LHC beams vertically. The tracking detectors consist of multi-layer scintillating fibre structures read out by Multi-Anode-Photo-Multipliers.

  4. Peginterferon Alfa-2b (PEG-Intron)

    MedlinePlus

    ... alpha-2b is a combination of interferon and polyethylene glycol, which helps the interferon stay active in ... 2b, other alpha interferons, any other medications, or polyethylene glycol (PEG). Ask your doctor if you are ...

  5. Peginterferon Alfa-2b Injection (Sylatron)

    MedlinePlus

    ... 2b injection is used in people with malignant melanoma (a life-threatening cancer that begins in certain ... is used to reduce the chance that malignant melanoma will come back and must be started within ...

  6. Darbepoetin alfa for anemia with myelodysplastic syndrome.

    PubMed

    Seastone, David J; Gerds, Aaron T

    2015-04-01

    The myelodysplastic syndromes are characterized by refractory cytopenias that lead to symptomatic anemia, bleeding, and increased risk for infections. For almost two decades, the use of darbepoetin and other erythropoietin stimulating agents to treat symptomatic anemia in lower-risk myelodysplastic syndromes has been a standard of care. This practice is supported by numerous Phase I/II studies and one Phase III study demonstrating the benefit of using erythropoietin stimulating agents alone, or in combination with granulocyte colony stimulating factor, for treatment of symptomatic anemia with the goal of decreasing red blood cell transfusion requirements. This review summarizes the published experience regarding the use of erythropoietin stimulating agents, with a special focus on darbepoetin, in patients with myelodysplastic syndrome and symptomatic anemia.

  7. No influence of scopolamine hydrobromide on odor detection performance of rats.

    PubMed

    Doty, Richard L; Bagla, Ritu; Misra, Robert; Mueller, Eric; Kerr, Kara-Lynne

    2003-11-01

    Despite speculation that the muscarinic cholinergic antagonist, scopolamine, may influence the olfactory sensitivity of rats, there have been no definitive studies on this point to date. In this study, we examined the influence of a range of doses of scopolamine hydrobromine (namely, 0.10, 0.125, 0.15 and 0.20 mg/kg i.p.) on the odor detection performance of 15 adult male Long-Evans rats to ethyl acetate. Air-dilution olfactometry and a go/no-go operant signal detection task were employed. The drug conditions and a saline control were administered to each animal in an order counterbalanced by Latin squares, with 2 day intervals interspersed between tests. Scopolamine had no significant influence on odor detection performance per se, as measured by percent correct S+ and S- responses and a non-parametric signal detection measure of sensitivity. This is in contrast to the relatively large effects previously observed in the same test paradigm for such drugs as the D-1 agonist SKF 38393 and the D-2 agonist quinpirole. These data suggest that scopolamine has no meaningful influence on a well-practiced odor detection task.

  8. A Protective Role of Arecoline Hydrobromide in Experimentally Induced Male Diabetic Rats

    PubMed Central

    Saha, Indraneel; Das, Joydeep; Maiti, Biswaranjan

    2015-01-01

    Objectives. Arecoline, the most potent and abundant alkaloid of betel nut, causes elevation of serum testosterone and androgen receptor expression in rat prostate, in addition to increase in serum insulin levels in rats, leading to insulin resistance and type 2 diabetes-like conditions. This study investigated the role of arecoline on the reproductive status of experimentally induced type 1 diabetic rats. Methods. Changes in the cellular architecture were analyzed by transmission electron microscopy. Blood glucose, serum insulin, testosterone, FSH, and LH were assayed. Fructose content of the coagulating gland and sialic acid content of the seminal vesicles were also analyzed. Results. Arecoline treatment for 10 days at a dose of 10 mg/kg of body weight markedly facilitated β-cell regeneration and reversed testicular and sex accessory dysfunctions by increasing the levels of serum insulin and gonadotropins in type 1 diabetic rats. Critical genes related to β-cell regeneration, such as pancreatic and duodenal homeobox 1 (pdx-1) and glucose transporter 2 (GLUT-2), were found to be activated by arecoline at the protein level. Conclusion. It can thus be suggested that arecoline is effective in ameliorating the detrimental effects caused by insulin deficiency on gonadal and male sex accessories in rats with type 1 diabetes. PMID:25695047

  9. Final Results of the Sunbelt Melanoma Trial: A Multi-Institutional Prospective Randomized Phase III Study Evaluating the Role of Adjuvant High-Dose Interferon Alfa-2b and Completion Lymph Node Dissection for Patients Staged by Sentinel Lymph Node Biopsy

    PubMed Central

    Egger, Michael E.; Edwards, Michael J.; Ross, Merrick I.; Reintgen, Douglas S.; Noyes, R. Dirk; Martin, Robert C.G.; Goydos, James S.; Beitsch, Peter D.; Urist, Marshall M.; Ariyan, Stephan; Sussman, Jeffrey J.; Davidson, B. Scott; Gershenwald, Jeffrey E.; Hagendoorn, Lee J.; Stromberg, Arnold J.; Scoggins, Charles R.

    2016-01-01

    Purpose The Sunbelt Melanoma Trial is a prospective randomized trial evaluating the role of high-dose interferon alfa-2b therapy (HDI) or completion lymph node dissection (CLND) for patients with melanoma staged by sentinel lymph node (SLN) biopsy. Patients and Methods Patients were eligible if they were age 18 to 70 years with primary cutaneous melanoma ≥ 1.0 mm Breslow thickness and underwent SLN biopsy. In Protocol A, patients with a single tumor-positive lymph node after SLN biopsy underwent CLND and were randomly assigned to observation versus HDI. In Protocol B, patients with tumor-negative SLN by standard histopathology and immunohistochemistry underwent molecular staging by reverse transcriptase polymerase chain reaction (RT-PCR). Patients positive by RT-PCR were randomly assigned to observation versus CLND versus CLND+HDI. Primary end points were disease-free survival (DFS) and overall survival (OS). Results In the Protocol A intention-to-treat analysis, there were no significant differences in DFS (hazard ratio, 0.82; P = .45) or OS (hazard ratio, 1.10; P = .68) for patients randomly assigned to HDI versus observation. In the Protocol B intention-to-treat analysis, there were no significant differences in overall DFS (P = .069) or OS (P = .77) across the three randomized treatment arms. Similarly, efficacy analysis (excluding patients who did not receive the assigned treatment) did not demonstrate significant differences in DFS or OS in Protocol A or Protocol B. Median follow-up time was 71 months. Conclusion No survival benefit for adjuvant HDI in patients with a single positive SLN was found. Among patients with tumor-negative SLN by conventional pathology but with melanoma detected in the SLN by RT-PCR, there was no OS benefit for CLND or CLND+HDI. PMID:26858331

  10. Methotrexate, Doxorubicin, and Cisplatin (MAP) Plus Maintenance Pegylated Interferon Alfa-2b Versus MAP Alone in Patients With Resectable High-Grade Osteosarcoma and Good Histologic Response to Preoperative MAP: First Results of the EURAMOS-1 Good Response Randomized Controlled Trial

    PubMed Central

    Bielack, Stefan S.; Smeland, Sigbjørn; Whelan, Jeremy S.; Marina, Neyssa; Jovic, Gordana; Hook, Jane M.; Krailo, Mark D.; Gebhardt, Mark; Pápai, Zsuzsanna; Meyer, James; Nadel, Helen; Randall, R. Lor; Deffenbaugh, Claudia; Nagarajan, Rajaram; Brennan, Bernadette; Letson, G. Douglas; Teot, Lisa A.; Goorin, Allen; Baumhoer, Daniel; Kager, Leo; Werner, Mathias; Lau, Ching C.; Sundby Hall, Kirsten; Gelderblom, Hans; Meyers, Paul; Gorlick, Richard; Windhager, Reinhard; Helmke, Knut; Eriksson, Mikael; Hoogerbrugge, Peter M.; Schomberg, Paula; Tunn, Per-Ulf; Kühne, Thomas; Jürgens, Heribert; van den Berg, Henk; Böhling, Tom; Picton, Susan; Renard, Marleen; Reichardt, Peter; Gerss, Joachim; Butterfass-Bahloul, Trude; Morris, Carol; Hogendoorn, Pancras C.W.; Seddon, Beatrice; Calaminus, Gabriele; Michelagnoli, Maria; Dhooge, Catharina; Sydes, Matthew R.; Bernstein, Mark

    2015-01-01

    Purpose EURAMOS-1, an international randomized controlled trial, investigated maintenance therapy with pegylated interferon alfa-2b (IFN-α-2b) in patients whose osteosarcoma showed good histologic response (good response) to induction chemotherapy. Patients and Methods At diagnosis, patients age ≤ 40 years with resectable high-grade osteosarcoma were registered. Eligibility after surgery for good response random assignment included ≥ two cycles of preoperative MAP (methotrexate, doxorubicin, and cisplatin), macroscopically complete surgery of primary tumor, < 10% viable tumor, and no disease progression. These patients were randomly assigned to four additional cycles MAP with or without IFN-α-2b (0.5 to 1.0 μg/kg per week subcutaneously, after chemotherapy until 2 years postregistration). Outcome measures were event-free survival (EFS; primary) and overall survival and toxicity (secondary). Results Good response was reported in 1,041 of 2,260 registered patients; 716 consented to random assignment (MAP, n = 359; MAP plus IFN-α-2b, n = 357), with baseline characteristics balanced by arm. A total of 271 of 357 started IFN-α-2b; 105 stopped early, and 38 continued to receive treatment at data freeze. Refusal and toxicity were the main reasons for never starting IFN-α-2b and for stopping prematurely, respectively. Median IFN-α-2b duration, if started, was 67 weeks. A total of 133 of 268 patients who started IFN-α-2b and provided toxicity information reported grade ≥ 3 toxicity during IFN-α-2b treatment. With median follow-up of 44 months, 3-year EFS for all 716 randomly assigned patients was 76% (95% CI, 72% to 79%); 174 EFS events were reported (MAP, n = 93; MAP plus IFN-α-2b, n = 81). Hazard ratio was 0.83 (95% CI, 0.61 to 1.12; P = .214) from an adjusted Cox model. Conclusion At the preplanned analysis time, MAP plus IFN-α-2b was not statistically different from MAP alone. A considerable proportion of patients never started IFN-α-2b or stopped

  11. Southwest Oncology Group S0008: A Phase III Trial of High-Dose Interferon Alfa-2b Versus Cisplatin, Vinblastine, and Dacarbazine, Plus Interleukin-2 and Interferon in Patients With High-Risk Melanoma—An Intergroup Study of Cancer and Leukemia Group B, Children's Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group

    PubMed Central

    Flaherty, Lawrence E.; Othus, Megan; Atkins, Michael B.; Tuthill, Ralph J.; Thompson, John A.; Vetto, John T.; Haluska, Frank G.; Pappo, Alberto S.; Sosman, Jeffrey A.; Redman, Bruce G.; Moon, James; Ribas, Antoni; Kirkwood, John M.; Sondak, Vernon K.

    2014-01-01

    Purpose High-dose interferon (IFN) for 1 year (HDI) is the US Food and Drug Administration–approved adjuvant therapy for patients with high-risk melanoma. Efforts to modify IFN dose and schedule have not improved efficacy. We sought to determine whether a shorter course of biochemotherapy would be more effective. Patients and Methods S0008 (S0008: Chemotherapy Plus Biological Therapy in Treating Patients With Melanoma) was an Intergroup phase III trial that enrolled high-risk patients (stage IIIA-N2a through IIIC-N3), randomly assigning them to receive either HDI or biochemotherapy consisting of dacarbazine, cisplatin, vinblastine, interleukin-2, IFN alfa-2b (IFN-α-2b) and granulocyte colony-stimulating factor given every 21 days for three cycles. Coprimary end points were relapse-free survival (RFS) and overall survival (OS). Results In all, 432 patients were enrolled. Grade 3 and 4 adverse events occurred in 57% and 7% of HDI patients and 36% and 40% of biochemotherapy patients, respectively. At a median follow-up of 7.2 years, biochemotherapy improved RFS (hazard ratio [HR], 0.75; 95% CI, 0.58 to 0.97; P = .015), with a median RFS of 4.0 years (95% CI, 1.9 years to not reached [NR]) versus 1.9 years for HDI (95% CI, 1.2 to 2.8 years) and a 5-year RFS of 48% versus 39%. Median OS was not different (HR, 0.98; 95% CI, 0.74 to 1.31; P = .55), with a median OS of 9.9 years (95% CI, 4.62 years to NR) for biochemotherapy versus 6.7 years (95% CI, 4.5 years to NR) for HDI and a 5-year OS of 56% for both arms. Conclusion Biochemotherapy is a shorter, alternative adjuvant treatment for patients with high-risk melanoma that provides statistically significant improvement in RFS but no difference in OS and more toxicity compared with HDI. PMID:25332243

  12. Recombinant Interferon Alfa-2b in Treating Patients With Melanoma

    ClinicalTrials.gov

    2016-05-17

    Stage IA Skin Melanoma; Stage IB Skin Melanoma; Stage IIA Skin Melanoma; Stage IIB Skin Melanoma; Stage IIC Skin Melanoma; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Skin Melanoma

  13. DIC Complicating APL Successfully Treated With Recombinant Thrombomodulin Alfa.

    PubMed

    Saito, Aki; Okamoto, Yasuhiro; Seki, Yuko; Matsunaga, Manaka; Nakagawa, Shunsuke; Kodama, Yuichi; Nishikawa, Takuro; Tanabe, Takayuki; Kawano, Yoshifumi

    2016-08-01

    An 8-year-old boy developed anorexia, fatigue, and fever. Laboratory examination revealed a high white blood cell (WBC) count of 145×10/μL with 97.5% abnormal promyelocytic cells that contained Auer bodies. Faggot cells were seen. He was diagnosed with acute promyelocytic leukemia. Later, a chromosome analysis showed 46,XY,t(15;17)(q22;q12). Promyelocytic Leukemia-retinoic acid receptor α-fused gene and chimeric mRNA were confirmed by fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction, respectively. He was complicated with disseminated intravascular coagulation (DIC) and his fibrin and fibrinogen degradation product at the onset was 37.6 μg/mL. Human recombinant thrombomodulin (rTM) was started for DIC. After dexamethasone was administered at a dose of 8 mg/m to prevent all-trans retinoic acid syndrome on day 1, all-trans retinoic acid was started at a dose of 45 mg/m on day 4. Cytarabine (100 mg/m/d) and daunorubicin (45 mg/m/d) were started on day 9. The WBC count gradually increased to 270×10/μL on day 8, and then decreased beginning on day 9. DIC improved after the initiation of chemotherapy and only minor petechia was noted. DIC did not become worse even after rTM was stopped on day 8. The risk of DIC and bleeding is high in the early stage of treatment for acute promyelocytic leukemia, especially in patients with a high WBC count. In our patient, rTM may have prevented fatal DIC and made it possible to safely administer induction chemotherapy.

  14. [The treatment of chronic myeloleukemia with recombinant alfa-2 interferon].

    PubMed

    Strozha, I; Petukhov, V; Bondare, D; Feldmane, G; Duks, A; Teilane, I; Medne, I; Mauritsas, M; Grinberga, L

    1993-01-01

    A trial has been conducted of recombinant alpha 2-interferon (reaferon) used in 32 patients with Ph'[correction of Rh']-positive chronic myeloid leukemia (CML). A chronic stage was in 3, transient in 3 and blast in 1 patients. 25 CML patients were newly diagnosed. The treatment lasted from 2 months to 3 years. Clinicohematological remission was confirmed conventionally and by the degree of Ph'-positive clone reduction. An attempt is made to clarify the mechanism underlying the resistance to reaferon basing on the immunological data (detection of antireaferon neutralizing antibodies). The authors propose a combined treatment (myelosan plus reaferon) of CML which has obvious advantages over myelosan monotherapy.

  15. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2004-01-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Know- ledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: ABI-007, Ad.Egr.TNF.11D, adefovir dipivoxil, AdPEDF.11, AES-14, albumex, alefacept, alemtuzumab, aliskiren fumarate, alvimopan hydrate, aAminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, anakinra, anti-IL-12 MAb, aprepitant, atazanavir sulfate, atrasentan, avanafil; Banoxantrone, BG-12, bimatoprost, bortezomib, bosentan; Calcipotriol/betamethasone dipropionate, caspofungin acetate, CBT-1, ciclesonide, clofarabine, conivaptan hydrochloride, CpG-7909, C-Vax, Cypher; DA-8159, DAC:GLP-1, darbepoetin alfa, darifenacin, duloxetine hydrochloride; Eculizumab, efalizumab, efaproxiral sodium, EGF vaccine, eletriptan, epratuzumab, erlotinib hydrochloride, escitalopram oxalate, ETC-642, etoricoxib, everolimus, exenatide; Gefitinib, IV gamma-globulin; Human insulin, gamma-hydroxybutyrate sodium; IDN-6556, iguratimod, imatinib mesylate, indiplon, ixabepilone; Laquinimod, LB-80380, lidocaine/prilocaineliraglutide, lopinavir, lopinavir/ritonavir, lucinactant; MAb-14.18, melatonin, MLN-591-DM1; NC-531, neridronic acid, nesiritide, neutrophil-inhibitory factor, niacin/lovastatin; Oblimersen sodium, olcegepant, oral Insulin, ORV-105; Palonosetron hydrochloride, PAmAb, pegaptanib sodium, peginterferon alfa-2a, pegvisomant, perifosine, pexelizumab, phenoxodiol, phenserine tartrate, pimecrolimus, pramlintide acetate, pregabalin, PRO-542, prostate cancer vaccine, PT-141; Ramelteon, rasagiline mesilate, rDNA insulin, reslizumab, rh-Lactoferrin, ribamidine hydrochloride, rosuvastatin calcium; S-8184l, SC-1, sorafenib, St. John's Wort extract, SU-11248; Taxus, telbivudine, tenofovir disoproxil fumarate, teriparatide

  16. Alglucosidase alfa treatment alleviates liver disease in a mouse model of glycogen storage disease type IV.

    PubMed

    Yi, Haiqing; Gao, Fengqin; Austin, Stephanie; Kishnani, Priya S; Sun, Baodong

    2016-12-01

    Patients with progressive hepatic form of GSD IV often die of liver failure in early childhood. We tested the feasibility of using recombinant human acid-α glucosidase (rhGAA) for treating GSD IV. Weekly intravenously injection of rhGAA at 40 mg/kg for 4 weeks significantly reduced hepatic glycogen accumulation, lowered liver/body weight ratio, and reduced plasma ALP and ALT activities in GSD IV mice. Our data suggests that rhGAA is a potential therapy for GSD IV.

  17. Interleukin-2 Plus Interferon Alfa in Treating Adults With Metastatic Cancer

    ClinicalTrials.gov

    2011-05-10

    Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Precancerous/Nonmalignant Condition; Unspecified Adult Solid Tumor, Protocol Specific

  18. Interleukin-12 Followed by Interferon Alfa in Treating Patients With Advanced Cancer

    ClinicalTrials.gov

    2013-01-31

    Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Precancerous Condition; Unspecified Adult Solid Tumor, Protocol Specific

  19. Differential Dynamics of CALR Mutant Allele Burden in Myeloproliferative Neoplasms during Interferon Alfa Treatment

    PubMed Central

    Holmström, Morten O.; Thomassen, Mads; Kruse, Torben A; Pallisgaard, Niels; Larsen, Thomas S.; de Stricker, Karin; Skov, Vibe; Hasselbalch, Hans C.

    2016-01-01

    Discovery of somatic mutations in the calreticulin gene (CALR) has identified a subgroup of Philadelphia-negative chronic myeloproliferative neoplasms (MPN) with separate haematological characteristics and prognosis. CALR mutations serve as novel markers both of diagnostic value and as targets for monitoring molecular responses during therapy. Interferon-α (IFN) selectively targets the malignant clone in a subset of MPN patients and can induce both haematological and molecular remissions in CALR mutated essential thrombocythemia (ET) patients. We investigated the response to IFN in a cohort of 21 CALR mutated MPN patients including ET, prefibrotic primary myelofibrosis (pre-PMF), and primary myelofibrosis (PMF) with a median follow-up of 31 months. For evaluation of a molecular response, we developed highly sensitive quantitative PCR (qPCR) assays for monitoring the mutant allele burden of the two most prevalent CALR mutations (type 1 and type 2). Thirteen patients (62%) experienced a decrease in the mutant allele burden with a median decline of 29% from baseline. However, only four patients, including patients with ET, pre-PMF, and PMF diagnosis, achieved molecular responder (MR) status with >50% reduction in mutant allele burden according to European LeukemiaNet (ELN) guidelines. MR patients displayed significant differences in the dynamics of the CALR mutant load with regard to time to response and dynamics in mutant allele burden after discontinuation of IFN treatment. Furthermore, we highlight the prognostic value of the CALR mutant allele burden by showing a close association with leucocyte- and platelet counts, hemoglobin concentration, in addition to plasma lactate dehydrogenase (LDH) irrespective of molecular response and treatment status. PMID:27764253

  20. [Alfa and beta diversity of reptilian assemblages in Zapatosa wetland complex, Colombia].

    PubMed

    Medina-Rangel, Guido Fabián

    2011-06-01

    Diversity is a property of community that can described, characterized, and understood according to the functioning of ecosystems. To study the richness and local abundance and species replacement between habitats around the Zapatosa's wetland complex (El Cesar Department), I carried out four field trips between November of 2006 and October of 2007. A total of 640 sampling hours/man analyzed five habitat types chasmophyte forest, dry forest, riparian forest, palm-grove and tree-lined savanna; with the exception of the palm-grove sampled at its 75%, the others were sampled up to their 80%. I found 847 reptiles that were distributed in 48 species. The group with the highest number of species was Colubridae with 14, followed by Gekkonidae with five. Five endemic species and eight with some conservation threat grade at a national level are reported. The riparian forest was the richest and most abundant habitat with 34 species and 196 individuals. For each habitat, Colubridae had the highest number of species, followed by the families Polychrotidae, Gekkonidae and Teiidae, in that order. The reptile species composition was not different between the tree-lined savanna and the chasmophyte forest, but differed among the tree-lined savanna and the riparian forest, palm-grove and dry forest habitats. The most important differences in the species composition among almost all the habitats were influenced by the species Anolis tropidogaster and Gonatodes albogularis, and the higher occurrence of Stenocercus erythrogaster in the chasmophyte forest. The species replacement had an average value of 50%; the biggest amounts of shared species were the lizards, while the snake Leptodeira septentrionalis was the only one present in all habitat types. The forest grows-among-rocks showed the biggest complementarity and number of unique species compared to the other habitats. The wetland complex provides two thirds of the reptile's species reported until now for the Caribbean region, and more than 80% of those reported for the El Cesar department. This wetland complex seems to behave as a center for low land species concentration as it hosts a high proportion of species from those places.

  1. Bell's palsy associated with chronic HCV infection before and during peginterferon alfa and ribavirin therapy.

    PubMed

    Jabbari, Hossain; Fakharzadeh, Elham; Merat, Shahin; Zamini, Hedyeh; Sharifi, Amir Houshang

    2011-05-01

    Neuropsychiatric side effects of peg interferon-α (PEG-IFN-α) therapy consist of a large spectrum of symptoms. Organic personality syndrome, organic affective syndrome, psychotic manifestations and seizures are more common side effects of PEG-IFN-α whereas cranial neuropathy and movement disorders are less common. Bell's palsy is often idiopathic, but has been linked to some viral infections, particularly with herpes viruses. Other infections, such as human immunodeficiency virus infection and Lyme disease, may also lead to idiopathic facial paralysis. Neither acute nor chronic Hepatitis C infection has been implicated previously in Bell's palsy, but PEG-IFN-α may play a role. Two patients with CHC who developed Bell's palsy before and during treatment with PEG-IFN-α and Ribavirin are presented here.

  2. Enhanced anti-melanoma efficacy of interferon alfa-2b via inhibition of Shp2.

    PubMed

    Win-Piazza, Hla; Schneeberger, Valentina E; Chen, Liwei; Pernazza, Daniele; Lawrence, Harshani R; Sebti, Said M; Lawrence, Nicholas J; Wu, Jie

    2012-07-01

    Interferon-α2b (IFN-α2b) is used to treat melanoma but there is a need to improve its efficacy. IFN-α2b signaling requires STAT1/STAT2 tyrosine phosphorylation and is subject to negative regulation by phosphatases. In this study, we determined whether inhibition of the protein tyrosine phosphatase Shp2 could enhance IFN-α2b responses in human melanoma cells. Shp2 knockdown increased IFN-α2b-stimulated STAT1 Tyr-701 phosphorylation and ISRE-luciferase activity even though it did not affect STAT2 Tyr-690 phosphorylation in A375 cells. In A375 tumor xenografts, Shp2 knockdown enhanced the anti-melanoma effect of IFN-α2b. Furthermore, the Shp2 inhibitor SPI-112Me increased the IFN-α2b-induced STAT1 activation and anti-proliferative response in A375 and SK-MEL-2 cells. These results demonstrate that inhibition of Shp2 can enhance the anti-melanoma activity of IFN-α2b.

  3. Storage and treatment of SNF of Alfa class nuclear submarines: current status and problems

    SciTech Connect

    Ignatiev, Sviatoslav; Zabudko, Alexey; Pankratov, Dmitry; Somov, Ivan; Suvorov, Gennady

    2007-07-01

    Available in abstract form only. Full text of publication follows: The current status and main problems associated with storage, defueling and following treatment of spent nuclear fuel (SNF) of Nuclear Submarines (NS) with heavy liquid metal cooled reactors are considered. In the final analysis these solutions could be realized in the form of separate projects to be funded through national and bi- and multilateral funding in the framework of the international collaboration of the Russian Federation on complex utilization of NS and rehabilitation of contaminated objects allocated in the North-West region of Russia. (authors)

  4. [Tumor necrosis factor alfa in cardiovascular diseases: molecular biology and genetics].

    PubMed

    Fragoso Lona, José Manuel; Sierra Martínez, Mónica; Vargas Alarcón, Gilberto; Barrios Rodas, Angélica; Ramírez Bello, Julián

    2013-01-01

    Cardiovascular diseases are a major public health problem globally. In 1997, cardiovascular disease caused 41% of deaths in the United States. It has been reported that about 60 million people in the United States have some form of cardiovascular disease. These entities are chronic conditions initiated by a dysregulation of the immune response. One gene and its protein product -tumor necrosis factor a (TNF-α)- a powerful pleiotropic cytokine with multiple cellular functions, plays a role in the inflammation, initiation, development, susceptibility, severity, and response to treatment, etc. of coronary artery disease (CAD). The focus of the present review is to summarize recent evidence showing the biological role of TNF-α in the initiation and progression of endothelial dysfunction and complications of atherosclerosis, and as a genetic variation of TNF-α confer susceptibility, severity, and treatment response in CAD: ST-segment elevation myocardial infarction and non-ST segment elevation myocardial infarction, unstable angina, and coronary restenosis.

  5. The Arecibo Legacy Fast ALFA Survey: The Galaxy Population Detected by ALFALFA

    NASA Astrophysics Data System (ADS)

    Huang, Shan; Haynes, Martha P.; Giovanelli, Riccardo; Brinchmann, Jarle

    2012-09-01

    Making use of H I 21 cm line measurements from the ALFALFA survey (α.40) and photometry from the Sloan Digital Sky Survey (SDSS) and Galaxy Evolution Explorer (GALEX), we investigate the global scaling relations and fundamental planes linking stars and gas for a sample of 9417 common galaxies: the α.40-SDSS-GALEX sample. In addition to their H I properties derived from the ALFALFA data set, stellar masses (M *) and star formation rates (SFRs) are derived from fitting the UV-optical spectral energy distributions. 96% of the α.40-SDSS-GALEX galaxies belong to the blue cloud, with the average gas fraction f H I ≡ M H I /M * ~ 1.5. A transition in star formation (SF) properties is found whereby below M * ~ 109.5 M ⊙, the slope of the star-forming sequence changes, the dispersion in the specific star formation rate (SSFR) distribution increases, and the star formation efficiency (SFE) mildly increases with M *. The evolutionary track in the SSFR-M * diagram, as well as that in the color-magnitude diagram, is linked to the H I content; below this transition mass, the SF is regulated strongly by the H I. Comparison of H I and optically selected samples over the same restricted volume shows that the H I-selected population is less evolved and has overall higher SFR and SSFR at a given stellar mass, but lower SFE and extinction, suggesting either that a bottleneck exists in the H I-to-H2 conversion or that the process of SF in the very H I-dominated galaxies obeys an unusual, low-efficiency SF law. A trend is found that, for a given stellar mass, high gas fraction galaxies reside preferentially in dark matter halos with high spin parameters. Because it represents a full census of H I-bearing galaxies at z ~ 0, the scaling relations and fundamental planes derived for the ALFALFA population can be used to assess the H I detection rate by future blind H I surveys and intensity mapping experiments at higher redshift. Based on observations made with the Arecibo Observatory. The Arecibo Observatory is operated by SRI International under a cooperative agreement with the National Science Foundation (AST-1100968) and in alliance with Ana G. Méndez-Universidad Metropolitana and the Universities Space Research Association.

  6. CromixSun: un nuovo strumento per osservare il Sole in luce H-alfa

    NASA Astrophysics Data System (ADS)

    Lugli, Marcello

    2005-08-01

    The paper illustrates the possibility to achieve positive and useful results also beyond any imagination and out of any orthodox scheme. More than true what A. Einstein said: "Imagination is more important than knowledge". Only by using and assembling together the simplest filters that actual technology is able to produce it was possible to create a narrow bandpass H-alpha instrument which has nothing to envy other similar devices and probably, it may offer something more than others.

  7. A Double Blind Comparative Trial of Powdered Ginger Root, Hyosine Hydrobromide, and Cinnarizine in the Prophylaxis of Motion Sickness Induced by Cross Coupled Stimulation,

    DTIC Science & Technology

    A double blind laboratory trial was conducted to study the relative effectiveness of powdered ginger root (1G), hyosine (0.6 mg), cinnarizine (15 mg...range of tests was carried out in the period between ninety minutes and two hours after taking the drug. The study confirmed the effectiveness of...report that powdered root ginger is of value in the prophylaxis of motion sickness. Significant differences in the results of performance tests were

  8. Cytotoxicity of the Urokinase-Plasminogen Activator Inhibitor Carbamimidothioic Acid (4-Boronophenyl) Methyl Ester Hydrobromide (BC-11) on Triple-Negative MDA-MB231 Breast Cancer Cells.

    PubMed

    Longo, Alessandra; Librizzi, Mariangela; Chuckowree, Irina S; Baltus, Christine B; Spencer, John; Luparello, Claudio

    2015-05-28

    BC-11 is an easily synthesized simple thiouronium-substituted phenylboronic acid, which has been shown to be cytotoxic on triple negative MDA-MB231 breast cancer cells by inducing a perturbation of cell cycle when administered at a concentration equal to its ED50 at 72 h (117 μM). Exposure of cells to BC-11, either pre-absorbed with a soluble preparation of the N-terminal fragment of urokinase-plasminogen activator (uPa), or in co-treatment with two different EGFR inhibitors, indicated that: (i) BC-11 acts via binding to the N-terminus of the enzyme where uPa- and EGF receptor-recognizing sites are present, thereby abrogating the growth-sustaining effect resulting from receptor binding; and (ii) the co-presence of the EGFR inhibitor PD153035 potentiates BC-11's cytotoxicity. Exposure of cells to a higher concentration of BC-11 corresponding to its ED75 at 72 h (250 μM) caused additional impairment of mitochondrial activity, the production of reactive oxygen species and promotion of apoptosis. Therefore, BC-11 treatment appears to show potential for the development of this class of compounds in the prevention and/or therapy of "aggressive" breast carcinoma.

  9. Gateways to Clinical Trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2002-04-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the world's first drug discovery and development portal, and provides information on study design, treatments, conclusions and references. This issue focuses on the following selection of drugs: Abiciximab, acetylcholine chloride, acetylcysteine, alefacept, alemtuzumab, alicaforsen, alteplase, aminopterin, amoxicillin sodium, amphotericin B, anastrozole, argatroban monohydrate, arsenic trioxide, aspirin, atazanavir, atorvastatin, augmerosen, azathioprine; Benzylpenicillin, BMS-284756, botulinum toxin type A, botulinum toxin type B, BQ-123, budesonide, BXT-51072; Calcium folinate, carbamazepine, carboplatin, carmustine, ceftriaxone sodium, cefuroxime axetil, chorionic gonadotropin (human), cimetidine, ciprofloxacin hydrochloride, cisplatin, citalopram hydrobromide, cladribine, clarithromycin, clavulanic acid, clofarabine, clopidogrel hydrogensulfate, clotrimazole, CNI-1493, colesevelam hydrochloride, cyclophosphamide, cytarabine; Dalteparin sodium, daptomycin, darbepoetin alfa, debrisoquine sulfate, dexrazoxane, diaziquone, didanosine, docetaxel, donezepil, doxorubicin hydrochloride liposome injection, DX-9065a; Eberconazole, ecogramostim, eletriptan, enoxaparin sodium, epoetin, epoprostenol sodium, erlizumab, ertapenem sodium, ezetimibe; Fampridine, fenofibrate, filgrastim, fluconazole, fludarabine phosphate, fluorouracil, 5-fluorouracil/epinephrine, fondaparinux sodium, formoterol fumarate; Gabapentin, gemcitabine, gemfibrozil, glatiramer; Heparin sodium, homoharringtonine; Ibuprofen, iloprost, imatinib mesilate, imiquimod, interferon alpha-2b, interferon alpha-2c, interferon-beta; KW-6002; Lamotrigine, lanoteplase, metoprolol tartrate, mitoxantrone hydrochloride; Naproxen sodium, naratriptan, Natalizumab, nelfinavir mesilate

  10. Radiation Therapy and Cisplatin With or Without Epoetin Alfa in Treating Patients With Cervical Cancer and Anemia

    ClinicalTrials.gov

    2014-12-29

    Anemia; Cervical Adenocarcinoma; Cervical Adenosquamous Carcinoma; Cervical Squamous Cell Carcinoma; Drug Toxicity; Radiation Toxicity; Stage IIB Cervical Cancer; Stage III Cervical Cancer; Stage IVA Cervical Cancer

  11. Ectoine and hydroxyectoine inhibit thermal-induced aggregation and increase thermostability of recombinant human interferon Alfa2b.

    PubMed

    Salmannejad, Faranak; Nafissi-Varcheh, Nastaran

    2017-01-15

    This study is to investigate whether ectoines (ectoine and hydroxyectoine) can reduce aggregation of rhIFNα2b in aqueous solutions on thermal stress. The effect of thermal stress condition on the stability was therefore investigated using size exclusion-high performance liquid chromatography (SE-HPLC), different spectroscopic measurements, dynamic light scattering (DLS), electrophoresis, and differential scanning calorimetry (DSC). All experiments were performed in a sodium phosphate buffer system (100mM, pH7). The protein samples (100μg/ml) were incubated at 50°C for 14days in the absence or presence (1, 10, 20, and 100mM) of ectoines. In summary, thermal-induced aggregation was reduced in the presence of ectoines, regardless of the ectoines concentration in different periods of incubation time by analyzing with SE-HPLC and turbidity measurement. The inhibitory effect of ectoines on the aggregation was shown by other techniques used. The optimal ectoines concentration was 10mM for aggregation reduction, so samples containing of 10mM of ectoines were selected for further evaluation. Secondary structural and conformational stability increased in presence of ectoines as measured by far-UV circular dichroism and fluorescence spectroscopy, respectively. DSC showed slight increase in Tm of interferon in the presence of ectoines. Hydroxyectoine had superior protein-stabilizing properties than ectoine. In conclusion, this study demonstrates that ectoine and hydroxyectoine are highly effective excipients which can significantly reduce the thermal-induced aggregation of rhIFNα2b at low concentration.

  12. Sciami meteorici minori d'Agosto: le Piscis Austrinidi, le alfa Capricornidi e le delta Acquaridi meridionali

    NASA Astrophysics Data System (ADS)

    Sigismondi, Costantino

    2016-09-01

    The Piscis Austrinids, PAU, Alpha Capricornids CAP, and Southern Delta Acquarids SDA meteors are minor shower during the month of August, occurring during the most famous Perseids shower. These rare meteors are 'fossil' of their parent body (comet or asteroid) already destroyed since several thousands of years. Useful observations can give information on their dynamics and density.

  13. Protective Effect of Infliximab, a Tumor Necrosis Factor-Alfa Inhibitor, on Bleomycin-Induced Lung Fibrosis in Rats.

    PubMed

    Altintas, Nejat; Erboga, Mustafa; Aktas, Cevat; Bilir, Bulent; Aydin, Murat; Sengul, Aysun; Ates, Zehra; Topcu, Birol; Gurel, Ahmet

    2016-02-01

    We aimed to investigate the preventive effect of Infliximab (IFX), a tumor necrosis factor (TNF)-α inhibitor, on bleomycin (BLC)-induced lung fibrosis in rats. Rats were assigned into four groups as follows: I-BLC group, a single intra-tracheal BLC (2.5 mg/kg) was installed; II-control group, a single intra-tracheal saline was installed; III-IFX + BLC group, a single-dose IFX (7 mg/kg) was administered intraperitoneally (i.p.), 72 h before the intra-tracheal BLC installation; IV-IFX group, IFX (7 mg/kg) was administered alone i.p. on the same day with IFX + BLC group. All animals were sacrificed on the 14th day of BLC installation. Levels of tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, interleukin (IL)-6, periostin, YKL-40, nitric oxide (NO) in rat serum were measured, as well as, myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activity, and reduced glutathione (GSH), hydroxyproline, malondialdehyde (MDA) content in lung homogenates. Lung tissues were stained with hematoxylin and eosin (H&E) for quantitative histological evaluation. The inducible nitric oxide synthase (iNOS) expression and cell apoptosis in the lung tissues were determined quantitatively by immunohistochemical staining (INOS) and by TUNNEL staining, respectively. BLC installation worsened antioxidant status (such as SOD, CAT, GPx, GSH, MPO), while it increased the serum TNF-α, TGF-β, IL-6, periostin, YKL-40, and lipid peroxidation, and collagen deposition, measured by MDA and hydroxyproline, respectively. IFX pretreatment improved antioxidant status as well as BLC-induced lung pathological changes, while it decreased the TNF-α, TGF-β, IL-6, periostin, YKL-40, lipid peroxidation and collagen deposition. Finally, histological, immunohistochemical, and TUNNEL evidence also supported the ability of IFX to prevent BLC-induced lung fibrosis. The results of the present study indicate that IFX pretreatment can attenuate BLC-induced pulmonary fibrosis.

  14. Risk of Orthopedic Surgical Site Infections in Patients with Rheumatoid Arthritis Treated with Antitumor Necrosis Factor Alfa Therapy

    PubMed Central

    da Cunha, Bernardo Matos; Maria Henrique da Mota, Licia; dos Santos-Neto, Leopoldo Luiz

    2012-01-01

    Introduction. International guidelines recommend interruption of anti-TNF medications in the perioperative period, but there are no randomized trials to support such recommendation. Objectives. To study literature evidence assessing the risk of surgical site infections in orthopedic surgery patients with RA using anti-TNF drugs, compared to untreated patients or those using conventional DMARD. Methods. Systematic review of cohort studies is concerning surgical site infections in orthopedic procedures in patients with RA. Results. Three studies were selected. Only one was considered of high-quality, albeit with low statistical power. The review resulted in inconclusive data, since the best quality study showed no significant differences between groups, while others showed increased risk of infections in patients using anti-TNF medications. Conclusion. It is unclear whether patients with RA using anti-TNF medications are at increased risk of surgical site infections. Randomized controlled trials or new high quality observational studies are needed to clarify the issue. PMID:22500176

  15. [Oligosymptomatic alimentary tract perforation in course of Crohn's disease in patient treated with anti-TNF alfa antibodies].

    PubMed

    Jałocha, Łukasz; Wojtuń, Stanisław; Wojtkowiak, Marek; Błaszak, Antoni; Dyrla, Przemysław; Gil, Jerzy

    2009-05-01

    Successful Crohn's disease conservative treatment is often associated with use of few, sometimes new drugs. Their clinical use apart from inflammatory process decrease is associated with some risk. In the paper we report a case of 23-year-old woman suffering from Crohn's disease treated successfully with anti-TNF antibodies. Apart from successful anti-inflammatory there were observed not symptomatic perforation of the alimentary tract. Patients treated with strong anti-inflammatory drugs require especially careful monitoring also because of possibility of occurrence of not symptomatic life-threatening conditions.

  16. Alfa-lipoic acid protects testosterone secretion pathway and sperm quality against 4-tert-octylphenol induced reproductive toxicity.

    PubMed

    Othman, Azza I; El-Missiry, Mohamed A; Koriem, Khaled M; El-Sayed, Aml A

    2012-07-01

    The protective effect of α-lipoic acid (LA) (50 mg/kg bw) against 4-tert-octylphenol (OP) (50 mg/kg bw) induced reproductive toxicity in male rats was studied. LA was injected 1h prior to OP administration three times a week. OP caused significant increase in oxidative stress in hypothalamus and epididymal sperm, disturbed hormonal levels in serum, decreased sperm quality, increased DNA fragmentation and loss of 35 and 95 kDa proteins in sperm, as well as elevated proliferating index in testis. LA protected against oxidative stress through promoting the levels of glutathione and glutathione-S-transferase in hypothalamus and sperm. In addition, LA prevented the decrease in testosterone, dehydroepiandrosterone sulfate, 3β-hydroxysteroid dehydrogenase, and inhibited the elevations in sex-hormone-binding globulin levels and showed normal sperm quality. LA modulated proliferation of germ cell, protected against DNA fragmentation and maintained membrane protein organization in the sperm. In conclusion, LA normalized oxidative stress and protected testosterone synthesis pathway across hypothalamus-testicular axis and sperm quality indicating its defensive influence against OP-induced oxidative reproductive dysfunction in male rats.

  17. Cryoglobulinemia-related vasculitis during effective anti-HCV treatment with PEG-interferon alfa-2b.

    PubMed

    De Blasi, T; Aguilar Marucco, D; Cariti, G; Maiello, A; De Rosa, F G; Di Perri, G

    2008-06-01

    HCV infection may be related to many extrahepatic manifestations including mixed cryoglobulinemia (MC). Clinical manifestations commonly associated to MC include arthralgia, purpura, vasculitis, peripheral neuropathy and renal function abnormalities. Treatment with interferon often leads to remission, especially in virological responders, or to disappearance of MC-related clinical manifestations. We report on a patient with chronic hepatitis C, deficit of G6P-DH, type II MC, who developed a cryoglobulinemic vasculitis with purpura, renal impairment and arterial hypertension, during treatment with PEG-interferon a-2b plus amantadine. The occurrence of purpuric lesions and MC-related nephropathy with increased cryocrit despite negative viremia, in a patient previously asymptomatic, during interferon treatment, is unusual.

  18. Evaluation of prognostic factors for Peg Interferon alfa-2b plus ribavirin treatment on HCV infected patients in Pakistan.

    PubMed

    Aziz, Hafsa; Gil, Muzaffar Latif; Waheed, Yasir; Adeeb, Uzama; Raza, Abida; Bilal, Iram; Athar, Muhammad Amin

    2011-04-01

    The effective standard therapeutic regimen for patients with chronic hepatitis C is pegylated interferon plus ribavirin. The efficacy of treatment in chronic hepatitis C is defined as absence of detectable virus at six months after treatment. Analysis of patient dependent and virus related factors that enable us to predict the response to antiviral treatment is very important. We prospectively studied 403 patients who received PEG-IFN alpha-2b 1.5 μg/kg/body weight plus ribavirin. Treatment was administrated for 24 weeks and 48 weeks for hepatitis C virus (HCV) genotypes 3 and 1, respectively. Out of 403 treated patients, 301 patients (74.7%) showed a sustained virologic response (SVR). Seven variables (age, sex, ethnic group, pretreatment viral load, HCV genotyping and pretreatment ALT) were chosen as possible predictors of SVR and were analysed by means of univariable and multivariable logistic regression analysis. Five variables were statistically significant (p<0.005) on univariable analysis: age, ethnic group, pretreatment viral load, response rate at week 4, and HCV genotype. In multivariable analysis independent factors associated with SVR were low pretreatment viral load (1.97; 95%CI, 1.06-3.66; p=0.03) and attainment of rapid virological response (RVR) (7.19; 95%CI, 4.15-12.45; p<0.001). Our findings support the association between viral load and SVR to PEG-IFN-alpha-2b plus ribavirin therapy. No achievement of RVR is an unfavorable marker for SVR. These findings suggest that all patients considered for treatment should have quantification of serum HCV RNA levels. The result can be used to counsel patients on the likelihood of achieving SVR and may influence the patient's decision on treatment. Future studies should confirm and explore this observation in other ethnic groups and in relation to HCV genotypes 1 and 3.

  19. [Study of the transplacental transfer of interferon alfa-2a on the model of isolated perfused cotyledon].

    PubMed

    Dumas, J C; Giroux, M; Teixeira, M G; Puel, J; Waysbort, A; Berrebi, A; Houin, G; Grandjean, H

    1993-01-01

    Interferon can be used for VIH+ pregnant women, to decrease materno-fetal contamination. Added to maternal circulation, its behaviour was studied by human placental cotyledon ex vivo perfusion. Human recombinant IFN 2a and reference substance 3H2O were injected in intervillous chamber and their behaviours in venous fetal and maternal circulations was followed. At steady state, in fetal circulation 3H2O concentration was 37% of injected rate whereas no IFN transfer rate was observed. In both venous circulations IFN amounts were lower than injected ones 56% versus of 82% for water (p < 0.05). IFN didn't cross placental filter and disappeared partially during placental contact.

  20. Understanding early serum hepatitis D virus and HBsAg kinetics during pegylated interferon-alfa therapy via mathematical modeling

    PubMed Central

    Guedj, Jeremie; Rotman, Yaron; Cotler, Scott J.; Koh, Christopher; Schmid, Peter; Albrecht, Jeff; Haynes-Williams, Vanessa; Liang, Jake T.; Hoofnagle, Jay H.; Heller, Theo; Dahari, Harel

    2014-01-01

    There is little information on the early kinetics of hepatitis delta virus (HDV) and hepatitis B surface antigen (HBsAg) during interferon-α therapy. Here a mathematical model was developed and fitted to frequent HDV and HBsAg kinetic data from 10 patients during the first 28 weeks of pegylated-interferon-α2a (peg-IFN) therapy. Three patients achieved a complete virological response (CVR), defined as undetectable HDV 6 months after treatment stopped with loss of HBsAg and anti-HBsAg seroconversion. After initiation of therapy a median delay of 9 days (interquartile range IQR:[5;15]) was observed with no significant changes in HDV level. Thereafter, HDV declined in a biphasic manner, where a rapid first-phase lasting for 25 days (IQR:[23;58]) was followed by a slower or plateau second-phase. The model predicts that the main effect of peg-IFN is to reduce HDV production/release with a median effectiveness of 96% (IQR:[93;99.8]). Median serum HDV half-life (t1/2) was estimated to 2.9 days (IQR:[1.5;5.3]) with pretreatment production and clearance of about 1010 (IQR:[109.8-1010.8]) virions/day. None of the patients with flat 2nd phase in HDV achieved CVR. HBsAg kinetics of decline paralleled the second-phase of HDV decline consistent with HBsAg-productive-infected cells being the main source of production of HDV, with a median t1/2 of 135 days (IQR:[20-460]. The interferon lambda-3 polymorphism (rs12979860) was not associated with kinetic parameters. Conclusions Modeling results provide insights into HDV-host dynamics, the relationship between serum HBsAg levels and HBsAg-infected cells, IFN's mode of action and its effectiveness. The observation that a flat second phase in HDV and HBsAg kinetics was associated with failure to achieve CVR provides the basis to develop early stopping rules during peg-IFN treatment in HDV-infected patients. PMID:25098971

  1. Alfa-glucosidase-inhibiting activity of some Mexican plants used in the treatment of type 2 diabetes.

    PubMed

    Andrade-Cetto, Adolfo; Becerra-Jiménez, Jaime; Cárdenas-Vázquez, René

    2008-02-28

    Type 2 diabetes is an endocrine disease, which accounts for 9% of deaths worldwide. The aim of oral therapy is to reach normoglycemia to prevent later complications. Among glucose-lowering medications, alpha-glucosidase inhibitors delay the absorption of ingested carbohydrates, reducing the postprandial glucose and insulin peaks. In the present study, we tested the butanolic extracts of four Mexican plants with respect to their alpha-glucosidase inhibition activity, without excluding other possible mechanisms of action. The plants Cecropia obtusifolia Bertol., Equisetum myriochaetum Schlecht & Cham, Acosmium panamense (Benth.) Yacolev and Malmea depressa (Baill) R.E. Fries are used in traditional medicine to treat type 2 diabetes. In previous studies, we have demonstrated these plants' hypoglycemic activity and determined the phytochemical composition of their extracts. Our results in n-STZ diabetic rats loaded with maltose showed that Malmea and Acosmium extracts decreased plasma glucose significantly from 30 min on resembling the effect of acarbose. Cecropia extract produced the highest reduction of plasma glucose, and at 90 min, the glucose level was lower than the fasting level, which suggests another mechanism of action. Equisetum did not exert any effect. In vitro assays of alpha-glucosidase activity showed an IC(50) of 14 microg/ml for Cecropia, 21 microg/ml for Malmea, and 109 microg/ml for Acosmium, which were lower than that of acarbose (128 microg/ml). Equisetum did not show any significant effect on this assay, either. These results contribute to understand the mechanism of action of these plants on glucose metabolism.

  2. Sialadenitis following low dose I-131 diagnostic thyroid scan with Thyrogen® (recombinant human thyroid stimulating hormone - thyrotropin alfa)

    PubMed Central

    Gonzalez, Marta E; Muttikkal, Thomas Jose Eluvathingal; Rehm, Patrice K

    2015-01-01

    Salivary dysfunction and sialadenitis are well known complications of radioiodine treatment for thyroid cancer. The parotid gland is more frequently affected and the salivary gland injury is dose related. The symptoms may develop shortly after therapeutic Iodine 131(I-131) administration or months later and progress with time. The development of unilateral parotiditis following a low dose, diagnostic I-131 scan performed following Thyrogen stimulation in a patient without prior history of sialadenitis is rare in our experience, and has not been reported in the medical literature. PMID:26622936

  3. [Designing of hybrid human interferon alfa-2 strain-producers and the use of enteropeptidase for obtaining N-terminal methionine-free interferons].

    PubMed

    Shirokov, D A; Riabichenko, V V; Akishina, R I; Ospel'nikova, T P; Glazunov, A V; Chestukhina, G G; Veĭko, V P

    2011-01-01

    A system for production of human interferon-alpha2a (IFN-alpha2a) and IFN-alpha2b lacking N-terminal methionine has been developed. Plasmids containing genes of hybrid IFN-alpha2 under the control of different promoters were constructed; a sequence encoding the enteropeptidase hydrolysis site being introduced in proximal part of the genes. As the result, 4 strains of Escherichia coli producing hybrid IFN-alpha2 have been obtained. The methodology for IFN-alpha2 renaturation, hydrolysis of its N-terminal part, chromatographic purification of N-terminal methionine-free IFN-alpha2 has been developed.

  4. Extended duration versus standard duration of peginterferon alfa-2a in treatment of chronic hepatitis B: A systematic review and meta-analysis.

    PubMed

    Wang, Zhengyan; Sun, Ling; Wu, Yuwan; Xia, Qing

    2016-04-01

    In the last decade, PEG-IFNa-2a has been widely used in the treatment of chronic hepatitis B (CHB). The current standard duration is 48 weeks; however, several studies based on small sample sizes have indicated that treatment extended beyond 48 weeks improved clinical outcomes than standard 48 weeks of therapy. Therefore, we performed a meta-analysis to compare the efficacy and safety of extended duration versus standard duration treatment with PEG-IFNa-2a monotherapy for patients with CHB. Four studies comprising of 350 patients were included in our study. Our analysis showed that extended treatment resulted in a higher HBsAg clearance rate compared with the standard treatment at the end of treatment, 24 and 48 weeks post-treatment [odds ratio (OR)=2.45, 95% confidence intervals (CI) (1.17-5.11), P=0.02; OR=3.17, 95% CI (1.62-6.21), P<0.01; OR=5.02, 95% CI (1.63-15.45), P<0.01, respectively]. Higher HBeAg seroconversion rates were also obtained in the extended treatment group than the standard treatment group at the end of treatment and 48 weeks post-treatment [OR=2.09, 95% CI (1.10-3.98), P=0.02, and OR=2.67, 95% CI (1.39-5.13), P<0.01, respectively]. In addition, extended treatment was superior to standard treatment in HBV-DNA inhibition rate at 48 weeks post-treatment [OR=3.15, 95% CI (1.51-6.57), P<0.01]. Therefore, extended treatment with PEG-IFNa-2a beyond 48 weeks may be a promising strategy to achieve higher rates of sustained HBV-DNA inhibition, HBeAg seroconversion and HBsAg clearance off-therapy for patients with CHB.

  5. Randomised clinical trial: escitalopram for the prevention of psychiatric adverse events during treatment with peginterferon-alfa-2a and ribavirin for chronic hepatitis C.

    PubMed

    de Knegt, R J; Bezemer, G; Van Gool, A R; Drenth, J P H; Hansen, B E; Droogleever Fortuyn, H A; Weegink, C J; Hengeveld, M W; Janssen, H L A

    2011-12-01

    BACKGROUND  Treatment of hepatitis C with peginterferon and ribavirin is associated with psychiatric side-effects, frequently necessitating dose reduction or therapy cessation. AIM  To assess the efficacy of prophylactic escitalopram to prevent psychiatric side-effects during peginterferon and ribavirin treatment in a randomised, double-blind, placebo-controlled trial. METHODS  Seventy-nine hepatitis C patients were treated with peginterferon and ribavirin. Patients received escitalopram (n = 40, 10 mg) or placebo (n = 39), which was initiated together with peginterferon and ribavirin. Primary outcomes were an increase of two points or more on the items reported sadness, inner tension and impaired concentration of the Montgomery-Asberg Depression Rating Scale, and hostile feelings of the Brief Anxiety Scale. Secondary outcome was the development of depression diagnosed by the Mini-International Neuropsychiatric Interview. Measurements were performed at baseline, week 4, 12 and 24 during anti-viral treatment, and 24 weeks thereafter. RESULTS  The incidence of psychiatric side-effects was significantly lower in patients treated with escitalopram compared with placebo for all primary and secondary outcomes, except for impaired concentration: reported sadness 27.5 vs. 48.7% (P = 0.052), inner tension 17.5 vs. 38.5% (P = 0.038), impaired concentration 55.0 vs. 66.7% (P = 0.288) and hostile feelings 22.5 vs. 43.6% (P = 0.046) (escitalopram vs. placebo, Chi-squared test). The sum scores of all four endpoints showed an overall beneficial effect of escitalopram (P = 0.009, Mann-Whitney U-test). Depression occurred in 12.5% of the patients in the escitalopram-group vs. 35.9% in the placebo-group (P = 0.015, Chi-squared test). CONCLUSIONS  Prophylactic treatment with escitalopram is effective in the prevention of psychiatric side-effects during interferon-based treatment of hepatitis C.

  6. ALTERED SENSITIVITY OF THE MOUSE FETUS TO IMPAIRED PROSTATIC BUD FORMATION BY DIOXIN: INFLUENCE OF GENETIC BACKGROUND AND NULL EXPRESSION OF TGF-ALFA AND EGF

    EPA Science Inventory

    Altered sensitivity of the mouse fetus to impaired prostatic bud formation by dioxin: Influence of genetic background and null expression of TGF and EGF.
    Rasmussen, N.T., Lin T-M., Fenton, S.E., Abbott, B.D. and R.E. Peterson.
    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)...

  7. Control of proteinuria with increased doses of agalsidase alfa in a patient with Fabry disease with atypical genotype-phenotype expression.

    PubMed

    Paliouras, Christos; Aperis, Georgios; Lamprianou, Foteini; Ntetskas, Giorgos; Roufas, Konstantinos; Alivanis, Polichronis

    2015-01-01

    Fabry disease is a rare X-linked lysosomal storage disorder of glycosphingolipids, caused by the partial or complete deficiency of the lysosomal enzyme alpha-galactosidase A (a-Gal A). The missense mutation pN215S usually causes a milder form of the disease with isolated cardiac involvement. We report a case of a male Fabry patient with the pN215S mutation and a generalized disease. He suffered a relapse in proteinuria which responded to increased doses of the administered recombinant enzyme. Individualization of enzyme replacement therapy must be considered in selected cases characterized by clinical deterioration.

  8. A chronic subdural hematoma in a patient receiving combination therapy with pegylated interferon alfa-2b and ribavirin for chronic hepatitis C.

    PubMed

    Goto, Takashi; Ohshima, Shigetoshi; Miura, Kouichi; Shibuya, Tomomi; Sato, Wataru; Dohmen, Takahiro; Kamada, Kentaro; Kanata, Ryo; Sakai, Toshitaka; Chiba, Mitsuru; Sugimoto, Yuko; Minami, Shinichiro; Ohnishi, Hirohide

    2013-01-01

    A 70-year-old man who suffered from chronic hepatitis C was infected with HCV genotype 1 and exhibited a high viral load. He had hypertension and had consumed the equivalent of 50 g of ethanol per day. He was treated with pegylated interferon and ribavirin. After 51 weeks, he developed an unsteady gait while walking and demonstrated Barre's sign on the right foot and a headache. Contrast computed tomography showed a subdural hematoma with a mass effect. The patient was treated with drainage and aspiration surgery via a burr hole. Following the drainage procedure, there were no neurological sequelae. Treatment with pegylated interferon and ribavirin was discontinued. Fortunately, a sustained virological response was achieved.

  9. High-Dose Recombinant Interferon Alfa-2B, Ipilimumab, or Pembrolizumab in Treating Patients With Stage III-IV High Risk Melanoma That Has Been Removed by Surgery

    ClinicalTrials.gov

    2017-04-12

    Metastatic Non-Cutaneous Melanoma; Non-Cutaneous Melanoma; Recurrent Melanoma of the Skin; Recurrent Non-Cutaneous Melanoma; Stage III Mucosal Melanoma of the Head and Neck; Stage III Skin Melanoma; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Skin Melanoma; Stage IVA Mucosal Melanoma of the Head and Neck; Stage IVB Mucosal Melanoma of the Head and Neck; Stage IVC Mucosal Melanoma of the Head and Neck

  10. The Struggle to Study. Financial Implications for Adults Studying in London. A Research Report Funded by London's Four Open College Networks: ALFA, CAWLOC, GLEAN, and OCSL.

    ERIC Educational Resources Information Center

    Sims, Anne; Goddard, Ty

    The four Open College Networks in London assessed the climate in inner London for adult students who wished to return to education and training. The research focussed on: the extent to which recent legislative changes threatened adult participation in education and training; the abolition of the Inner London Education Authority (ILEA) and…

  11. [Anticholinergics for overactive bladder: does subtype selectivity play a role?].

    PubMed

    Michel, M C; Barendrecht, M M; Oelke, M

    2006-07-01

    Anticholinergics act in the treatment of overactive bladder by blocking muscarinic receptors of which five subtypes exist. Their desired effects occur via M(3) receptors, but a role for M(2) receptors is being discussed. Adverse effects such as dry mouth and constipation occur also via M(3) receptors, but M(2) and M(1) receptors can mediate side effects in the heart or on cognitive function, respectively. Therefore, an M(3)-selective drug such as darifenacin could theoretically be less effective but also have fewer cardiac or central nervous side effects. However, the limited available clinical data do not support a smaller efficacy or better general tolerability. The lack of adverse effects on cognitive function is well documented for darifenacin, but it cannot yet be determined definitively whether this discriminates it from other modern anticholinergics.

  12. Formulation and Evaluation of Galantamine Gel as Drug Reservoir in Transdermal Patch Delivery System

    PubMed Central

    Fong Yen, Woo; Basri, Mahiran; Ahmad, Mansor; Ismail, Maznah

    2015-01-01

    Galantamine hydrobromide is formulated in tablets and capsules prescribed through oral delivery for the treatment of Alzheimer's disease. However, oral delivery of drugs can cause severe side effects such as nausea, vomiting, and gastrointestinal disturbance. Transdermal delivery of galantamine hydrobromide could avoid these unwanted side effects. In this work, galantamine hydrobromide was formulated in gel drug reservoir which was then fabricated in the transdermal patch. The in vitro drug release studies revealed that the drug release from the donor chamber to receptor chamber of Franz diffusion cell was affected by the amount of polymer, amount of neutralizer, amount of drug, types of permeation enhancer, and amount of permeation enhancer. Visual observations of the gels showed that all formulated gels are translucent, homogeneous, smooth, and stable. These gels have pH in the suitable range for skin. The gel also showed high drug content uniformity. Hence, this formulation can be further used in the preparation of transdermal patch drug delivery system. PMID:25853145

  13. Incidental findings on brain MRI of cognitively normal first-degree descendants of patients with Alzheimer's disease: a cross-sectional analysis from the ALFA (Alzheimer and Families) project

    PubMed Central

    Brugulat-Serrat, Anna; Rojas, Santiago; Bargalló, Nuria; Conesa, Gerardo; Minguillón, Carolina; Fauria, Karine; Gramunt, Nina; Molinuevo, José Luis; Gispert, Juan Domingo

    2017-01-01

    Objectives To describe the prevalence of brain MRI incidental findings (IF) in a cohort of cognitively normal first-degree descendants of patients with Alzheimer's disease (AD). Design Cross-sectional observational study. Setting All scans were obtained with a 3.0 T scanner. Scans were evaluated by a single neuroradiologist and IF recorded and categorised. The presence of white matter hyperintensities (WMH) was determined with the Fazekas scale and reported as relevant if ≥2. Participants 575 participants (45–75 years) underwent high-resolution structural brain MRI. Participants were cognitively normal and scored over the respective cut-off values in all the following neuropsychological tests: Mini-Mental State Examination (≥26), Memory Impairment Screen (≥6), Time Orientation Subtest of the Barcelona Test II (≥68), verbal semantic fluency (naming animals ≥12). Clinical Dementia Rating (CDR) had to be 0. Results 155 participants (27.0%) presented with at least one IF. Relevant WMH were present in 7.8% of the participants, and vascular abnormalities, cyst and brain volume loss in 10.7%, 3.1% and 6.9% of the study volunteers, respectively. Neoplastic brain findings were found in 2.4% of participants and within these, meningiomas were the most common (1.7%) and more frequently found in women. A positive correlation between increasing age and the presence of IF was found. Additionally, brain atrophy greater than that expected by age was significantly more prevalent in participants without a parental history of AD. Conclusions Brain MRIs of healthy middle-aged participants show a relatively high prevalence of IF even when study participants have been screened for subtle cognitive alterations. Most of our participants are first-degree descendants of patients with AD, and therefore these results are of special relevance for novel imaging studies in the context of AD prevention in cognitively healthy middle-aged participants. Trial registration number NCT02198586. PMID:28341686

  14. Randomized comparison of double induction and timed-sequential induction to a "3 + 7" induction in adults with AML: long-term analysis of the Acute Leukemia French Association (ALFA) 9000 study.

    PubMed

    Castaigne, Sylvie; Chevret, Sylvie; Archimbaud, Eric; Fenaux, Pierre; Bordessoule, Dominique; Tilly, Hervé; de Revel, Thierry; Simon, Marc; Dupriez, Brigitte; Renoux, Michel; Janvier, Maud; Micléa, Jean-Michel; Thomas, Xavier; Bastard, Christian; Preudhomme, Claude; Bauters, Francis; Degos, Laurent; Dombret, Hervé

    2004-10-15

    Between 1990 and 1996, we conducted a randomized trial in adults with newly diagnosed acute myeloid leukemia (AML) in order to compare relapse-free interval (RFI) after double induction (arm B), timed-sequential induction (arm C), or control "3 + 7" induction (arm A). Patients achieving complete remission (CR) after induction +/- salvage received the same consolidation chemotherapy, which included a dosage stratification according to patient's age (younger or older than 50 years). This long-term analysis was performed in 592 patients (arm A/B/C, 197/198/197 patients). Overall CR rate was 76% without differences between the 3 arms, even if a salvage course was less frequently needed in arm B. Treatment-related mortality, either during the induction or the postremission phase, was not significantly higher in arms B and C than in arm A. Among the 449 CR patients, 250 relapsed (arm A/B/C, 90/87/73 patients) without significant differences in RFI in arms B and C versus arm A (P = .39 and .15, by the Gray test). However, when analyzing the 345 patients younger than 50, RFI was significantly improved in younger patients receiving timed-sequential induction (P = .038 by the Gray test), while not in those receiving double induction. Event-free survival and overall survival were similar in the 3 randomization arms.

  15. Fabrication and Test of MC/BZY Proton Conductor

    DTIC Science & Technology

    2014-01-01

    BaZr0.8Y0.2O2.9) electrolyte was made by classical solid state reaction. The staring precursors for BZY are BaCO3 (99.8%, Alfa Aesar), ZrO2 (99.7...Synthesis of Molten Carbonate and Infiltration Li/K and Li/Na carbonate were prepared by melting lithium carbonate (99%, Alfa Aesar) and potassium...carbonate (99%, Alfa Aesar) in 62:38 (mol%), lithium carbonate (99%, Alfa Aesar) and sodium carbonate (99%, Alfa Aesar) in 52:48 (mol%) at 650oC for 2

  16. Analysis of Dextromethorphan in Cough Drops and Syrups: A Medicinal Chemistry Laboratory

    ERIC Educational Resources Information Center

    Hamilton, Todd M.; Wiseman, Frank L., Jr.

    2009-01-01

    Fluorescence spectroscopy is used to determine the quantity of dextromethorphan hydrobromide (DM) in over-the-counter (OTC) cough drops and syrups. This experiment is appropriate for an undergraduate medicinal chemistry laboratory course when studying OTC medicines and active ingredients. Students prepare the cough drops and syrups for analysis,…

  17. Galantamine-loaded solid-lipid nanoparticles for enhanced brain delivery: preparation, characterization, in vitro and in vivo evaluations.

    PubMed

    Misra, Shubham; Chopra, Kanwaljit; Sinha, V R; Medhi, Bikash

    2016-05-01

    Galantamine hydrobromide, a promising acetylcholinesterase inhibitor is reported to be associated with cholinergic side effects. Its poor brain penetration results in lower bioavailability to the target site. With an aim to overcome these limitations, solid-lipid nanoparticulate formulation of galantamine hydrobromide was developed employing biodegradable and biocompatible components. The selected galantamine hydrobromide-loaded solid-lipid nanoparticles offered nanocolloidal with size lower than 100 nm and maximum drug entrapment 83.42 ± 0.63%. In vitro drug release from these spherical drug-loaded nanoparticles was observed to be greater than 90% for a period of 24 h in controlled manner. In vivo evaluations demonstrated significant memory restoration capability in cognitive deficit rats in comparison with naive drug. The developed carriers offered approximately twice bioavailability to that of plain drug. Hence, the galantamine hydrobromide-loaded solid-lipid nanoparticles can be a promising vehicle for safe and effective delivery especially in disease like Alzheimer's.

  18. VA and DoD Operating as One

    DTIC Science & Technology

    2011-01-25

    Dextromethorphan Hydrobromide U UD ŕ RFO DoD Menthol + Cetylpyridinium Chloride, lozenge, I USE AS DIRECTED FOR COUGH I DoD ACETAMINOPHEN. 325 MG. TABLET...ORAL TAKE 1·2 TABS EVERY 4-6HOUR DoD BISMUTH SU8SAUCYLATE. 262 MG. TAB C~ CHEW 2 TABS EVERY 1/2 HOUR DoD Menthol + Cetylpyridinium Chloride

  19. Effects of dopaminergic compounds on carbonic anhydrase isozymes I, II, and VI.

    PubMed

    Sentürk, Murat; Ekinci, Deniz; Göksu, Süleyman; Supuran, Claudiu T

    2012-06-01

    Studies on carbonic anhydrase (CA, EC 4.2.1.1) inhibitors have increased due to several therapeutic applications while there are few investigations on activators. Here we investigated CA inhibitory and activatory capacities of a series of dopaminergic compounds on human carbonic anhydrase (hCA) isozymes I, II, and VI. 2-Amino-1,2,3,4-tetrahydronaphthalene-6,7-diol hydrobromide and 2-amino-1,2,3,4-tetrahydronaphthalene-5,6-diol hydrobromide were found to show effective inhibitory action on hCA I and II whereas 2-amino-5,6-dibromoindan hydrobromide and 2-amino-5-bromoindan hydrobromide exhibited only moderate inhibition against both isoforms, being more effective inhibitors of hCA VI. K(i) values of the molecules 3-6 were in the range of 41.12-363 μM against hCA I, of 0.381-470 μM against hCA II and of 0.578-1.152 μM against hCA VI, respectively. Compound 7 behaved as a CA activator with K(A) values of 27.3 μM against hCA I, of 18.4 μM against hCA II and of 8.73 μM against hCA VI, respectively.

  20. Free-surface phenomena under low- and zero-gravity conditions

    NASA Technical Reports Server (NTRS)

    Coles, D.

    1985-01-01

    An apparatus to measure contact angle was constructed to exploit the proposed internal-corner criterion. If 2 alfa is the internal angle between two intersecting vertical planes and gamma is the contact angle, a meniscus at the corner rises to a finite height if alfa + gamma pi/2 and to an infinite height if alfa + gamma pi/2. The apparatus operates by decreasing the angle alfa from pi/2 until the meniscus height changes abruptly. A number of liquids are tested on glass and plexiglas.

  1. Evaluation of a Novel Rapid Test System for the Detection of Specific IgE to Hymenoptera Venoms

    PubMed Central

    Pfender, Nikolai; Lucassen, Ralf; Offermann, Nadine; Schulte-Pelkum, Johannes; Fooke, Margrit; Jakob, Thilo

    2012-01-01

    Background. The Allergy Lateral Flow Assay (ALFA) is a novel rapid assay for the detection of sIgE to allergens. The objective of this study is the evaluation of ALFA for the detection of sIgE to bee venom (BV) and wasp venom (WV) in insect venom allergic patients. Methods. Specific IgE to BV and WV was analyzed by ALFA, ALLERG-O-LIQ, and ImmunoCAP in 80 insect venom allergic patients and 60 control sera. Sensitivity and specificity of ALFA and correlation of ALFA and ImmunoCAP results were calculated. Results. The sensitivity/specificity of ALFA to the diagnosis was 100%/83% for BV and 82%/97% for WV. For insect venom allergic patients, the Spearman correlation coefficient for ALFA versus ImmunoCAP was 0.79 for BV and 0.80 for WV. However, significant differences in the negative control groups were observed. Conclusion. ALFA represents a simple, robust, and reliable tool for the rapid detection of sIgE to insect venoms. PMID:22500188

  2. Toxicity Assessment of Six Titanium Dioxide Nanoparticles in Human Epidermal Keratinocytes

    EPA Science Inventory

    Toxicity Assessment of Six Titanium Dioxide Nanoparticles in Human Epidermal Keratinocytes Nanoparticle uptake in cells may be an important determinant of their potential cytotoxic and inflammatory effects. Six commercial TiO2 NP (A=Alfa Aesar,10nm, A*=Alfa Aesar 32nm, B=P25 27...

  3. 49 CFR Appendix A to Part 593 - List of Vehicles Determined To Be Eligible for Importation

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 1994 156 Alfa Romeo Spider 1987 70 Alfa Romeo Spyder 1992 503 Alpina B12 5.0 Sedan 1988-1994 41 Alpina B12 2-door Coupe 1989-1996 43 Aston Martin Vanquish 2002-2004 430 Aston Martin Vantage 2006-2007...

  4. 77 FR 14593 - Unblocking of Specially Designated Nationals and Blocked Persons Pursuant to Executive Order 12978

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-12

    ... (Colombia) (individual) 3. CASQUETE VARGAS, Orlando, c/o ALFA PHARMA S.A., Bogota, Colombia; c/o... PHARMA DE COLOMBIA S.A., Bogota, Colombia; DOB 7 Jan 1957; Cedula No. 19270159 (Colombia) (individual) 4.../o ALFA PHARMA S.A., Bogota, Colombia; c/o PENTACOOP LTDA., Bogota, Colombia; c/o PENTA PHARMA...

  5. Airborne testing of three antimotion sickness preparations

    NASA Technical Reports Server (NTRS)

    Johnson, W. H.; Money, K. E.; Graybiel, A.

    1976-01-01

    Thirteen human volunteers were exposed to weekly flights in which standardized, steep turns were used to produce motion sickness. A combination of promethazine hydrochloride (25 mg) plus ephedrine sulphate (25 mg) was found to be equally as effective as the combination of 1-scopolamine hydrobromide (0.35 mg) plus d-amphetamine sulphate (5 mg). Droperidol (2.5 mg) was indistinguishable from the placebo. It was concluded that the treatment of choice for motion sickness is promethazine plus ephedrine.

  6. A novel sulfonamidoglycosylation of glycals.

    PubMed

    Colinas, Pedro A; Bravo, Rodolfo D

    2003-11-13

    [reaction: see text] The sulfonamidoglycosylation of benzylated glycals using a catalytic amount of triphenylphosphine hydrobromide proceeded in a highly stereoselective fashion to give the beta anomers with good to high yields. This process was demonstrated with d-galactal and d-glucal. Two of the new N-2-(deoxyglycosyl)sulfonamides were tested as inhibitors of tumor cell growth in vitro and showed antiproliferative properties in the micromolar range.

  7. Pharmacological modulation of cold-induced pain in cutaneous leiomyomata.

    PubMed

    Archer, C B; Whittaker, S; Greaves, M W

    1988-02-01

    In two patients with painful cutaneous leiomyomata, induction of pain by the application of an ice cube allowed assessment of a number of topical and systemic treatments aimed at reducing or preventing the pain. In one patient the alpha-adrenoceptor blocker, phenoxybenzamine alleviated cold-induced pain. In the second patient, topical 9% hyoscine hydrobromide (an anticholinergic agent) decreased pain induced by the ice cube, but was not helpful in reducing lesional pain due to cold weather.

  8. Evaluation of growth promotion and inhibition from mycobactins and nonmycobacterial siderophores (Desferrioxamine and FR160) in Mycobacterium aurum.

    PubMed Central

    Bosne-David, S; Bricard, L; Ramiandrasoa, F; DeRoussent, A; Kunesch, G; Andremont, A

    1997-01-01

    Heterologous mycobactins and the synthetic FR160 [N4-nonyl,N1,N8-bis(2,3-dihydroxybenzoyl) spermidine hydrobromide (C3 0H4 6N3, O6 Br)] promoted growth in Mycobacterium aurum in low concentrations. They were otherwise highly inhibitory, as opposed to homologous mycobactin, which was strictly growth promoting. Desferrioxamine B (Desferal) had no significant effect on growth. PMID:9257775

  9. Simultaneous determination of six toxic alkaloids in human plasma and urine using capillary zone electrophoresis coupled to time-of-flight mass spectrometry.

    PubMed

    Yu, Zhuhong; Wu, Zhongping; Gong, Feijun; Wong, Rong; Liang, Chen; Zhang, Yurong; Yu, Yunqiu

    2012-10-01

    A novel capillary zone electrophoresis separation coupled to electro spray ionization time-of-flight mass spectrometry method was developed for the simultaneous analysis of six toxic alkaloids: brucine, strychnine, atropine sulfate, anisodamine hydrobromide, scopolamine hydrobromide and anisodine hydrobromide in human plasma and urine. To obtain optimal sensitivity, a solid-phase extraction method using Oasis MCX cartridges (1 mL, 30 mg; Waters, USA) for the pretreatment of samples was used. All compounds were separated by capillary zone electrophoresis at 25 kV within 12 min in an uncoated fused-silica capillary of 75 μm id × 100 cm and were detected by time-of-flight mass spectrometry. This method was validated with regard to precision, accuracy, sensitivity, linear range, limit of detection (LOD), and limit of quantification (LOQ). In the plasma and urine samples, the linear calibration curves were obtained over the range of 0.50-100 ng/mL. The LOD and LOQ were 0.2-0.5 ng/mL and 0.5-1.0 ng/mL, respectively. The intra- and interday precision was better than 12% and 13%, respectively. Electrophoretic peaks could be identified by mass analysis.

  10. Management of female urinary incontinence: A survey of urogynaecologists' view on the NICE guideline.

    PubMed

    Balachandran, A; Monga, A; Duckett, J

    2016-05-01

    We conducted a survey to obtain the opinions of urogynaecologists regarding the National Institute for Health and Care Excellence or NICE 2013 urinary incontinence guideline and whether it would change their current practice. A closed format questionnaire was sent electronically to all members of the British Society of Urogynaecology or BSUG between January and March 2014. There were three major areas of disagreement. First, 70.2% of respondents disagreed that a multidisciplinary team review was necessary before invasive treatment for urinary incontinence. Second, 53.8% of respondents disagreed that preoperative urodynamic studies were not required in stress urinary incontinence diagnosed clinically. Third, 58.6% of respondents disagreed that oxybutynin, tolterodine and darifenacin should be used as first-line drug therapy for overactive bladder. The questionnaire demonstrates that there are significant concerns leading to more than a third of respondents not altering their current practice in line with the entire guideline.

  11. Treatment of dysautonomia associated with Parkinson's disease.

    PubMed

    Mostile, Giovanni; Jankovic, Joseph

    2009-12-01

    Non-motor symptoms are increasingly recognized to adversely impact on the quality of life of patients with in Parkinson's disease (PD), particularly as the disease progresses. Autonomic symptom severity in patients with PD seems to correlate with older age, greater disease severity, psychiatric complications, sleep disorders, and higher doses of dopaminergic medication. The following therapeutic strategies are frequently used in the treatment of PD-related dysautonomia: 1. Orthostatic hypotension: fludrocortisone, midodrine, and droxidopa; 2. Sialorrhea: glycopyrrolate and botulinun toxin injections; 3. Constipation: symbiotic yogurt and bulking agents, macrogol, lubiprostone, mosapride citrate and tegaserod, pyridostigmine bromide, botulinum toxin injections and sacral nerve stimulation; 4. Urinary frequency: oxybutynin, tolterodine, solifenacin, darifenacin, botulinum toxin injections; 5. Erectile dysfunction: sildenafil and other phosphodiesterase type 5 inhibitors. More effective symptomatic and pathogenesis-targeted therapies are needed to ameliorate the non-motor symptoms of PD that usually do not respond well to dopaminergic medications.

  12. Muscarinic receptor-mediated excitation of rat intracardiac ganglion neurons.

    PubMed

    Hirayama, Michiko; Ogata, Masanori; Kawamata, Tomoyuki; Ishibashi, Hitoshi

    2015-08-01

    Modulation of the membrane excitability of rat parasympathetic intracardiac ganglion neurons by muscarinic receptors was studied using an amphotericin B-perforated patch-clamp recording configuration. Activation of muscarinic receptors by oxotremorine-M (OxoM) depolarized the membrane, accompanied by repetitive action potentials. OxoM evoked inward currents under voltage-clamp conditions at a holding potential of -60 mV. Removal of extracellular Ca(2+) markedly increased the OxoM-induced current (IOxoM). The inward IOxoM in the absence of extracellular Ca(2+) was fully inhibited by removal of extracellular Na(+), indicating the involvement of non-selective cation channels. The IOxoM was inhibited by organic cation channel antagonists including SKF-96365 and ML-204. The IOxoM was antagonized by muscarinic receptor antagonists with the following potency: 4-DAMP > pirenzepine = darifenacin > methoctramine. Muscarinic toxin 7 (MT-7), a highly selective inhibitor for M1 receptor, produced partial inhibition of the IOxoM. In the presence of MT-7, concentration-inhibition curve of the M3-preferring antagonist darifenacin was shifted to the left. These results suggest the contribution of M1 and M3 receptors to the OxoM response. The IOxoM was inhibited by U-73122, a phospholipase C inhibitor. The membrane-permeable IP3 receptor blocker xestospongin C also inhibited the IOxoM. Furthermore, pretreatment with thapsigargin and BAPTA-AM inhibited the IOxoM, while KN-62, a blocker of Ca(2+)/calmodulin-dependent protein kinase II, had no effect. These results suggest that the activation mechanism involves a PLC pathway, release of Ca(2+) from intracellular Ca(2+) stores and calmodulin. The cation channels activated by muscarinic receptors may play an important role in neuronal membrane depolarization in rat intracardiac ganglion neurons.

  13. Pharmacological Characterization of a Novel Beta 3 Adrenergic Agonist, Vibegron: Evaluation of Antimuscarinic Receptor Selectivity for Combination Therapy for Overactive Bladder.

    PubMed

    Di Salvo, J; Nagabukuro, H; Wickham, L A; Abbadie, C; DeMartino, J A; Fitzmaurice, A; Gichuru, L; Kulick, A; Donnelly, M J; Jochnowitz, N; Hurley, A L; Pereira, A; Sanfiz, A; Veronin, G; Villa, K; Woods, J; Zamlynny, B; Zycband, E; Salituro, G M; Frenkl, T; Weber, A E; Edmondson, S D; Struthers, M

    2017-02-01

    Although the physiologic role of muscarinic receptors in bladder function and the therapeutic efficacy of muscarinic antagonists for the treatment of overactive bladder are well established, the role of β3-adrenergic receptors (β3ARs) and their potential as therapeutics is just emerging. In this manuscript, we characterized the pharmacology of a novel β3AR agonist vibegron (MK-4618, KRP-114V) and explored mechanistic interactions of β3AR agonism and muscarinic antagonism in urinary bladder function. Vibegron is a potent, selective full β3AR agonist across species, and it dose dependently increased bladder capacity, decreased micturition pressure, and increased bladder compliance in rhesus monkeys. The relaxation effect of vibegron was enhanced when combined with muscarinic antagonists, but differentially influenced by muscarinic receptor subtype selectivity. The effect was greater when vibegron was co-administered with tolterodine, a nonselective antagonist, compared with coadministration with darifenacin, a selective M3 antagonist. Furthermore, a synergistic effect for bladder strip relaxation was observed with the combination of a β3AR agonist and tolterodine in contrast to simple additivity with darifenacin. To determine expression in rhesus bladder, we employed a novel β3AR agonist probe, [(3)H]MRL-037, that selectively labels β3 receptors in both urothelium and detrusor smooth muscle. Vibegron administration caused a dose-dependent increase in circulating glycerol and fatty acid levels in rhesus and rat in vivo, suggesting these circulating lipids can be surrogate biomarkers. The translation of our observation to the clinic has yet to be determined, but the combination of β3AR agonists with M2/M3 antimuscarinics has the potential to redefine the standard of care for the pharmacological treatment of overactive bladder.

  14. Optimization and qualification of capillary zone electrophoresis method for glycoprotein isoform distribution of erythropoietin for quality control laboratory.

    PubMed

    Zhang, Junge; Chakraborty, Utpal; Villalobos, Annabelle P; Brown, John M; Foley, Joe P

    2009-10-15

    The European Pharmacopoeia (Ph. Eur.) monograph for Erythropoietin Concentrated Solution describes a capillary zone electrophoresis method for identification of recombinant human erythropoietin. However, this method has shown poor reproducibility due to inadequate capillary conditioning. We have modified the Ph. Eur. method to make it more robust and suitable for the quality control laboratory for the analysis of epoetin alfa and epoetin alfa after formulation with polysorbate 80. This study qualified the modified method by showing improved robustness and reproducibility. The study also characterized and qualified a secondary standard of epoetin alfa as a substitute for the primary standard, Ph. Eur. erythropoietin Biological Reference Preparation, which is available in limited supply. Four sets of analyses were performed to assess repeatability, intermediate precision, and the secondary standard. The results showed that the modified method is suitable for its intended purpose to test epoetin alfa and formulated epoetin alfa samples. The epoetin alfa secondary standard is a suitable substitute for the primary standard. Further, we developed a procedure for the removal of polysorbate 80 from formulated epoetin alfa, allowing the material to be analyzed by the modified Ph. Eur. method.

  15. Synthesis and Reactivity of Aluminized Fluorinated Acrylic (AIFA) Nanocomposites (Postprint)

    DTIC Science & Technology

    2012-06-18

    conditions for the synthesis of AlFA composites. Composite PAM-co-nAl (g) PFDMA (g) AIBN (g) Cyclohexanone (mL) AlFA-0 – 50.0 0.50 75 AlFA-10 5.0 45.0...250 mL of cyclohexanone and transferred to the reaction vessel and stirred (235 rpm). A nitrogen atmosphere was established and maintained in the reac...for 4 h. The functionalized particles were iso lated by vacuum filtration over a 0.2 lm PTFE membrane (Cole Parmer) and washed with cyclohexanone and

  16. [Intragenic deletions of NRXN1: three new case reports and a review of the phenotype].

    PubMed

    Galán-Sánchez, Francisco; Esteban-Cantó, Vanessa; Blaya-Fernández, Pedro; Jadraque-Rodríguez, Rocío; Manchón-Trives, Irene; Alcaraz-Más, Luis

    2015-03-01

    Objetivo. Aportar datos sobre el fenotipo determinado por las microdeleciones de los exones alfa del gen NRXN1. Casos clinicos. Se estudian tres casos neuropediatricos con microdeleciones intragenicas NRXN1 alfa. El fenotipo en estos tres casos es inespecifico, con retraso mental leve-moderado, trastornos de comportamiento y escasos rasgos dismorficos o malformaciones. Conclusion. El fenotipo encontrado en las microdeleciones de los exones alfa del gen NRXN1 es claramente distinguible del fenotipo encontrado en las microdeleciones de los exones beta, con macrocefalia, epilepsia y retraso mental.

  17. Myelodysplastic Syndromes

    MedlinePlus

    ... as fatigue and to prevent bleeding and infections. Blood transfusions Blood transfusions can be used to replace red blood cells, ... darbepoetin alfa (Aranesp), can reduce the need for blood transfusions by increasing red blood cells. Others may help ...

  18. Simeprevir

    MedlinePlus

    Simeprevir is used along with ribavirin (Copegus, Rebetol) and peginterferon alfa (Pegasys) to treat chronic hepatitis C (an ongoing viral infection that damages the liver). Simeprevir is in a class of medications called protease ...

  19. 32. VIEW LOOKING INSIDE 'BRAVO' SILO. GRAFFITI IS YELLOWCOLORED LION, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    32. VIEW LOOKING INSIDE 'BRAVO' SILO. GRAFFITI IS YELLOW-COLORED LION, SAME AS IN 'ALFA' Marilyn Ziemer, photographer, March 1988 - Mount Gleason Nike Missile Site, Angeles National Forest, South of Soledad Canyon, Sylmar, Los Angeles County, CA

  20. Identification of mission sensitivities for high-power electric propulsion systems

    NASA Technical Reports Server (NTRS)

    Frisbee, Robert H.; Moeller, Robert C.

    2005-01-01

    This paper presents the results of mission analyses that expose various mission performance sensitivities and system advantages of the ALFA technology for a small but representative subset of nuclear electric propulsion (NEP) missions considered under NASA's Project Prometheus.

  1. Training Strategy: Computer Education for Teachers in Uruguay.

    ERIC Educational Resources Information Center

    Grunberg, Jorge

    1987-01-01

    Described is the Alfa Project in Uruguay, designed to integrate computer education into secondary schools through teacher-training. Both teacher-users and teacher-authors were considered. Course objectives, curriculum content, and teaching guidelines are presented. (MNS)

  2. Sofosbuvir

    MedlinePlus

    ... medication (peginterferon alfa [Pegasys] to treat chronic hepatitis C (an ongoing viral infection that damages the liver). ... Rebetol) in people with liver cancer and hepatitis C infection who are waiting for a liver transplant ...

  3. Rapid Gel Cast Prototyping of Complex Paraelectric (Ba,Sr)TiO(3)/MgO Composites

    DTIC Science & Technology

    2003-04-03

    40 wt% BaO. 55Sro.45TiO 3 / 60 wt% MgO (see ref. 1) MgCO 3 (Alfa Aesar, MA) + 3 wt% oxalic acid (Fisher Scientific, NY) MgO (Alfa Aesar, MA...the particles with oxalic acid to produce a thin surface layer of magnesium oxalate (cf. Figure 3b). Figure 3. Green body interior a) 40wt% Ba

  4. Stereocontrolled semi-syntheses of deguelin and tephrosin.

    PubMed

    Russell, David A; Freudenreich, Julien J; Ciardiello, Joe J; Sore, Hannah F; Spring, David R

    2017-02-21

    We describe stereocontrolled semi-syntheses of deguelin and tephrosin, anti-cancer rotenoids isolated from Tephrosia vogelii. Firstly, we present a new two-step transformation of rotenone into rot-2'-enonic acid via a zinc-mediated ring opening of rotenone hydrobromide. Secondly, following conversion of rot-2'-enonic acid into deguelin, a chromium-mediated hydroxylation provides tephrosin as a single diastereoisomer. An Étard-like reaction mechanism is proposed to account for the stereochemical outcome. Our syntheses of deguelin and tephrosin are operationally simple, scalable and high yielding, offering considerable advantages over previous methods.

  5. Influence of mixed-ligand complexes on retention and distribution of radioniobium in mice

    SciTech Connect

    Gachalyi, A.; Namenyi, J.; Szegedi, I.; Varga, L.P.

    1987-11-01

    The individual effects of desferrioxamine B (DFOA), Na3Ca diethylenetriaminepentaacetic acid (DTPA), Na-salicylate, DL-penicillamine, and 2-aminoethylisothiouronium bromide hydrobromide, as well as the effect of mixed-ligand treatment on the retention and elimination of /sup 95/Nb in mice have been examined. It was found that /sup 95/Nb could easily be mobilized by a single dose of DFOA, but the best result was obtained with the DFOA and DTPA combination. Mixed-ligand treatment did not change the deposition characteristics and translocation kinetics of /sup 95/Nb.

  6. Crystal structures and related to noncentrosymmetricity properties of 4-aminomorpholinium salts

    NASA Astrophysics Data System (ADS)

    Owczarek, Magdalena; Miniewicz, Andrzej; Szklarz, Przemysław; Jakubas, Ryszard

    2016-11-01

    The performed analysis of crystal structures deposited in Cambridge Structural Database shows that simple salts of amines with N-attached six-membered aliphatic ring favor an acentric arrangement of molecules in a solid state and, therefore, might be suitable candidates for applications that require piezoelectric, ferroelectric, or second-order nonlinear optical properties. Herein we report that hydrochloride and hydrobromide of 4-aminomorpholine indeed crystallize in polar (Pca21) and non-centrosymmetric (C2221) space groups, respectively-the feature that gives rise to their nonlinear properties. While dielectric spectroscopy confirms piezoelectric nature of the hydrochloride salt, second harmonic generation measurements unequivocally prove nonlinear optical properties of both analyzed compounds.

  7. Experimental Papillary Necrosis of the Kidney

    PubMed Central

    Solez, K.; Miller, M.; Quarles, P. A.; Finer, P. M.; Heptinstall, R. H.

    1974-01-01

    To test the thesis that vasoconstriction plays a significant role in the pathogenesis of papillary necrosis caused by bromoethylamine hydrobromide (BEA), medullary plasma flow was determined in rats treated with BEA. Medullary blood flow was normal ½ to 1 hour after BEA treatment, and was actually elevated 6 hours after BEA. There was no increase in plasma levels of prostaglandins A and E, which would have been expected if there had been medullary ischemia. Pretreatment with reserpine, which inhibited the development of papillary necrosis, had little effect on medullary plasma flow. These observations do not support the notion that vasoconstriction is the mechanism by which BEA causes papillary necrosis. PMID:4472110

  8. Failure of MK-801 to suppress D1 receptor-mediated induction of locomotor activity and striatal preprotachykinin mRNA expression in the dopamine-depleted rat.

    PubMed

    Campbell, B M; Kreipke, C W; Walker, P D

    2006-01-01

    N-methyl-D-aspartate receptor antagonism exerts suppressive influences over dopamine D1 receptor-mediated striatal gene expression and locomotor behavior in the intact rat. The present study examined the effects of the N-methyl-D-aspartate receptor antagonist MK-801 on locomotor activity and striatal preprotachykinin mRNA expression stimulated by the D1 agonist (+/-)6-chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide in rats with bilateral dopamine lesions. Two months after neonatal dopamine lesions with 6-hydroxydopamine, rats were challenged with (+/-)6-chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (1.0 mg/kg) 15 min after administration of the N-methyl-D-aspartate receptor antagonist MK-801 (0.1 mg/kg). In the intact rat, MK-801 prevented the induction of striatal preprotachykinin mRNA by D1 agonism. Similarly, direct infusion of (+/-)6-chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (3.0 microg) into the intact striatum produced an increase in locomotor activity that was suppressed by MK-801 (1.0 microg) co-infusion. In the dopamine-depleted rat, MK-801 (0.1 mg/kg) administered prior to (+/-)6-chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (1.0 mg/kg) increased, rather than suppressed, striatal preprotachykinin mRNA levels. Intrastriatal infusion of MK-801 (1.0 microg) failed to inhibit D1-mediated induction of motor activity in dopamine-depleted animals. Together, these data provide further support that N-methyl-D-aspartate receptor antagonists lose their ability to block D1-mediated behavioral activation following dopamine depletion. The activation, rather than suppression, of tachykinin neurons of the direct striatonigral pathway may play a facilitatory role in this mechanism.

  9. Evidence for a M1 muscarinic receptor on the endothelium of human pulmonary veins

    PubMed Central

    Walch, Laurence; Gascard, Jean-Pierre; Dulmet, Elisabeth; Brink, Charles; Norel, Xavier

    2000-01-01

    To characterize the muscarinic receptors on human pulmonary veins associated with the acetylcholine (ACh)-induced relaxation, isolated venous and arterial preparations were pre-contracted with noradrenaline (10 μM) and were subsequently challenged with ACh in the absence or presence of selective muscarinic antagonists.ACh relaxed venous preparations derived from human lung with a pD2 value of 5.82±0.09 (n=16). In venous preparations where the endothelium had been removed, the ACh relaxations were abolished (n=4). ACh relaxed arterial preparations with a pD2 value of 7.06±0.14 (n=5).Atropine (1 μM), the non selective antagonist for muscarinic receptors, inhibited ACh-induced relaxations in human pulmonary veins. The affinity value (pKB value) for atropine was: 8.64±0.10 (n=5). The selective muscarinic antagonists (darifenacin (M3), himbacine (M2,M4), methoctramine (M2) and pFHHSiD (M1,M3)) also inhibited ACh-induced relaxations in venous preparations. The pKB values obtained for these antagonists were not those predicted for the involvement of M2–5 receptors in the ACh-induced relaxation in human pulmonary veins.The pKB value for darifenacin (1 μM) was significantly greater in human pulmonary arterial (8.63±0.14) than in venous (7.41±0.20) preparations derived from three lung samples.In human pulmonary veins, the pKB values for pirenzepine (0.5 and 1 μM), a selective antagonist for M1 receptors, were: 7.89±0.24 (n=7) and 8.18±0.22 (n=5), respectively. In the venous preparations, the pKB values derived from the functional studies with all the different muscarinic antagonists used were correlated (r=0.89; P=0.04; slope=0.78) with the affinity values (pKi values) previously published for human cloned m1 receptors in CHO cells.These results suggest that the relaxations induced by ACh are due to the activation of M1 receptors on endothelial cells in isolated human pulmonary veins. PMID:10781000

  10. Alternative to Ph. Eur. pour-plate method for detection of microbial contamination in non-sterile pharmaceutical preparations.

    PubMed

    Palicz, A; Paul, A; Hofmann, A; Denzel, K

    2016-01-01

    The current European Pharmacopoeia (Ph. Eur.) texts for Interferon (IFN)-alfa-2 include a nonspecific photometric protein assay using albumin as calibrator and a highly variable cell-based assay for the potency determination of the protective effects. A request was expressed by the Official Medicines Control Laboratories (OMCLs) for improved methods for the batch control of recombinant interferon alfa-2 bulk and market surveillance testing of finished products, including those formulated with Human Serum Albumin (HSA). A HPLC method was developed at the Medical Products Agency (MPA, Sweden) for the testing of IFN-alfa-2 products. An initial collaborative study run under the Biological Standardisation Programme (BSP; study code BSP039) revealed the need for minor changes to improve linearity of the calibration curves, assay reproducibility and robustness. The goal of the collaborative study, coded BSP071, was to transfer and further validate this improved HPLC method. Ten laboratories participated in the study. Four marketed IFN-alfa-2 preparations (one containing HSA) together with the Ph. Eur. Chemical Reference Substance (CRS) for IFN-alfa-2a and IFN-alfa-2b, and in-house reference standards from two manufacturers were used for the quantitative assay. The modified method was successfully transferred to all laboratories despite local variation in equipment. The resolution between the main and the oxidised forms of IFN-alfa-2 was improved compared to the results from the BSP039 study. The improved method even allowed partial resolution of an extra peak after the principal peak. Symmetry of the main IFN peak was acceptable for all samples in all laboratories. Calibration curves established with the Ph. Eur. IFN-alfa-2a and IFN-alfa-2b CRSs showed excellent linearity with intercepts close to the origin and coefficients of determination greater than 0.9995. Assay repeatability, intermediate precision and reproducibility varied with the tested sample within acceptable

  11. Matching-adjusted indirect comparisons of efficacy of BAY 81-8973 vs two recombinant factor VIII for the prophylactic treatment of severe hemophilia A

    PubMed Central

    Pocoski, Jennifer; Li, Nanxin; Ayyagari, Rajeev; Church, Nikki; Maas Enriquez, Monika; Xiang, Quer; Kelkar, Sneha; Du, Ella X; Wu, Eric Q; Xie, Jipan

    2016-01-01

    Background No head-to-head trials comparing recombinant factor VIII (rFVIII) products currently exist. This was a matching-adjusted indirect comparison (MAIC) study of efficacy of BAY 81-8973 with antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM) and turoctocog alfa for the prophylaxis of severe hemophilia A. Methods A systematic literature review was conducted to identify trials of rAHF-PFM and turoctocog alfa. Comparisons were conducted using BAY 81-8973 individual patient data (IPD) from LEOPOLD trials and published data from rAHF-PFM and turoctocog alfa trials. Differences in outcome reporting were reconciled using transformation of BAY 81-8973 IPD. Patients in pooled LEOPOLD trials were weighted to match baseline characteristics for rAHF-PFM or turoctocog alfa trials using MAICs. After matching, annualized bleed rates (ABRs) were compared using weighted t-tests. Results Two rAHF-PFM trials and one turoctocog alfa trial were identified. In these trials, rFVIIIs were dosed thrice weekly or every other day; in LEOPOLD trials, BAY 81-8973 was dosed twice- or thrice weekly. Three MAICs were conducted because the two rAHF-PFM trials calculated ABRs differently, matching for age, race, and weight (turoctocog alfa only). BAY 81-8973 had similar ABR of all bleeds vs rAHF-PFM (two trials: 4.8 vs 6.3, 1.9 vs 1.8 [square root transform]) and lower ABR of spontaneous bleeds and trauma bleeds (2.6 vs 4.1, 2.1 vs 4.7; both P<0.05). BAY 81-8973 showed lower ABR of all bleeds and spontaneous bleeds vs turoctocog alfa (4.3 vs 6.5, 2.8 vs 4.3; both P<0.05) and similar ABR of trauma bleeds (1.5 vs 1.6). In subgroup analysis, twice-weekly BAY 81-8973 had similar ABRs of all bleeds, spontaneous bleeds, and trauma bleeds compared to rAHF-PFM and turoctocog alfa. Conclusion This indirect comparison found that prophylaxis with BAY 81-8973, even including the lower frequency of two times a week and lower factor VIII consumption, has efficacy comparable to r

  12. Updates from guardian™: a comprehensive registration programme.

    PubMed

    Ozelo, Margareth C

    2015-12-01

    Turoctocog alfa is an approved B-domain truncated recombinant factor VIII concentrate for adults and children with haemophilia A. Clinical data for turoctocog alfa have been reported from the guardian(™) 1, guardian(™) 2 and guardian(™) 3 phase III trials. guardian(™) 1 and guardian(™) 3 phase III trials enrolled 150 adolescents/adults (≥ 12 yr), and 63 children (<12 yr), respectively, with previously treated severe haemophilia A and no history of inhibitors; 188 of these patients continued into the ongoing guardian(™) 2 extension trial. In the three trials, patients have received prophylaxis with turoctocog alfa three times weekly or every second day, with breakthrough bleeds resolved to an expected postinjection level of ≥ 0.50 IU/mL. No safety concerns have arisen, and no patients have developed confirmed inhibitors (primary endpoint). Indeed, no confirmed inhibitors have been detected in >200 patients treated for a cumulative total of >54,000 exposure days in the phase III trials. Pooled efficacy data show a favourable long-term effect of turoctocog alfa on annualised bleeding rate and a success rate for haemostatic response of 86%; 90% of bleeds were resolved with 1-2 doses. This article reviews the clinical development of turoctocog alfa with reference to the guardian(™) clinical programme, describing results obtained to date and ongoing trials.

  13. Effect of patient exclusion criteria on the efficacy of erythropoiesis-stimulating agents in patients with cancer-related anemia.

    PubMed

    Littlewood, Timothy J; Schenkel, Brad; Liss, Martin

    2005-05-01

    Comparison of the efficacies of erythropoiesis-stimulating agents (ESAs) between different clinical trials is becoming increasingly common, although differences in study design and populations evaluated can have a considerable effect on results. A comparison of two seemingly similar trials of ESAs, one of epoetin alfa and the other of epoetin beta, showed that only 27% of the 115 patients with hematologic malignancies who received epoetin alfa in the epoetin alfa trial met the inclusion criteria for the epoetin beta trial. The mean hemoglobin increase from baseline to week 16 of epoetin alfa therapy in the patients who met these inclusion criteria was 3.3 g/dl. This is substantially higher than the mean hemoglobin increase of 2.2 g/dl from baseline to week 16 of epoetin alfa therapy in the patients who did not meet the epoetin beta study inclusion criteria. These results demonstrate the considerable effects that exclusion criteria can have on trial results and highlight the value of scrutinizing the study design details of clinical trials before comparing outcome data between trials.

  14. Using an open source observational tool to measure the influence of the doctor's consulting style and the computer system on the outcomes of the clinical consultation.

    PubMed

    De Lusignan, Simon; Kumarapeli, Pushpa; Debar, Safia; Kushniruk, Andre W; Pearce, Chris

    2009-01-01

    Computerization of general practice is an international phenomenon. Many of the Electronic Patient Record (EPR) systems have developed organically with considerable variation in their interface and functionality. Consequently they have differing impact on the clinical consultation. There is a dearth of tools available to study their impact on the consultation. The objective is to use ALFA to film and analyze a simulated clinical consultation. We used the ALFA (Activity Log File Aggregation) open source toolkit, to make video based observation and analysis of the computer mediated consultation. ALFA enables precise comparison of core elements of EPR systems. It allows multiple video channels including screen capture, data about computer use, and verbal interactions to be synchronized, timed and navigated through for analysis. The toolkit is free and can be downloaded under an open source license from www.biomedicalinformatics.info/alfa/. Its outputs, which include Unified Modelling Language (UML), provide the evidence-base for assessing the impact of the computer on the consultation the designing of EPR systems. ALFA has been used to compare different brands of primary care computer systems; nurse case-load selection and consultation in psychiatry.

  15. Polymeric membrane sensors for the selective determination of dextromethorphan in pharmaceutical preparations.

    PubMed

    El-Naby, Eman H

    2008-01-01

    The construction and electrochemical response characteristics of poly(vinyl chloride) matrix ion-selective electrodes (ISEs) for dextromethorphan (DXM) hydrobromide are described. The membranes incorporate ion-association complexes of DXM with reineckate salt {[Cr(NH3)2(SCN)4]NH4} or phosphomolybdic acid [H3(PMo12O40)], as electroactive materials and dioctylphthalate or dibutylsebacate as a plasticizing solvent mediator. The sensors display a fast, stable and linear response with slopes of 54.4 to 59.5 mV/decade at pH 2.5-6.5 and a detection limit of 1.0 x 10(-6) M. Moreover, the sensors exhibit very good selectivity for DXM over opiate alkaloids, as well as organic and inorganic cations. The sensors proved to be useful for the determination of 5.0 x 10(-5)-1.0 x 10(-3) M DXM hydrobromide in pure as well as in dosage forms by direct potentiometry and standard addition methods. Determination of 5.0 x 10(-4) M DXM using the standard addition method and a sensor based on phosphomolybdate and dioctylphthalate shows an average recovery of 99.8% and a relative standard deviation (RSD) of 0.4%.

  16. The Styx field trial

    PubMed Central

    Gemmell, M. A.

    1968-01-01

    An assessment was made of the effectiveness of the generally accepted methods recommended for controlling hydatid disease during the course of a field-trial, initiated in 1943 in an isolated region of New Zealand. The results obtained during the first 21 years are described. Basically, the trial was an attempt to compare the effectiveness of a general public health educational programme and an anthelmintic programme using arecoline hydrobromide for treatment of dogs with that of a specific educational programme using this compound as a diagnostic agent. Arecoline hydrobromide was found to be too uncertain in its action to be of practical value as an anthelmintic. The development of diagnostic techniques, described in this paper, made it possible to use the compound for diagnostic purposes and thus for educational purposes, since each dog could be examined for tapeworms in the presence of the owner. Using changes in the annual prevalence rate in sheep of the cysts of E. granulosus and those of T. hydatigena as the principal indicators, the conclusion has been reached that the specific diagnostic approach achieved more success than the general educational and treatment programme. The principal reason for this appears to be that the former approach induced a greater awareness in owners of the need for strict management to prevent dogs gaining access to infective raw offal than that stimulated in the community when the dogs were dosed but not examined. ImagesFIG. 2FIG. 4FIG. 5 PMID:5303843

  17. [Alpha-lipoic acid triggers elimination of cells with abnormal nuclei in human carcinoma epidermoid cell line].

    PubMed

    Kisurina-Evgen'eva, O P; Onishchenko, G E

    2010-01-01

    The skin is usually exposed to adverse environmental conditions that may cause pathological cell proliferation and cellular transformations leading to the formation of malignant cells. Antioxidants may affect these processes and induce the elimination of transformed cell. The purpose of this work was to investigate the effect of alfa-lipoic acid on human carcinoma epidermoid cell line A431. Our results showed that alfa-lipoic acid induced inhibition of cell proliferation or stimulated apoptotic cell death. Cells with abnormal nuclei were eliminated by apoptosis. Electron microscopy showed that survived cells had typical for control cells shape and organization of the nuclei, organization of the cytoplasm and organelles. Thus, alfa-lipoic acid not only triggered apoptosis of carcinoma cells, but it may also activate the mechanism of elimination of cells with abnormal chromosome number.

  18. VizieR Online Data Catalog: AGES HI sources in NGC 7448 field (Taylor+, 2014)

    NASA Astrophysics Data System (ADS)

    Taylor, R.; Minchin, R. F.; Herbst, H.; Davies, J. I.; Rodriguez, R.; Vazquez, C.

    2015-04-01

    Observations of this field began in June 2008 and were completed in November 2011, using the 7-beam ALFA (Arecibo L-band Feed Array) instrument on the Arecibo telescope in spectral line mode. The field observed to full depth spans 5 degrees of R.A. by 4 degrees of declination centred on NGC 7448. Due to ALFA.s hexagonal beam arrangement, a small area outside this range is also included at a lower sensitivity. The full spatial range of the data considered here is from 22:49:00 to 23:10:50 in R.A, and from +13:51:00 to +18:06:00 in declination. (2 data files).

  19. Adhesion analysis of non-woven natural fibres in unsaturated polyester resin

    NASA Astrophysics Data System (ADS)

    Omri, Med Amin; Triki, A.; Guicha, M.; Ben Hassen, Med; Arous, M.; Ahmed El Hamzaoui, H.; Bulou, A.

    2015-03-01

    The presence of wool fibres in non-woven Alfa fibres sheet was investigated as a mean of improving adhesion of Alfa fibre-reinforced unsaturated polyester composite. FT-IR and Raman spectroscopy results revealed that such improvement could occur by a decrease in the hydrophilic character of the Alfa fibres owing to the presence of wool fibres. Hence, physical and chemical interactions could happen between the reinforcement and the matrix as demonstrated by FT-IR and Raman spectroscopy results. Tensile testing performed on this composite confirmed that such adhesion could occur according to its excellent specific parameters despite of its low tensile strength attributed to a higher fibre to fibre contact of wool fibres.

  20. MACC1 mediates acetylcholine-induced invasion and migration by human gastric cancer cells

    PubMed Central

    Xia, Jianling; Zhou, Rui; Wu, Zhenzhen; Zhao, Yang; Shi, Min

    2016-01-01

    The neurotransmitter acetylcholine (ACh) promotes the growth and metastasis of several cancers via its M3 muscarinic receptor (M3R). Metastasis-associated in colon cancer-1 (MACC1) is an oncogene that is overexpressed in gastric cancer (GC) and plays an important role in GC progression, though it is unclear how MACC1 activity is regulated in GC. In this study, we demonstrated that ACh acts via M3Rs to promote GC cell invasion and migration as well as expression of several markers of epithelial-mesenchymal transition (EMT). The M3R antagonist darifenacin inhibited GC cell activity in both the presence and absence of exogenous ACh, suggesting GC cells secrete endogenous ACh, which then acts in an autocrine fashion to promote GC cell migration/invasion. ACh up-regulated MACC1 in GC cells, and MACC1 knockdown using siRNA attenuated the effects of ACh on GC cells. AMP-activated protein kinase (AMPK) served as an intermediate signal between ACh and MACC1. These findings suggest that ACh acts via a M3R/AMPK/MACC1 signaling pathway to promote GC cell invasion/migration, which provides insight into the mechanisms underlying GC growth and metastasis and may shed light on new targets for GC treatment. PMID:26919111

  1. Acetylcholine acts through M3 muscarinic receptor to activate the EGFR signaling and promotes gastric cancer cell proliferation

    PubMed Central

    Yu, Huangfei; Xia, Hongwei; Tang, Qiulin; Xu, Huanji; Wei, Guoqing; Chen, Ying; Dai, Xinyu; Gong, Qiyong; Bi, Feng

    2017-01-01

    Acetylcholine (ACh), known as a neurotransmitter, regulates the functions of numerous fundamental central and peripheral nervous system. Recently, emerging evidences indicate that ACh also plays an important role in tumorigenesis. However, little is known about the role of ACh in gastric cancer. Here, we reported that ACh could be auto-synthesized and released from MKN45 and BGC823 gastric cancer cells. Exogenous ACh promoted cell proliferation in a does-dependent manner. The M3R antagonist 4-DAMP, but not M1R antagonist trihexyphenidyl and M2/4 R antagonist AFDX-116, could reverse the ACh-induced cell proliferation. Moreover, ACh, via M3R, activated the EGFR signaling to induce the phosphorylation of ERK1/2 and AKT, and blocking EGFR pathway by specific inhibitor AG1478 suppressed the ACh induced cell proliferation. Furthermore, the M3R antagonist 4-DAMP and darifenacin could markedly inhibit gastric tumor formation in vivo. 4-DAMP could also significantly enhance the cytotoxic activity of 5-Fu against the MKN45 and BGC823 cells, and induce the expression of apoptosis-related proteins such as Bax and Caspase-3. Together, these findings indicated that the autocrine ACh could act through M3R and the EGFR signaling to promote gastric cancer cells proliferation, targeting M3R or EGFR may provide us a potential therapeutic strategy for gastric cancer treatment. PMID:28102288

  2. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2003-01-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 81C6; Adefovir dipivoxil, Agalsidase alfa, AGM-1470, albumin interferon alfa, alefacept, alosetron hydrochloride, anakinra, anti-CTLA-4 Mab, aprepitant, aripiprazole, atazanavir; BAY-43-9006, BBR-3438, beta-L-Fd4C, bimatoprost, bortezomib, bosentanBR96-doxorubicin; Caspofungin acetate, ciclesonide, cilengitide, cilomilast, COL-1621, COL-3, CpG-7909, cyclosporine; DCVax-Brain, dexmethylphenidate hydrochloride, dexosome vaccine (melanoma), donepezil hydrochloride, drotrecogin alfa (activated), DTI-015, [99Tc]-DTPA-mannosyldextran, duloxetine hydrochloride; Emivirine, emtricitabine, entecavir, epothilone B, estradiol-MNP, etonogestrel/etonogestrel/ethinylestradiol, etoricoxib; Febuxostat, fondaparinux sodium, fosamprenavir calcium; Gefitinib, GVS-111; Heparinase I, HspE7, human alpha-glucosidase, human insulin; Imatinib mesylate, INGN-241, interferon alfa B/D hybrid, interferon alfa Biphasix, ISIS-14803; Lanicemine hydrochloride, 1311-lipiodol, liposome-encapsulated mitoxantrone, lixivaptan, lumiracoxib, lupus-AHP, LY-466700; Marimastat, MEN-10755, micafungin sodium; Nitronaproxen, NSC-683864 Omalizumab, oral insulin; Palonosetron hydrochloride, peginterferon alfa-2a, pimecrolimus, pralnacasan, pramlintide acetate, pregabalin, pyrazoloacridine; R-165335, ranolazine, risperidone, RPR-109881;, RSD-1235, Satraplatin, seocalcitol, sertindole, SMART anti-interferon gamma antibody, sulfasalazine; T-138067, TAK-013, tegaserod maleate, telithromycin, tenofovir disoproxil fumarate, teriparatide, tiotropium bromide, tipifarnib, TP-38; Valdecoxib, vatalanib succinate, voriconazole; ZD-9331.

  3. Analysis of Double Layer and Adsorption Effects at the Alkaline Polymer Electrolyte-Electrode Interface

    DTIC Science & Technology

    2011-10-05

    27 The tests for ethylene glycol, glycerol, methanol, erythritol, and xylitol as fuel in 1 M KOH resulted in the power densities of 9.5, 6.5, 6.0...need to dispose of the reaction products also increases the complexity of the fuel cell system and operation. Downloaded 17 Oct 2011 to...electrode assemblies (MEAs) were prepared using commercial PtRu (Alfa Aesar, 4.0 mgPtRu/cm2) or Pt (Alfa Aesar, 2.0 mgPt/cm2) anodes on Toray paper, Pt

  4. Immunologic Approaches for Oncolytic Viral Therapy of Prostate Cancer

    DTIC Science & Technology

    2005-02-01

    12 and interferon alfa - 2b : phase I trial of patients with metastatic renal cell carcinoma or malignant melanoma. J Clin Oncol. 22: 2891-2900. 6...Alatrash G., et al. (2004). Clinical and immunologic effects of subcutaneously administered interleukin-12 and interferon alfa - 2b : phase I trial of...tumor growth monitored. As illustrated in Fig 2B , NV1023 was significantly more effective than G207, G47A or mock (pɘ.05, student’s t test; days

  5. Nanomagnetics

    DTIC Science & Technology

    2006-05-01

    iron nitrate (Fe(NO3)39H2O), 99.99% pure, was supplied by the Alfa Aesar company (www.alfa.com). • Hexahydrated samarium nitrate (Sm(NO3)36H2O), 99.9...under vacuum condition. Figure 1 depicts the setup for the reflux procedure. After measured amounts of nitric acid, iron nitrate, samarium nitrate...in diameter and 5–20 µm long on the average) in 20-g nitric acid (HNO3) containing 0.8 g of hydrated iron nitrate (Fe(NO3)39H2O), which is ~5% w/w

  6. Route of administration for erythropoiesis-stimulating agents: patient and nursing considerations.

    PubMed

    Holloway, Maggie

    2007-01-01

    Several clinical studies have indicated that compared with intravenous (IV) administration, subcutaneous (SC) administration of Epoetin alfa may result in a dose-sparing effect in patients on hemodialysis. However, data also indicate wide inter-patient variability in response, with many patients requiring the same or a higher dose following conversion to SC administration. Convenience favors IV administration of Epoetin alfa in patients on hemodialysis, and patient preferences and comfort should also be primary considerations. For patients who prefer SC injections, the nurse's coordination of the required dosing, administration, and operational factors is key to maintaining and improving anemia-related outcomes.

  7. Assessing the endosulfan contamination in an unconfined aquifer.

    PubMed

    Atasoy, Ayse Dilek; Mermut, Ahmet Ruhi; Yesilnacar, Mehmet Irfan

    2012-02-01

    Groundwater samples were analyzed in order to elucidate the fate of endosulfan in the soil and its release mechanism into water of an unconfined aquifer. Residual alfa endosulfan was determined in all the wells; however, beta endosulfan was below 0.001 μg/L. Maximum adsorption rates of alfa and beta endosulfan were 91%-86% on the topsoil; 87%-91% on the subsoil, respectively. About 13%-23% desorption rate on the topsoil and subsoil exhibited the probability of endosulfan movement in the soil. The study showed that a hydrophobic-moderately persistent pesticide can reach to groundwater despite the high clay content of soil.

  8. Oxidant-induced cardiomyocyte injury: identification of the cytoprotective effect of a dopamine 1 receptor agonist using a cell-based high-throughput assay.

    PubMed

    Gerö, Domokos; Módis, Katalin; Nagy, Nóra; Szoleczky, Petra; Tóth, Zoltán Dóri; Dormán, György; Szabó, Csaba

    2007-11-01

    Myocyte injury due to myocardial reperfusion injury plays a crucial role in the pathogenesis of acute myocardial infarction even after successful coronary revascularization. Identification of compounds that reduce reperfusion-associated myocyte death is important. Therefore, we developed an in vitro model of myocardial reperfusion injury in H9c2 rat cardiomyocytes and applied a cell-based high-throughput approach to screen a standard library of pharmacologically active compounds (LOPAC) in order to identify drugs with cardioprotective effects. Oxidative stress was induced with hydrogen peroxide (H2O2) treatment, which resulted in approximately 50% reduction in cell viability. Test compounds were added at a 3-microM final concentration as a pretreatment or in a delayed fashion (30 min after the peroxide challenge in order to imitate pharmacological treatment following angioplasty). Cells were cultured for 3 or 24 h. Viability was quantitated with the methylthiazolyldiphenyl-tetrazolium bromide method. Cytotoxicity and cytoprotection were also evaluated by measuring the lactate dehydrogenase activity in the cell culture supernatant. The screening identified a number of compounds with cytoprotective action, including molecules that are known to interfere with components of DNA repair and cell cycle progression, e.g. poly(ADP-ribose) polymerase (PARP) inhibitors, topoisomerase inhibitors, and cyclin dependent kinase inhibitors, or reduce energy consumption by interfering with cardiac myofilament function. A number of dopamine D1 receptor agonists also provided significant cytoprotection at 3 h, but only three of them showed a similar effect at 24 h: chloro- and bromo-APB and chloro-PB hydrobromide. Chloro-APB hydrobromide significantly reduced peroxide-induced PARP activation in the myocytes independently of its action on dopamine D1 receptors, but lacked PARP inhibitor capacity in a cell-free PARP assay system. In conclusion, the pattern of cytoprotective drugs

  9. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2007-11-01

    1-Octanol, 9vPnC-MnCc; Abiraterone acetate, Adalimumab, Adefovir dipivoxil, Alemtuzumab, Aliskiren fumarate, Aminolevulinic acid hexyl ester, Amlodipine besylate/atorvastatin calcium, Amrubicin hydrochloride, Anakinra, Aripiprazole, ARRY-520, AS-1404, Asimadoline, Atazanavir sulfate, AVE-0277, Azelnidipine; Bevacizumab, Bimatoprost, Boceprevir, Bortezomib, Bosentan, Botulinum toxin type B; Certolizumab pegol, Cetuximab, Clevudine, Contusugene ladenovec, CP-751871, Crofelemer, Cypher, CYT006-AngQb; Darbepoetin alfa, Desmopressin, Dexlansoprazole, DG-041; E-5555, Ecogramostim, Entecavir, Erlotinib hydrochloride, Escitalopram oxalate, Eszopiclone, Everolimus, Ezetimibe, Ezetimibe/simvastatin; Falecalcitriol, Fampridine, Fesoterodine fumarate, Fingolimod hydrochloride; Gefitinib, Ghrelin (human), GS-7904L, GV-1001; HT-1001; Insulin detemir, ISIS-112989, Istradefylline; Laquinimod sodium, Latanoprost/timolol maleate, Lenalidomide, Levobetaxolol hydrochloride, Liposomal doxorubicin, Liposomal morphine sulfate, Lubiprostone, Lumiracoxib, LY-518674; MEM-1003, Mesna disulfide, Mipomersen sodium, MM-093, Mycophenolic acid sodium salt; Naptumomab estafenatox, Natalizumab; Olmesartan medoxomil, Olmesartan medoxomil/hydrochlorothiazide; Paclitaxel nanoparticles, Paclitaxel poliglumex, Pasireotide, Pazufloxacin mesilate, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ribavirin, Pegvisomant, Pemetrexed disodium, Pimagedine, Pimecrolimus, Pramlintide acetate, Prasterone, Pregabalin, Prulifloxacin; QAE-397; Rec-15/2615, RFB4(dsFv)-PE38, rhGAD65, Roflumilast, Romiplostim, Rosuvastatin calcium, Rotigotine, Rupatadine fumarate; Safinamide mesilate, SIR-Spheres, Sitagliptin phosphate, Sodium phenylacetate, Sodium phenylacetate/Sodium benzoate, Sorafenib, SSR-244738; Taribavirin hydrochloride, Taxus, Teduglutide, Tegaserod maleate, Telaprevir, Telbivudine, Tenofovir disoproxil fumarate, Tigecycline, Tiotropium bromide, Trabectedin, Travoprost

  10. Chemically Functional Alkanethiol Derivitized Magnetic Nanoparticles

    DTIC Science & Technology

    2003-01-01

    agents in medical imaging technologies7, and ’spintronics’ 8 (i.e., spin-based data transfer and storage). For example, Co and FePt nanoparticles have been...with a personal computer. Pt microelectrodes (25pin diameter) were created by flame-sealing Pt microwire (Alfa Aesar) in glass capillaries. The sealed

  11. Effects of switching from a reduced dose imiglucerase to velaglucerase in type 1 Gaucher disease: clinical and biochemical outcomes

    PubMed Central

    van Dussen, Laura; Cox, Timothy M.; Hendriks, Erik J.; Morris, Elizabeth; Akkerman, Erik M.; Maas, Mario; Groener, Johanna E. M.; Aerts, Johannes M.F.G.; Deegan, Patrick B.; Hollak, Carla E. M.

    2012-01-01

    This paper describes the effects of a switch to velaglucerase alfa in a group of adult patients with type 1 Gaucher disease, all of whom had previously had their dose reduced as a consequence of the worldwide imiglucerase shortage. Thirty-two patients from two large European Gaucher centers switched to treatment with velaglucerase alfa after 1-8.5 months of dose reduction. The course of important Gaucher disease parameters was studied at four time points: one year before the shortage, just before the shortage, before a switch to velaglucerase and after up to one year of treatment with velaglucerase. These parameters included hemoglobin concentration, platelet count, plasma chitotriosidase activity in all patients, and spleen and liver volumes (as well as bone marrow fat fraction images) in 10 patients. Decreases in platelet counts as a result of reduced treatment with imiglucerase were quickly restored on treatment with velaglucerase alfa. Chitotriosidase activity declined overall after switching. Five out of 10 patients had an increase in liver volume of at least 10% after six months of velaglucerase treatment, which was reversible in 3. Most patients received infusions at home and no important side effects were observed. Velaglucerase alfa appears to be a safe and effective alternative for imiglucerase. PMID:22773601

  12. Electronic Publishing in Librarianship and Information Science in Latin America--A Step towards Development?

    ERIC Educational Resources Information Center

    Johnson, Ian M.; Cano, Virginia

    2008-01-01

    Introduction: This paper draws on the results of studies undertaken between 2004 and 2007 as part of Project REVISTAS, supported by the European Commission's ALFA Programme. Method: A variety of methods was employed over the life of the project, including analysis of directories, a survey of universities in the region believed to be offering…

  13. [Nutritional condition and serum protein concentration in children (6-12 years old) of Chacopata Sucre State, Venezuela (December--January, 1997)].

    PubMed

    Vásquez, Solange; García, Andrés Gerardi; Lugo, Raquel Salazar

    2004-01-01

    A biochemical and anthropometrical study of 175 children (6-12 years old) from Chacopata, Sucre State was done (December--January, 1997). The children were evaluated by combined anthropometrical indicators (OMS), clinical, nutritional and biochemical tests. The results showed 81.71% well-nourished children, 4.57% obese children and 13.72% with some degree of undernutrition: 3.43% acute undernourished and 10.29% chronic undernourished. Total seric proteins including fractions: albumin, alfa-1 alfa-2, beta and gamma globulins as well as total globulins and albumin/globulin indexes were at the normal reference range for children (6-12 years old). A significative increase in alfa-1 globulin (0.18+/-0.08 g/dl; 8-9 years old group) and decrease of alfa-2 globulin (0.71+/-0.11 g/dl; 10-12 year old group) was observed. Biochemical results associated with nutritional condition showed normal values, moreover, this biochemical index decreased in the undernourished group. A significant decrease of the seric beta globulin in the undernourished children (0.72+/-0,12 g/dl) with respect to the well-nourished children (0.79+/-0.15) was found. In children (6-12 years old) from Chacopata, compensated chronic undernourishement is prevalent.

  14. Trace gas fluxes from a northern mixed-grass prairie interseeded with alfalfa

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The role of legumes in improving soil fertility, forage quantity and quality is well established, however what is less clear is the extent that the nitrogen fixed by legumes may drive increased trace gas emissions. A chronosequence study in native prairie that had been interseed with the legume alfa...

  15. Testing Adjuvant Ipilimumab in Advanced Melanoma

    Cancer.gov

    In this clinical trial, patients with stage III or stage IV melanoma that has been completely resected will be randomly assigned to receive post-surgical treatment with either ipilimumab or high-dose interferon alfa-2b, the current standard of care.

  16. African Americans Respond Poorly to Hepatitis C Treatment

    ERIC Educational Resources Information Center

    Black Issues in Higher Education, 2004

    2004-01-01

    African Americans have a significantly lower response rate to treatment for chronic hepatitis C than non-Hispanic Whites, according to a new study led by Duke University Medical Center researchers. Some African Americans--19 percent--did respond to the drug combination of peginterferon alfa-2b and ribavirin. But in non-Hispanic Whites with the…

  17. The Training of Music Teachers in Colombia: A Descriptive Analysis

    ERIC Educational Resources Information Center

    Nayibe Cárdenas Soler, Ruth; Lorenzo Quiles, Oswaldo; Hargreaves, David J.

    2015-01-01

    This study is an evaluative analysis of 13 Music Education programs in Colombia that provide training for secondary school music teachers for 6th to 11th grade in the Colombian education system. The study utilized an analysis matrix from the International Research Project ALFA II-0448-A, which developed a similar study with Latin American and…

  18. Temporal Stability of Solid Oxidizers at High Temperature and Humidity

    DTIC Science & Technology

    1985-09-30

    neutralized to maintain mission capability. The decon process could require washdown of the impacted sur- faces, washdown with water, fresh or sea, with...Fairlawtn, NJ Lithco, Lithium Corporation of America, Bessemer City, NC Interox America, Houston, TX Olin Chemicals, Stamford, CT Alfa Products, Danvers

  19. [The role of pro- and antioxidant processes in the liver tissue of guinea pigs in pathogenesis of allergic alveolitis].

    PubMed

    Shchepans'kyĭ, F I; Reheda, M S

    2005-01-01

    It was shown that allergic alveolitis development is accompanied by increase of superoxyddismutase and catalase activity as well as an increase of dien conjugates and malonic dialdehyde content in Guinea pig liver. The administration of alfa-tokoferol acetate, an antioxidant resulted in decrease of these indices in the liver tissue that testifies its correcting influence upon PLO and antioxidant system processes.

  20. Comparative drought response in eleven diverse alfalfa accessions

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Alfalfa (Medicago sativa L.) production is often negatively affected by drought stress. This is particularly true for alfalfa that is cultivated on rangeland. Thus, the development of drought-tolerant alfalfa cultivars is of great significance. A greenhouse study was conducted to evaluate 11 alfa...

  1. JPRS Report, East Europe.

    DTIC Science & Technology

    1990-02-28

    arise on CEMA’s ruins? Central European Common Market Advocated Several months ago I read a statement made by Zbigniew Brzezinski in which he...engineering and implementation partner- ship Alfa which began operation in 1987 with an initial [Article by Piotr Ceglowski: "Difficult Approach to

  2. Impact of Safety-Related Dose Reductions or Discontinuations on Sustained Virologic Response in HCV-Infected Patients: Results from the GUARD-C Cohort

    PubMed Central

    Foster, Graham R.; Coppola, Carmine; Derbala, Moutaz; Ferenci, Peter; Orlandini, Alessandra; Reddy, K. Rajender; Tallarico, Ludovico; Shiffman, Mitchell L.; Ahlers, Silke; Bakalos, Georgios; Hassanein, Tarek

    2016-01-01

    Background Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. Methods A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0–9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. Results SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced ≥1 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with ≥1 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not ≥5. Conclusions In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with

  3. Effect of repeated co-treatment with fluoxetine and amantadine on the behavioral reactivity of the central dopamine and serotonin system in rats.

    PubMed

    Rogóz, Zofia; Skuza, Grazyna

    2009-01-01

    In the present study we found that repeated co-treatment with fluoxetine and amantadine for 14 days (but not for 7 days) enhanced the hyperactivity induced by amphetamine or quinpirole (a dopamine D(2/3) agonist), compared to treatment with either drug alone. Whereas repeated co-treatment with fluoxetine and amantadine for 7 days more potently inhibited the behavioral syndrome evoked by the 5-hydroxytryptamine (5-HT)(1A) receptor agonist (+/-)-8-hydroxy-2(di-n-propylamino)-tetralin hydrobromide (8-OH-DPAT), it did not change the action of the 5-HT(2) receptor agonist (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (/+/-/-DOI). The obtained results support the hypothesis that repeated co-treatment with fluoxetine and amantadine may evoke more effective antidepressant activity than treatment with fluoxetine alone. Moreover, our results suggest that 5-HT(1A) receptors are useful targets for the development of more rapidly acting and more effective medication.

  4. Metronidazole-Induced Bullous Pemphigoid: A Case Report

    PubMed Central

    Moitra, Saibal; Banerjee, Indranil; Sikder, Ayan; Das, Prasanta

    2015-01-01

    Bullous pemphigoid is an autoimmune cutaneous blistering disorder, the exact pathogenesis of which is still not fully elucidated. Drug-induced bullous pemphigoid eruptions are rare but have been reported earlier with the use of frusemide, psoralens, ibuprofen, galantamine hydrobromide, ACE inhibitors like captopril, spironolactone, penicillin, ampicillin, levofloxacin, penicillamine. We hereby report a case of metronidazole induced bullous pemphigoid (BP) in a 52-year-old male patient suffering from liver abscess following 4 days of drug administration. The skin biopsy findings obtained from the patient were consistent with the diagnosis of bullous pemphigoid (BP). Metronidazole was discontinued and symptomatic treatment was offered to the patient. Following withdrawal of metronidazole, the bullae subsided in the next 7-10 days without any significant residual scarring. The causality assessment performed as per the Naranjo algorithm revealed the case to be probable (Naranjo score 7). PMID:26816913

  5. Effect of age on upregulation of the cardiac adrenergic beta receptors

    SciTech Connect

    Tumer, N.; Houck, W.T.; Roberts, J.

    1990-03-01

    Radioligand binding studies were performed to determine whether upregulation of postjunctional beta receptors occurs in sympathectomized hearts of aged animals. Fischer 344 rats 6, 12, and 24 months of age (n = 10) were used in these experiments. To produce sympathectomy, rats were injected with 6-hydroxydopamine hydrobromide (6-OHDA; 2 x 50 mg/kg iv) on days 1 and 8; the animals were decapitated on day 15. The depletion of norepinephrine in the heart was about 86% in each age group. 125I-Iodopindolol (IPIN), a beta adrenergic receptor antagonist, was employed to determine the affinity and total number of beta adrenergic receptors in the ventricles of the rat heart. The maximal number of binding sites (Bmax) was significantly elevated by 37%, 48%, and 50% in hearts from sympathectomized 6-, 12-, and 24-month-old rats, respectively. These results indicate that beta receptor mechanisms in older hearts can respond to procedures that cause upregulation of the beta adrenergic receptors.

  6. Therapeutic effectiveness of medications taken during spaceflight

    NASA Technical Reports Server (NTRS)

    Pool, Sam L.; Putcha, Lakshmi

    1992-01-01

    The therapeutic effectiveness of medications during spaceflight is considered in light of extensive anecdotal and experimental evidence. Attention is given to a range of medications for space motion sickness, sleeplessness, and physical discomfort. About 70 individual cases are reviewed in which crewmembers used such medications as: (1) scopolamine hydrobromide, dextroamphetamine sulfate, and promethazine hydrochloride for motion sickness; (2) metoclopramide hydrochloride and naloxone hydrochloride for bowel motility; and (3) aspirin and acetaminophen for headache and back pain. The effectiveness of orally ingested medications for space motion sickness is shown to be very low, while promethazine hydrochloride is effective when administered intramuscularly. The medications for pain are shown to be generally effective, and the use of sleep-inducing medications is limited by potentially detrimental performance effects.

  7. Multivariate optimization and validation of a capillary electrophoresis method for the simultaneous determination of dextromethorphan hydrobromur, phenylephrine hydrochloride, paracetamol and chlorpheniramine maleate in a pharmaceutical preparation using response surface methodology.

    PubMed

    Palabiyik, I Murat; Onur, Feyyaz

    2010-01-01

    A fast, accurate, precise and sensitive capillary electrophoresis method for the simultaneous determination of dextromethorphan hydrobromide, phenylephrine hydrochloride, paracetamol and chlorpheniramine maleate has been developed. Response surface methodology with a central composite design was used for optimization of the concentration of the buffer, pH of the buffer and applied voltage. Therefore, working with Na(2)HPO(4) buffer (pH 8.00, 0.01 M) at 20 kV as an applied voltage in the capillary electrophoresis method were found to be suitable; under these optimal conditions, these four active ingredients were separated in about 7 min. This developed method was validated and successfully applied to a pharmaceutical preparation, sugar-coated tablet, and the results were compared with a high-performance liquid chromatographic method developed by us.

  8. Inhibition of artificially induced cough in man by bronchodilators.

    PubMed Central

    Lowry, R; Higenbottam, T; Johnson, T; Godden, D

    1987-01-01

    1. The antitussive properties of bronchodilators were evaluated in a total of 47 normal volunteers. 2. Cough was induced by inhalation of ultrasonically nebulized solutions of distilled water and hypotonic saline. 3. Inhaled fenoterol hydrobromide (360 micrograms; 20 volunteers) and inhaled ipratropium bromide (72 micrograms; 14 volunteers) both significantly reduced couch compared with placebo (P less than 0.01). Oral salbutamol sulphate (4 mg; 11 volunteers) and oral pirenzepine hydrochloride (50 mg; 14 volunteers) had lesser effects. 4. Cough inhibition correlated with a small but statistically significant degree of bronchodilatation as measured by specific airway conductance (sGaw) and forced expiratory volume in one second (FEV1) in six normal subjects studied with each treatment in a placebo controlled, double blind study (r = 0.67, P less than 0.001). 5. Small reductions in airway tone are associated with a reduced cough response elicited by inhaled ultrasonically nebulized distilled water. PMID:3689630

  9. Alkaloids from Hippeastrum papilio.

    PubMed

    de Andrade, Jean Paulo; Berkov, Strahil; Viladomat, Francesc; Codina, Carles; Zuanazzi, José Angelo S; Bastida, Jaume

    2011-08-18

    Galanthamine, an acetylcholinesterase inhibitor marketed as a hydrobromide salt (Razadyne®, Reminyl®) for the treatment of Alzheimer's disease (AD), is obtained from Amaryllidaceae plants, especially those belonging to the genera Leucojum, Narcissus, Lycoris and Ungernia. The growing demand for galanthamine has prompted searches for new sources of this compound, as well as other bioactive alkaloids for the treatment of AD. In this paper we report the isolation of the new alkaloid 11β-hydroxygalanthamine, an epimer of the previously isolated alkaloid habranthine, which was identified using NMR techniques. It has been shown that 11β-hydroxygalanthamine has an important in vitro acetylcholinesterase inhibitory activity. Additionally, Hippeastrum papilio yielded substantial quantities of galanthamine.

  10. Separation of cold medicine ingredients using a precise MEKC method at elevated pH.

    PubMed

    Hasemann, Phillip; ter Balk, Marieke; Preu, Lutz; Wätzig, Hermann

    2007-06-01

    An MEKC method was developed in order to separate a cold medicine formulation containing acetaminophen, ephedrine sulfate, doxylamine succinate, and dextromethorphan hydrobromide as active pharmaceutical ingredients. Because of their similar physical and chemical properties, it was a challenge to separate the basic compounds without sample pretreatment. In addition, the high content of alcohol and sucrose together with the variety of further excipients had to be considered. Thus, the complex matrix required several optimization steps. These included the search for the optimum pH and for a suitable sodium dodecyl sulfate concentration to avoid matrix-capillary wall interaction and to ensure precision. As a second developing step, an internal standard (benzocaine) was chosen to guarantee a high level of quantitative performance. An RSD% value of the peak areas between 1.0 and 2.0 was reached. The employed method development strategy can be generalized to similar separation approaches in the future.

  11. Intramolecular N→Sn coordination in tin(II) and tin(IV) compounds based on enantiopure ephedrine derivatives.

    PubMed

    Zöller, Thomas; Iovkova-Berends, Ljuba; Berends, Thorsten; Dietz, Christina; Bradtmöller, Gerrit; Jurkschat, Klaus

    2011-09-05

    The syntheses and molecular structures of the intramolecularly coordinated tin(II) compounds {CH(2)N(Me)CH(Me)CH(Ph)O}(2)SnL (2, L = lone pair; 4, L = W(CO)(5); 5, L = Cr(CO)(5)) and of the related hydroxido-substituted tin(IV) compound [{CH(2)N(Me)CH(Me)CH(Ph)O}(2)Sn(OH)](2)O, 6a, are reported. Also reported are the molecular structures of the enantiopure N,N'-ethylenebis-(1R,2S)-ephedrine, {CH(2)N(Me)CH(Me)CH(Ph)OH}(2) (1), and its hydrobromide {CH(2)N(Me)CH(Me)CH(Ph)OH}(2)·HBr (1a).

  12. C.E.R.A. once every 4 weeks corrects anaemia and maintains haemoglobin in patients with chronic kidney disease not on dialysis

    PubMed Central

    Locatelli, Francesco; Woitas, Rainer P.; Laville, Maurice; Tobe, Sheldon W.; Provenzano, Robert; Golper, Thomas A.; Ruangkanchanasetr, Prajej; Lee, Ho Yung; Wu, Kwan-Dun; Nowicki, Michal; Ladanyi, Agnes; Martínez-Castelao, Alberto; Beyer, Ulrich; Dougherty, Frank C.

    2011-01-01

    Background. No previous randomized controlled studies have been reported examining de novo, once every 4 weeks (Q4W) administration of erythropoiesis-stimulating agents in chronic kidney disease (CKD) patients. We report results from a randomized multinational study that compared continuous erythropoietin receptor activator (C.E.R.A.) Q4W with darbepoetin alfa once weekly (QW) or every 2 weeks (Q2W) for the correction of anaemia in non-dialysis CKD patients. Methods. Patients were randomized (1:1) to receive either 1.2 μg/kg C.E.R.A. Q4W or darbepoetin alfa QW/Q2W during a 20-week correction period and an 8-week evaluation period. Two primary end points were assessed: the haemoglobin (Hb) response rate and the change in average Hb concentration between baseline and evaluation. Results. The Hb response rate for C.E.R.A. was 94.1%, significantly higher than the protocol-specified 60% response rate [95% confidence interval (CI): 89.1, 97.3; P < 0.0001] and comparable with darbepoetin alfa (93.5%; 95% CI: 88.4, 96.8; P < 0.0001). C.E.R.A. Q4W was non-inferior to darbepoetin alfa QW/Q2W, with similar mean Hb changes from baseline of 1.62 g/dL and 1.66 g/dL, respectively. Patients receiving C.E.R.A. showed a steady rise in Hb, with fewer patients above the target range during the first 8 weeks compared with darbepoetin alfa [39 patients (25.8%) versus 72 patients (47.7%); P < 0.0001]. Adverse event rates were comparable between the treatment groups. Conclusion. C.E.R.A. Q4W successfully corrects anaemia and maintains stable Hb levels within the recommended target range in non-dialysis CKD patients. PMID:21505096

  13. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2005-04-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity. prous.com. This issue focuses on the following selection of drugs: ABX-IL-8, Acclaim, adalimumab, AGI-1067, alagebrium chloride, alemtuzumab, Alequel, Androgel, anti-IL-12 MAb, AOD-9604, aripiprazole, atomoxetine hydrochloride; Biphasic insulin aspart, bosentan, botulinum toxin type B, bovine lactoferrin, brivudine; Cantuzumab mertansine, CB-1954, CDB-4124, CEA-TRICOM, choriogonadotropin alfa, cilansetron, CpG-10101, CpG-7909, CTL-102, CTL-102/CB-1954; DAC:GRF, darbepoetin alfa, davanat-1, decitabine, del-1 Genemedicine, dexanabinol, dextofisopam, dnaJP1, dronedarone hydrochloride, dutasteride; Ecogramostim, eletriptan, emtricitabine, EPI-hNE-4, eplerenone, eplivanserin fumarate, erlotinib hydrochloride, ertapenem sodium, escitalopram oxalate, esomeprazole magnesium, etoricoxib, ezetimibe; Falecalcitriol, fingolimod hydrochloride; Gepirone hydrochloride; HBV-ISS, HSV-2 theracine, human insulin; Imatinib mesylate, Indiplon, insulin glargine, ISAtx-247; L612 HuMAb, levodopa/carbidopa/entacapone, lidocaine/prilocaine, LL-2113AD, lucinactant, LY-156735; Meclinertant, metelimumab, morphine hydrochloride, morphine-6-glucuronide; Natalizumab, nimotuzumab, NX-1207, NYVAC-HIV C; Omalizumab, onercept, osanetant; PABA, palosuran sulfate, parathyroid hormone (human recombinant), parecoxib sodium, PBI-1402, PCK-3145, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, pemetrexed disodium, pimecrolimus, PINC, pregabalin; Ramelteon, rasagiline mesilate, rasburicase, rimonabant hydrochloride, RO-0098557, rofecoxib, rosiglitazone maleate/metformin hydrochloride; Safinamide mesilate, SHL-749, sitaxsentan sodium, sparfosic acid, SprayGel, squalamine, St. John's Wort

  14. Inhibition by 5-hydroxytryptamine and noradrenaline in substantia gelatinosa of guinea-pig spinal trigeminal nucleus.

    PubMed

    Grudt, T J; Williams, J T; Travagli, R A

    1995-05-15

    1. Whole-cell and intracellular recordings were made from neurons in slices of guinea-pig spinal trigeminal nucleus pars caudalis. 2. 5-Hydroxytryptamine (5-HT) hyperpolarized 70% of neurons by activating 5-HT1A receptors. The effect was mimicked by 5-carboxamidotryptamine (5-CT) and (+/-)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronapthalene hydrobromide (8-OH-DPAT) and antagonized by 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)-butyl]-piperazine hydrobromide (NAN 190) and pindobind-5-HT1A. Nine per cent of the neurons were depolarized by 5-HT. 3. In about 20% of recordings, 5-HT also evoked repetitive inhibitory postsynaptic potentials that were mediated by glycine. 4. Noradrenaline (NA) hyperpolarized 71% of neurons. This effect was mediated by activation of alpha 2-adrenoceptors, since 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK14304) also caused a hyperpolarization and idazoxan (1 microM) blocked the hyperpolarization to both NA and UK14304. Phenylephrine depolarized a subset of neurons and this depolarization was blocked by prazosin, suggesting an action mediated by activation of alpha 1-adrenoceptors. 5. NA also evoked repetitive GABAA-mediated inhibitory postsynaptic potentials in about 20% of recordings. The increase in synaptic activity was mimicked by phenylephrine and blocked by prazosin. 6. These results indicate that there are at least two mechanisms through which 5-HT and NA inhibit neurons: (i) in many cells both 5-HT and NA mediate a hyperpolarization through an increase of a potassium conductance; (ii) 5-HT and NA also activated GABA- and glycine-containing interneurons to cause IPSPs in separate groups of cells.

  15. The dopamine D(1) receptor agonist SKF-82958 serves as a discriminative stimulus in the rat.

    PubMed

    Haile, C N; Carey, G; Varty, G B; Coffin, V L

    2000-01-28

    We examined the discriminative stimulus effects of the high-efficacy dopamine D(1) receptor agonist (+/-)6-chloro-7, 8-dihydroxy-3-ally1-phenyl-2,3,4,5-tetrahydro-1H-3benzazepine++ + hydrobromide (SKF-82958) in rats trained to discriminate SKF-82958 (0.03 mg/kg) from vehicle in a two-lever food-reinforced drug discrimination task. SKF-82958 produced dose-related increases in responding to the SKF-82958 appropriate lever with full substitution occurring at the training dose. Pretreatment with the dopamine D(1)/D(5) receptor antagonist (-)-trans-6,7,7a,8,9, 13b-hexahydro-3-chloro-2hydroxy-N-methyl-5H-benzo-[d]naphtho -¿2, 1-b¿azepine (SCH-39166) (0.01 mg/kg) attenuated the discriminative stimulus effects of SKF-82958. Pretreatment with the dopamine D(2) receptor antagonist raclopride (0.03 mg/kg) had no effect. The high-efficacy dopamine D(1) receptor agonist R(+)6chloro-7, 8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF-81297) fully substituted for SKF-82958, whereas the low-efficacy dopamine D(1) receptor agonist (+/-)1-phenyl-2,3,4, 5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF-38393) produced only partial substitution. The dopamine D(2) receptor agonist trans-(+/-)-4,4a,5,6,7,8,8a, 9-octahydro-5-propyl-1H-propyl-1H-pyrazolo[3,4-g]quinoline dihydrochloride (quinpirole) and the indirect dopamine agonist cocaine did not substitute fully for the SKF-82958 discriminative stimulus cue. These results demonstrate that the high-efficacy dopamine D(1) receptor agonist SKF-82958 can serve as an effective discriminative stimulus in the rat, and that these effects are mediated by a dopamine D(1)-like receptor mechanism.

  16. Muscarinic receptors stimulate cell proliferation in the human urothelium-derived cell line UROtsa.

    PubMed

    Arrighi, Nicola; Bodei, Serena; Lucente, Alessandra; Michel, Martin C; Zani, Danilo; Simeone, Claudio; Cunico, Sergio Cosciani; Spano, PierFranco; Sigala, Sandra

    2011-10-01

    The widespread non-neuronal synthesis of acetylcholine (ACh) has changed the paradigm of ACh acting solely as a neurotransmitter. Indeed, the presence of ACh in many types of proliferating cells suggests a role for this neurotransmitter in the control of cell division. The parasympathetic system is a major pathway regulating micturition, but ACh-mediated control plays a more complex role than previously described, acting not only in the detrusor muscle, but also influencing detrusor function through the activity of urothelial muscarinic receptors. Here we investigated the role of muscarinic receptors in mediating cell proliferation in the human UROtsa cell line, which is a widely used experimental model to study urothelium physiology and pathophysiology. Our results demonstrate that UROtsa cells express the machinery for ACh synthesis and that muscarinic receptors, with the rank order of M3>M2>M5>M1=M4, are present and functionally linked to their known second messengers. Indeed, the cholinergic receptor agonist carbachol (CCh) (1-100 μM) concentration-dependently raised IP(3) levels, reaching 66±5% over basal. The forskolin-mediated adenylyl cyclase activation was reduced by CCh exposure (forskolin: 1.4±0.14 pmol/ml; forskolin+100 μM CCh: 0.84±0.12 pmol/ml). CCh (1-100 μM) concentration-dependently increased UROtsa cell proliferation and this effect was inhibited by the non-selective antagonist atropine and the M(3)-selective antagonists darifenacin and J104129. Finally, CCh-induced cell proliferation was blocked by selective PI-3 kinase and ERK activation inhibitors, strongly suggesting that these intracellular pathways mediate, at least in part, the muscarinic receptor-mediated cell proliferation.

  17. Different muscarinic receptor subtypes modulate proliferation of primary human detrusor smooth muscle cells via Akt/PI3K and map kinases.

    PubMed

    Arrighi, Nicola; Bodei, Serena; Zani, Danilo; Michel, Martin C; Simeone, Claudio; Cosciani Cunico, Sergio; Spano, Pierfranco; Sigala, Sandra

    2013-08-01

    While acetylcholine (ACh) and muscarinic receptors in the bladder are mainly known for their role in the regulation of smooth muscle contractility, in other tissues they are involved in tissue remodelling and promote cell growth and proliferation. In the present study we have used primary cultures of human detrusor smooth muscle cells (HDSMCs), in order to investigate the role of muscarinic receptors in HDSMC proliferation. Samples were obtained as discarded tissue from men >65 years undergoing radical cystectomy for bladder cancer and cut in pieces that were either immediately frozen or placed in culture medium for the cell culture establishment. HDSMCs were isolated from samples, propagated and maintained in culture. [(3)H]-QNB radioligand binding on biopsies revealed the presence of muscarinic receptors, with a Kd of 0.10±0.02nM and a Bmax of 72.8±0.1fmol/mg protein. The relative expression of muscarinic receptor subtypes, based on Q-RT-PCR, was similar in biopsies and HDSMC with a rank order of M2≥M3>M1>M4>M5. The cholinergic agonist carbachol (CCh, 1-100μM) concentration-dependently increased [(3)H]-thymidine incorporation (up to 46±4%). This was concentration-dependently inhibited by the general muscarinic receptor antagonist atropine and by subtype-preferring antagonists with an order of potency of darifenacin >4-DAMP>AF-DX 116. The CCh-induced cell proliferation was blocked by selective PI-3 kinase and ERK activation inhibitors, strongly suggesting that these intracellular pathways mediate, at least in part, the muscarinic receptor-mediated cell proliferation. This work shows that M2 and M3 receptors can mediate not only HDSM contraction but also proliferation; they may also contribute bladder remodelling including detrusor hypertrophy.

  18. An integrative review of standardized clinical evaluation tool utilization in anticholinergic drug trials for neurogenic lower urinary tract dysfunction

    PubMed Central

    Stothers, L; Tsang, B; Nigro, M; Lazare, D; Macnab, A

    2016-01-01

    Study design: To review prospective and randomized trials studying anticholinergic therapy for neurogenic bladder in SCI to identify whether trials included standardized clinical evaluation tools and reporting measures now recognized to enhance clinical trial data. Methods: A systematic search via EMBASE, MEDLINE, CENTRAL, CINAHL (Cumulative Index to Nursing and Allied Health Literature), HTA (Health Technology Assessment), CMR (Comprehensive Microbial Resource), HAPI (Health and Psychosocial Instruments) and PsycINFO using the key term spinal cord injury crossed with oxybutynin, tolterodine, darifenacin, solifenacin, fesoterodine, trospium chloride, propiverine, propantheline and anticholinergic(s) for 1946–2015 inclusive. We then collated whether standardized clinical tools, measures and descriptors were used within each study identified: American Spine Injury Association (ASIA) impairment scale; symptom scores validated in SCI; technical methodology for urodynamics/video urodynamics; urinary diaries; and standardized urologic terminology. Results: A total of 1225 entries with 610 unique articles were identified, 14 randomized and 16 prospective studies. In 6/30 the population comprised SCI patients with neurogenic bladder alone; the remainder included mixed neurogenic etiologies. Classification using the ASIA impairment scale was used in <10% of studies; none used symptom scores validated in SCI; <50% reported urodynamic test methodology fully, incorporated urinary diaries or used International Continence Society Standardization Subcommittee urinary tract terminology. Conclusion: Integrative review of trials from 1946 to 2015 identified infrequent use of standardized clinical evaluation tools and reporting measures. Data from future trials evaluating therapies for neurogenic bladder would likely be more applicable to specific SCI patients if current standardized classification and descriptors now available were used consistently: for example, the ASIA scale

  19. A short review of drug-food interactions of medicines treating overactive bladder syndrome.

    PubMed

    Paśko, Paweł; Rodacki, Tomasz; Domagała-Rodacka, Renata; Owczarek, Danuta

    2016-12-01

    Background Overactive bladder syndrome is a condition where one or more of the symptoms such as pollakiuria, urgent need to urinate, nocturia and urinary incontinence is observed. Its prevalence ranges between 7 and 27 % in men and 9-43 % in women. The role of a pharmacist is to educate the patient on medications administration scheme, and drug interactions with particular food or food components. Aim of the review To assess a potential impact of food and fruit juice on the pharmacokinetic and therapeutic effects of medications used in treating overactive bladder syndrome. This information will enhance pharmaceutical care and is vital and helpful for pharmacists counseling their patients. Method In order to gather information on interactions of medications employed in bladder dysfunctions, the English language reports published in the PubMed, Embase, Cochrane and CINAHL database over the years 1996-2015 were studied. Additionally, other resources, namely drugs.com, Medscape, UpToDate, Micromedex, Medical Letter, as well as Stockley Drugs Interaction electronic publication were included in the study. The analysis also covered product data sheets for particular medicinal products. Results Meals and the consumption of grapefruit juice were found to exert a diversified effect on the pharmacokinetics of drugs employed in overactive bladder syndrome therapy. Neither tolterodine, nor mirabegron interact with food and citrus fruit juice, whereas darifenacin, fesoterodine, oxybutynin and solifenacin do interact with grapefruit and others citrus fruit juice. The effects of such interactions may potentially be negative to patients. Trospium absorption is significantly decreased by food. Conclusion For selected medicines used in treating bladder dysfunctions food and grapefruit juice consumption may significantly affect efficacy and safety of the therapy. All information on the topic is likely to enhance the quality of pharmaceutical care.

  20. Role of antimuscarinics in the treatment of nonneurogenic daytime urinary incontinence in children.

    PubMed

    Nijman, Rien J M

    2004-03-01

    Idiopathic or "functional" urinary incontinence in children--incontinence with no known neurologic or anatomic cause--may take the form of urge incontinence, the most common type of incontinence, which is characterized by detrusor overactivity during the filling phase, or dysfunctional voiding. The latter may be classified as staccato voiding (periodic bursts of pelvic floor activity with prolonged voiding and, in some cases, residual urine), interrupted voiding (insufficient bladder emptying, infrequent voiding with several phases of micturition), or "lazy bladder" syndrome (infrequent voiding and large bladder capacity). The etiology of functional incontinence is unknown. Theories include genetic predisposition, recurrent urinary tract infections, immaturity or too-early toilet training, and sexual abuse. A severe form of urge incontinence, nonneurogenic neurogenic (Hinman) bladder, may be the end stage of dysfunctional voiding, but an occult neurologic component should also be considered. Diagnostic procedures recommended for children with urinary incontinence include careful history taking, a voiding diary, and physical examination to identify symptoms and to minimize the need for invasive procedures. Treatments include behavioral modification, biofeedback, antibiotics, anticholinergics, counseling, and neuromodulation. The antimuscarinics oxybutynin and tolterodine are, at present, the most commonly used drugs to treat incontinence. Common side effects with these agents (ie, reduced saliva production and worsening constipation) can be severe and can cause up to 10% of children using oxybutynin to discontinue treatment. Current evidence suggests that tolterodine may have a more favorable safety profile than oxybutynin. In addition, new antimuscarinics in the pipeline, eg, darifenacin and solifenacin, are expected to possess more favorable safety and tolerability profiles and may therefore help to alleviate these limitations.

  1. Retinopathy in chronic hepatitis C patients during interferon treatment with ribavirin

    PubMed Central

    Jain, K; Lam, W; Waheeb, S; Thai, Q; Heathcote, J

    2001-01-01

    AIM—To assess the ocular effect of interferon alfa 2b prescribed with ribavirin in patients undergoing therapy for chronic hepatitis C.
METHODS—19 patients with chronic hepatitis C who satisfied the follow up criteria were assessed for ocular complications using slit lamp biomicroscopy and indirect ophthalmoscopy before, during, and after the treatment at regular intervals.
RESULTS—8/19 patients, while on treatment, developed an asymptomatic retinopathy. Among these 3/8 were relapsers and 5/9 were non-responders to interferon monotherapy. All retinal changes faded, often while the patients continued the therapy. There was no significant association in occurrence of retinopathy with haematological and/or biochemical changes.
CONCLUSION—Retinopathy was more common in interferon monotherapy non-responders than relapsers when treated with interferon alfa 2b with the addition of ribavirin. The changes were transient, disappearing while the patients were still being treated.

 PMID:11567959

  2. Biodegradable packaging materials conception based on starch and polylactic acid (PLA) reinforced with cellulose.

    PubMed

    Masmoudi, Fatma; Bessadok, Atef; Dammak, Mohamed; Jaziri, Mohamed; Ammar, Emna

    2016-10-01

    The plastic materials used for packaging are increasing leading to a considerable amount of undegradable solid wastes. This work deals with the reduction of conventional plastics waste and the natural resources preservation by using cellulosic polymers from renewable resources (alfa and luffa). Plasticized starch films syntheses were achieved at a laboratory scale. These natural films showed some very attractive mechanical properties at relatively low plasticizers levels (12 to 17 % by weight). Furthermore, mixtures including polylactic acid polymer (PLA) and cellulose fibers extracted from alfa and luffa were investigated by melt extrusion technique. When used at a rate of 10 %, these fibers improved the mixture mechanical properties. Both developed materials were biodegradable, but the plasticized starch exhibited a faster biodegradation kinetic compared to the PLA/cellulose fibers. These new materials would contribute to a sustainable development and a waste reduction.

  3. Experimental study of the rigidity and transparency to ionizing radiation of composite materials used in the enclosure under pressure of the Micromegas detector

    NASA Astrophysics Data System (ADS)

    Harbaoui, Imen; Besbes, Hatem; Chafra, Moez

    Innovation in the field of nuclear imaging is necessarily followed by a radical change in the detection principle. The gas detector Micromegas (Mesh Micro Structure Gaseous) could be an interesting option, thanks to the stability and robustness of such a detector. Thus, it was necessary to study the implementation of the detector enclosure in composite materials. The focus of the present study was the robustness and gamma rays transparency of a set of composites. The studied composites were reinforced with vegetable fibers (alfa), and synthetic fibers. The mechanical properties of all composites specimen were evaluated by three-point bending test, whereas, gamma ray transparency was evaluated by the exposition of composites specimen to a mono-energetic gamma ray beam emitted by a Technetium 99-m source. Findings revealed that the biocomposite materials using alfa fiber and Polymethyl Methacrylate matrix are very promising as long as they present good robustness and high gamma ray transparency in diagnostic range.

  4. Mechanism of action of guanfacine: a postsynaptic differential approach to the treatment of attention deficit hyperactivity disorder (adhd).

    PubMed

    Alamo, Cecilio; López-Muñoz, Francisco; Sánchez-García, Javier

    2016-05-01

    The treatment of ADHD has focused on the use of psychostimulants drugs such as methylphenidate or amphetamine and derivatives, or not stimulants agents, such as atomoxetine. These agents act mainly on catecholaminergic presynaptic mechanisms. Recently the European Medicines Agency (EMA) has approved another not psychostimulant drug, guanfacine extended release (ER), as a new option to the treatment of ADHD, which acts at postsynaptic level. Guanfacine stimulates postsynaptic alfa-2A adrenergic receptors so it inhibits the production of cAMP and closes HCN channels enhancing the effectiveness of the signal of the pyramidal neurons of the prefrontal cortex (PFC), thus improving working memory and attention. In addition, stimulation of the alpha-2A receptors promotes growth and maturation of the dendritic spines of pyramidal neurons of the medial PFc, that are associated with brain function such as learning and memory. In contrast with psychostimulants or atomoxetine, guanfacine mimics noradrenaline stimulation of postsynaptic receptors alfa-2A on the PFC.

  5. [Benefits of spironolactone as the optimal treatment for drug resistant hypertension. Pathway-2 trial review].

    PubMed

    Prado, J C; Ruilope, L M; Segura, J

    Pathway-2 is the first randomised, double-blind and crossover trial that compares spironolactone as a fourth drug with alfa-blocker, beta-blocker and placebo. This study shows that spironolactone is the drug with more possibilities of success for the management of patients with difficult-to-treat hypertension in patients with a combination of three drugs and poor control. The results validate the widespread treatment with mineralocorticoid receptor antagonists in resistant hypertension.

  6. Human chorionic gonadotropin and CA 15-3 producing adenocarcinoma.

    PubMed

    Uçkaya, G; Ozet, A; Arpaci, A; Kömürcü, S

    1998-01-01

    50 years old man suffering from primary lung adenocarcinoma presented with high levels of both beta subunit human chorionic gonadotropin (beta HCG) and cancer antigen 15-3 (CA 15-3) in the absence of elevated carcinoembrionic antigen (CEA), alfa fetoprotein (AFP) and carbohydrate antigen 19-9 (CA 19-9). Although beta HCG or CA 15-3 high levels were reported in adenocarcinoma of lung, this is the first report of a patient with high levels of both markers.

  7. Influence Of Zwitterions on Properties and Morphology of Ionomers: Implications for Electro-Active Applications

    DTIC Science & Technology

    2010-08-01

    acrylate and n-butyl acrylate ( nBA ) based sulfobetaine-containing polymers.13,14 They demonstrated that the incorporation of zwitterionic functionalities...propanesulfonate (SBMA). Through copolymerizing the two charge-containing monomers with nBA , a series of zwitterionomers and their corresponding...graciously provided by Raschig GmbH. n-Butyl acrylate ( nBA ), dimethyl sulfoxide (DMSO, 99.9+%) and hydroquinone (99%) were purchased from Alfa Aesar. 2

  8. Influence of Zwitterions on Thermomechanical Properties and Morphology of Acrylic Copolymers: Implications for Electroactive Applications

    DTIC Science & Technology

    2011-09-30

    properties of ethyl acrylate and n-butyl acrylate ( nBA )-based sulfobetaine-containing copolymers.10,11 They found that the incorporation of...ammonio]-1-propanesulfonate (SBMA), a zwitterionic mono- mer. Copolymerization of both charge-containing monomers with nBA elucidates the influence of...3-[[2-(methacryloyloxy)ethyl]- (dimethyl)ammonio]-1-propanesulfonate (SBMA), was generously provided by Raschig GmbH. n-Butyl acrylate ( nBA , Alfa

  9. Improvement with ongoing Enzyme Replacement Therapy in advanced late-onset Pompe disease: a case study.

    PubMed

    Case, Laura E; Koeberl, Dwight D; Young, Sarah P; Bali, Deeksha; DeArmey, Stephanie M; Mackey, Joanne; Kishnani, Priya S

    2008-12-01

    Benefits of enzyme replacement therapy with Myozyme (alglucosidase alfa), anecdotally reported in late-onset Pompe disease, range from motor and pulmonary improvement in less severely affected patients, to stabilization with minimal improvement in those with advanced disease. We report a case of a 63-year-old patient with significant morbidity who made notable motor and pulmonary function gains after two years on therapy. Thus, improvements in those with advanced disease may be possible after long-term treatment.

  10. Fuel Cells Using the Protic Ionic Liquid and Rotator Phase Solid Electrolyte Principles

    DTIC Science & Technology

    2008-02-13

    was obtained from Alfa Aesar. Anhydrous difluorophosphoric acid was obtained from SynQuest Labs Inc. Anhydrous formic acid (HFm, 98%) was obtained from...monoprotonated salt of hydrazine and formic acid . Viscosities. The viscosities measured on these liquids, shown in Figure 6 for the same representative series as...concept of ionic liquids, formed by proton transfer from Bronsted acid to Bronsted base, serving as the proton transport media in fuel cells is evaluated

  11. Missile Survey: Ballistic and Cruise Missiles of Foreign Countries

    DTIC Science & Technology

    2004-03-05

    AS - 19 Koala ALCM 4000 875? Terminated Alfa Supersonic CM 600 In Development SS-N-6 Serb SLBM 16 16 3,000 680 Liquid All Removed from Subs SS-N-8...SUPPLEMENTARY NOTES 14. ABSTRACT 15. SUBJECT TERMS 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT Same as Report (SAR) 18. NUMBER OF...Reduction Agency’s Weapons of Mass Destruction Terms Reference Handbook defines a ballistic missile as “ a missile that is guided during powered flight and

  12. International Symposium on Air Breathing Engines (5th)

    DTIC Science & Technology

    1981-05-29

    favorably received by specialists in that area while also having some morsels of interest to the research community. US papers covered the status of power...plant controls, turbine-diagnostics effectiveness, life-cycle cost considerations, and a review and status of environmental effects of aircraft...04 Diagnostic and Monitoring of Turboprop Engines Ingg. 0. Natale and V.P. Riviello , Alfa Romeo, Italy 05 The Engineering Basis for the Application of

  13. Effect of Hemodilution on Coagulation and Recombinant Factor VIIa Efficacy in Human Blood In Vitro

    DTIC Science & Technology

    2011-11-01

    agent approved for use in the treatment of hemophilia A and B with inhibitors, acquired hemophilia , congenital factor VII deficiency, and Glanzmann...373–381. 12. Croom KF, McCormack PL. Recombinant factor VIIa (eptacog alfa): a review of its use in congenital hemophilia with inhibitors, acquired... hemophilia , and other congenital bleeding disorders. BioDrugs. 2008; 22:121–136. 13. Mackman N. Tissue-specific hemostasis: role of tissue factor. J

  14. The Effects of rhBMP-2 Released from Biodegradable Polyurethane/Microsphere Composite Scaffolds on New Bone Formation in Rat Femora

    DTIC Science & Technology

    2009-09-17

    was purchased from Alfa Aesar (Ward Hill, MA). Dichloromethane ( DCM ) and glucose were from Acros Organics (Morris Plains, NJ). Hexamethylene diiso...and PEG (4600 Da), at a ratio of 9:1, were dissolved in DCM at polymer concentrations of 10% and 5% for large and small size particles, respec- tively...A glucose solution of BSA–FITC (fluoroisothiocyanate-labeled bovine serum albumin) or rhBMP-2 was added to the polymer DCM solution, followed by soni

  15. 28th Annual JPMorgan Healthcare Conference--Human Genome Sciences and Celgene.

    PubMed

    Gale, Sophie; Croasdell, Gary

    2010-03-01

    The JPMorgan Healthcare Conference, held in San Francisco, included presentations by various pharmaceutical companies summarizing their achievements in 2009 and expectations for 2010. This conference report highlights presentations from Human Genome Sciences Inc and Celgene Corp. Investigational drugs from Human Genome Sciences, including belimumab (in collaboration with GlaxoSmithKline plc), albinterferon alfa-2b (with Novartis AG), mapatumumab (with Takeda Pharmaceutical Co Ltd) and HGS-1029, and from Celgene, including romidepsin, pomalidomide, apremilast and PDA-001 (Celgene Cellular Therapeutics), are discussed.

  16. Instrumentation for Monitoring Breath Biomarkers for Diagnosis of Health Condition, Toxic Exposure and Disease

    DTIC Science & Technology

    2007-12-01

    response to respiratory viral infections. It also has been identified in acute lung injury and ARDS . ALFA monitoring will be used to monitor impending...the research community in the field of acute lung injury, airway acidification, and prognostic lung health assessment. Honors/Awards: Respiratory ...COVERED (From - To) 27-12-2007 FINAL REPORT From 30-9-2005 to 29-9-2007 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Instrumentation for Monitoring Breath

  17. Instrumentation for Monitoring Breath Biomarkers for Diagnosis of Health Condition Toxic Exposure and Disease

    DTIC Science & Technology

    2007-12-01

    27-12-2007 FINAL REPORT From 30-9-2005 to 29-9-2007 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Instrumentation for Monitoring Breath Biomarkers for...identified in acute lung injury and ARDS . ALFA monitoring will be used to monitor impending deterioration of lung status in patients on mechanical...valuable nature has been accumulated enabling Respiratory Research, Inc. to uniquely serve the needs of the research community in the field of acute lung

  18. Ground-up-to-Space (GUTS) Laser Propagation Code Description and Manual

    DTIC Science & Technology

    1984-06-01

    prograz applica- tion cr" scattering aid absorption. GllSflvG allows tie user tc describe the neam at the aperture in terms of the electromagnetic field ...tc compute iriadiance at the target given a model atmosphere/ laser device parameters, and simple target engagement geon - etry. The transmitter...IIAGRAM 4 9 I. SUBROUTINE DESCRIPTION 62 1. AESORE and SCAI 62 2. AIFS acd ALFA 63 3. UOCST 64 4. FIELD 66 5. FARFLI 67 6- BQIREI 69 7. DETWAV 70 8

  19. Demonstration of the B4C/NaIO4/PTFE Delay in the U.S. Army Hand-Held Signal

    DTIC Science & Technology

    2015-05-20

    consisting of boron carbide, sodium periodate, and polytetrafluoroethylene (PTFE), provided an Received: March 26, 2015 Revised: May 11, 2015...AEE material. Sodium periodate was obtained from Alfa Aesar and was separated into fractions using a 325 mesh (44 μm) screen; only the fine material was...used. PTFE powder (type FL1650) was obtained from AGC Chemicals. For the fine sodium periodate fraction, a Malvern Morphologi G3S optical microscopy

  20. A Summary Report on the Solubility of Depleted U(3)O(8) in Simulated Lung Fluid, Ringer’s Solution and Ringer’s Lactate,

    DTIC Science & Technology

    1981-08-01

    PHOTOGRAPHIC PLATES PLATES PAGE I Depleted Uranium Powder Sample Before Addition to Test Solution ............................... 4 II Depleted Uranium...was 99% pure depleted U308 . This heavy metal is an olive green powder obtained from the Alfa Division of Ventron Corporation in Danvers, MA. Plate I...PLATE I Depleted Uranium Powder Sample Before Addition To Test Solutions 351 hot plate-stirrer. The desired temperature was to approximate that of

  1. Cellulose fibers obtained by organosolv process from date palm rachis (Phoenix dactylifera L.)

    NASA Astrophysics Data System (ADS)

    Ammar, H.; Abid, M.; Abid, S.

    2012-02-01

    In this preliminary study, the chemical composition of Tunisian DPR was established and discussed. The main characteristic of this agri-residue was its high lignin content in comparison with that of alfa plant. CIMV process was used to selectively separate cellulose fibres, hemicelluloses and lignin at atmospheric pressure. The obtained unbleached pulp was analysed in accordance with Kappa index and degree of polymerisation and then bleached by treating successively with peroxyacids and hydrogen peroxide in basic media.

  2. Regulation of Breast Carcinoma Growth and Neovascularization by Novel Peptide Sequences in Thrombospondin

    DTIC Science & Technology

    1998-09-01

    B., Mulliken, J. B., and Folkman, J. Interferon alfa -2a therapy for life-threatening hemangiomas of infancy, N. Engl. J. Med. 326: 1456-1463, 1992. 8...angiogenic factors have also been identified, including thrombospondin (5, 6), interferon - alpha (7), platelet factor 4 (8), SPARC (9...inhibited by 60% for MDA-MB-435 cells with a 90% reduction in 31SO 4 incorporation (Fig. 2B ). RGD 8 peptides did not inhibit adhesion of MDA-MB-435 cells on

  3. Patients with Fabry disease after enzyme replacement therapy dose reduction versus treatment switch.

    PubMed

    Weidemann, Frank; Krämer, Johannes; Duning, Thomas; Lenders, Malte; Canaan-Kühl, Sima; Krebs, Alice; Guerrero González, Hans; Sommer, Claudia; Üçeyler, Nurcan; Niemann, Markus; Störk, Stefan; Schelleckes, Michael; Reiermann, Stefanie; Stypmann, Jörg; Brand, Stefan-Martin; Wanner, Christoph; Brand, Eva

    2014-04-01

    Because of the shortage of agalsidase-beta in 2009, many patients with Fabry disease were treated with lower doses or were switched to agalsidase-alfa. This observational study assessed end-organ damage and clinical symptoms during dose reduction or switch to agalsidase-alfa. A total of 105 adult patients with Fabry disease who had received agalsidase-beta (1.0 mg/kg body weight) for ≥1 year were nonrandomly assigned to continue this treatment regimen (regular-dose group, n=38), receive a reduced dose of 0.3-0.5 mg/kg (dose-reduction group, n=29), or switch to 0.2 mg/kg agalsidase-alfa (switch group) and were followed prospectively for 1 year. We assessed clinical events (death, myocardial infarction, severe arrhythmia, stroke, progression to ESRD); changes in cardiac, renal, and neurologic function; and Fabry-related symptoms (neuropathic pain, hypohidrosis, diarrhea, and disease severity scores). Organ function and Fabry-related symptoms remained stable in the regular-dose group. In contrast, estimated GFR decreased by about 3 ml/min per 1.73 m(2) (P=0.01) in the dose-reduction group, and the median albumin-to-creatinine ratio increased from 114 (0-606) mg/g to 216 (0-2062) mg/g (P=0.03) in the switch group. Furthermore, mean Mainz Severity Score Index scores and frequencies of pain attacks, chronic pain, gastrointestinal pain, and diarrhea increased significantly in the dose-reduction and switch groups. In conclusion, patients receiving regular agalsidase-beta dose had a stable disease course, but dose reduction led to worsening of renal function and symptoms. Switching to agalsidase-alfa is safe, but microalbuminuria may progress and Fabry-related symptoms may deteriorate.

  4. Data collecting and treatment control system in the «Alpha-Electron» space experiment on board the International Space Station

    NASA Astrophysics Data System (ADS)

    Galper, A. M.; Batischev, A. G.; Naumov, P. P.; Naumov, P. Yu

    2017-01-01

    The fast multilayer scintillation detector of the new telescope-spectrometer for the ALFA-ELECTRON space experiment is in ground testing mode now. Modules of data control system for spectrometer are discussed. The structure of the main data format and functional blocks for data treatment are presented. The device will planned to install on the outer surface of the Russian Segment (RS) of the International Space Station (ISS) in 2018.

  5. A Fundamental Electrochemical Investigation of Bromoaluminate and Mixed Chloro-Bromoaluminate Room Temperature Molten Salt Systems

    DTIC Science & Technology

    1989-03-01

    The authors wish to acknowledge the invaluable assistance of John L. Pflug, and Fred C. Kibler. iv CONTENTS C HA PT ER PA GE 1. INTRODUCTION...tribromide 16 was prepared by the method described by Chattaway and Hoyle . Nine grams of tetramethylammonium bromide were dissolved in 60 mL of 95% ethyl...Force Academy. 90 16. Chattaway, Frederick Daniel; Hoyle , George; J. Am. Chem. Soc. 1923 45 654-662. 17. Alfa Catalog 1986 p552. 18. Buckles Robert E

  6. Atomic Layer Deposition of Metal Oxides on sp2-Graphitic Carbon Substrates

    DTIC Science & Technology

    2014-03-31

    Na2SO4 Aqueous Electrolyte ………………………………...11 iv Approved for public release; distribution unlimited. 1.0 SUMMARY This research concentrated on the...sodium sulfate (Alfa Aesar, 99.99% metals basis) aqueous electrolyte under a continuous argon (Airgas, Prepurified) purge. Platinum counter electrodes...of the semi-circle is indicative of the charge-transfer resistance for the electrode/ electrolyte interface. A smaller radius indicates a lower

  7. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2004-04-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies Knowledge Area of Prous Science Integrity(R), the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: ABI-007, adalimumab, adefovir dipivoxil, alefacept, alemtuzumab, 3-AP, AP-12009, APC-8015, L-Arginine hydrochloride, aripiprazole, arundic acid, avasimibe; Bevacizumab, bivatuzumab, BMS-181176, BMS-184476, BMS-188797, bortezomib, bosentan, botulinum toxin type B, BQ-123, BRL-55730, bryostatin 1; CEP-1347, cetuximab, cinacalcet hydrochloride, CP-461, CpG-7909; D-003, dabuzalgron hydrochloride, darbepoetin alfa, desloratadine, desoxyepothilone B, dexmethylphenidate hydrochloride, DHA-paclitaxel, diflomotecan, DN-101, DP-b99, drotrecogin alfa (activated), duloxetine hydrochloride, duramycin; Eculizumab, Efalizumab, EKB-569, elcometrine, enfuvirtide, eplerenone, erlotinib hydrochloride, ertapenem sodium, eszopiclone, everolimus, exatecan mesilate, ezetimibe; Fenretinide, fosamprenavir calcium, frovatriptan; GD2L-KLH conjugate vaccine, gefitinib, glufosfamide, GTI-2040; Hexyl insulin M2, human insulin, hydroquinone, gamma-Hydroxybutyrate sodium; IL-4(38-37)-PE38KDEL, imatinib mesylate, indisulam, inhaled insulin, ixabepilone; KRN-5500; LY-544344; MDX-210, melatonin, mepolizumab, motexafin gadolinium; Natalizumab, NSC-330507, NSC-683864; 1-Octanol, omalizumab, ortataxel; Pagoclone, peginterferon alfa-2a, peginterferon alfa-2b, pemetrexed disodium, phenoxodiol, pimecrolimus, plevitrexed, polyphenon E, pramlintide acetate, prasterone, pregabalin, PX-12; QS-21; Ragaglitazar, ranelic acid distrontium salt, RDP-58, recombinant glucagon-like peptide-1 (7-36) amide, repinotan hydrochloride, rhEndostatin, rh-Lactoferrin, (R)-roscovitine; S-8184, semaxanib, sitafloxacin hydrate, sitaxsentan sodium, sorafenib, synthadotin

  8. Speciation and Geochemistry of Tungsten in Soil

    DTIC Science & Technology

    2006-11-01

    sodium tungstate dihydrate was purchased from Sigma Aldrich (St. Louis, MO) and Alfa Aesar (Ward Hill, MA), respectively. Single element and mixed...yielding an amorphous tungsten oxide (WO3) coating. This coating rapidly dissolves to yield the tungstate anion (WO42-), which can migrate in...well characterized. Tungsten exists in most environmental matrices as the soluble and mobile tungstate anion, which can polymerize with itself and

  9. Local Atomic Structure Deviation from Average Structure of Na0.5Bi0.5TiO3: Combined X-ray and Neutron Total Scattering Study

    DTIC Science & Technology

    2013-03-27

    calcination of the particles, and after sintering and densification of polycrystalline materials) to examine the possible influences of strain, grain...and Na2CO3 (99.5% purity, Alfa Aesar) were first calcined at 800 ◦C for 2 h and some powder was retained for structural characterization after this...synthesis step (hereafter referred to as “ calcined ”). Samples were then also sintered and densified into pellets at 1100 ◦C for 1 h. The sintered pellets

  10. Synthesis and Properties of Hexachloromolybdates(V) and Related Species.

    DTIC Science & Technology

    1983-11-04

    Tetraphenylarsonium Chloride Anhydrous tetraethylamnonium chloride was prepared from commercial tetraethylammonium chloride monohydrate (ex Aldrich...by continuous evacuation at 110 0C for 24 hours. Similarly anhydrous tetraphenylarsonium chloride was prepared by continuous evacuation of the...arringtons), anhydrous chromium(III) chloride (ex Alfa Products), CrCl 3 ,6H2 0 (ex VDH), MnCl 2 .4H2 0 (ex 1DH), FeCI 2 .6H 2 0 (ex East Anglia Chemicals

  11. Enzymes approved for human therapy: indications, mechanisms and adverse effects.

    PubMed

    Baldo, Brian A

    2015-02-01

    Research and drug developments fostered under orphan drug product development programs have greatly assisted the introduction of efficient and safe enzyme-based therapies for a range of rare disorders. The introduction and regulatory approval of 20 different recombinant enzymes has enabled, often for the first time, effective enzyme-replacement therapy for some lysosomal storage disorders, including Gaucher (imiglucerase, taliglucerase, and velaglucerase), Fabry (agalsidase alfa and beta), and Pompe (alglucosidase alfa) diseases and mucopolysaccharidoses I (laronidase), II (idursulfase), IVA (elosulfase), and VI (galsulfase). Approved recombinant enzymes are also now used as therapy for myocardial infarction (alteplase, reteplase, and tenecteplase), cystic fibrosis (dornase alfa), chronic gout (pegloticase), tumor lysis syndrome (rasburicase), leukemia (L-asparaginase), some collagen-based disorders such as Dupuytren's contracture (collagenase), severe combined immunodeficiency disease (pegademase bovine), detoxification of methotrexate (glucarpidase), and vitreomacular adhesion (ocriplasmin). The development of these efficacious and safe enzyme-based therapies has occurred hand in hand with some remarkable advances in the preparation of the often specifically designed recombinant enzymes; the manufacturing expertise necessary for commercial production; our understanding of underlying mechanisms operative in the different diseases; and the mechanisms of action of the relevant recombinant enzymes. Together with information on these mechanisms, safety findings recorded so far on the various adverse events and problems of immunogenicity of the recombinant enzymes used for therapy are presented.

  12. GALFA-HI: A Targeted Search For Star Formation on the Far Side of the Milky Way

    NASA Astrophysics Data System (ADS)

    Stantzos, Nicholas; Gostisha, M.; Benjamin, R.; Gibson, S.; Koo, B.; Douglas, K. A.; Kang, J.; Park, G.; Peek, J. E. G.; Korpela, E. J.; Heiles, C.; Newton, J. H.

    2012-01-01

    The I-GALFA Survey provides a unique window on the spiral structure of the Milky Way as it contains three coherent 21 cm features that have been identified as spiral arms: the Perseus Arm, the Outer Arm, and the recently discovered Outer Scutum-Centaurus Arm. Moreover, all three of these arms lie beyond the solar circle (although the Perseus arm is thought to cross interior to the solar circle for l< 50 degrees), so this gas does not suffer the kinematic distance ambiguity encountered in the inner Galaxy. We use this data and the CO surveys compiled by Dame et al (2001) to target a search for distant star formation regions seen in the Spitzer Space Telescope/GLIMPSE and WISE mid-infrared all-sky surveys. We characterize the HI arms, and present the star formation regions that may be potentially associated with these three arms. Many of these objects will need spectroscopic follow-up, but some have been previously identified in the Green Bank Telescope HII Region Discovery Survey of Anderson et al (2011). The Inner Galaxy ALFA (I-GALFA) survey is part of the Galactic ALFA HI data set obtained with the Arecibo L-band Feed Array (ALFA) on the Arecibo 305m telescope. Arecibo Observatory is part of the National Astronomy and Ionosphere Center, operated sequentially by Cornell University and Stanford Research Institute under Cooperative Agreement with the U.S. National Science Foundation.

  13. Mechanical Properties of Aluminum Matrix Composite Reinforced by Carbothermally Reduced of Fly Ash

    SciTech Connect

    Jamasri; Wildan, M. W.; Sulardjaka; Kusnanto

    2011-01-17

    The addition of fly ash into aluminum as reinforcement can potentially reduce the production cost and density of aluminum. However, mechanical properties of aluminum matrix composite reinforced by fly ash (MMC ALFA) have some limitations due to the characteristic of fly ash. In this study, a carbothermal reduction process of fly ash and activated carbon powder with particle size <32 {mu}m was performed prior to produce MMC ALFA.The process was carried out in a furnace at 1300 deg. C in vacuum condition under argon flow. Synthesis product was analyzed by XRD with Cu-K{sub {alpha}} radiation. From XRD analysis, it shows that the synthesis process can produce SiC powder. The synthesis product was subsequently used as reinforcement particle. Aluminum powder was mixed with 5, 10 and 15% of the synthesized powder, and then uni-axially compacted at pressure of 300 MPa. The compacted product was sintered for 2 hours in argon atmosphere at temperature variation of 550 and 600 deg. C. Flexural strength, hardness and density of MMC ALFA's product were respectively evaluated using a four point bending test method based on ASTM C1161 standard, Brinell hardness scale and Archimedes method. The result of this study shows that the increase of weight of reinforcement can significantly increase the hardness and flexural strength of MMCs. The highest hardness and flexural strength of the MMC product are 300 kg/mm{sup 2} and 107.5 MPa, respectively.

  14. Enzyme replacement therapy for treating mucopolysaccharidosis type IVA (Morquio A syndrome): effect and limitations

    PubMed Central

    Tomatsu, Shunji; Sawamoto, Kazuki; Shimada, Tsutomu; Bober, Michael B.; Kubaski, Francyne; Yasuda, Eriko; Mason, Robert W.; Khan, Shaukat; Alméciga-Díaz, Carlos J.; Barrera, Luis A.; Mackenzie, William G.

    2015-01-01

    Introduction Following a Phase III, randomized, double-blind, placebo (PBO)-controlled, multinational study in subjects with mucopolysaccharidosis IVA (MPS IVA), enzyme replacement therapy (ERT) of elosulfase alfa has been approved in several countries. The study was designed to evaluate safety and efficacy of elosulfase alfa in patients with MPS IVA aged 5 years and older. Areas covered Outcomes of clinical trials for MPS IVA have been described. Subjects received either 2.0 mg/kg/week, 2.0 mg/kg/every other week, or PBO, for 24 weeks. The primary endpoint was the change from baseline 6-min walk test (6MWT) distance compared to PBO. The 6MWT results improved in patients receiving 2 mg/kg weekly compared to PBO. The every other week regimen resulted in walk distances comparable to PBO. There was no change from baseline in the 3 Min Stair Climb Test in both treatment groups. Following completion of the initial study, patients, who continued to receive elosulfase alfa 2 mg/kg weekly (QW) for another 48 weeks (for a total of up to 72-week exposure), did not show additional improvement on 6MWT. Expert opinion We suggest that ERT is a therapeutic option for MPS IVA, providing a modest effect and the majority of the effects are seen in the soft tissues. PMID:26973801

  15. Mechanical Properties of Aluminum Matrix Composite Reinforced by Carbothermally Reduced of Fly Ash

    NASA Astrophysics Data System (ADS)

    Jamasri, Wildan, M. W.; Sulardjaka, Kusnanto

    2011-01-01

    The addition of fly ash into aluminum as reinforcement can potentially reduce the production cost and density of aluminum. However, mechanical properties of aluminum matrix composite reinforced by fly ash (MMC ALFA) have some limitations due to the characteristic of fly ash. In this study, a carbothermal reduction process of fly ash and activated carbon powder with particle size <32 μm was performed prior to produce MMC ALFA. The process was carried out in a furnace at 1300° C in vacuum condition under argon flow. Synthesis product was analyzed by XRD with Cu-Kα radiation. From XRD analysis, it shows that the synthesis process can produce SiC powder. The synthesis product was subsequently used as reinforcement particle. Aluminum powder was mixed with 5, 10 and 15% of the synthesized powder, and then uni-axially compacted at pressure of 300 MPa. The compacted product was sintered for 2 hours in argon atmosphere at temperature variation of 550 and 600° C. Flexural strength, hardness and density of MMC ALFA's product were respectively evaluated using a four point bending test method based on ASTM C1161 standard, Brinell hardness scale and Archimedes method. The result of this study shows that the increase of weight of reinforcement can significantly increase the hardness and flexural strength of MMCs. The highest hardness and flexural strength of the MMC product are 300 kg/mm2 and 107.5 MPa, respectively.

  16. Fabry disease and enzyme replacement therapy in classic patients with same mutation: different formulations--different outcome?

    PubMed

    Politei, J; Schenone, A B; Cabrera, G; Heguilen, R; Szlago, M

    2016-01-01

    We describe the results of the multidisciplinary evaluation in patients with Fabry disease and the same genetic mutation and their outcomes using different approved enzyme replacement therapy (ERT). We measured baseline data and serial results of neuropathic pain assessment and renal, cardiac and cerebrovascular functioning. Pain scale showed improvement in all male cases treated with agalsidasa beta. A mild improvement was detected in agalsidasa alfa-treated patients after 1 year with posterior increase. During the agalsidase beta shortage, two male patients were switched to agalsidasa alfa, after 1 year both cases presented an increase in scale values. Renal evolution showed a tendency toward a decrease in proteinuria in patients using agalsidase beta and worsening with agalsidase alfa. We found improvement in two females using agalsidase beta and no changes in the other cases regarding cardiac functioning. Brain magnetic resonance imaging (MRI) showed increase of white matter lesions in four patients. Improvement and stabilization in neuropathic pain, renal and cardiac functioning and brain MRI were found mainly in patients treated with agalsidase beta. Following the reported recommendations on reintroduction of agalsidase beta after the enzyme shortage, we decided to switch all patients to agalsidase beta.

  17. Lucinactant attenuates pulmonary inflammatory response, preserves lung structure, and improves physiologic outcomes in a preterm lamb model of RDS

    PubMed Central

    Wolfson, Marla R.; Wu, Jichuan; Hubert, Terrence L.; Gregory, Timothy J.; Mazela, Jan; Shaffer, Thomas H.

    2013-01-01

    Background Acute inflammatory responses to supplemental oxygen and mechanical ventilation have been implicated in the pathophysiological sequelae of respiratory distress syndrome (RDS). Although surfactant replacement therapy (SRT) has contributed to lung stability, the effect on lung inflammation is inconclusive. Lucinactant contains sinapultide (KL4), a novel synthetic peptide that functionally mimics surfactant protein B, a protein with anti-inflammatory properties. We tested the hypothesis that lucinactant may modulate lung inflammatory response to mechanical ventilation in the management of RDS and may confer greater protection than animal-derived surfactants. Methods Preterm lambs (126.8 ± 0.2 SD d gestation) were randomized to receive lucinactant, poractant alfa, beractant, or no surfactant and studied for 4 h. Gas exchange and pulmonary function were assessed serially. Lung inflammation biomarkers and lung histology were assessed at termination. Results SRT improved lung compliance relative to no SRT without significant difference between SRT groups. Lucinactant attenuated lung and systemic inflammatory response, supported oxygenation at lower ventilatory requirements, and preserved lung structural integrity to a greater degree than either no SRT or SRT with poractant alfa or beractant. Conclusion These data suggest that early intervention with lucinactant may more effectively mitigate pulmonary pathophysiological sequelae of RDS than the animal-derived surfactants poractant alfa or beractant. PMID:22821059

  18. The modelling of symmetric airfoil vortex generators

    NASA Technical Reports Server (NTRS)

    Reichert, B. A.; Wendt, B. J.

    1996-01-01

    An experimental study is conducted to determine the dependence of vortex generator geometry and impinging flow conditions on shed vortex circulation and crossplane peak vorticity for one type of vortex generator. The vortex generator is a symmetric airfoil having a NACA 0012 cross-sectional profile. The geometry and flow parameters varied include angle-of-attack alfa, chordlength c, span h, and Mach number M. The vortex generators are mounted either in isolation or in a symmetric counter-rotating array configuration on the inside surface of a straight pipe. The turbulent boundary layer thickness to pipe radius ratio is delta/R = 0. 17. Circulation and peak vorticity data are derived from crossplane velocity measurements conducted at or about 1 chord downstream of the vortex generator trailing edge. Shed vortex circulation is observed to be proportional to M, alfa, and h/delta. With these parameters held constant, circulation is observed to fall off in monotonic fashion with increasing airfoil aspect ratio AR. Shed vortex peak vorticity is also observed to be proportional to M, alfa, and h/delta. Unlike circulation, however, peak vorticity is observed to increase with increasing aspect ratio, reaching a peak value at AR approx. 2.0 before falling off.

  19. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2010-09-01

    Aclidinium bromide, AE-37, Alemtuzumab, AMA1-C1/ISA 720, Amlodipine besylate/atorvastatin calcium, Arachidonic acid, Arbaclofen placarbil, Aripiprazole, ARQ-621, Azelnidipine, Azilsartan medoxomil potassium; Bevacizumab, Biphasic insulin aspart, Bortezomib; Choriogonadotropin alfa, CTS-1027; Dapagliflozin, Dasatinib, Deforolimus, Degarelix acetate, Denufosol tetrasodium, Desvenlafaxine succinate, Dronedarone hydrochloride, Duloxetine hydrochloride, Dutasteride; Enfuvirtide, Entecavir, Etaracizumab, Everolimus, Exenatide, Ezetimibe; Ferric carboxymaltose, Fludarabine, Foretinib; Gefitinib, GFT-505, GSK-256066; HPV-6/11/16/18, HuM195/rGel, HyperAcute-Lung cancer vaccine; I5NP, Imatinib mesylate, Imexon, Insulin detemir, Insulin glargine, Ivabradine hydrochloride; L2G7, Lacosamide, Lapatinib ditosylate, Lenalidomide, Lidocaine/prilocaine, Liposomal vincristine, Liraglutide, Lixivaptan; Meningococcal (groups A, C, Y and W-135) oligosaccharide diphtheria CRM197 conjugate vaccine, Methoxy polyethylene glycol-epoetin-β, Mirabegron, Morphine/oxycodone, MR Vaccine, MSC-1936369B, Mycophenolic acid sodium salt; Narlaprevir, N-Desmethylclozapine; Ocriplasmin, Olaparib, Olmesartan medoxomil, Olmesartan medoxomil/azelnidipine, ONO-5334, ONO-8539; Palifermin, Panitumumab, Pardoprunox hydrochloride, PCV7, Peginterferon alfa-2a, Peginterferon alfa-2b, Pemetrexed disodium, Pexelizumab, PF-337210, Pitavastatin calcium; Raltegravir potassium, Recombinant interleukin-7, Regadenoson, Reniale, Roflumilast, Rosuvastatin calcium; Safinamide mesilate, SB-1518, SCH-527123, Selumetinib, Sipuleucel-T, Solifenacin succinate, Sorafenib, Sunitinib malate; Tadalafil, Talaporfin sodium, Tanespimycin, Technosphere/Insulin, Telaprevir, Telatinib, Telcagepant, Telmisartan/hydrochlorothiazide, Teriparatide, Testosterone transdermal gel, TH-302, Tiotropium bromide, Tocilizumab, Trabedersen, Tremelimumab; Valsartan/amlodipine besylate, Vernakalant hydrochloride, Visilizumab, Voreloxin, Vorinostat.

  20. Mannose receptor-mediated delivery of moss-made α-galactosidase A efficiently corrects enzyme deficiency in Fabry mice.

    PubMed

    Shen, Jin-Song; Busch, Andreas; Day, Taniqua S; Meng, Xing-Li; Yu, Chun I; Dabrowska-Schlepp, Paulina; Fode, Benjamin; Niederkrüger, Holger; Forni, Sabrina; Chen, Shuyuan; Schiffmann, Raphael; Frischmuth, Thomas; Schaaf, Andreas

    2016-03-01

    Enzyme replacement therapy (ERT) is an effective treatment for several lysosomal storage disorders (LSDs). Intravenously infused enzymes are taken up by tissues through either the mannose 6-phosphate receptor (M6PR) or the mannose receptor (MR). It is generally believed that M6PR-mediated endocytosis is a key mechanism for ERT in treating LSDs that affect the non-macrophage cells of visceral organs. However, the therapeutic efficacy of MR-mediated delivery of mannose-terminated enzymes in these diseases has not been fully evaluated. We tested the effectiveness of a non-phosphorylated α-galactosidase A produced from moss (referred to as moss-aGal) in vitro and in a mouse model of Fabry disease. Endocytosis of moss-aGal was MR-dependent. Compared to agalsidase alfa, a phosphorylated form of α-galactosidase A, moss-aGal was more preferentially targeted to the kidney. Cellular localization of moss-aGal and agalsidase alfa in the heart and kidney was essentially identical. A single injection of moss-aGal led to clearance of accumulated substrate in the heart and kidney to an extent comparable to that achieved by agalsidase alfa. This study suggested that mannose-terminated enzymes may be sufficiently effective for some LSDs in which non-macrophage cells are affected, and that M6P residues may not always be a prerequisite for ERT as previously considered.

  1. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2008-09-01

    Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com.This issue focuses on the following selection of drugs: ABT-263, AC-2307, Aclidinium bromide, Adefovir dipivoxil, ADH-1, Agatolimod sodium, Alefacept, Aliskiren fumarate, Aminolevulinic acid methyl ester, Anakinra, Apaziquone, Aprepitant, Aripiprazole, ASM-8, Atiprimod hydrochloride, AVE-0277, AVE-1642, AVE-8062, Axitinib, Azacitidine, AZD-0530; Bazedoxifene acetate, Bevacizumab, Bexarotene, BI-2536, Biphasic insulin aspart, BMS-387032, BMS-663513, Bortezomib, BQ-123, Brivanib alaninate, BSI-201; Caspofungin acetate, CDX-110, Cetuximab, Ciclesonide, CR-011, Cypher; Daptomycin, Darbepoetin alfa, Dasatinib, Decitabine, Deferasirox, Denosumab, Dexlansoprazole, Dexmethylphenidate hydrochloride, DNA-Hsp65 vaccine, Dovitinib, Drotrecogin alfa (activated), DTaP-HBV-IPV/Hibvaccine, DTaP-IPV-HB-PRP-T, Duloxetine hydrochloride, Dutasteride; Ecogramostim, Elacytarabine, Emtricitabine, Endothelin, Entecavir, Eplivanserin fumarate, Escitalopram oxalate, Everolimus, Ezetimibe, Ezetimibe/simvastatin; Farletuzumab, Fesoterodine fumarate, Fibrin sealant (human), Fulvestrant; Gefitinib, Gemtuzumab ozogamicin, Glufosfamide, GSK-1562902A; Hib-TT; Imatinib mesylate, IMC-11F8, Imidazoacridinone, IMP-321, INCB-18424, Indiplon, Indisulam, INNO-406, Irinotecan hydrochloride/Floxuridine, ITF-2357, Ixabepilone; KRN-951; Lasofoxifene tartrate; Lenalidomide, LGD-4665, Lonafarnib, Lubiprostone, Lumiliximab; MDX-1100, Melan-A/MART-1/gp100/IFN-alfa, Methyl-CDDO, Metreleptin, MLN-2704, Mycophenolic acid sodium salt; Na-ASP-2, Naproxcinod, Nilotinib hydrochloride monohydrate, NPI-2358; Oblimersen sodium, Odanacatib; Paclitaxel nanoparticles, PAN-811, Panobinostat, PBI-1402, PC-515, Peginterferon alfa

  2. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2005-01-01

    Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: (-)-Epigallocatechin gallate; ACP-103, Ad.Egr.TNF.11 D, adalimumab, AF-IL 12, AIDSVAX gp120 B/B, alefacept, alemtuzumab, a-Galactosylceramide, ALVAC vCP 1452, alvimopan hydrate, alvocidib hydrochloride, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, anakinra, anidulafungin, antarelix, aprepitant, aripiprazole, arsenic sulfide, asoprisnil, atazanavir sulfate, atomoxetine hydrochloride; Bevacizumab, bimatoprost, BMS-184476, bortezomib, bosentan, botulinum toxin type B, BrachySil, brivudine; Caffeine, calcipotriol/betamethasone dipropionate, cannabidiol, capsaicin for injection, caspofungin acetate, CC-4047, cetuximab, CGP-36742, clofazimine, CpG-7909, Cypher; Darbepoetin alfa, dextromethorphan/quinidine sulfate, dimethylfumarate, dronabinol/cannabidiol, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Ecogramostim, efalizumab, eletriptan, emtricitabine, enfuvirtide, eplerenone, esomeprazole magnesium, estradiol acetate, eszopiclone, etoricoxib, exenatide, ezetimibe, ezetimibe/simvastatin; Fampridine, fondaparinux sodium, fosamprenavir calcium; Gefitinib, GPI-0100; hA 20, HTU-PA, human insulin, HuOKT 3 gamma 1(Ala 234-Ala 235), hyaluronic acid; Icatibant, imatinib mesylate, Indiplon, INKP-100, INKP-102, iodine (I131) tositumomab, istradefylline, IV gamma-globulin, ivabradine hydrochloride, ixabepilone; Lacosamide, landiolol, lanthanum carbonate, lasofoxifene tartrate, LB-80380, lenalidomide, lidocaine/tetracaine, linezolid, liposomal doxorubicin, liposomal vincristine sulfate, lopinavir, lopinavir/ritonavir, lumiracoxib, lurtotecan; Maribavir, morphine glucuronide, MVA-5 T

  3. Improved delivery of fenoterol plus ipratropium bromide using Respimat compared with a conventional metered dose inhaler.

    PubMed

    Goldberg, J; Freund, E; Beckers, B; Hinzmann, R

    2001-02-01

    Asthma can be effectively treated by the use of bronchodilator therapies administered by inhalation. The objective of this study was to describe the dose-response relationship of combined doses of fenoterol hydrobromide (F) and ipratropium bromide (I) (F/I) delivered via Respimat, a soft mist inhaler, and to establish the Respimat dose which is as efficacious and as safe as the standard marketed dose of F/I (100/40 microg) which is delivered via a conventional metered dose inhaler (MDI). In a double-blind (within device) cross-over study with a balanced incomplete block design, 62 patients with stable bronchial asthma (mean forced expiratory volume in one second (FEV1) 63% predicted) were randomized at five study centres to receive five out of eight possible treatments: placebo, F/I 12.5/5, 25/10, 50/20, 100/40 or 200/80 microg delivered via Respimat; F/I 50/20 or 100/40 microg delivered via MDI. Pulmonary function results were based on the per-protocol dataset, comprising 47 patients. All F/I doses produced greater increases in FEV1 than placebo. A log-linear dose-response was obtained for the average increase in FEV1 up to 6 h (AUC0-6 h) and peak FEV1 across the dose range administered by Respimat. Statistically, therapeutic equivalence was not demonstrated between any F/I dose administered by Respimat compared with the MDI. However 12.5/5 and 25/10 microg F/I administered via Respimat were closest (slightly superior) to the F/I dose of 100/40 microg delivered via MDI. Pharmacokinetic data from 34 patients indicated a two-fold greater systemic availability of both drugs following inhalation by Respimat compared to MDI. In general, the active treatments were well tolerated and safe with regard to vital signs, electrocardiography, laboratory parameters and adverse events. In conclusion, combined administration of fenoterol hydrobromide and ipratropium bromide via Respimat, is as effective and as safe as higher doses given via a metered dose inhaler.

  4. Effects of silk fibroin in murine dry eye

    PubMed Central

    Kim, Chae Eun; Lee, Ji Hyun; Yeon, Yeung Kyu; Park, Chan Hum; Yang, JaeWook

    2017-01-01

    The study aimed to investigate the effects of silk fibroin in a mouse model of dry eye. The experimental dry eye mouse model was developed using more than twelve-weeks-old NOD.B10.H2b mice exposing them to 30–40% ambient humidity and injecting them with scopolamine hydrobromide for 10 days. Tear production and corneal irregularity score were measured by the instillation of phosphate buffered saline or silk fibroin. Corneal detachment and conjunctival goblet cell density were observed by hematoxylin and eosin or periodic acid Schiff staining in the cornea or conjunctiva. The expression of inflammatory markers was detected by immunohistochemistry in the lacrimal gland. The silk group tear production was increased, and corneal smoothness was improved. The corneal epithelial cells and conjunctival goblet cells were recovered in the silk groups. The expression of inflammatory factors was inhibited in the lacrimal gland of the silk group. These results show that silk fibroin improved the cornea, conjunctiva, and lacrimal gland in the mouse model of dry eye. These findings suggest that silk fibroin has anti-inflammatory effects in the experimental models of dry eye. PMID:28281688

  5. Rabies virus inactivation by binary ethylenimine: new method for inactivated vaccine production.

    PubMed Central

    Larghi, O P; Nebel, A E

    1980-01-01

    The inactivation dynamics of rabies virus (PV strain) by binary ethylenimine, and the immunogenic properites and the stability of the vaccines prepared using this agent, were studied. Binary ethylenimine at a final concentration of 0.01 M was prepared wtih 2-bromoethylamine hydrobromide in alkaline solutions, either separately from or in suspensions of rabies virus propagated in BHK cells. The infectivity of virus suspensions containing more than 108 plaque-forming units per 0.1 ml was inactivated in 2 h when the inactivating agent was prepared before its addition to the suspensions, and in3 h when prepared directly in the suspensions. Liquid vaccines prepared in this manner and stored at different temperatures maintained potency for 1 month at 37 degrees C and for 6 months at 4 degrees C and 22 to 25 degrees C. Lyophilized vaccine maintained its potency for 6 months at the three temperatures. The inactivated vaccine mixed with aluminum or oil adjuvant at high dilutions protected guinea pigs against challenge. This safer procedure for rabies virus inactivation offers promise for the production of effective vaccines for the immunization of dogs and cattle. PMID:7358836

  6. Effects of silk fibroin in murine dry eye

    NASA Astrophysics Data System (ADS)

    Kim, Chae Eun; Lee, Ji Hyun; Yeon, Yeung Kyu; Park, Chan Hum; Yang, Jaewook

    2017-03-01

    The study aimed to investigate the effects of silk fibroin in a mouse model of dry eye. The experimental dry eye mouse model was developed using more than twelve-weeks-old NOD.B10.H2b mice exposing them to 30–40% ambient humidity and injecting them with scopolamine hydrobromide for 10 days. Tear production and corneal irregularity score were measured by the instillation of phosphate buffered saline or silk fibroin. Corneal detachment and conjunctival goblet cell density were observed by hematoxylin and eosin or periodic acid Schiff staining in the cornea or conjunctiva. The expression of inflammatory markers was detected by immunohistochemistry in the lacrimal gland. The silk group tear production was increased, and corneal smoothness was improved. The corneal epithelial cells and conjunctival goblet cells were recovered in the silk groups. The expression of inflammatory factors was inhibited in the lacrimal gland of the silk group. These results show that silk fibroin improved the cornea, conjunctiva, and lacrimal gland in the mouse model of dry eye. These findings suggest that silk fibroin has anti-inflammatory effects in the experimental models of dry eye.

  7. Radiation protection of male fertility in mouse and rat by a combination of 5-hydroxy-L-tryptophan and a thiol compound (AET).

    PubMed

    George, S; Chuttani, K; Basu, S K

    1992-01-01

    Sperm abnormalities and fall in total sperm count following different doses (4 Gy, 5 Gy and 6 Gy) of whole body gamma irradiation (WBGR) were studied in adult male Swiss strain A mice. The protecting ability of a combination of 5-hydroxy-L-tryptophan (5-HTP, 100 mg/kg) and 2-aminoethyl isothiuronium bromide hydrobromide (AET, 20 mg/kg) was also investigated. Pretreatment with a 5-HTP+AET formulation i.p., 30 min before irradiation modified the fall in sperm counts significantly. Exposures to 4 Gy, 5 Gy and 6 Gy WBGR caused marked increase of sperm abnormalities which could be significantly reduced by pretreatment with 5-HTP-AET. WBGR with 4 Gy, 5 Gy and 6 Gy produced a short period of sterility associated with oligospermia but these abnormalities were corrected by pretreatment with 5-HTP+AET. This finding was supported by breeding experiments in pretreated adult male Sprague-Dawley rats which showed delivery of normal offsprings in drug-protected irradiated groups in contrast to irradiated controls.

  8. Pharmacokinetic Effects of Isavuconazole Coadministration With the Cytochrome P450 Enzyme Substrates Bupropion, Repaglinide, Caffeine, Dextromethorphan, and Methadone in Healthy Subjects.

    PubMed

    Yamazaki, Takao; Desai, Amit; Goldwater, Ronald; Han, David; Howieson, Corrie; Akhtar, Shahzad; Kowalski, Donna; Lademacher, Christopher; Pearlman, Helene; Rammelsberg, Diane; Townsend, Robert

    2017-01-01

    This report describes phase 1 clinical trials performed to assess interactions of oral isavuconazole at the clinically targeted dose (200 mg, administered as isavuconazonium sulfate 372 mg, 3 times a day for 2 days; 200 mg once daily [QD] thereafter) with single oral doses of the cytochrome P450 (CYP) substrates: bupropion hydrochloride (CYP2B6; 100 mg; n = 24), repaglinide (CYP2C8/CYP3A4; 0.5 mg; n = 24), caffeine (CYP1A2; 200 mg; n = 24), dextromethorphan hydrobromide (CYP2D6/CYP3A4; 30 mg; n = 24), and methadone (CYP2B6/CYP2C19/CYP3A4; 10 mg; n = 23). Compared with each drug alone, coadministration with isavuconazole changed the area under the concentration-time curves (AUC∞ ) and maximum concentrations (Cmax ) as follows: bupropion, AUC∞ reduced 42%, Cmax reduced 31%; repaglinide, AUC∞ reduced 8%, Cmax reduced 14%; caffeine, AUC∞ increased 4%, Cmax reduced 1%; dextromethorphan, AUC∞ increased 18%, Cmax increased 17%; R-methadone, AUC∞ reduced 10%, Cmax increased 3%; S-methadone, AUC∞ reduced 35%, Cmax increased 1%. In all studies, there were no deaths, 1 serious adverse event (dextromethorphan study; perioral numbness, numbness of right arm and leg), and adverse events leading to study discontinuation were rare. Thus, isavuconazole is a mild inducer of CYP2B6 but does not appear to affect CYP1A2-, CYP2C8-, or CYP2D6-mediated metabolism.

  9. pH-Sensitive ionomeric particles obtained via chemical conjugation of silk with poly(amino acid)s.

    PubMed

    Serban, Monica A; Kaplan, David L

    2010-12-13

    Silk-fibroin-based biomaterials have been widely utilized for a range of biomaterial-related systems. For all these previously reported systems, the β-sheet forming feature of the silk was the key stabilizing element of the final material structure. Herein, we describe a different strategy, based on the engineering of silk-based ionomers that can yield stable colloidal composites or particle suspensions through electrostatic interactions. These silk-based ionomers were obtained by carbodiimide-mediated coupling of silk fibroin with polylysine hydrobromide and polyglutamic acid sodium salts, respectively. Colloidal composites could be obtained by mixing the ionomeric pair at high concentration (i.e., 25% w/v), while combining them at lower concentrations (i.e., 5% w/v) yielded particle suspensions. The assembly of the ionomers was driven by electrostatic interactions, pH-dependent, and reversible. The network assembly appeared to be polarized, with the interacting poly(amino acid) chains clustered to the core of the particles and the silk backbone oriented outward. In agreement with this assembly mode, doxorubicin, a hydrophilic antitumor drug, could be released at a slow rate, in a pH-dependent manner, indicating that the inside of the ionomeric particles was mainly hydrophilic in nature.

  10. Optogenetic versus electrical stimulation of dopamine terminals in the nucleus accumbens reveals local modulation of presynaptic release

    PubMed Central

    Melchior, James R.; Ferris, Mark J.; Stuber, Garret D.; Riddle, David R.; Jones, Sara R.

    2015-01-01

    The nucleus accumbens is highly heterogeneous, integrating regionally distinct afferent projections and accumbal interneurons, resulting in diverse local microenvironments. Dopamine (DA) neuron terminals similarly express a heterogeneous collection of terminal receptors that modulate DA signaling. Cyclic voltammetry is often used to probe DA terminal dynamics in brain slice preparations; however, this method traditionally requires electrical stimulation to induce DA release. Electrical stimulation excites all of the neuronal processes in the stimulation field, potentially introducing simultaneous, multi-synaptic modulation of DA terminal release. We used optogenetics to selectively stimulate DA terminals and used voltammetry to compare DA responses from electrical and optical stimulation of the same area of tissue around a recording electrode. We found that with multiple pulse stimulation trains, optically stimulated DA release increasingly exceeded that of electrical stimulation. Furthermore, electrical stimulation produced inhibition of DA release across longer duration stimulations. The GABAB antagonist, CGP 55845, increased electrically stimulated DA release significantly more than light stimulated release. The nicotinic acetylcholine receptor antagonist, dihydro-β-erythroidine hydrobromide, inhibited single pulse electrically stimulated DA release while having no effect on optically stimulated DA release. Our results demonstrate that electrical stimulation introduces local multi-synaptic modulation of DA release that is absent with optogenetically targeted stimulation. PMID:26011081

  11. Polythiophene derivative on quartz resonators for miRNA capture and assay.

    PubMed

    Palaniappan, Al; Cheema, Jamal Ahmed; Rajwar, Deepa; Ammanath, Gopal; Xiaohu, Liu; Koon, Lim Seng; Yi, Wang; Yildiz, Umit Hakan; Liedberg, Bo

    2015-12-07

    A novel approach for miRNA assay using a cationic polythiophene derivative, poly[3-(3'-N,N,N-triethylamino-1'-propyloxy)-4-methyl-2,5-thiophene hydrobromide] (PT), immobilized on a quartz resonator is proposed. The cationic PT enables capturing of all RNA sequences in the sample matrix via electrostatic interactions, resulting in the formation of PT-RNA duplex structures on quartz resonators. Biotinylated peptide nucleic acid (b-PNA) sequences are subsequently utilized for the RNA assay, upon monitoring the PT-RNA-b-PNA triplex formation. Signal amplification is achieved by anchoring avidin coated nanoparticles to b-PNA in order to yield responses at clinically relevant concentration regimes. Unlike conventional nucleic acid assay methodologies that usually quantify a specific sequence of RNA, the proposed approach enables the assay of any RNA sequence in the sample matrix upon hybridization with a PNA sequence complementary to the RNA of interest. As an illustration, successful detection of mir21, (a miRNA sequence associated with lung cancer) is demonstrated with a limit of detection of 400 pM. Furthermore, precise quantification of mir21 in plasma samples is demonstrated without requiring PCR and sophisticated instrumentation.

  12. Roles of dopaminergic innervation of nucleus accumbens shell and dorsolateral caudate-putamen in cue-induced morphine seeking after prolonged abstinence and the underlying D1- and D2-like receptor mechanisms in rats

    PubMed Central

    Gao, Jun; Li, Yonghui; Zhu, Ning; Brimijoin, Stephen; Sui, Nan

    2013-01-01

    Drug-associated cues can elicit relapse to drug seeking after abstinence. Studies with extinction–reinstatement models implicate dopamine (DA) in the nucleus accumbens shell (NAshell) and dorsolateral caudate-putamen (dlCPu) in cocaine seeking. However, less is known about their roles in cue-induced opiate seeking after prolonged abstinence. Using a morphine self-administration and abstinence–relapse model, we explored the roles of NAshell and dlCPu DA and the D1/D2-like receptor mechanisms underlying morphine rewarding and/or seeking. Acquisition of morphine self-administration was examined following 6-Hydroxydopamine hydrobromide (6-OHDA) lesions of the NAshell and dlCPu. For morphine seeking, rats underwent 3 weeks’ morphine self-administration followed by 3 weeks’ abstinence from morphine and the training environment. Prior to testing, 6-OHDA, D1 antagonist SCH23390, or D2 antagonist eticlopride was locally injected; then rats were exposed to morphine-associated contextual and discrete cues. Results show that acquisition of morphine self-administration was inhibited by NAshell (not dlCPu) lesions, while morphine seeking was attenuated by lesions of either region, by D1 (not D2) receptor blockade in NAshell, or by blockade of either D1 or D2 receptors in dlCPu. These data indicate a critical role of dopaminergic transmission in the NAshell (via D1-like receptors) and dlCPu (via D1- and D2-like receptors) in morphine seeking after prolonged abstinence. PMID:23151613

  13. Identification of vitamin B1 metabolism as a tumor-specific radiosensitizing pathway using a high-throughput colony formation screen

    PubMed Central

    Buffa, Francesca M.; Yu, Sheng; Ebner, Daniel V.; Howarth, Alison; Folkes, Lisa K.; Budwal, Balam; Chu, Kwun-Ye; Durrant, Lisa; Muschel, Ruth J.; McKenna, W. Gillies; Higgins, Geoff S.

    2015-01-01

    Colony formation is the gold standard assay for determining reproductive cell death after radiation treatment, since effects on proliferation often do not reflect survival. We have developed a high-throughput radiosensitivity screening method based on clonogenicity and screened a siRNA library against kinases. Thiamine pyrophosphokinase-1 (TPK1), a key component of Vitamin B1/thiamine metabolism, was identified as a target for radiosensitization. TPK1 knockdown caused significant radiosensitization in cancer but not normal tissue cell lines. Other means of blocking this pathway, knockdown of thiamine transporter-1 (THTR1) or treatment with the thiamine analogue pyrithiamine hydrobromide (PyrH) caused significant tumor specific radiosensitization. There was persistent DNA damage in cells irradiated after TPK1 and THTR1 knockdown or PyrH treatment. Thus this screen allowed the identification of thiamine metabolism as a novel radiosensitization target that affects DNA repair. Short-term modulation of thiamine metabolism could be a clinically exploitable strategy to achieve tumor specific radiosensitization. PMID:25788274

  14. Peripheral 5-HT1A and 5-HT7 Serotonergic Receptors Modulate Parasympathetic Neurotransmission in Long-Term Diabetic Rats

    PubMed Central

    Restrepo, Beatriz; Martín, María Luisa; San Román, Luis; Morán, Asunción

    2010-01-01

    We analyzed the modulation of serotonin on the bradycardia induced in vivo by vagal electrical stimulation in alloxan-induced long-term diabetic rats. Bolus intravenous administration of serotonin had a dual effect on the bradycardia induced either by vagal stimulation or exogenous Ach, increasing it at low doses and decreasing it at high doses of 5-hydroxytryptamine (5-HT), effect reproduced by 5-carboxamidotryptamine maleate (5-CT), a 5-HT1/7 agonist. The enhancement of the bradycardia at low doses of 5-CT was reproduced by 5-HT1A agonist 8-hydroxy-2-dipropylaminotetralin hydrobromide (8-OH-DPAT) and abolished by WAY-100,635, 5-HT1A antagonist. Pretreatment with 5-HT1 antagonist methiothepin blocked the stimulatory and inhibitory effect of 5-CT, whereas pimozide, 5-HT7 antagonist, only abolished 5-CT inhibitory action. In conclusion, long-term diabetes elicits changes in the subtype of the 5-HT receptor involved in modulation of vagally induced bradycardia. Activation of the 5-HT1A receptors induces enhancement, whereas attenuation is due to 5-HT7 receptor activation. This 5-HT dual effect occurs at pre- and postjunctional levels. PMID:21403818

  15. Combination antitumor effect with central nervous system depressants on rat ascites hepatomas.

    PubMed

    Koshiura, R; Miyamoto, K; Sanae, F

    1980-02-01

    Combined effect of twenty-one central nervous system depressants with several antitumor agents was studied in the in vitro and in vivo experimental systems, using rat ascites hepatoma call lines, AH13 and AH44, sensitive and insensitive to alkylating agents, respectively. Reserpine remarkably enhanced the cytotoxic effect of 1-(gamma-chloropropyl)-2-chloromethylpiperidine hydrobromide (CAP-2) both on AH13 and AH44 cells. In the in vivo combined experiments, reserpine also synergistically enhanced the life-prolonging effect of CAP-2 on AH13-bearing rats and, although CAP-2 was not potent on the prolongation of life span of AH44-bearing rats and reserpine was also ineffective at the doses examined, the life span of tumor-bearing rats receiving the combined administration was apparently prolonged compared with control groups. Thus, there was a parallelism between in vitro and in vivo experiments. These findings suggested that the antitumor-enhancing effect of reserpine might be due to the direct action on the tumor cells, and a possible mechanism that reserpine inhibited the DNA damage-repairing activity of the cells was contradictory. Other mechanisms are also discussed.

  16. Vortioxetine for the treatment of major depression.

    PubMed

    Dhir, A

    2013-12-01

    Vortioxetine (Lu-AA-21004; 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine hydrobromide) is a novel orally active molecule that is being investigated by Lundbeck and Takeda for the treatment of major depression and generalized anxiety disorders. Vortioxetine has a unique "multi-modal" mechanism of action. It inhibits the activity of serotonin transporters and is an agonist of serotonin 5-HT1A receptor, partial agonist of 5-HT1B and antagonist of 5-HT3A, 5-HT7 and 5-HT1D receptors. Vortioxetine has been effective in various animal models of depression and anxiety and clinical studies have shown the antidepressant and antianxiety properties of vortioxetine in a dose range of 5-20 mg/day. Vortioxetine reverses cognitive decline in patients with depression making it a unique molecule. The molecule lacks any serious side effects and drug-drug interactions. However, dose adjustments are required if vortioxetine is co-administered with rifampicin or bupropion. The molecule is under review by various regulatory agencies around the world for the treatment of major depression.

  17. Fluorescent bovine serum albumin interacting with the antitussive quencher dextromethorphan: a spectroscopic insight.

    PubMed

    Durgannavar, Amar K; Patgar, Manjanath B; Nandibewoor, Sharanappa T; Chimatadar, Shivamurti A

    2016-05-01

    The interaction of dextromethorphan hydrobromide (DXM) with bovine serum albumin (BSA) is studied by using fluorescence spectra, UV-vis absorption, synchronous fluorescence spectra (SFS), 3D fluorescence spectra, Fourier transform infrared (FTIR) spectroscopy and circular dichroism under simulated physiological conditions. DXM effectively quenched the intrinsic fluorescence of BSA. Values of the binding constant, K(A), are 7.159 × 10(3), 9.398 × 10(3) and 16.101 × 10(3)  L/mol; the number of binding sites, n, and the corresponding thermodynamic parameters ΔG°, ΔH° and ΔS° between DXM and BSA were calculated at different temperatures. The interaction between DXM and BSA occurs through dynamic quenching and the effect of DXM on the conformation of BSA was analyzed using SFS. The average binding distance, r, between the donor (BSA) and acceptor (DXM) was determined based on Förster's theory. The results of fluorescence spectra, UV-vis absorption spectra and SFS show that the secondary structure of the protein has been changed in the presence of DXM.

  18. [Rapid identification 15 effective components of anti common cold medicine with MRM by LC-MS/MS].

    PubMed

    Jiang, Jian-Guo; Zhang, Xi-Ru; Zhang, Yi-Hua; Song, Geng-Shen

    2013-01-01

    This paper reports the establishment of a method for rapid identification 15 effective components of anti common cold medicine (paracetamol, aminophenazone, pseudoephedrine hydrochloride, methylephedrine hydrochloride, caffeine, amantadine hydrochloride, phenazone, guaifenesin, chlorphenamine maleate, dextromethorphen hydrobromide, diphenhydramine hydrochloride, promethazine hydrochloride, propyphenazone, benorilate and diclofenac sodium) with MRM by LC-MS/MS. The samples were extracted by methanol and were separated from a Altantis T3 column within 15 min with a gradient of acetonitrile-ammonium acetate (containing 0.25% glacial acetic acid), a tandem quadrupole mass spectrometer equipped with electrospray ionization source (ESI) was used in positive ion mode, and multiple reaction monitoring (MRM) was performed for qualitative analysis of these compounds. The minimum detectable quantity were 0.33-2.5 microg x kg(-1) of the 15 compounds. The method is simple, accurate and with good reproducibility for rapid identification many components in the same chromatographic condition, and provides a reference for qualitative analysis illegally added chemicals in anti common cold medicine.

  19. Development and validation of a generic high-performance liquid chromatography for the simultaneous separation and determination of six cough ingredients: Robustness study on core-shell particles.

    PubMed

    Yehia, Ali Mohamed; Essam, Hebatallah Mohamed

    2016-09-01

    A generally applicable high-performance liquid chromatographic method for the qualitative and quantitative determination of pharmaceutical preparations containing phenylephrine hydrochloride, paracetamol, ephedrine hydrochloride, guaifenesin, doxylamine succinate, and dextromethorphan hydrobromide is developed. Optimization of chromatographic conditions was performed for the gradient elution using different buffer pH values, flow rates and two C18 stationary phases. The method was developed using a Kinetex® C18 column as a core-shell stationary phase with a gradient profile using buffer pH 5.0 and acetonitrile at 2.0 mL/min flow rate. Detection was carried out at 220 nm and linear calibrations were obtained for all components within the studied ranges. The method was fully validated in agreement with ICH guidelines. The proposed method is specific, accurate and precise (RSD% < 3%). Limits of detection are lower than 2.0 μg/mL. Qualitative and quantitative responses were evaluated using experimental design to assist the method robustness. The method was proved to be highly robust against 10% change in buffer pH and flow rate (RSD% < 10%), however, the flow rate may significantly influence the quantitative responses of phenylephrine, paracetamol, and doxylamine (RSD% > 10%). Satisfactory results were obtained for commercial combinations analyses. Statistical comparison between the proposed chromatographic and official methods revealed no significant difference.

  20. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2002-01-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses, which has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the world's first drug discovery and development portal, providing information on study design, treatments, conclusions and references. This issue focuses on the following selection of drugs: Abacavir sulfate; abciximab; abetimus sodium; adalimumab; aldesleukin; almotriptan; alteplase; amisulpride; amitriptyline hydrochloride; amoxicillin trihydrate; atenolol; atorvastatin calcium; atrasentan; Beclometasone dipropionate; bosentan; Captopril; ceftriaxone sodium; cerivastatin sodium; cetirizine hydrochloride; cisplatin; citalopram hydrobromide; Dalteparin sodium; darusentan; desirudin; digoxin; Efalizumab; enoxaparin sodium; ertapenem sodium; esomeprazole magnesium; estradiol; ezetimibe; Famotidine; farglitazar; fluorouracil; fluticasone propionate; fosamprenavir sodium; Glibenclamide; glucosamine sulfate; Heparin sodium; HSPPC-96; hydrochlorothiazide; Imatinib mesilate; implitapide; Lamivudine; lansoprazole; lisinopril; losartan potassium; l-Propionylcarnitine; Melagatran; metformin hydrochloride; methotrexate; methylsulfinylwarfarin; Nateglinide; norethisterone; Olmesartan medoxomil; omalizumab; omapatrilat; omeprazole; oseltamivir phosphate; oxatomide; Pantoprazole; piperacillin sodium; pravastatin sodium; Quetiapine hydrochloride; Rabeprazole sodium; raloxifene hydrochloride; ramosetron hydrochloride; ranolazine; rasburicase; reboxetine mesilate; recombinant somatropin; repaglinide; reteplase; rosiglitazone; rosiglitazone maleate; rosuvastatin calcium; Sertraline; simvastatin; sumatriptan succinate; Tazobactam sodium; tenecteplase; tibolone; tinidazole; tolterodine tartrate; troglitazone; Uniprost; Warfarin sodium; Ximelagatran.

  1. Spectrophotometric determination of some anti-tussive and anti-spasmodic drugs through ion-pair complex formation with thiocyanate and cobalt(II) or molybdenum(V)

    NASA Astrophysics Data System (ADS)

    El-Shiekh, Ragaa; Zahran, Faten; El-Fetouh Gouda, Ayman Abou

    2007-04-01

    Two rapid, simple and sensitive extractive specrophotometric methods has been developed for the determination of anti-tussive drugs, e.g., dextromethorphan hydrobromide (DEX) and pipazethate hydrochloride (PiCl) and anti-spasmodic drugs, e.g., drotaverine hydrochloride (DvCl) and trimebutine maleate (TM) in bulk and in their pharmaceutical formulations. The proposed methods depend upon the reaction of cobalt(II)-thiocyanate (method A) and molybdenum(V)-thiocyanate ions (method B) with the cited drugs to form stable ion-pair complexes which extractable with an n-butnol-dichloromethane solvent mixture (3.5:6.5) and methylene chloride for methods A and B, respectively. The blue and orange red color complexes are determined either colorimetrically at λmax 625 nm (using method A) and 467 or 470 nm for (DEX and PiCl) or (DvCl and TM), respectively (using method B). The concentration range is 20-400 and 2.5-50 μg mL -1 for methods A and B, respectively. The proposed method was successfully applied for the determination of the studied drugs in pure and in pharmaceutical formulations applying the standard additions technique and the results obtained in good agreement well with those obtained by the official method.

  2. Spectrophotometric determination of some anti-tussive and anti-spasmodic drugs through ion-pair complex formation with thiocyanate and cobalt(II) or molybdenum(V).

    PubMed

    El-Shiekh, Ragaa; Zahran, Faten; El-Fetouh Gouda, Ayman Abou

    2007-04-01

    Two rapid, simple and sensitive extractive specrophotometric methods has been developed for the determination of anti-tussive drugs, e.g., dextromethorphan hydrobromide (DEX) and pipazethate hydrochloride (PiCl) and anti-spasmodic drugs, e.g., drotaverine hydrochloride (DvCl) and trimebutine maleate (TM) in bulk and in their pharmaceutical formulations. The proposed methods depend upon the reaction of cobalt(II)-thiocyanate (method A) and molybdenum(V)-thiocyanate ions (method B) with the cited drugs to form stable ion-pair complexes which extractable with an n-butnol-dichloromethane solvent mixture (3.5:6.5) and methylene chloride for methods A and B, respectively. The blue and orange red color complexes are determined either colorimetrically at lambdamax 625 nm (using method A) and 467 or 470 nm for (DEX and PiCl) or (DvCl and TM), respectively (using method B). The concentration range is 20-400 and 2.5-50 microg mL-1 for methods A and B, respectively. The proposed method was successfully applied for the determination of the studied drugs in pure and in pharmaceutical formulations applying the standard additions technique and the results obtained in good agreement well with those obtained by the official method.

  3. Simultaneous determination of ambroxol and salbutamol in human plasma by ultra-performance liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study.

    PubMed

    Guo, Zhening; Chen, Yangsheng; Ding, Xiaoliang; Huang, Chenrong; Miao, Liyan

    2016-11-01

    A rapid, selective and sensitive liquid chromatography-tandem mass spectrometry assay method was developed for simultaneous determination of ambroxol and salbutamol in human plasma using citalopram hydrobromide as internal standard (IS). The sample was alkalinized with ammonia water (33:67, v/v) and extracted by single liquid-liquid extraction with ethyl acetate. Separation was achieved on Waters Acquity UPLC BEH C18 column using a gradient program at a flow rate of 0.2 mL/min. Detection was performed using electrospray ionization in positive ion multiple reaction monitoring mode by monitoring the ion transitions m/z 378.9 → 263.6 (ambroxol), m/z 240.2 → 147.7 (salbutamol) and m/z 325.0 → 261.7 (IS). The total analytical run time was relatively short (3 min). Calibration curves were linear in the concentration range of 0.5-100.0 ng/mL for ambroxol and 0.2-20.0 ng/mL for salbutamol, with intra- and inter-run precision (relative standard deviation) <15% and accuracy (relative error) ranging from 97.7 to 112.1% for ambroxol and from 94.5 to 104.1% for salbutamol. The method was successfully applied in a clinical pharmacokinetic study of the compound ambroxol and salbutamol tablets.

  4. Simultaneous quantitative analysis of dextromethorphan, dextrorphan and chlorphenamine in human plasma by liquid chromatography-electrospray tandem mass spectrometry.

    PubMed

    Ding, Ying; Huang, Kai; Chen, Lan; Yang, Jie; Xu, Wen-Yan; Xu, Xue-Jiao; Duan, Ru; Zhang, Jing; He, Qing

    2014-03-01

    A sensitive and accurate HPLC-MS/MS method was developed for the simultaneous determination of dextromethorphan, dextrorphan and chlorphenamine in human plasma. Three analytes were extracted from plasma by liquid-liquid extraction using ethyl acetate and separated on a Kromasil 60-5CN column (3 µm, 2.1 × 150 mm) with mobile phase of acetonitrile-water (containing 0.1% formic acid; 50:50, v/v) at a flow rate of 0.2 mL/min. Quantification was performed on a triple quadrupole tandem mass spectrometer in multiple reaction monitoring mode using positive electrospray ionization. The calibration curve was linear over the range of 0.01-5 ng/mL for dextromethorphan, 0.02-5 ng/mL for dextrorphan and 0.025-20 ng/mL for chlorphenamine. The lower limits of quantification for dextromethorphan, dextrorphan and chlorphenamine were 0.01, 0.02 and 0.025 ng/mL, respectively. The intra- and inter-day precisions were within 11% and accuracies were in the range of 92.9-102.5%. All analytes were proved to be stable during sample storage, preparation and analytic procedures. This method was first applied to the pharmacokinetic study in healthy Chinese volunteers after a single oral dose of the formulation containing dextromethorphan hydrobromide (18 mg) and chlorpheniramine malaeate (8 mg).

  5. Using an innovative combination of quality-by-design and green analytical chemistry approaches for the development of a stability indicating UHPLC method in pharmaceutical products.

    PubMed

    Boussès, Christine; Ferey, Ludivine; Vedrines, Elodie; Gaudin, Karen

    2015-11-10

    An innovative combination of green chemistry and quality by design (QbD) approach is presented through the development of an UHPLC method for the analysis of the main degradation products of dextromethorphan hydrobromide. QbD strategy was integrated to the field of green analytical chemistry to improve method understanding while assuring quality and minimizing environmental impacts, and analyst exposure. This analytical method was thoroughly evaluated by applying risk assessment and multivariate analysis tools. After a scouting phase aimed at selecting a suitable stationary phase and an organic solvent in accordance with green chemistry principles, quality risk assessment tools were applied to determine the critical process parameters (CPPs). The effects of the CPPs on critical quality attributes (CQAs), i.e., resolutions, efficiencies, and solvent consumption were further evaluated by means of a screening design. A response surface methodology was then carried out to model CQAs as function of the selected CPPs and the optimal separation conditions were determined through a desirability analysis. Resulting contour plots enabled to establish the design space (DS) (method operable design region) where all CQAs fulfilled the requirements. An experimental validation of the DS proved that quality within the DS was guaranteed; therefore no more robustness study was required before the validation. Finally, this UHPLC method was validated using the concept of total error and was used to analyze a pharmaceutical drug product.

  6. Food restriction and streptozotocin differentially modify sensitivity to the hypothermic effects of direct- and indirect-acting serotonin receptor agonists in rats.

    PubMed

    Li, Jun-Xu; Koek, Wouter; France, Charles P

    2009-06-24

    Food restriction and experimentally-induced diabetes (streptozotocin) can modify serotonin (5-HT) neurotransmission and sensitivity to drugs acting on 5-HT systems. This study examined the effects of food restriction and streptozotocin on the hypothermic effects of the 5-HT(1A) receptor agonist (+)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT), the 5-HT(2) receptor agonist (+/-)-2,5-dimethoxy-4-methylamphetamine hydrochloride (DOM), the 5-HT releaser fenfluramine, and the selective 5-HT reuptake inhibitor (SSRI) fluoxetine. All four drugs significantly decreased body temperature in free feeding rats. Limiting rats to 10 g/day of food for 7 days decreased body weight and sensitivity to 8-OH-DPAT induced hypothermia, without affecting sensitivity to DOM, fenfluramine, or fluoxetine induced hypothermia. Subsequently, 7 days of free feeding restored body weight and sensitivity to 8-OH-DPAT. Sensitivity to all drugs was significantly decreased 7 days after 50 mg/kg streptozotocin; subsequently, 10 days of insulin replacement restored sensitivity to all drugs. These results extend to body temperature the observation that food restriction and experimentally-induced diabetes differentially modify sensitivity to drugs acting on 5-HT systems and they further suggest that the clinical response to therapeutic drugs acting on 5-HT systems might be impacted by nutritional and insulin status.

  7. Spectrophotometric determination of pipazethate HCl, dextromethorphan HBr and drotaverine HCl in their pharmaceutical preparations.

    PubMed

    Amin, Alaa S; El-Sheikh, Ragaa; Zahran, Faten; Gouda, Ayman Abou El-fetouh

    2007-07-01

    A simple, accurate and highly sensitive spectrophotometric method is proposed for the rapid determination of pipazethate hydrochloride, dextromethorphan hydrobromide and drotaverine hydrochloride using chromotrope 2B (C2B) and chromotrope 2R (C2R). The method consists of extracting the formed ion-associates into chloroform in the case of pipazethate HCl and dextromethorphan HBr or into methylene chloride in the case of drotaverine HCl. The ion-associates exhibit absorption maxima at 528, 540 and 532 nm with C2B and at 526, 517 and 522 nm with C2R for pipazethate HCl, dextromethorphan HBr and drotaverine HCl, respectively. The calibration curves resulting from the measurements of absorbance-concentration relations (at the optimum reaction conditions) of the extracted ion-pairs are linear over the concentration range 4.36-52.32 microg mL(-1) for pipazethate, 3.7-48.15 microg mL(-1) for dextromethorphan and 4.34-60.76 microg mL(-1) for drotaverine, respectively. The effect of acidity, reagent concentration, time, solvent and stoichiometric ratio of the ion-associates were estimated. The molar absorptivity and Sandell sensitivity of the reaction products were calculated. Statistical treatment of the results reflects that the procedure is precise, accurate and easily applied for the determination of the drugs under investigation in pure form and in their pharmaceutical preparations.

  8. Cholinergic modulation of pavlovian fear conditioning: effects of intrahippocampal scopolamine infusion.

    PubMed

    Gale, G D; Anagnostaras, S G; Fanselow, M S

    2001-01-01

    Cholinergic neurotransmission has been implicated in the acquisition of a variety of tasks, including Pavlovian fear conditioning. To more precisely define the role of cholinergic modulation in this process, the effect of site-specific cholinergic antagonism was assessed. Male Long-Evans rats were implanted with chronic, bilateral cannulae aimed at the dorsal hippocampus. Infusions of scopolamine hydrobromide (50 microg bilaterally) or phosphate-buffered saline (PBS) were made immediately prior to a signaled Pavlovian fear conditioning procedure. On consecutive days following training, all rats were given independent tests assessing freezing to both the training context and the tone conditional stimulus (CS). Relative to PBS infused controls, rats that received intrahippocampal infusions of scopolamine showed a significant attenuation of contextual freezing but comparable levels of freezing to the tone CS. Neither shock sensitivity nor general activity levels differed between rats infused with scopolamine or PBS. These findings suggest that fear conditioning to context, but not discrete CS, requires intact cholinergic neurotransmission in the hippocampus.

  9. Polyelectrolyte multilayer capsules with quantum dots for biomedical applications.

    PubMed

    Adamczak, M; Hoel, H J; Gaudernack, G; Barbasz, J; Szczepanowicz, K; Warszyński, P

    2012-02-01

    The aim of this work was to encapsulate the CdTe quantum dots within the nanocapsules that were prepared by the layer-by-layer adsorption of polyelectrolytes. Two different polyelectrolyte pairs were used as components of the shell: synthetic polycation poly(allyamine hydrochloride) (PAH), together with anionic poly(sodium styrene sulfonate) (PSS), and biocompatible cationic poly-L-lysine hydrobromide in a pair with biocompatible anionic poly-D-glutamic acid sodium salt (PGA). The saturation method was used for formation of consecutive layers on the initial CdTe-polyelectrolyte complex. A growth of the polyelectrolyte shell was followed with the electrophoretic mobility and light scattering measurements, in order to determine the zeta potential and the size of capsules, respectively. The fluorescent spectra of the quantum dots, which are embedded within the capsules, were characterized with spectrofluorimeter. Later on, they were deposited on a negatively charged mica surface and studied by the means of atomic force microscopy (AFM). In order to estimate the cytotoxicity of capsules, their influence on the B-lymphoblastoid cell line proliferation and on unspecific binding to the P-blood mononuclear cells was examined using the flow cytometry.

  10. Effects of chronic scopolamine administration on spatial working memory and hippocampal receptors related to learning.

    PubMed

    Doguc, Duygu K; Delibas, Namik; Vural, Huseyin; Altuntas, Irfan; Sutcu, Recep; Sonmez, Yonca

    2012-12-01

    Scopolamine has been used in neuropsychopharmacology as a standard drug that leads to symptoms mimicking cognitive deficits seen during the aging process in healthy humans and animals. Scopolamine is known to be a nonselective muscarinic receptor blocker, but its chronic effect on the expression of certain hippocampal receptors is not clear. The aim of the present study was to determine the effect of chronic scopolamine administration on hippocampal receptor expression and spatial working memory in two different learning tasks, the water maze and the eight-arm radial maze. Male rats (8-12 months) were trained in both tasks. Subsequently, different groups received physiological saline or 0.1, 0.8, or 2 mg/kg scopolamine hydrobromide, respectively, for 15 days. After drug administration, the rats were retested for both tasks, and hippocampal expressions of NR2A, NR2B, nAChRα7, and mAChRM1 receptors were assessed by western blotting analysis. In both tasks, the spatial working memory was decreased dose dependently in all groups compared with the control group. In terms of receptor expressions, 0.8 and 2 mg/kg scopolamine administration significantly decreased NR2A protein expression, which corroborates suggestions of an interaction between cholinergic and glutamatergic receptors in the hippocampus.

  11. Performance- and task-dependent effects of the dopamine D1/D5 receptor agonist SKF 38393 on learning and memory in the rat.

    PubMed

    Amico, Francesco; Spowart-Manning, Laura; Anwyl, Roger; Rowan, Michael J

    2007-12-22

    Dopamine D(1)/D(5) receptor agonists may enhance cognition by mimicking dopamine's neurophysiological actions on the processes underlying learning and memory. The present study examined the task- and performance- dependence of the cognitive effects of a partial agonist at dopamine D(1)/D(5) receptors, SKF 38393 [(+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrobromide], in rats. Spatial working memory was assessed in a T-maze, spatial reference memory in a water maze and habituation learning in a novel environment, a hole board. The muscarinic acetylcholine receptor antagonist scopolamine (1.5 mg/kg, i.p.) was used to cause an impairment of performance of these learning tasks. Administration of SKF 38393 (6 mg/kg, i.p.) alone had no significant effect on spontaneous alternation in the T-maze, latency to escape to a hidden platform in the water maze or the habituation of spontaneous behaviour in the hole board. In contrast, in scopolamine-treated rats, whereas SKF 38393 prevented the scopolamine-induced deficit in the T-maze, it exacerbated the impairment in the water maze and did not significantly alter the disruption of habituation. These results suggest that dopamine D(1)/D(5) receptor activation has performance- and task-dependent effects on cognitive function.

  12. Sympathetic Nervous System Control of Carbon Tetrachloride-Induced Oxidative Stress in Liver through α-Adrenergic Signaling

    PubMed Central

    Lin, Jung-Chun; Peng, Yi-Jen; Wang, Shih-Yu; Young, Ton-Ho; Salter, Donald M.; Lee, Herng-Sheng

    2016-01-01

    In addition to being the primary organ involved in redox cycling, the liver is one of the most highly innervated tissues in mammals. The interaction between hepatocytes and sympathetic, parasympathetic, and peptidergic nerve fibers through a variety of neurotransmitters and signaling pathways is recognized as being important in the regulation of hepatocyte function, liver regeneration, and hepatic fibrosis. However, less is known regarding the role of the sympathetic nervous system (SNS) in modulating the hepatic response to oxidative stress. Our aim was to investigate the role of the SNS in healthy and oxidatively stressed liver parenchyma. Mice treated with 6-hydroxydopamine hydrobromide were used to realize chemical sympathectomy. Carbon tetrachloride (CCl4) injection was used to induce oxidative liver injury. Sympathectomized animals were protected from CCl4 induced hepatic lipid peroxidation-mediated cytotoxicity and genotoxicity as assessed by 4-hydroxy-2-nonenal levels, morphological features of cell damage, and DNA oxidative damage. Furthermore, sympathectomy modulated hepatic inflammatory response induced by CCl4-mediated lipid peroxidation. CCl4 induced lipid peroxidation and hepatotoxicity were suppressed by administration of an α-adrenergic antagonist. We conclude that the SNS provides a permissive microenvironment for hepatic oxidative stress indicating the possibility that targeting the hepatic α-adrenergic signaling could be a viable strategy for improving outcomes in patients with acute hepatic injury. PMID:26798417

  13. In vitro activities of novel catecholate siderophores against Plasmodium falciparum.

    PubMed Central

    Pradines, B; Ramiandrasoa, F; Basco, L K; Bricard, L; Kunesch, G; Le Bras, J

    1996-01-01

    The activities of novel iron chelators, alone and in combination with chloroquine, quinine, or artemether, were evaluated in vitro against susceptible and resistant clones of Plasmodium falciparum with a semimicroassay system. N4-nonyl,N1,N8-bis(2,3-dihydroxybenzoyl) spermidine hydrobromide (compound 7) demonstrated the highest level of activity: 170 nM against a chloroquine-susceptible clone and 1 microM against a chloroquine-resistant clone (50% inhibitory concentrations). Compounds 6, 8, and 10 showed antimalarial activity with 50% inhibitory concentrations of about 1 microM. Compound 7 had no effect on the activities of chloroquine, quinine, and artemether against either clone, and compound 8 did not enhance the schizontocidal action of either chloroquine or quinine against the chloroquine-resistant clone. The incubation of compound 7 with FeCI3 suppressed or decreased the in vitro antimalarial activity of compound 7, while no effect was observed with incubation of compound 7 with CuSO4 and ZnSO4. These results suggest that iron deprivation may be the main mechanism of action of compound 7 against the malarial parasites. Chelator compounds 7 and 8 primarily affected trophozoite stages, probably by influencing the activity of ribonucleotide reductase, and thus inhibiting DNA synthesis. PMID:8878587

  14. The first proton sponge-based amino acids: synthesis, acid-base properties and some reactivity.

    PubMed

    Ozeryanskii, Valery A; Gorbacheva, Anastasia Yu; Pozharskii, Alexander F; Vlasenko, Marina P; Tereznikov, Alexander Yu; Chernov'yants, Margarita S

    2015-08-21

    The first hybrid base constructed from 1,8-bis(dimethylamino)naphthalene (proton sponge or DMAN) and glycine, N-methyl-N-(8-dimethylamino-1-naphthyl)aminoacetic acid, was synthesised in high yield and its hydrobromide was structurally characterised and used to determine the acid-base properties via potentiometric titration. It was found that the basic strength of the DMAN-glycine base (pKa = 11.57, H2O) is on the level of amidine amino acids like arginine and creatine and its structure, zwitterionic vs. neutral, based on the spectroscopic (IR, NMR, mass) and theoretical (DFT) approaches has a strong preference to the zwitterionic form. Unlike glycine, the DMAN-glycine zwitterion is N-chiral and is hydrolytically cleaved with the loss of glycolic acid on heating in DMSO. This reaction together with the mild decarboxylative conversion of proton sponge-based amino acids into 2,3-dihydroperimidinium salts under air-oxygen was monitored with the help of the DMAN-alanine amino acid. The newly devised amino acids are unique as they combine fluorescence, strongly basic and redox-active properties.

  15. Higher lung deposition with Respimat Soft Mist inhaler than HFA-MDI in COPD patients with poor technique.

    PubMed

    Brand, Peter; Hederer, Bettina; Austen, George; Dewberry, Helen; Meyer, Thomas

    2008-01-01

    Aerosols delivered by Respimat Soft Mist Inhaler (SMI) are slower-moving and longer-lasting than those from pressurized metered-dose inhalers (pMDIs), improving the efficiency of pulmonary drug delivery to patients. In this four-way cross-over study, adults with chronic obstructive pulmonary disease (COPD) and with poor pMDI technique received radiolabelled Berodual (fenoterol hydrobromide 50 microg/ipratropium bromide 20 microg) via Respimat SMI or hydrofluoroalkane (HFA)-MDI (randomized order) on test days 1 and 2, with no inhaler technique training. The procedure was repeated on test days 3 and 4 after training. Deposition was measured by gamma scintigraphy. All 13 patients entered (9 males, mean age 62 years; FEV1 46% of predicted) inhaled too fast at screening (peak inspiratory flow rate [IF]: 69-161 L/min). Whole lung deposition was higher with Respimat SMI than with pMDI for untrained (37% of delivered dose vs 21% of metered dose) and trained patients (53% of delivered vs 21% of metered dose) (P(Sign-Test) = 0.15; P(ANOVA) < 0.05). Training also improved inhalation profiles (slower average and peak IF as well as longer breath-hold time). Drug delivery to the lungs with Respimat SMI is more efficient than with pMDI, even with poor inhaler technique. Teaching patients to hold their breath as well as to inhale slowly and deeply increased further lung deposition using Respimat SMI.

  16. Low incidence of paradoxical bronchoconstriction in asthma and COPD patients during chronic use of Respimat soft mist inhaler.

    PubMed

    Hodder, Rick; Pavia, Demetri; Dewberry, Helen; Alexander, Karen; Iacono, Philippe; Ponitz, Hans; Beck, Ekkehard

    2005-09-01

    Respimat Soft Mist Inhaler (SMI) is a new-generation inhaler that offers improved lung deposition compared with chlorofluorocarbon metered dose inhalers (CFC-MDIs). Bronchodilators administered via Respimat SMI are preserved and stabilised with low concentrations of benzalkonium chloride and ethylene diamine tetra-acetic acid, both of which have been reported to cause dose-related paradoxical bronchoconstriction. The aim of this analysis was to compare the incidence of paradoxical bronchoconstriction after chronic use of bronchodilators via Respimat SMI and CFC-MDI. Data from three clinical trials, in which patients with asthma or chronic obstructive pulmonary disease (COPD) received ipratropium bromide alone or in combination with fenoterol hydrobromide, or placebo via Respimat SMI or CFC-MDI for 12 weeks, were included in the analysis. In order to evaluate the risk of paradoxical bronchoconstriction, we identified four respiratory events that might have occurred within 30 min of inhalation on four test days; these were: 'bronchospasm', 'other respiratory adverse events', 'rescue medication use' and 'asymptomatic drop in FEV(1) 15% from baseline'. In total, 631 asthma and 1538 COPD patients participated in the three studies. No occurrences of bronchospasm were reported with Respimat SMI on any test day. Overall, the incidence of respiratory events possibly indicative of paradoxical bronchoconstriction was low and similar for both devices. There was no increase in the incidence of events during 12 weeks' treatment. Delivery of bronchodilators by Respimat SMI is safe with regard to paradoxical bronchoconstriction during chronic use in patients with asthma or COPD.

  17. Rheological characterization and drug release studies of gum exudates of Terminalia catappa Linn.

    PubMed

    Kumar, Sadhis V; Sasmal, Dinakar; Pal, Subodh C

    2008-01-01

    The present study was undertaken to evaluate the gum exudates of Terminalia catappa Linn. (TC gum) as a release retarding excipient in oral controlled drug delivery system. The rheological properties of TC gum were studied and different formulation techniques were used to evaluate the comparative drug release characteristics. The viscosity was found to be dependent on concentration and pH. Temperature up to 60 degrees C did not show significant effect on viscosity. The rheological kinetics evaluated by power law, revealed the shear thinning behavior of the TC gum dispersion in water. Matrix tablets of TC gum were prepared with the model drug dextromethorphan hydrobromide (DH) by direct compression, wet granulation and solid dispersion techniques. The dissolution profiles of the matrix tablets were compared with the pure drug containing capsules using the USP Basket apparatus with 500 ml phosphate buffer of pH 6.8 as a dissolution medium. The drug release from the compressed tablets containing TC gum was comparatively sustained than pure drug containing capsules. Even though all the formulation techniques showed reduction of dissolution rate, aqueous wet granulation showed the maximum sustained release of more than 8 h. The release kinetics estimated by the power law revealed that the drug release mechanism involved in the dextromethorphan matrix is anomalous transport as indicated by the release exponent n values. Thus the study confirmed that the TC gum might be used in the controlled drug delivery system as a release-retarding polymer.

  18. Disposition and pharmacokinetics in rats of McN-5707, a potential antidepressant drug

    SciTech Connect

    Ng, K.T.; Holland, M.L.; Hills, J.F.; Uetz, J.A.

    1986-03-01

    A single 80 mg/kg oral solution dose of McN-5707-/sup 14/C x HBr (trans-6-(2-chlorophenyl)-1,2,3,5,6,10b-hexahydropyrrolo(2,1-a)isoquinoline hydrobromide (1:1)) was administered orally to 40 Wistar rats. Total /sup 14/C concentrations in plasma were high (> 4.5 ..mu..g x equiv/mL) for at least 24 hours after dosing. Unchanged McN-5707 represented < 10% of the total /sup 14/C concs in plasma at 45 min and < 1% at 24 hours after dosing. In the 8 days following dose administration, 23% of the dose was excreted in urine and 70% of the dose was excreted in feces. Analysis (HPLC and TLC) of glusulase treated urine, plasma and fecal samples revealed the presence of multiple metabolites of McN-5707. Unchanged McN-5707 was found only in fecal extracts (2-7% of dose). Single solution doses of McN-5707 x HBr were administered p.o. (20 mg/kg) and i.v. (4 mg/kg) to 39 Wistar rats. Plasma samples were analyzed for McN-5707 using a capillary GC assay. These studies indicated that McN-5707 was well absorbed and extensively metabolized in rats following oral doses.

  19. Buspirone enhances immobility in the forced swim test in mice.

    PubMed

    Kitamura, Y; Nagatani, T

    1996-11-01

    We studied the effects of buspirone and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) on duration of immobility in mice in the forced swim test. Buspirone [3-10 mg/kg, intraperitoneally (IP)] potently and dose dependently increased the duration of immobility in mice. In contrast, following a single dose of 8-OH-DPAT (1-3 mg/kg, IP), there was a dose-dependent decrease in the duration of immobility. Pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (200 mg/kg, IP, 3 days before further drug treatment) did not alter the effects of buspirone or 8-OH-DPAT. The increase in the duration of immobility induced by buspirone (3 mg/kg, IP) was blocked by NAN-190 [1-(2-methoxyphenyl)-4-(4-[2-phthalimido]butyl)-piperazine hydrobromide, 1 mg/kg, IP], a postsynaptic 5-HT1A receptor antagonist. However, the effect of 8-OH-DPAT (1 mg/kg, IP) was not blocked by NAN-190 (1 mg/kg, IP). The effect of buspirone (3 mg/kg, IP) was blocked by apomorphine (0.3 mg/kg, IP), a dopamine receptor agonist. Based on the results of this study, it is suggested that the effects of buspirone and of 8-OH-DPAT on immobility in the forced swim test may occur through different mechanisms.

  20. Pharmacological and signalling properties of a D2-like dopamine receptor (Dop3) in Tribolium castaneum.

    PubMed

    Verlinden, Heleen; Vleugels, Rut; Verdonck, Rik; Urlacher, Elodie; Vanden Broeck, Jozef; Mercer, Alison

    2015-01-01

    Dopamine is an important neurotransmitter in the central nervous system of vertebrates and invertebrates. Despite their evolutionary distance, striking parallels exist between deuterostomian and protostomian dopaminergic systems. In both, signalling is achieved via a complement of functionally distinct dopamine receptors. In this study, we investigated the sequence, pharmacology and tissue distribution of a D2-like dopamine receptor from the red flour beetle Tribolium castaneum (TricaDop3) and compared it with related G protein-coupled receptors in other invertebrate species. The TricaDop3 receptor-encoding cDNA shows considerable sequence similarity with members of the Dop3 receptor class. Real time qRT-PCR showed high expression in both the central brain and the optic lobes, consistent with the role of dopamine as neurotransmitter. Activation of TricaDop3 expressed in mammalian cells increased intracellular Ca(2+) signalling and decreased NKH-477 (a forskolin analogue)-stimulated cyclic AMP levels in a dose-dependent manner. We studied the pharmacological profile of the TricaDop3 receptor and demonstrated that the synthetic vertebrate dopamine receptor agonists, 2 - amino- 6,7 - dihydroxy - 1,2,3,4 - tetrahydronaphthalene hydrobromide (6,7-ADTN) and bromocriptine acted as agonists. Methysergide was the most potent of the antagonists tested and showed competitive inhibition in the presence of dopamine. This study offers important information on the Dop3 receptor from Tribolium castaneum that will facilitate functional analyses of dopamine receptors in insects and other invertebrates.

  1. Atypical effect of dopamine in modulating the functional inhibition of NMDA receptors of cultured retina cells.

    PubMed

    Do Nascimento, J L; Kubrusly, R C; Reis, R A; De Mello, M C; De Mello, F G

    1998-02-05

    Cultured retina cells released accumulated [3H]GABA (gamma-aminobutyric acid) when stimulated by L-glutamate, N-methyl-D-aspartate (NMDA) and kainate. In the absence of Mg2+, dopamine at 200 microM (IC50 60 microM), inhibited in more than 50% the release of [3H]GABA induced by L-glutamate and NMDA, but not by kainate. This effect was not blocked by the D1-like dopamine receptor antagonist, R-(+)-7-chloro-8-hydroxy-3-methyl- -phenyl-2,3,4,5-tetrahydro- H-3-benzazepine hydrochloride (SCH 23390), neither by haloperidol nor spiroperidol (dopamine D2-like receptor antagonists). The dopamine D1-like receptor agonist R(+)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,diol hydrochloride (SKF 38393) at 50 microM, but not its enantiomer, also inhibited the release of [3H]GABA induced by NMDA, but not by kainate; an effect that was not prevented by the antagonists mentioned above. (+/-)-6-Chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin e hydrobromide (SKF 812497) had no effect. Neither 8BrcAMP (5 mM) nor forskolin (10 microM) inhibited the release of [3H]GABA. Our results suggest that dopamine and (+)-SKF 38393 inhibit the glutamate and NMDA-evoked [3H]GABA release through mechanisms that seem not to involve known dopaminergic receptor systems.

  2. The synthesis of desired functional groups on PEI microgel particles for biomedical and environmental applications

    NASA Astrophysics Data System (ADS)

    Sahiner, Nurettin; Demirci, Sahin; Sahiner, Mehtap; Al-Lohedan, Hamad

    2015-11-01

    Polyethyleneimine (PEI) microgels were synthesized by micro emulsion polymerization technique and converted to positively charged forms by chemical treatments with various modifying agents with different functional groups, such as 2-bromoethanol (-OH), 4-bromobutyronitrile (-CN), 2-bromoethylamine hydrobromide (-NH2), and glycidol (-OH). The functionalization of PEI microgels was confirmed by FT-IR, TGA and zeta potential measurements. Furthermore, a second modification of the modified PEI microgels was induced on 4-bromo butyronitrile-modified PEI microgels (PEI-CN) by amidoximation, to generate new functional groups on the modified PEI microgels. The PEI and modified PEI microgels were also tested for their antimicrobial effects against various bacteria such as Bacillus subtilis ATCC 6633, Escherichia coli ATCC 8739 and Staphylococcus aureus ATCC 25323. Moreover, the PEI-based particles were used for removal of organic dyes such as methyl orange (MO) and congo red (CR). The absorption capacity of PEI-based microgels increased with modification from 101.8 mg/g to 218.8 mg/g with 2-bromoethylamine, 216.2 m/g with 1-bromoethanol, and 224.5 mg/g with 4-bromobutyronitrile for MO. The increase in absorption for CR dyes was from 347.3 mg/g to 390.4 mg/g with 1-bromoethanol, 399.6 mg/g with glycidol, and 349.9 mg/g with 4-bromobutyronitrile.

  3. [Efficacy of tumor necrosis factor-alpha inhibitors in fistulising perianal Crohn's disease].

    PubMed

    Bor, Renáta; Farkas, Klaudia; Bálint, Anita; Szűcs, Mónika; Abrahám, Szabolcs; Baradnay, Gellért; Wittmann, Tibor; Szepes, Zoltán; Nagy, Ferenc; Molnár, Tamás

    2013-12-08

    Bevezetés: A tumornekrózis-faktor-alfa-gátlókat egyre gyakrabban alkalmazzák a súlyos Crohn-betegség kezelésében. Célkitűzés: A szerzők retrospektív módon értékelték a perianalis fisztulázó Crohn-betegség miatt indított anti-TNF-alfa terápia rövid és hosszú távú hatékonyságát. Módszer: Tumornekrózis-faktor-alfa-gátló kezelésben részesült 68 betegnél meghatározták a luminaris és perianalis aktivitás változását, a komplett fisztulazáródás arányát és a műtéti beavatkozások szükségességét. Eredmények: A kezelés megkezdése után 12 héttel a betegek több mint 80%-ánál a perianalis aktivitás csökkent, 60%-ukban komplett remissziót láttak. Egyéves kezelés alatt a betegek harmadánál a fisztulák záródtak, de a biológiai szer elhagyását követően minden második személynél a sipolyok recidiváltak. Legtöbb esetben a tumornekrózis-faktor-alfa-gátló mellett szükség volt immunszuppresszív kezelésre. A befejezett egyéves terápia alatt a betegek 45%-ánál legalább egy alkalommal végeztek sebészi beavatkozást, többségében ismételt seton-drenázst vagy tályogfeltárást. Következtetések: A tumornekrózis-faktor-alfa-gátló kezelés hatékony a perianalis Crohn-betegség kezelésében. Az immunszuppresszív szerek sok esetben nem hagyhatók el, és nagy arányban van szükség rectummegtartó sebészi beavatkozásokra. A terápia elhagyása utáni magas sipolyrecidíva-arány miatt mérlegelendő a folyamatos tumornekrózis-faktor-alfa-gátló kezelés. Orv. Hetil., 2013, 154(49), 1943–1948.

  4. Enzyme replacement therapy for Anderson-Fabry disease: A complementary overview of a Cochrane publication through a linear regression and a pooled analysis of proportions from cohort studies

    PubMed Central

    El Dib, Regina; Gomaa, Huda; Ortiz, Alberto; Politei, Juan; Kapoor, Anil; Barreto, Fellype

    2017-01-01

    Background Anderson-Fabry disease (AFD) is an X-linked recessive inborn error of glycosphingolipid metabolism caused by a deficiency of alpha-galactosidase A. Renal failure, heart and cerebrovascular involvement reduce survival. A Cochrane review provided little evidence on the use of enzyme replacement therapy (ERT). We now complement this review through a linear regression and a pooled analysis of proportions from cohort studies. Objectives To evaluate the efficacy and safety of ERT for AFD. Materials and methods For the systematic review, a literature search was performed, from inception to March 2016, using Medline, EMBASE and LILACS. Inclusion criteria were cohort studies, patients with AFD on ERT or natural history, and at least one patient-important outcome (all-cause mortality, renal, cardiovascular or cerebrovascular events, and adverse events) reported. The pooled proportion and the confidence interval (CI) are shown for each outcome. Simple linear regressions for composite endpoints were performed. Results 77 cohort studies involving 15,305 participants proved eligible. The pooled proportions were as follows: a) for renal complications, agalsidase alfa 15.3% [95% CI 0.048, 0.303; I2 = 77.2%, p = 0.0005]; agalsidase beta 6% [95% CI 0.04, 0.07; I2 = not applicable]; and untreated patients 21.4% [95% CI 0.1522, 0.2835; I2 = 89.6%, p<0.0001]. Effect differences favored agalsidase beta compared to untreated patients; b) for cardiovascular complications, agalsidase alfa 28% [95% CI 0.07, 0.55; I2 = 96.7%, p<0.0001]; agalsidase beta 7% [95% CI 0.05, 0.08; I2 = not applicable]; and untreated patients 26.2% [95% CI 0.149, 0.394; I2 = 98.8%, p<0.0001]. Effect differences favored agalsidase beta compared to untreated patients; and c) for cerebrovascular complications, agalsidase alfa 11.1% [95% CI 0.058, 0.179; I2 = 70.5%, p = 0.0024]; agalsidase beta 3.5% [95% CI 0.024, 0.046; I2 = 0%, p = 0.4209]; and untreated patients 18.3% [95% CI 0.129, 0.245; I2 = 95% p < 0

  5. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2009-03-01

    ABT-869, Acadesine, Acetylsalicylic acid/omeprazole, Adefovir, Adefovir dipivoxil, AEG-35156, Agatolimod sodium, Albiglutide, Alemtuzumab, Alipogene tiparvovec, Alogliptin benzoate, AMG-386, Amrubicin hydrochloride, Apremilast, Aripiprazole, Asoprisnil, Atorvastatin/fenofibrate, AVN-944, Axitinib; Belinostat, Bevacizumab, BHT-3021, BI-2536, Biapenem, Bilastine, Biphasic insulin aspart, Blinatumomab, Bortezomib, Bosentan; Catumaxomab, CD-NP, Cediranib, Certolizumab pegol, Cetuximab, Choline fenofibrate, Ciclesonide, CK-1827452,Clevudine, Clofarabine, CSL-360, CYT-997; Dapagliflozin, Darinaparsin, Denosumab, Densiron 68, Desloratadine, Dulanermin; Edoxaban tosilate, Emtricitabine, Entecavir, Erlotinib hydrochloride, Everolimus, Exenatide, Ezetimibe, Ezetimibe/simvastatin; Fidaxomicintiacumiv, Fulvestrant; G-207, GCR-8015, Gefitinib, Ghrelin (human), Glufosfamide; HPV16L1E7CVLP; Ibutamoren mesilate, Imatinib mesylate, Insulin detemir, Insulin glargine, Iodine (I131) tositumomab, Istaroxime, ITMN-191, Ixabepilone; JZP-4, Lenalidomide; Levetiracetam, Linaclotide acetate, Liposomal cytarabine/daunorubicin, Liposomal doxorubicin, Liraglutide, LY-518674; Milatuzumab, MMR-V, Motesanib diphosphate, Mycophenolic acid sodium salt; Niacin/simvastatin; Obatoclax mesylate, Odanacatib; Paclitaxel nanoparticles, Paclitaxel-eluting stent, Pazufloxacin, PBT-2, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ribavirin, Pemetrexed disodium, Perampanel, PfCP2.9, Pitavastatin calcium, Poly I:CLC, Pomalidomide, Pralatrexate, Pramlintide acetate, Prucalopride; rhGAD65, Roflumilast; RTS,S/AS02D; SCH-530348, Semagacestat, Sirolimus-eluting coronary stent, Sirolimus-Eluting Stent, SIR-Spheres, Sivelestat sodium hydrate, Sorafenib, Sunitinib malate; Tadalafil, Tafluprost, Tanespimycin, Teduglutide, Telaprevir, Telbivudine, Tenofovir disoproxil fumarate, Tiotropium bromide, TMC-435350, Tositumomab/iodine (I131) tositumomab, Travoprost/timolol, Triciribine

  6. [Aicardi-Goutieres syndrome due to mutation of the IFIH1 gene with pontine involvement. A case report].

    PubMed

    Florido-Rodriguez, A; Eiris-Punal, J; Barros-Angueira, F; Toledo-Bravo de Laguna, L; Santana-Artiles, A; Sebastian-Garcia, I; Santana-Rodriguez, A; Cabrera-Lopez, J C

    2016-10-01

    Introduccion. El sindrome de Aicardi-Goutieres es una rara encefalopatia subaguda progresiva de inicio precoz –generalmente en el primer año de vida– caracterizada por retraso psicomotor, microcefalia, alteraciones en la sustancia blanca cerebral, calcificaciones intracraneales, pleocitosis y niveles elevados de interferon alfa en el liquido cefalorraquideo. Asocia un incremento en la expresion de los genes estimulados por interferon en la sangre periferica, hecho conocido como interferon signature. Los niveles de genes estimulados por interferon se han postulado como un buen biomarcador, pues se mantienen elevados en la sangre periferica en el tiempo y son mas sensibles, en comparacion con las determinaciones de interferon alfa y neopterinas en el liquido cefalorraquideo, las cuales descienden a partir del año de vida. Hasta la fecha se han descrito mutaciones en siete genes que sobreestimulan la via del interferon alfa, y el ultimo en descubrirse ha sido el IFIH1 (interferon induced with helicase C domain 1), con un patron de herencia autosomico dominante. Caso clinico. Se presenta el primer caso descrito en la bibliografia hispana debido a mutacion de novo en el gen IFIH1. Se expone el cuadro clinico, los estudios realizados y la revision de los aspectos clinicos, neurorradiologicos y geneticos. Conclusiones. La herencia de las mutaciones descritas para el sindrome de Aicardi-Goutieres era clasicamente autosomica recesiva, pero estos hallazgos muestran que mutaciones autosomicas dominantes en el gen IFIH1 pueden causar la enfermedad. Como hallazgo de neuroimagen no descrito previamente, presenta una lesion de encefalomalacia quistica en la protuberancia.

  7. Side effects of cytokines approved for therapy.

    PubMed

    Baldo, Brian A

    2014-11-01

    Cytokines, currently known to be more than 130 in number, are small MW (<30 kDa) key signaling proteins that modulate cellular activities in immunity, infection, inflammation and malignancy. Key to understanding their function is recognition of their pleiotropism and often overlapping and functional redundancies. Classified here into 9 main families, most of the 20 approved cytokine preparations (18 different cytokines; 3 pegylated), all in recombinant human (rh) form, are grouped in the hematopoietic growth factor, interferon, platelet-derived growth factor (PDGF) and transforming growth factor β (TGFβ) families. In the hematopoietin family, approved cytokines are aldesleukin (rhIL-2), oprelvekin (rhIL-11), filgrastim and tbo-filgrastim (rhG-CSF), sargramostim (rhGM-CSF), metreleptin (rh-leptin) and the rh-erythropoietins, epoetin and darbepoietin alfa. Anakinra, a recombinant receptor antagonist for IL-1, is in the IL-1 family; recombinant interferons alfa-1, alfa-2, beta-1 and gamma-1 make up the interferon family; palifermin (rhKGF) and becaplermin (rhPDGF) are in the PDGF family; and rhBMP-2 and rhBMP-7 represent the TGFβ family. The main physicochemical features, FDA-approved indications, modes of action and side effects of these approved cytokines are presented. Underlying each adverse events profile is their pleiotropism, potency and capacity to release other cytokines producing cytokine 'cocktails'. Side effects, some serious, occur despite cytokines being endogenous proteins, and this therefore demands caution in attempts to introduce individual members into the clinic. This caution is reflected in the relatively small number of cytokines currently approved by regulatory agencies and by the fact that 14 of the FDA-approved preparations carry warnings, with 10 being black box warnings.

  8. Erythropoietin reduces cumulative nephrotoxicity from cisplatin and enhances renal tubular cell proliferation.

    PubMed

    Zafirov, Dimce; Petrusevska, G; Sikole, Aleksandar; Trojacanec, J; Labacevski, N; Kostova, E; Jakovski, K; Atanasovska, E; Petrov, S

    2008-12-01

    Cisplatin, a heavy metal complex, is one of the most active drugs used in the treatment of several human malignancies. However, high-dose therapy with cisplatin is limited by its cumulative nephrotoxicity. The main objectives of this study were to determine the role of recombinant human erythropoietin (Epoetin alfa) in the prevention of nephrotoxicity induced experimentally in Wistar rats by long-term administration of cisplatin (2 mg/kg/b.w./week) over eight weeks, and an evaluation of its effect on renal tubular cell proliferation. The animals were randomly assigned into three groups, each including 25 rats. Group 1 (CP) received only cisplatin (2 mg/kg/b.w./week), group 2 (CP+EPO) received cisplatin (2 mg/kg/b.w./week) and epoetin alfa (150 IE/kg/b.w./three times a week), and group 3 (control group) received only saline. During the study, the following tests for the assessment of the renal function and renal damages were performed: determination of concentration of serum creatinine and BUN and determination of total protein quantity in 24-hour urine samples. At the end of the study, the abdomen was opened and both kidneys of the rats were removed and sent for histological and morphometric analysis. Ki-67 was used as a tool to determine a proliferative index. The results obtained have shown that epoetin alfa significantly reduced the functional renal failures and renal damages, and increased toleration of high doses of cisplatin. At the same time, our results with regard to tubular proliferative index have confirmed that one of the possible mechanisms by which erythropoietin accomplishes its renoprotective effect is stimulation of tubular cell proliferation and regeneration.

  9. Fabry disease in children and the effects of enzyme replacement treatment.

    PubMed

    Pintos-Morell, Guillem; Beck, Michael

    2009-11-01

    Fabry disease is a rare, X-linked inborn error of glycosphingolipid catabolism caused by a deficiency in the activity of the lysosomal enzyme, alpha-galactosidase A. In affected patients, the enzyme substrate, globotriaosylceramide (Gb3), accumulates in cells of various tissues and organs. Lysosomal accumulation of Gb3 begins in utero, and signs and symptoms of Fabry disease emerge in childhood and adolescence. The earliest presenting symptoms are typically neuropathic pain and gastrointestinal problems, which can have a substantial impact on health-related quality of life. Life-threatening major organ involvement is rare in young patients, but signs of kidney dysfunction (e.g., proteinuria), left ventricular hypertrophy, and stroke have been reported in children. There are two enzyme preparations for therapy: agalsidase alfa and beta. In two clinical trials of enzyme replacement therapy (ERT) with agalsidase alfa, including 37 children, boys demonstrated reductions in plasma Gb3 levels, and both boys and girls reported reductions in neuropathic pain and in the use of neuropathic pain medications. Heart rate variability, which is reduced in boys with Fabry disease, was statistically significantly improved with 6 months of agalsidase alfa treatment. In a single clinical study of agalsidase beta in children (n =16), skin Gb3 deposits and plasma Gb3 levels were reduced in boys. Differences exist in the administration and the safety profile of these two enzyme formulations. Follow-up of these cohorts and additional studies will be necessary to fully evaluate long-term efficacy of ERT in children with Fabry disease.

  10. Strange Stars, Neutron Stars and Pulsar Emission

    NASA Astrophysics Data System (ADS)

    Benvenuto, O. G.; Horvath, J. E.

    1990-11-01

    RESUMEN. Se ha conjeturado que una partlecula de dieciocho quarks, sin Carga, sin espi'n y sin colar (quark-alfa) podri'a ser estable a ba5as tern peraturas y presiones aiTh COfl respecto a materia extrafla. Presentamos en este trabajo la estmctura de estrellas extraflas incluyendo los efectos y apariencia de parti'culas uark-alfa en las capas exteriores. La estruc tura interna ya no es hoinogenea del centro a la superficie, sino que muestra un centro de materia extrafla, capas s6lidas y una costra delgada de materia normal en la superficie. La superficie de materia nonnal permite la fornaci6n de una magnetosfera, la que se piensa sea el sitlo en donde ocurre la emisi6n del pulsar. La superficie de superflui'do ayuda a explicar el fen6rneno de `glitch', el cual ba sido observado en muchos pulsares. Se discute la ecuaci6n de estado para rnateria quark-alfa relevante en este regimen. ABSTIZACT:It has been conjectured that an quark, uncharged, spinless and colorless particle Cquark-alpha) could be stable at low pressures and temperatures even with respect to strange matter. We present in work tlie structure of stars including the effects of the appearance of quark-alpi' particles ii their outer layers. The internal structure is no longer from tlie center to the surface, but show a strange matter core, a solid and superfluid layers and a thin crust of normal matter at the surface. The normal matter surface allows tlie fon tion of a magnetosphere, whicl is to be tl place where pulsar emission occurs. A superfluid layer helps to explain tlie glitch , wlflch has been observed in . equation of state for quark-alpha matter relevant in regime is also discussed. Keq LA)OtL : ARY S - OF STATF - ?.ACT

  11. Hypophosphatasia - pathophysiology and treatment

    PubMed Central

    Millán, José Luis; Plotkin, Horacio

    2013-01-01

    English Summary Hypophosphatasia (HPP) is the inborn-error-of-metabolism caused by loss-of-function mutation(s) in the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNAP). The disease has been classified according to patient age when the first signs and symptoms manifest; i.e., perinatal, infantile, childhood, adult HPP. Other types include odonto HPP and perinatal benign. Babies with the perinatal/infantile forms of HPP often die with severe rickets and respiratory insufficiency and sometimes hypercalcemia and vitamin B6-responsive seizures. The primary biochemical defect in HPP is a deficiency of TNAP activity that leads to elevated circulating levels of substrates, in particular inorganic pyrophosphate (PPi), a potent calcification inhibitor. To-date, the management of HPP has been essentially symptomatic or orthopedic. However, enzyme replacement therapy with mineral-targeting TNAP (sALP-FcD10, also known as ENB-0040 or asfotase alfa) has shown promising results in a mouse model of HPP (Alpl−/− mice). Administration of mineral-targeting TNAP from birth increased survival and prevented the seizures, rickets, as well as all the tooth abnormalities, including dentin, acellular cementum, and enamel defects in this model of severe HPP. Clinical trials using mineral-targeting TNAP in children 3 years of age or younger with life-threatening HPP was associated with healing of the skeletal manifestations of HPP as well as improved respiratory and motor function. Improvement is still being observed in the patients receiving continued asfotase alfa therapy, with more than 3 years of treatment in some children. Enzyme replacement therapy with asfotase alfa has to-date been successful in patients with life-threatening HPP. PMID:25254037

  12. Discussion remarks on the role of wood and chitin constituents during carbonization

    NASA Astrophysics Data System (ADS)

    Ilnicka, Anna; Lukaszewicz, Jerzy

    2015-03-01

    Nature is a source of some biomaterials like wood and chitin which can be successfully transformed into chars of advanced structural/surface parameters. The manuscript is discursive and suggests that particular components of the materials (cellulose, lignin, hemicellulose, alfa-chitin fibrils, mineral-protein matrix) play a specific role in the manufacturing of porous chars. It is proposed that some of the components (hemicellulose and mineral-protein matrixes) behave like a natural soft template during carbonization of wood and chitin. It is suggested why particular components and derivatives of wood and chitin (cellulose and chitosan) can not form porous carbonaceous matrixes when are carbonized separately.

  13. [Current recommendations for the treatment of iron deficiency anemia].

    PubMed

    Schaefer, R M; Huch, R; Krafft, A

    2007-04-04

    Iron deficiency is a frequent complication in chronically ill patients and in pregnant women. Iron status can now be characterised precisely and relatively easily by determining serum ferritin, transferritin saturation and if necessary hypochromic erythrocytes and the haemoglobin content of erythrocytes (CHr). Oral iron replacement is usually restricted by limited absorption and low tolerability. Intravenous iron therapy is possible in such cases and can be combined with rHuEPO (e.g. EPREX/ epoetin alfa) in severe cases. Iron saccharate (VENOFER) is commercially available in Switzerland and this permits high dose iron replacement without any danger of anaphylaxis or acute iron toxicity.

  14. High-Sensitivity Conjugated Polymer/Nanoparticle Nanocomposite for Infrared Sensor Applications III

    DTIC Science & Technology

    2010-08-25

    Experimental Materials: Lead(II) oxide (PbO, 99.99%) was obtained from Alfa Aesar. Selenium (Se, 99.9%), oleic acid (OA, tech. 90%), trioctylphosphine (TOP...Law, O. E. Semonin, R. J. Ellingson, A. J. Nozik, Nano Lett. 2009, 9, 836–845. [15] V. Sukhovatkin, S. Hinds, L. Brzozowski, E. H. Sargent, Science...Norris, C. D. Frisbie, Nano Lett. 2009, 9, 3848–3852. [21] J. M. Luther, M. Law, Q. Song, C. L. Perkins, M. C. Beard, A. J. Nozik, ACS Nano 2008, 2

  15. Large-scale production of pharmaceutical proteins in plant cell culture-the Protalix experience.

    PubMed

    Tekoah, Yoram; Shulman, Avidor; Kizhner, Tali; Ruderfer, Ilya; Fux, Liat; Nataf, Yakir; Bartfeld, Daniel; Ariel, Tami; Gingis-Velitski, Svetlana; Hanania, Uri; Shaaltiel, Yoseph

    2015-10-01

    Protalix Biotherapeutics develops recombinant human proteins and produces them in plant cell culture. Taliglucerase alfa has been the first biotherapeutic expressed in plant cells to be approved by regulatory authorities around the world. Other therapeutic proteins are being developed and are currently at various stages of the pipeline. This review summarizes the major milestones reached by Protalix Biotherapeutics to enable the development of these biotherapeutics, including platform establishment, cell line selection, manufacturing process and good manufacturing practice principles to consider for the process. Examples of the various products currently being developed are also presented.

  16. Purification of alpha-1-antitrypsin monomer by preparative electrophoresis.

    PubMed Central

    Spada, F; Candiano, G; Sergi, C; Ghiggeri, G M; Callea, F; Gusmano, R

    1994-01-01

    Alfa-1-antitrypsin (alpha 1AT) was purified by pseudoligand chromatography and preparative electrophoresis from the serum of a patient with alpha 1AT deficiency. The combination of the two techniques yielded a high grade batch of alpha 1AT monomer and this was successfully used to purify the protein from the serum of PiMIM1, PiMIM2, and PiZZ phenotype subjects. This procedure should facilitate structural studies of alpha 1AT variants susceptible to intracellular accumulation. Images PMID:8089226

  17. Sequence analysis of a 10 kb DNA fragment from yeast chromosome VII reveals a novel member of the DnaJ family.

    PubMed

    Rodriguez-Belmonte, E; Rodriguez-Torres, A M; Tizon, B; Cadahia, J L; Gonzalez-Siso, I; Ramil, E; Becerra, M; Gonzalez-Dominguez, M; Cerdan, E

    1996-02-01

    We report the sequence analysis of a 10 kb DNA fragment of Saccharomyces cerevisiae chromosome VII. This sequence contains four complete open reading frames (ORFs) of greater than 100 amino acids. There are also two incomplete ORFs flanking the extremes: one of these, G2868, is the 5' part of the SCS3 gene (Hosaka et al., 1994). ORFs G2853 and G2856 correspond to the genes CEG1, coding for the alfa subunit of the mRNA guanylyl transferase and a 3' gene of unknown function previously sequenced (Shibagaki et al., 1992). G2864 is identical to SOH1 also reported (Fan and Klein, 1994).

  18. Recent advances in the treatment of orthostatic hypotension

    NASA Technical Reports Server (NTRS)

    Robertson, D.; Davis, T. L.

    1995-01-01

    Orthostatic hypotension is a fall in blood pressure on standing that causes symptoms of dizziness, visual changes, and discomfort in the head and neck. The goal of treatment is the improvement of the patient's functional capacity, rather than a target blood pressure. For treatment to be successful, it must be individualized. Non-pharmalogic interventions include carefully managed exercise, scheduled activities, and monitoring of the environmental temperature. Agents such as fludrocortisone, midodrine, and epoetin alfa offer successful pharmacologic interventions. Although these measures ease the symptoms of orthostatic hypotension, current approaches neither reverse nor stabilize the disease process in autonomic disorders.

  19. VizieR Online Data Catalog: AGES sources in Virgo cluster (Taylor+, 2012)

    NASA Astrophysics Data System (ADS)

    Taylor, R.; Davies, J. I.; Auld, R.; Minchin, R. F.

    2013-04-01

    Two areas of the Virgo cluster have been selected for study with AGES, VC1 and VC2. This paper examines the VC1 area while Paper II (2013MNRAS.428..459T) will consider VC2 and compare the results of the two areas. Observations were taken in 2008 January-June, 2009 February-June, 2010 January-June and 2011 January, using the Arecibo L-band Feed Array (ALFA) instrument on the Arecibo telescope in spectral line mode. (4 data files).

  20. Biological agents: investigation into leprosy and other infectious diseases before indication*

    PubMed Central

    Antônio, João Roberto; Soubhia, Rosa Maria Cordeiro; Paschoal, Vania Del Arco; Amarante, Carolina Forte; Travolo, Ana Regina Franchi

    2013-01-01

    Biological agents are widely used for various immune-mediated diseases, with remarkable effectiveness in the treatment of rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, ankylosing spondylitis and Crohn's disease. However, attention needs to be drawn to the adverse effects of these therapies and the risk of reactivating underlying granulomatous infectious diseases such as tuberculosis, leprosy, syphilis, leishmaniasis, among others. The objective of this paper is to describe a case of leprosy in a patient with RA using anti-TNF alfa, demonstrating the need for systematic investigation of skin lesions suggestive of leprosy in patients who require rheumatoid arthritis therapeutic treatment, especially in endemic regions like Brazil. PMID:24346871

  1. Non-depleting anti-CD4 monoclonal antibody induces immune tolerance to ERT in a murine model of Pompe disease.

    PubMed

    Sun, Baodong; Banugaria, Suhrad G; Prater, Sean N; Patel, Trusha T; Fredrickson, Keri; Ringler, Douglas J; de Fougerolles, Antonin; Rosenberg, Amy S; Waldmann, Herman; Kishnani, Priya S

    2014-01-01

    Approximately 35-40% of patients with classic infantile Pompe disease treated with enzyme replacement therapy (ERT) develop high, sustained antibody titers against the therapeutic enzyme alglucosidase alfa, which abrogates the treatment efficacy. Induction of antigen-specific immune tolerance would greatly enhance ERT for these patients. Here we show that a short-course treatment with non-depleting anti-CD4 monoclonal antibody successfully induced long-term ERT-specific immune tolerance in Pompe disease mice. Our data suggest an effective adjuvant therapy to ERT.

  2. Exploratory Development of an Electrically Rechargeable Lithium Battery.

    DTIC Science & Technology

    1980-10-01

    evacuated quartz tube at 650 0C (Eqn. 2) 6500C 13 V20 + 4V 5 V6 01 3 (2) The material prepared by this method is stoichiometric V601 3, i.e., V02.1 7 (ii...Ventron) and 1.02g (20 mmoles) of V powder (Alfa- Ventron, -325 mesh) was heated in an evacuated, sealed, quartz tube at 650*C. Samples were prepared...oxide in a sealed, evacuated quartz tube for 16 hr at 650’C. Although the X-ray pattern did not show any significant change, SEM data revealed that the

  3. VizieR Online Data Catalog: Dimethyl sulfide laboratory um, mm & FIR spectra (Jabri+, 2016)

    NASA Astrophysics Data System (ADS)

    Jabri, A.; Nguyen, H. V. L.; Mouhib, H.; Tchana, F. K.; Manceron, L.; Stahl, W.; Kleiner, I.

    2016-02-01

    DMS was purchased from Alfa Aesar GmbH & Co KG, Karlsruhe, Germany and used without further purification. The microwave spectrum was measured in the frequency range 2-40GHz using two Molecular Beam Fourier Transform MicroWave (MB-FTMW) spectrometers in Aachen, Germany. The millimeter spectrum was recorded in the 50-110GHz range. The FIR spectrum was measured for the first time at high resolution using the FT spectrometer and the newly built cryogenic cell at the French synchrotron SOLEIL. (3 data files).

  4. Search and Rescue and Enforcement of Laws and Treaties Intelligence System

    DTIC Science & Technology

    1987-09-01

    miss alfa 05/05/1985 1 miss cocaine 05/20/1986 1 Constance 01/09/1986 3 miss barbs 02/05/1986 3 miss cocaine 06/01/1985 3 miss cannibis 05/18...in 01/86 in san francisco, ca suspected of being used in major drug operations miss cannibis miss cocaine 05/18/1985 vessel stolen in san diego...Date: 08/15/1987 Page; Vessel Name miss barbs miss cannibis miss cocaine miss cocaine miss everyday miss mariposa Date of Intelligence

  5. Classification of stevia sweeteners in soft drinks using liquid chromatography and time-of-flight mass spectrometry.

    PubMed

    Kakigi, Y; Suzuki, T; Icho, T; Uyama, A; Mochizuki, N

    2013-01-01

    The aim of this study was to develop a comprehensive analytical method for the characterisation of stevia sweeteners in soft drinks. By using LC and time-of-flight MS, we detected 30 steviol glycosides from nine stevia sweeteners. The mass spectral data of these compounds were applied to the analysis to determine steviol glycosides in nine soft drinks. On the basis of chromatographic data and principal-component analysis, these soft drinks were classified into three groups, and the soft drinks of each group, respectively, contained high-rebaudioside A extract, normal stevia extract or alfa-glucosyltransferase-treated stevia extract.

  6. Inter-Service/Agency Automated Message Processing Exchange Program. Functional Requirements Description and Interface Control Document.

    DTIC Science & Technology

    1983-11-01

    sustained basis is 50 KBPS (77 line blocks per second; which is expected to equate to 3 output messages per second, 3.5.1.1.1 Input Traffic...letter or letters that equate to the specific addressees »tor example NSA/DELTA or MSA/ALFA CHARLIE). A P D may contain more than...Special] SEC TCC Note that an error in R-Community TRC field is coded as -TRC whether or not a true TRC may have been intenced . The same is true of

  7. Hepatitis C pharmacogenetics: state of the art in 2010.

    PubMed

    Afdhal, Nezam H; McHutchison, John G; Zeuzem, Stefan; Mangia, Alessandra; Pawlotsky, Jean-Michel; Murray, Jeffrey S; Shianna, Kevin V; Tanaka, Yasuhito; Thomas, David L; Booth, David R; Goldstein, David B

    2011-01-01

    In 2009, a correlated set of polymorphisms in the region of the interleukin-28B (IL28B) gene were associated with clearance of genotype 1 hepatitis C virus (HCV) in patients treated with pegylated interferon-alfa and ribavirin. The same polymorphisms were subsequently associated with spontaneous clearance of HCV in untreated patients. The link between IL28B genotype and HCV clearance may impact decisions regarding initiation of current therapy, the design and interpretation of clinical studies, the economics of treatment, and the process of regulatory approval for new anti-HCV therapeutic agents.

  8. Noninvasive sensors in critical care medicine: near-infrared spectroscopy for the detection of altered microvascular blood flow in severe sepsis and septic shock

    NASA Astrophysics Data System (ADS)

    Walz, J. Matthias; Soller, Babs; Soyemi, Olusola; Yang, Ye; Landry, Michelle; Heard, Stephen O.

    2006-10-01

    It is estimated that 750,000 cases of severe sepsis occur in the United States annually, at least 225,000 of which are fatal, resulting in significant utilization of healthcare resources and expenses. Significant progress in the understanding of pathophysiology and treatment of this condition has been made lately. Among the newer treatment strategies for critically ill patients are the administration of early goal directed therapy, and Recombinant Human Activated Protein C (Drotrecogrin alfa (activated) [DTAA]) for severe sepsis. However, mortality remains unacceptably high.

  9. A Study of Outpatient Pharmacy Utilization at Naval Hospital, Camp Lejeune

    DTIC Science & Technology

    2002-07-01

    19,987.42 OLANZAPINE 70 $16,476.76 ROFECOXIB 144 $12,906.11 ONDANSETRON HCL 28 $12,544.56 LORATADINE 150 $11,556.35 EPOETIN ALFA 4 $11,151.22 TERBINAFINE ... TERBINAFINE HCL 52 $9,643.24 ROSIGLITAZONE MALEATE 74 $9,427.86 ESOMEPRAZOLE MAG TRIHYDRATE 68 $8,499.17 ZOLPIDEM TARTRATE 165 $8,144.94 VENLAFAXINE HCL 94...151 $23,206.70 LORATADINE 139 $14,480.45 INTERFERON BETA-1A 9 $12,244.64 TERBINAFINE HCL 35 $12,211.46 ROFECOXIB 78 $9,912.65 SILDENAFIL CITRATE 117

  10. Diffraction and forward physics results of the ATLAS experiment from the Run I

    SciTech Connect

    Taševský, Marek

    2015-04-10

    Various aspects of forward physics have been studied by the ATLAS collaboration using data from Run I at the LHC. In this text, main results of four published analyses are summarized, all based on data from proton-proton collisions at √(s)=7 TeV collected in 2010 or 2011. Two analyses deal with the diffractive signature, one based on single-sided events, the other on large rapidity gaps in soft events. In addition, a recent measurement of the total pp cross section using the ALFA subdetector and a recent study of higher-order QCD effects using a jet veto are discussed.

  11. Anemia and iron deficiency in heart failure.

    PubMed

    Gunawardena, Shanti; Dunlap, Mark E

    2012-12-01

    Anemia is a common comorbidity in heart failure (HF), and is associated with increased morbidity and mortality. However, it remains unclear whether anemia is merely a marker of poor prognosis or whether anemia itself confers risk. The pathogenesis of anemia in HF is multifactorial. Iron deficiency also confers risk in HF, either with or without associated anemia, and treatment of iron deficiency improves the functional status of patients with HF. An ongoing large clinical trial studying the use of darbepoetin-alfa in patients with anemia and systolic HF is expected to provide information that should improve our understanding of anemia in HF.

  12. Development of a Data Driven Three-dimensional Magnetohydrodynamic Model With Radiation Effects to Study Photosphere-Coronal Coupling

    DTIC Science & Technology

    2011-02-09

    accomplished not only the goals stated in the proposal but also beyond. There are three major achievements: ( i ) a sufficient condition for solar eruption...Investigators: S. T. Wu, P.I. and: AiHua Wang, Co- I , Center for Space Plasma and Aeronomic Research, and Department of Mechanical & Aerospace Engineering...22:10 22:20 22:30 22:40 22:50 23:00 23:10 23:20 23:30 23:40 23:50 Time (UT) 0 1 2 3 4 5 6 Lss flux I alfa FIGURE 1. The simulated non

  13. Identification of recombinant human EPO variants in greyhound plasma and urine by ELISA, LC-MS/MS and western blotting: a comparative study.

    PubMed

    Timms, Mark; Steel, Rohan; Vine, John

    2016-02-01

    The recombinant human erythropoietins epoetin alfa (Eprex®), darbepoetin (Aranesp®) and methoxy polyethylene glycol-epoetin beta (Mircera®) were administered to greyhounds for 7, 10 and 14 days respectively. Blood and urine samples were collected and analysed for erythropoietin by ELISA, LC-MS/MS and western blotting. Limits of confirmation in plasma for western blotting and LC-MS/MS methods ranged from a low of 2.5mIU/mL, and closely matched the sensitivity of ELISA screening.

  14. Experiments with a small behaviour controlled planetary rover

    NASA Technical Reports Server (NTRS)

    Miller, David P.; Desai, Rajiv S.; Gat, Erann; Ivlev, Robert; Loch, John

    1993-01-01

    A series of experiments that were performed on the Rocky 3 robot is described. Rocky 3 is a small autonomous rover capable of navigating through rough outdoor terrain to a predesignated area, searching that area for soft soil, acquiring a soil sample, and depositing the sample in a container at its home base. The robot is programmed according to a reactive behavior control paradigm using the ALFA programming language. This style of programming produces robust autonomous performance while requiring significantly less computational resources than more traditional mobile robot control systems. The code for Rocky 3 runs on an eight bit processor and uses about ten k of memory.

  15. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2009-12-01

    [Methoxy-(11)C]PD-153035, 2-Methoxyestradiol; Adalimumab, Adecatumumab, Adefovir dipivoxil, ADH-1, ADX-10059, Aflibercept, AIR-human growth hormone, Aliskiren fumarate, AMG-221, Amlodipine besylate/olmesartan medoxomil, Aprepitant; Bavituximab, Bevacizumab, Bexarotene, BIBW-2992, BMS-690514, Bortezomib, Bosentan, Briakinumab; Capecitabine, Certolizumab pegol, Cetuximab, Cholecalciferol, Choline fenofibrate, Chorionic gonadotropin (human), Cixutumumab, Clopidogrel, CP-690550 citrate; Dabigatran, Dacetuzumab, Daclizumab, Dapagliflozin, Darbepoetin alfa, Dasatinib, Denosumab; Efavirenz, Elisidepsin, Enoxaparin, Enzastaurin hydrochloride, Eribulin mesilate, Erlotinib hydrochloride, Everolimus, Exenatide; Fenobam, Figitumumab, Filibuvir, Fondaparinux sodium, Fresolimumab; Gefitinib, Golimumab, Golnerminogene pradenovec; Ifosfamide, Imatinib mesylate, Ipilimumab, Ivabradine hydrochloride, Ixabepilone; Lapatinib ditosylate, Lenalidomide, Levocetirizine dihydrochloride, Liposomal vincristine, Liraglutide; M-118, Masitinib mesylate, Metformin hydrochloride, Micafungin sodium, Moxifloxacin hydrochloride; Neratinib; Oblimersen sodium, Ofatumumab, Olmesartan medoxomil; Paclitaxel nanoparticles, Palifosfamide lysine, Panobacumab, Panobinostat, Patupilone, Peginterferon alfa-2a, Pegylated arginine deiminase 20000, Piclozotan hydrochloride hydrate, Pixantrone maleate, Prasterone, Prasugrel, Prednisone, Progesterone, Prucalopride, pVGI.1 (VEGF-2); Retigabine, rhFSH, Rituximab, Rivaroxaban, Rosuvastatin calcium; Salinosporamide A, Selumetinib, Sipuleucel-T, Somatropin, Sorafenib, SSR-244738, Sunitinib malate; Tamoxifen citrate, Teduglutide, Telavancin hydrochloride, Telmisartan, Telmisartan/amlodipine, Telmisartan/hydrochlorothiazide, Temsirolimus, Tenofovir disoproxil fumarate, Tipifarnib, Tolvaptan, Trastuzumab, Trastuzumab-MCC-DM1, Travoprost, Tremelimumab; Valsartan/amlodipine besylate, Valsartan/amlodipine besylate/hydrochlorothiazide, Valsartan/hydrochlorothiazide, Vandetanib

  16. Effect of anti-epileptic drugs in pregnancy and teratogenesis.

    PubMed

    Lakshmi, Sowbhagya; Sunanda, Kulkarni

    2008-07-01

    Epilepsy raises special concern in women during pregnancy. Antiepileptic drugs are known to induce major and minor malformations in the foetus. Aim of the study was to find an association between maternal serum alpha fetoprotein levels, foetal abnormalities and antiepileptic drugs mediated teratogenicity. Maternal serum alpha feto protein levels, kidney and liver function tests in age matched normal pregnant women and seizure free epileptic pregnant women during 12-14 weeks of gestation were estimated. Cases were subjected to ultrasonography at 11(th)-14(th) week of pregnancy and again at 20(th) week of pregnancy. maternal serum alfa feto protein was assayed by a specific Electro Chemiluminescence Immuno Assay test. There was no significant difference in kidney and liver function tests in cases as compared to controls. There were elevated levels of alpha feto protein in cases as compared to controls but this was not statistically significant. No anomalies were detected in ultrasound reports. Most women had normal full term delivery with healthy children but of low birth weight. No correlation was seen between maternal serum alfa feto protein levels and antiepileptic drug leading to teratogenesis.

  17. Gonadotropin therapy in assisted reproduction: an evolutionary perspective from biologics to biotech

    PubMed Central

    Leão, Rogério de Barros F.; Esteves, Sandro C.

    2014-01-01

    Gonadotropin therapy plays an integral role in ovarian stimulation for infertility treatments. Efforts have been made over the last century to improve gonadotropin preparations. Undoubtedly, current gonadotropins have better quality and safety profiles as well as clinical efficacy than earlier ones. A major achievement has been introducing recombinant technology in the manufacturing processes for follicle-stimulating hormone, luteinizing hormone, and human chorionic gonadotropin. Recombinant gonadotropins are purer than urine-derived gonadotropins, and incorporating vial filling by mass virtually eliminated batch-to-batch variations and enabled accurate dosing. Recombinant and fill-by-mass technologies have been the driving forces for launching of prefilled pen devices for more patient-friendly ovarian stimulation. The most recent developments include the fixed combination of follitropin alfa + lutropin alfa, long-acting FSH gonadotropin, and a new family of prefilled pen injector devices for administration of recombinant gonadotropins. The next step would be the production of orally bioactive molecules with selective follicle-stimulating hormone and luteinizing hormone activity. PMID:24714837

  18. Glycosylation and functionality of recombinant β-glucocerebrosidase from various production systems.

    PubMed

    Tekoah, Yoram; Tzaban, Salit; Kizhner, Tali; Hainrichson, Mariana; Gantman, Anna; Golembo, Myriam; Aviezer, David; Shaaltiel, Yoseph

    2013-09-25

    The glycosylation of recombinant β-glucocerebrosidase, and in particular the exposure of mannose residues, has been shown to be a key factor in the success of ERT (enzyme replacement therapy) for the treatment of GD (Gaucher disease). Macrophages, the target cells in GD, internalize β-glucocerebrosidase through MRs (mannose receptors). Three enzymes are commercially available for the treatment of GD by ERT. Taliglucerase alfa, imiglucerase and velaglucerase alfa are each produced in different cell systems and undergo various post-translational or post-production glycosylation modifications to expose their mannose residues. This is the first study in which the glycosylation profiles of the three enzymes are compared, using the same methodology and the effect on functionality and cellular uptake is evaluated. While the major differences in glycosylation profiles reside in the variation of terminal residues and mannose chain length, the enzymatic activity and stability are not affected by these differences. Furthermore, the cellular uptake and in-cell stability in rat and human macrophages are similar. Finally, in vivo studies to evaluate the uptake into target organs also show similar results for all three enzymes. These results indicate that the variations of glycosylation between the three regulatory-approved β-glucocerebrosidase enzymes have no effect on their function or distribution.

  19. Glycosylation and functionality of recombinant β-glucocerebrosidase from various production systems

    PubMed Central

    Tekoah, Yoram; Tzaban, Salit; Kizhner, Tali; Hainrichson, Mariana; Gantman, Anna; Golembo, Myriam; Aviezer, David; Shaaltiel, Yoseph

    2013-01-01

    The glycosylation of recombinant β-glucocerebrosidase, and in particular the exposure of mannose residues, has been shown to be a key factor in the success of ERT (enzyme replacement therapy) for the treatment of GD (Gaucher disease). Macrophages, the target cells in GD, internalize β-glucocerebrosidase through MRs (mannose receptors). Three enzymes are commercially available for the treatment of GD by ERT. Taliglucerase alfa, imiglucerase and velaglucerase alfa are each produced in different cell systems and undergo various post-translational or post-production glycosylation modifications to expose their mannose residues. This is the first study in which the glycosylation profiles of the three enzymes are compared, using the same methodology and the effect on functionality and cellular uptake is evaluated. While the major differences in glycosylation profiles reside in the variation of terminal residues and mannose chain length, the enzymatic activity and stability are not affected by these differences. Furthermore, the cellular uptake and in-cell stability in rat and human macrophages are similar. Finally, in vivo studies to evaluate the uptake into target organs also show similar results for all three enzymes. These results indicate that the variations of glycosylation between the three regulatory-approved β-glucocerebrosidase enzymes have no effect on their function or distribution. PMID:23980545

  20. Clinical effectiveness of contemporary dentin bonding agents

    PubMed Central

    Krithikadatta, Jogikalmat

    2010-01-01

    Aim: The purpose of this paper is to review the literature on the clinical effectiveness of contemporary resin-based dentin bonding agents primarily focussing on the longevity of restoration. Materials and Methods: The literature published from June 2004 up to September 2010 was reviewed for clinical trials that tested the effectiveness of dentin bonding agents in the longevity of noncarious class V restoration. Results of each study reported using the USPHS criteria for clinical assessment of restoration were included and tabulated. The American Dental Association guidelines for dentin and enamel adhesives were used as a reference to compare the performance of individual bonding agents. Kruskal–Wallis followed by Mann–Whitney U was done to compare the mean Alfa score percentage for the three categories of bonding systems [etch-and-rinse (ER), self-etch primer (SEP), and self-etch-adhesive (SEA)]. Results: A comparison of the mean Alfa score percentages revealed no difference between the ER, SEP, and SEA categories of bonding systems except for marginal adaptation where ER was found to be superior to SEA. Conclusion: The clinical effectiveness of resin-based bonding agents is comparable among the three categories. PMID:21217944

  1. Gender-related differences in kidney of rats with chronic renal failure.

    PubMed

    Lemos, Carla C S; Mandarim-de-Lacerda, Carlos A; Carvalho, Jorge J; Bregman, Rachel

    2014-04-01

    Chronic renal failure is characterized by adaptive mechanisms secondary to the loss of functioning nephrons. Clinical and experimental studies suggest participation of gender-related hormones on renal function and progression of chronic renal failure. We evaluated the effect of castration on renal alterations in male and female Wistar control rats and after 30 days of chronic renal failure (CRF) induced by 5/6 nephrectomy. The CRF male group showed higher proteinuria. Glomerular hypertrophy was similar among groups. Podocyte morphology showed disorders of foot processes and thickening of the basement membrane in the CRF male group. The CRF female group showed fewer alterations compared to males. Castration changed the profile in CRF male animals and the filtration barrier was preserved. CRF males showed the presence of alfa-smooth muscle actin suggesting an early prefibrotic event in this group. After castration this phenomenon was not observed. Noteworthy, in females, castration exacerbated the presence of alfa-smooth muscle actin. In summary, proteinuria was higher in males and appeared early in the course of CRF, probably contributing to fibrotic events. Data were influenced by gender suggesting that male sex hormones aggravate renal alterations.

  2. Evaluation of High-Power Solar Electric Propulsion using Advanced Ion, Hall, MPD, and PIT Thrusters for Lunar and Mars Cargo Missions

    NASA Technical Reports Server (NTRS)

    Frisbee, Robert H.

    2006-01-01

    This paper presents the results of mission analyses that expose the advantages and disadvantages of high-power (MWe-class) Solar Electric Propulsion (SEP) for Lunar and Mars Cargo missions that would support human exploration of the Moon and Mars. In these analyses, we consider SEP systems using advanced Ion thrusters (the Xenon [Xe] propellant Herakles), Hall thrusters (the Bismuth [Bi] propellant Very High Isp Thruster with Anode Layer [VHITAL], magnetoplasmadynamic (MPD) thrusters (the Lithium [Li] propellant Advanced Lithium-Fed, Applied-field Lorentz Force Accelerator (ALFA2), and pulsed inductive thruster (PIT) (the Ammonia [NH3] propellant Nuclear-PIT [NuPIT]). The analyses include comparison of the advanced-technology propulsion systems (VHITAL, ALFA2, and NuPIT) relative to state-of-theart Ion (Herakles) propulsion systems and quantify the unique benefits of the various technology options such as high power-per-thruster (and/or high power-per-thruster packaging volume), high specific impulse (Isp), high-efficiency, and tankage mass (e.g., low tankage mass due to the high density of bismuth propellant). This work is based on similar analyses for Nuclear Electric Propulsion (NEP) systems.

  3. [Prefrontal Symptoms Inventory (PSI): ecological validity and convergence with neuropsychological measures].

    PubMed

    Pedrero-Perez, E J; Ruiz-Sanchez de Leon, J M; Rojo-Mota, G; Morales-Alonso, S; Pedrero-Aguilar, J; Lorenzo, I; Gonzalez, A

    2016-09-16

    Introduccion. El inventario de sintomas prefrontales (ISP) es un cuestionario autoinformado creado en España que interroga sobre alteraciones cognitivas, emocionales y comportamentales en las actividades de la vida diaria y que resulta aplicable tanto en poblacion general como en multiples poblaciones clinicas. Existe una version abreviada de 20 items (ISP-20) con excelentes propiedades psicometricas para el cribado. Objetivo. Estudiar la validez convergente y divergente del ISP e ISP-20, analizando como sus escalas reflejan las consecuencias cotidianas de deficits reales hallados en evaluacion neuropsicologica mediante pruebas de ejecucion. Pacientes y metodos. Se estudiaron 52 personas con adiccion a sustancias en tratamiento (31 varones y 21 mujeres) a las que se administro el ISP junto con una bateria de exploracion neuropsicologica abreviada centrada en describir procesos atencionales, mnemicos y ejecutivos. Resultados. Ambas versiones del ISP presentan optimas propiedades psicometricas (0,78 > alfa > 0,94 para la version completa de 46 items y 0,7 > alfa > 0,89 para la version abreviada de 20 items). Los resultados confirman las hipotesis sobre su validez: la escala de problemas en la ejecucion se relaciona con la capacidad para resolver tests que presumiblemente valoran funciones ejecutivas de origen prefrontal (validez convergente), mientras que las escalas de problemas en el control emocional y problemas en la conducta social no se relacionan con dichas capacidades cognitivas (validez discriminante). Conclusiones. El ISP es una prueba clinicamente util, psicometricamente valida y aplicable en multiples poblaciones clinicas.

  4. The analgesic and anti-inflammatory effects of shark cartilage are due to a peptide molecule and are nitric oxide (NO) system dependent.

    PubMed

    Fontenele, J B; Araújo, G B; de Alencar, J W; Viana, G S

    1997-11-01

    The present work shows an antinociceptive and dose-dependent effect of shark cartilage hydrosoluble fraction (HF) on writhing and formalin tests in mice. The effect was not altered by thalidomide, a known inhibitor of tumor necrosis factor-alfa (TNF-alfa) synthesis. Similarly, the antinociceptive effect did not change in the presence of naloxone, indicating that the opioid system is not involved. However, the effect observed was blocked by L-arginine, a NO synthesis substrate, and it was potentiated by L-NAME, suggesting a role of the NO system in the shark cartilage antinociceptive effect. Effects similar to those seen with the HF were detected with peak II from gel filtration chromatography. The increase in vascular permeability induced by serotonin in rats was significantly abolished by the HF at the dose of 2 mg/kg, p.o., and again it was not potentiated by thalidomide. The observed blockade in the vascular permeability increase induced by histamine was detected only with a higher dose (10 mg/kg, p.o.).

  5. SETIBURST: A Robotic, Commensal, Realtime Multi-science Backend for the Arecibo Telescope

    NASA Astrophysics Data System (ADS)

    Chennamangalam, Jayanth; MacMahon, David; Cobb, Jeff; Karastergiou, Aris; Siemion, Andrew P. V.; Rajwade, Kaustubh; Armour, Wes; Gajjar, Vishal; Lorimer, Duncan R.; McLaughlin, Maura A.; Werthimer, Dan; Williams, Christopher

    2017-02-01

    Radio astronomy has traditionally depended on observatories allocating time to observers for exclusive use of their telescopes. The disadvantage of this scheme is that the data thus collected is rarely used for other astronomy applications, and in many cases, is unsuitable. For example, properly calibrated pulsar search data can, with some reduction, be used for spectral line surveys. A backend that supports plugging in multiple applications to a telescope to perform commensal data analysis will vastly increase the science throughput of the facility. In this paper, we present “SETIBURST,” a robotic, commensal, realtime multi-science backend for the 305 m Arecibo Telescope. The system uses the 1.4 GHz, seven-beam Arecibo L-band Feed Array (ALFA) receiver whenever it is operated. SETIBURST currently supports two applications: SERENDIP VI, a SETI spectrometer that is conducting a search for signs of technological life, and ALFABURST, a fast transient search system that is conducting a survey of fast radio bursts (FRBs). Based on the FRB event rate and the expected usage of ALFA, we expect 0–5 FRB detections over the coming year. SETIBURST also provides the option of plugging in more applications. We outline the motivation for our instrumentation scheme and the scientific motivation of the two surveys, along with their descriptions and related discussions.

  6. Kidney transplantation in patients with Fabry disease.

    PubMed

    Cybulla, Markus; Walter, Kerstin Nanette; Schwarting, Andreas; Divito, Raffaelle; Feriozzi, Sandro; Sunder-Plassmann, Gere

    2009-04-01

    Little is known about the effects of enzyme replacement therapy (ERT) in kidney transplant recipients with Fabry disease. Clinical characteristics of transplant recipients in the Fabry Outcome Survey (FOS) were therefore examined in patients with Fabry disease with or without ERT. Of the 837 European patients in FOS (March 2006), 34 male patients and two female patients had received kidney transplants. Mean age at transplantation was 37.6 +/- 10.9 years, mean time since transplantation was 7.7 +/- 6.4 years, median estimated glomerular filtration rate (eGFR) was 44.4 ml/min/1.73 m(2), and median proteinuria was 296 mg/24 h. Of 27 patients with baseline data, 59% had hypertension, 74% had left ventricular hypertrophy, 22% had cardiac valve disease, 30% had arrhythmia, and 22% had transient ischaemic attacks and 15% stroke. Twenty patients (74%; two female patients, 18 male patients) were receiving ERT with agalsidase alfa. At enrollment or at the start of ERT, median eGFRs were 59 and 35 ml/min/1.73 m(2) (P = 0.05) and median proteinuria levels were 240 and 420 mg/24 h (not significant) in treated and untreated patients respectively. Renal function remained stable in patients receiving ERT. In conclusion, agalsidase alfa is well tolerated in patients with Fabry disease who have undergone renal transplantation.

  7. Enzyme replacement therapy in two Japanese siblings with Fabry disease, and its effectiveness on angiokeratoma and neuropathic pain.

    PubMed

    Furujo, Mahoko; Kubo, Toshihide; Kobayashi, Masahisa; Ohashi, Toya

    2013-11-01

    Enzyme replacement therapy (ERT) for Fabry disease does not show a clear benefit in angiokeratoma. We describe two Japanese siblings with Fabry disease, who were diagnosed when angiokeratomas were found on the older sibling at the age of 13 years. Neither of the boys complained of pain, while both suffered from hypohidrosis. We evaluated the safety and efficacy of ERT with recombinant human agalsidase alfa (Replagal®, Dainippon-Sumitomo Pharma. Co., Osaka, Japan) in these siblings over a 5-year period. In both siblings, sweating was observed 3 months after the initiation of ERT, which motivated them to adhere to ERT. Pain sensation was regained after 12 to 36 months of ERT, followed by a decrease after 48 to 60 months. Angiokeratomas on the lateral side of the knee of the older sibling partially disappeared after 48 months of ERT. Although the height of both siblings at baseline was lower than the corresponding average age-related heights in the normal Japanese population, during ERT they were within, or close to, the average +1 standard deviation in the non-Fabry population. Their growth rate seemed to indicate catch-up growth. Other clinical symptoms were maintained at baseline levels. Immunoglobulin G anti-agalsidase alfa antibodies were not detected in both sibling during ERT, and no infusion-associated reaction was observed. The treatment was generally well tolerated. ERT was a safe and effective treatment for angiokeratoma and neuropathic pain for these two siblings with Fabry disease.

  8. Analysis of GALFACTS Data for the Study of Variable Radio Sources

    NASA Astrophysics Data System (ADS)

    Barenfeld, Scott; Ghosh, T.; Salter, C.

    2011-01-01

    The G-ALFA Continuum Transit Survey (GALFACTS) is a spectro-polarimetric survey of Arecibo Observatory's visible sky from 1225-1525 MHz, using the Arecibo L-band Feed Array (ALFA). Among the survey's many scientific goals is a large-scale statistical study on the short-term variability of the flux density and polarization of radio sources. Every point in the sky is observed twice, with less than a month between observations, making this the largest systematic search for variability ever conducted. In this poster, we present the development of computer code to aid in this search, and some preliminary results from this code. The code takes GALFACTS data in the form of time series for 2048 individual spectral channels, containing positions and full-stokes antenna temperatures, and turns these into a list of individual radio sources with their positions and Stokes-I temperatures. We first ran the code for the field surrounding the radio source S0206+330, of known flux density, as a test. Once a working code was completed, it was run on the field of another radio source, S0311+307.

  9. [Guidelines for monitoring late-onset Pompe disease.Sociedad Española de Medicina Interna (SEMI), Sociedad Española de Neurología (SEN) y Sociedad Española de Neumología y CirugíaTorácica (SEPAR)].

    PubMed

    Gutiérrez-Rivas, Eduardo; Illa, Isabel; Pascual-Pascual, Samuel I; Pérez-López, Jordi; Vílchez-Padilla, Juan J; Bautista-Lorite, Juan; Barrot, Emilia; López de Munain, Adolfo

    2015-04-01

    Although treatment with alglucosidase alfa has helped improve the prognosis of patients with late-onset Pompe disease, both the development of the disease and the effectiveness of the treatment need to be monitored on a regular basis. This is the reason that has led a committee of Spanish experts to draw up a series of guidelines on how to follow up these patients. The committee proposes a model of follow-up tests for late-onset Pompe disease. First of all, the nutritional status and swallowing function must be evaluated. Second, and due to the variability of the clinical features, the committee recommends the simultaneous use of several scales to measure different functions and parameters. Thus, muscular force is assessed with the Medical Research Council scale; motor functioning, with the six-minute walk test and timed tests; disability, with the Rasch-built Pompe-specific Activity scale; respiratory functioning, with measurement of the forced vital capacity and oxygen saturation; and fatigue, with the fatigue intensity scale. Lastly, the safety and tolerability of enzyme replacement therapy are controlled by registering and treating the potential side effects and measurement of the anti-alglucosidase alfa antibodies. A number of different general recommendations are also included.

  10. Erythropoiesis stimulating agents: approaches to modulate activity

    PubMed Central

    Sinclair, Angus M

    2013-01-01

    Recombinant human erythropoietin (rHuEPO), such as the approved agents epoetin alfa and epoetin beta, has been used successfully for over 20 years to treat anemia in millions of patients. However, due to the relatively short half-life of the molecule (approximately 8 hours), frequent dosing may be required to achieve required hemoglobin levels. Therefore, a need was identified in some anemic patient populations for erythropoiesis stimulating agents with longer half-lives that required less frequent dosing. This need led to the development of second generation molecules which are modified versions of rHuEPO with improved pharma-cokinetic and pharmacodynamic properties such as darbepoetin alfa, a hyperglycosylated analog of rHuEPO, and pegzyrepoetin, a pegylated rHuEPO. Third generation molecules, such as peginesatide, which are peptide mimetics that have no sequence homology to rHuEPO have also recently been developed. The various molecular, pharmacokinetic, and pharmacodynamic properties of these and other erythropoiesis stimulating agents will be discussed in this review. PMID:23847411

  11. The emerging role of biosimilar epoetins in nephrology in the United States.

    PubMed

    Fishbane, Steven; Shah, Hitesh H

    2015-04-01

    Biologic drugs, including epoetin, continue to play an important role in the management of medical conditions. However, biologics are costly and soon many of the patents on these drugs will expire, making way for non-brand name products (ie, biosimilars). It is only by introducing competition to the marketplace that costs will de-escalate. In Europe, a specific regulatory pathway for approving biosimilars has been in place since 2005. A similar review pathway in the United States has been developed by the US Food and Drug Administration. These guidelines for approving biosimilars are stringent, requiring preclinical pharmacodynamic and toxicologic studies, clinical studies to demonstrate bioequivalence and efficacy, and long-term postmarketing studies to monitor drug safety. Biosimilar epoetin has been used in Europe since 2007, and a wealth of data has been collected. These studies and reports indicate that the efficacy and safety profiles of biosimilar epoetin are similar to those of originator epoetin alfa. Biosimilars of epoetin alfa are expected to be among the first biosimilar agents to be approved for use in the United States. The availability of lower cost epoetins may have significant impact on the treatment of anemia of chronic kidney disease.

  12. Anti-erythropoietin and anti-thrombopoietin antibodies induced after administration of recombinant human erythropoietin.

    PubMed

    Shin, Sug Kyun; Pack, Seung Pil; Oh, Jin-Gyo; Kang, Nam Kyu; Chang, Myung Hee; Chung, Yoon Hee; Kim, Sung-Jo; Lee, Jong Wook; Heo, Tae-Hwe

    2011-12-01

    Recombinant human erythropoietin (rhEPO) has been successfully used for correcting renal anemia. However, recent studies have raised some concerns about the safety of rhEPO treatment due to its immunogenic side effect - pure red cell aplasia (PRCA). We now report a case of development of anti-EPO neutralizing antibodies (Abs) implicated in thrombocytopenia as well as erythrocytopenia. A 35-year-old man had a history of administering rhEPO (epoetin alfa, epoetin beta and darbepoetin alfa) for 2years to treat renal anemia. The hematological parameters were collected. Anti-EPO, anti-platelet, and anti-thrombopoietin (TPO) Ab assays were performed to test the presence of autoreactive Abs. After performing antibody assays due to severe resistance to rhEPO treatment, a high titer of anti-EPO neutralizing Abs was detected. However, unexpectedly, this patient also showed thrombocytopenia rather than PRCA. We investigated the cause of the marked thrombocytopenia and found anti-TPO Abs in patient serum. To our best knowledge, this is the first report of the development of anti-TPO Abs during rhEPO treatment for anemia.

  13. [Effect of alcohol on electrical organisation in the brain during a visuospatial working memory task and its relationship with the menstrual cycle].

    PubMed

    Sanz-Martin, Araceli; Hernández-González, Marisela; Guevara, Miguel Ángel; Santana, Gloria; Gumá-Díaz, Emilio

    2014-02-01

    Introduccion. El metabolismo del alcohol y el desempeño de muchas funciones cognitivas pueden variar a lo largo del ciclo menstrual. Tanto la ingestion de alcohol como las variaciones hormonales durante el ciclo menstrual se asocian con cambios caracteristicos en la actividad electroencefalografica. Objetivo. Determinar si la actividad electroencefalografica durante una tarea de memoria de trabajo es afectada por el consumo agudo de alcohol, y si dicha actividad varia en funcion del ciclo menstrual. Sujetos y metodos. Muestra de 24 mujeres que ingirieron alcohol o placebo durante las fases folicular y lutea temprana. Se registro el electroencefalograma durante la ejecucion de una tarea de memoria de trabajo visuoespacial. Resultados. Aunque el alcohol no deterioro el rendimiento de la tarea de memoria de trabajo, si produjo en el electroencefalograma una disminucion de la potencia relativa de theta y una menor correlacion frontoparietal derecha en las bandas theta y alfa2. Unicamente las mujeres alcoholizadas en la fase folicular presentaron una mayor potencia relativa de alfa1, que podria indicar menor nivel de alertamiento y atencion. Conclusiones. Estos resultados contribuyen a una mejor comprension de los mecanismos cerebrales que subyacen a los cambios cognitivos con el alcohol y su relacion con el ciclo menstrual.

  14. Large format array NIR detectors for future ESA astronomy missions: characterization and comparison

    NASA Astrophysics Data System (ADS)

    Gooding, David; Crouzet, Pierre-Elie; Duvet, Ludovic; Prod'homme, Thibaut; Smit, Hans; Ter Haar, Jörg; Blommaert, Sander; Visser, Ivo; Lemmel, Frederic; Heijnen, Jerko; Van Der Luijt, Cornelis; Butler, Bart; Beaufort, Thierry

    2016-08-01

    The Payload Technology Validation section in the Future Missions office of ESA's Science directorate at ESTEC provides testing support to present and future missions at different stages in their lifetime, from early technology developments to mission operation validation. In this framework, a test setup to characterize near-infrared (NIR) detectors has been created. In the context of the Astronomy Large Format Array for the near-infrared ("ALFA-N") technology development program, detectors from different suppliers are tested. We report on the characterization progress of the ALFA-N detectors, for which a series of rigorous tests have been performed on two different detectors; one provided by CEA/Leti-CEA/IRFU-SOFRADIR, France and the other by SELEX- UK/ATC, UK. Experimental techniques, the test bench and methods are presented. The conversion gain of two different detectors is measured using the photon transfer curve method. For a Leti LPE detector the persistence effect has been probed across a range of illumination levels to reveal a sharp linear increase of persistence below full-well and a plateauing beyond saturation. The same detector has been proton irradiated which has resulted in no significant dark current increase.

  15. [Validity and consistency of the ECAVIPEP and CAVE scales to assess quality of life in paediatric patients with epilepsy].

    PubMed

    García-Galicia, Arturo; García-Carrasco, Mario; Montiel-Jarquín, Álvaro J; García-Cuautitla, Marco A; Barragán-Hervella, Rodolfo G; Romero-Figueroa, M Socorro

    2014-10-01

    Introduccion. La epilepsia tiene un alto impacto en la calidad de vida del niño, por lo que es importante contar con instrumentos validados y consistentes para su evaluacion. Objetivo. Comparar la validez y consistencia de una nueva escala de calidad de vida para pacientes epilepticos pediatricos (ECAVIPEP) de un hospital mexicano con la escala CAVE ampliamente validada. Pacientes y metodos. Estudio comparativo, en el que se analiza la validez y consistencia de una nueva escala para evaluar la epilepsia en niños. Se realizo en niños epilepticos de 4-10 años mediante la aplicacion de una escala de calidad de vida, comparandola con la escala CAVE ampliamente validada. Se utilizo el alfa de Cronbach y la rho de Spearman para la validez y la consistencia. Resultados. Fueron 114 pacientes, 72 (63,1%) niños y 42 (36,8%) niñas. La consistencia interna dio un valor del alfa de Cronbach de 0,673. Para el analisis de validez convergente, comparando las puntuaciones obtenidas por la CAVE y por la ECAVIPEP, se obtuvo una rho de Spearman de 0,670 (p menor que 0). Conclusion. La ECAVIPEP es una escala valida y consistente para la evaluacion en niños de 4-10 años con epilepsia.

  16. The non-haematopoietic biological effects of erythropoietin.

    PubMed

    Arcasoy, Murat O

    2008-04-01

    In the haematopoietic system, the principal function of erythropoietin (Epo) is the regulation of red blood cell production, mediated by its specific cell surface receptor (EpoR). Following the cloning of the Epo gene (EPO) and characterization of the selective haematopoietic action of Epo in erythroid lineage cells, recombinant Epo forms (epoetin-alfa, epoetin-beta and the long-acting analogue darbepoetin-alfa) have been widely used for treatment of anaemia in chronic kidney disease and chemotherapy-induced anaemia in cancer patients. Ubiquitous EpoR expression in non-erythroid cells has been associated with the discovery of diverse biological functions for Epo in non-haematopoietic tissues. During development, Epo-EpoR signalling is required not only for fetal liver erythropoiesis, but also for embryonic angiogenesis and brain development. A series of recent studies suggest that endogenous Epo-EpoR signalling contributes to wound healing responses, physiological and pathological angiogenesis, and the body's innate response to injury in the brain and heart. Epo and its novel derivatives have emerged as major tissue-protective cytokines that are being investigated in the first human studies involving neurological and cardiovascular diseases. This review focuses on the scientific evidence documenting the biological effects of Epo in non-haematopoietic tissues and discusses potential future applications of Epo and its derivatives in the clinic.

  17. The level of major proteins and minerals in the blood serum of chickens fed diets with pure cellulose.

    PubMed

    Bogusławska-Tryk, Monika; Szymeczko, Roman; Piotrowska, Anna

    2012-01-01

    The aim of the research was to determine the concentration of total protein and its fractions as well as the concentration of selected mineral components in the blood serum of male broiler chickens Cobb 500 fed diets with different cellulose content. Blood samples were collected for examination from the birds' pterygoid canal veins on their 42 day of age. There was no influence of cellulose preparation on the content of total protein and its fractions: albumins, alfa1-, alfa2-, beta-, gamma-globulins, albumin to globulin ratio, inorganic phosphorus, sodium, potassium, chloride and iron concentrations in blood serum. The highest calcium concentration (P < 0.05) was detected in the blood serum of males fed a diet with the highest cellulose content (0.75-0.95%). Simultaneously, a tendency of increased calcium content was observed along with an increased amount of pure cellulose in diets. The lowest magnesium level (P < 0.05) was observed in the blood of birds fed diets with the lowest amount of cellulose (0.25-0.45%). The magnesium level in the blood of birds fed a diet with higher amounts of cellulose did not considerably differ from the control group. Results from the current study suggest that introduction of a limited amount of pure cellulose into the diet of broiler chickens does not affect total protein concentration and protein fractions but can influence the mineral content in the blood serum.

  18. Chronic hepatitis B with type I diabetes mellitus and autoimmune thyroiditis development during interferon alpha therapy.

    PubMed

    Kose, Sukran; Gozaydin, Ayhan; Akkoclu, Gulgun; Ece, Gulfem

    2012-04-13

    Interferon alpha is a molecule frequently used in the treatment of chronic hepatitis B, C, and D, with immunomodulatory and antiviral activity. It is also used in some cancer types. It has been widely claimed that interferon alpha triggers autoimmunity, with its broad adverse effect profile. Here we present the case of a 29-year-old male patient with chronic hepatitis B diagnosis who developed type 1 diabetes mellitus and autoimmune thyroiditis during treatment with interferon alfa-2b. Within four months of initiation of treatment with interferon alfa-2b, the patient presented to our clinic with dry mouth, urinary frequency (8 to 10 times per day), drinking plenty of water, night time urination, and tiredness. He was admitted to the clinic when his fasting blood glucose level was detected to be high. After examinations, the patient was diagnosed with type 1 diabetes and autoimmune thyroiditis and began to receive treatment with insulin and propranolol. Fasting blood glucose levels were controlled and thyroid hormones decreased to normal levels within one month after the treatments began. For patients who will receive treatment with interferon alpha, especially those individuals with chronic hepatitis, pancreatic autoantibodies should be checked and close monitoring should be performed as there may be glucose tolerance impairment in patients with high titers. In addition, follow-up with thyroid function tests should be performed prior to and during the treatment.

  19. [Factors related to residual renal function loss in patients in peritoneal dialysis].

    PubMed

    Munguía-Miranda, Catarina; Ventura-García, María de Jesús; Ávila-Díaz, Marcela; Orihuela-Rodríguez, Oscar; Paniagua-Sierra, José Ramón

    2015-01-01

    Introducción: la conservación de la función renal residual (FRR) en los pacientes en diálisis peritoneal (DP) tiene una clara influencia sobre la calidad de vida, independientemente de que su preservación ha demostrado influir en la mayor supervivencia de los pacientes. El objetivo del presente estudio fue conocer los factores relacionados con pérdida de la FRR en un grupo de pacientes prevalentes en diálisis peritoneal continua ambulatoria (DPCA). Métodos: se trata de un estudio de análisis de resultados secundarios. Se incluyeron 43 adultos con diabetes tipo 2 (DT2), con FRR conservada, a quienes se les dio seguimiento durante un año. Resultados: los factores relacionados con la pérdida de la FRR fueron: género masculino (p = 0.042), presión arterial sistólica (p = 0.009) y diastólica (p = 0.006), hemoglobina (p = 0.008), aclaramiento peritoneal de creatinina (p = 0.014), ultrafiltración (p = 0.017), niveles de factor de necrosis tumoral alfa (FNT–alfa) en plasma (p = 0.022) y dializado (p = 0.008). Conclusiones: es importante conocer los factores relacionados con pérdida de la FRR en nuestros pacientes para evitar la pérdida gradual de la misma y sus implicaciones sobre la mortalidad y calidad de vida.

  20. The Arecibo Galaxy Environment Survey IX: the isolated galaxy sample

    NASA Astrophysics Data System (ADS)

    Minchin, R. F.; Auld, R.; Davies, J. I.; Karachentsev, I. D.; Keenan, O. C.; Momjian, E.; Rodriguez, R.; Taber, T.; Taylor, R.

    2016-02-01

    We have used the Arecibo L-band Feed Array (ALFA) to map three regions, each of 5 deg2, around the isolated galaxies NGC 1156, UGC 2082, and NGC 5523. In the vicinity of these galaxies we have detected two dwarf companions: one near UGC 2082, previously discovered by the Arecibo Legacy Fast ALFA (ALFALFA) survey, and one near NGC 1156, discovered by this project and reported in an earlier paper. This is significantly fewer than the 15.4^{+1.7}_{-1.5} that would be expected from the field H I mass function from ALFALFA or the 8.9 ± 1.2 expected if the H I mass function from the Local Group applied in these regions. The number of dwarf companions detected is, however, consistent with a flat or declining H I mass function as seen by a previous, shallower, H I search for companions to isolated galaxies. We attribute this difference in H I mass functions to the different environments in which they are measured. This agrees with the general observation that lower ratios of dwarf to giant galaxies are found in lower density environments.

  1. A Search for Fast Radio Bursts in GALFACTS data

    NASA Astrophysics Data System (ADS)

    Cohen, Tyler; Salter, Christopher J.; Ghosh, Tapasi

    2016-01-01

    Fast Radio Bursts (FRBs) are transient radio sources whose high dispersion measures suggest they are of extra-galactic origin. They are particularly difficult to detect because, unlike other fast radio transients, they are non-recurring events. At present, 11 such bursts have been detected, 10 by the Parkes Radio Telescope and one by Arecibo Observatory. The G-ALFA Continuum Transit Survey (GALFACTS) is the highest resolution, full-Stokes, radio-continuum survey of the foreground sky. The Arecibo radio telescope is the largest single-aperture telescope in the world, offering the superior point-source sensitivity necessary to detect additional FRBs. GALFACTS utilizes Arecibo's ALFA receiver, an L-band 7-beam feed array, to produce a high-time (1 ms), low-spectral (MHz) resolution (HTLS) data stream between 1225 and 1525 MHz. We used ``Red_Transient", a robust search pipeline developed by A.A. Deshpande, to de-disperse the HTLS data with the intention of detecting FRBs in the ~30% of the total sky surveyed by GALFACTS. Concurrently, the student produced a similar search pipeline to calibrate HTLS data and validate detections by ``Red_Transient". Here, we present the results of initial processing runs on the first several days of GALFACTS observations. Currently, no FRB detections have been found. However, the detection of pulses from the known pulsar J1916+1312 indicates that ``Red_Transient" is capable of detecting fast transient signals present in the data stream.

  2. Ionic liquid self-combustion synthesis of BiOBr/Bi24O31Br10 heterojunctions with exceptional visible-light photocatalytic performances

    NASA Astrophysics Data System (ADS)

    Li, Fa-Tang; Wang, Qing; Ran, Jingrun; Hao, Ying-Juan; Wang, Xiao-Jing; Zhao, Dishun; Qiao, Shi Zhang

    2014-12-01

    Heterostructured BiOBr/Bi24O31Br10 nanocomposites with surface oxygen vacancies are constructed by a facile in situ route of one-step self-combustion of ionic liquids. The compositions can be easily controlled by simply adjusting the fuel ratio of urea and 2-bromoethylamine hydrobromide (BTH). BTH serves not only as a fuel, but also as a complexing agent for ionic liquids and a reactant to supply the Br element. The heterojunctions show remarkable adsorptive ability for both the cationic dye of rhodamine B (RhB) and the anionic dye of methylene orange (MO) at high concentrations, which is attributed to the abundant surface oxygen vacancies. The sample containing 75.2% BiOBr and 24.8% Bi24O31Br10 exhibits the highest photocatalytic activity. Its reaction rate constant is 4.0 and 9.0 times that of pure BiOBr in degrading 50 mg L-1 of RhB and 30 mg L-1 of MO under visible-light (λ > 400 nm) irradiation, respectively, which is attributed to the narrow band gap and highly efficient transfer efficiency of charge carriers. Different photocatalytic reaction processes and mechanisms over pure BiOBr and heterojunctions are proposed.Heterostructured BiOBr/Bi24O31Br10 nanocomposites with surface oxygen vacancies are constructed by a facile in situ route of one-step self-combustion of ionic liquids. The compositions can be easily controlled by simply adjusting the fuel ratio of urea and 2-bromoethylamine hydrobromide (BTH). BTH serves not only as a fuel, but also as a complexing agent for ionic liquids and a reactant to supply the Br element. The heterojunctions show remarkable adsorptive ability for both the cationic dye of rhodamine B (RhB) and the anionic dye of methylene orange (MO) at high concentrations, which is attributed to the abundant surface oxygen vacancies. The sample containing 75.2% BiOBr and 24.8% Bi24O31Br10 exhibits the highest photocatalytic activity. Its reaction rate constant is 4.0 and 9.0 times that of pure BiOBr in degrading 50 mg L-1 of RhB and 30 mg

  3. Long-Term Citalopram Treatment Alters the Stress Responses of the Cortical Dopamine and Noradrenaline Systems: the Role of Cortical 5-HT1A Receptors

    PubMed Central

    Kaneko, Fumi; Kishikawa, Yuki; Hanada, Yuuki; Yamada, Makiko; Kakuma, Tatsuyuki; Kawahara, Hiroshi; Nishi, Akinori

    2016-01-01

    Background: Cortical dopamine and noradrenaline are involved in the stress response. Citalopram, a selective serotonin reuptake inhibitor, has direct and indirect effects on the serotonergic system. Furthermore, long-term treatment with citalopram affects the dopamine and noradrenaline systems, which could contribute to the therapeutic action of antidepressants. Methods: The effects of long-term treatment with citalopram on the responses of the dopamine and noradrenaline systems in the rat prefrontal cortex to acute handling stress were evaluated using in vivo microdialysis. Results: Acute handling stress increased dopamine and noradrenaline levels in the prefrontal cortex. The dopamine and noradrenaline responses were suppressed by local infusion of a 5-HT1A receptor agonist, 7-(Dipropylamino)-5,6,7,8-tetrahydronaphthalen-1-ol;hydrobromide, into the prefrontal cortex. The dopamine response was abolished by long-term treatment with citalopram, and the abolished dopamine response was reversed by local infusion of a 5-HT1A receptor antagonist, (Z)-but-2-enedioic acid;N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-pyridin-2-ylcyclohexanecarboxamide into the prefrontal cortex. On the other hand, long-term treatment with citalopram reduced the basal noradrenaline levels (approximately 40% of the controls), but not the basal dopamine levels. The noradrenaline response was maintained despite the low basal noradrenaline levels. Signaling from the 5-HT1A receptors and α2-adrenoceptors was not involved in the decrease in the basal noradrenaline levels but partially affected the noradrenaline response. Conclusions: Chronic citalopram treatment differentially suppresses the dopamine and noradrenaline systems in the prefrontal cortex, and the dopamine stress response was preferentially controlled by upregulating 5-HT1A receptor signaling. Our findings provide insight into how antidepressants modulate the dopamine and noradrenaline systems to overcome acute stress. PMID

  4. Galantamine is a novel post-exposure therapeutic against lethal VX challenge.

    PubMed

    Hilmas, Corey J; Poole, Melissa J; Finneran, Kathryn; Clark, Matthew G; Williams, Patrick T

    2009-10-15

    The ability of galantamine hydrobromide (GAL HBr) treatment to antagonize O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX)-induced lethality, impairment of muscle tension, and electroencephalographic (EEG) changes was assessed in guinea pigs. Guinea pigs were challenged with 16.8 microg/kg VX (2LD50). One min after challenge, animals were administered 0.5 mg/kg atropine sulfate (ATR) and 25 mg/kg pyridine-2-aldoxime methochloride (2-PAM). In addition, guinea pigs were given 0, 1, 2, 4, 8 or 10 mg/kg GAL as a post-exposure treatment immediately prior to ATR and 2-PAM. Animals were either monitored for 24-h survival, scheduled for electroencephalography (EEG) recording, or euthanized 60 min later for measurement of indirectly-elicited muscle tension in the hemidiaphragm. Post-exposure GAL therapy produced a dose-dependent increase in survival from lethal VX challenge. Optimal clinical benefits were observed in the presence of 10 mg/kg GAL, which led to 100% survival of VX-challenged guinea pigs. Based on muscle physiology studies, GAL post-exposure treatment protected the guinea pig diaphragm, the major effector muscle of respiration, from fatigue, tetanic fade, and muscular paralysis. Protection against the paralyzing effects of VX was dose-dependent. In EEG studies, GAL did not alter seizure onset for all doses tested. At the highest dose tested (10 mg/kg), GAL decreased seizure duration when administered as a post-exposure treatment 1 min after VX. GAL also reduced the high correlation associated between seizure activity and lethality after 2LD50 VX challenge. GAL may have additional benefits both centrally and peripherally that are unrelated to its established mechanism as a reversible acetylcholinesterase inhibitor (AChEI).

  5. Synaptic modulation of excitatory synaptic transmission by nicotinic acetylcholine receptors in spinal ventral horn neurons.

    PubMed

    Mine, N; Taniguchi, W; Nishio, N; Izumi, N; Miyazaki, N; Yamada, H; Nakatsuka, T; Yoshida, M

    2015-04-02

    Nicotinic acetylcholine receptors (nAChRs) are distributed widely in the central nervous system and play important roles in higher brain functions, including learning, memory, and recognition. However, functions of the cholinergic system in spinal motoneurons remain poorly understood. In this study, we investigated the actions of presynaptic and postsynaptic nAChRs in spinal ventral horn neurons by performing whole-cell patch-clamp recordings on lumbar slices from male rats. The application of nicotine or acetylcholine generated slow inward currents and increased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs). Slow inward currents by acetylcholine or nicotine were not inhibited by tetrodotoxin (TTX) or glutamate receptor antagonists. In the presence of TTX, the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) were also increased by acetylcholine or nicotine. A selective α4β2 nicotinic receptor antagonist, dihydro-β-erythroidine hydrobromide (DhβE), significantly decreased nicotine-induced inward currents without affecting the enhancement of sEPSCs and mEPSCs. In addition, a selective α7 nicotinic receptor antagonist, methyllycaconitine, did not affect either nicotine-induced inward currents or the enhancement of sEPSCs and mEPSCs. These results suggest that α4β2 AChRs are localized at postsynaptic sites in the spinal ventral horn, non-α4β2 and non-α7 nAChRs are located presynaptically, and nAChRs enhance excitatory synaptic transmission in the spinal ventral horn.

  6. Effect of GDNF on depressive-like behavior, spatial learning and key genes of the brain dopamine system in genetically predisposed to behavioral disorders mouse strains.

    PubMed

    Naumenko, Vladimir S; Kondaurova, Elena M; Bazovkina, Daria V; Tsybko, Anton S; Ilchibaeva, Tatyana V; Khotskin, Nikita V; Semenova, Alina A; Popova, Nina K

    2014-11-01

    The effect of glial cell line-derived neurotrophic factor (GDNF) on behavior and brain dopamine system in predisposed to depressive-like behavior ASC (Antidepressant Sensitive Cataleptics) mice in comparison with the parental "nondepressive" CBA mice was studied. In 7days after administration (800ng, i.c.v.) GDNF decreased escape latency time and the path traveled to reach hidden platform in Morris water maze in ASC mice. GDNF enhanced depressive-like behavioral traits in both "nondepressive" CBA and "depressive" ASC mice. In CBA mice, GDNF decreased functional response to agonists of D1 (chloro-APB hydrobromide) and D2 (sumanirole maleate) receptors in tail suspension test, reduced D2 receptor gene expression in the substantia nigra and increased monoamine oxydase A (MAO A) gene expression in the striatum. GDNF increased D1 and D2 receptor genes expression in the nucleus accumbens of ASC mice but failed to alter expression of catechol-O-methyltransferase, dopamine transporter, MAO B and tyrosine hydroxylase genes in both investigated mouse strains. Thus, GDNF produced long-term genotype-dependent effect on behavior and the brain dopamine system. GDNF pretreatment (1) reduced D1 and D2 receptors functional responses and D2 receptor gene expression in s. nigra of CBA mice; (2) increased D1 and D2 receptor genes expression in n. accumbens of ASC mice and (3) improved spatial learning in ASC mice. GDNF enhanced depressive-like behavior both in CBA and ASC mice. The data suggest that genetically defined variance in the cross-talk between GDNF and brain dopamine system contributes to the variability of GDNF-induced responses and might be responsible for controversial GDNF effects.

  7. Morphological Alterations of the Palpebral Conjunctival Epithelium in a Dry Eye Model

    PubMed Central

    Henriksson, Johanna Tukler; De Paiva, Cintia S.; Farley, William; Pflugfelder, Stephen C.; Burns, Alan R.; Bergmanson, Jan P.G.

    2012-01-01

    Purpose To investigate the normal palpebral conjunctival histology in C57BL/6 mice, and the structural changes that occur in a dry eye model. Methods 24 male and female C57BL/6 mice, 8 untreated (UT) and 16 exposed to experimental ocular surface desiccating stress (DS). Ocular dryness was induced by administration of scopolamine hydrobromide (0.5 mg/0.2 ml) QID for 5 (DS5) or 10 (DS10) days. Counts and measurements were obtained using anatomical reference points and goblet cell density was investigated with a variety of stains. Results Near the junction between the lid margin and the normal palpebral conjunctiva, the epithelium had an average thickness of 45.6±10.5μm, 8.8±2.0 cell layers, versus 37.7±5.6μm, 7.4±1.3 layers in DS10 (P<0.05). In the goblet cell populated palpebral region the normal epithelium was thicker (P<0.05) than in DS5 and DS10. In the control, 43% of the goblet cells were covered by squamous epithelium, compared to 58% (DS5) and 63% (DS10) (P<0.05). A decreased number of Periodic Acid Schiff (PAS) and Alcian blue stained goblet cells was observed in the dry eye. Not all goblet cells stained with PAS and Alcian blue. Conclusions The mouse palpebral conjunctival epithelium was structurally similar to the human. After DS the palpebral conjunctival epithelium decreased in thickness and goblet cell access to the surface appeared to be inhibited by surrounding epithelial cells, potentially slowing down their migration to the surface. Differential staining with PAS and Alcian blue suggests there may be different subtypes of conjunctival goblet cells. PMID:23146932

  8. Activation of the gut calcium-sensing receptor by peptide agonists reduces rapid elevation of plasma glucose in response to oral glucose load in rats.

    PubMed

    Muramatsu, Maya; Hira, Tohru; Mitsunaga, Arimi; Sato, Eri; Nakajima, Shingo; Kitahara, Yoshiro; Eto, Yuzuru; Hara, Hiroshi

    2014-06-15

    The calcium-sensing receptor (CaSR) is expressed in various tissues, including the gastrointestinal tract. To investigate the role of gut CaSR on glycemic control, we examined whether single oral administration of CaSR agonist peptides affected the glycemic response in rats. Glucose tolerance tests were performed under oral or duodenal administration of various CaSR agonist peptides (γGlu-Cys, protamine, and poly-d-lysine hydrobromide) in conscious rats. Involvement of CaSR was determined by using a CaSR antagonist. Signaling pathways underlying CaSR agonist-modified glycemia were investigated using gut hormone receptor antagonists. The gastric emptying rate after the administration of CaSR agonist peptides was measured by the phenol red recovery method. Oral and duodenal administration of CaSR agonist peptides attenuated glycemic responses under the oral glucose tolerance test, but the administration of casein did not. The promotive effect on glucose tolerance was weakened by luminal pretreatment with a CaSR antagonist. Treatment with a 5-HT3 receptor antagonist partially diminished the glucose-lowering effect of peptides. Furthermore, the gastric emptying rate was decreased by duodenal administration of CaSR agonist peptides. These results demonstrate that activation of the gut CaSR by peptide agonists promotes glucose tolerance in conscious rats. 5-HT3 receptor and the delayed gastric emptying rate appear to be involved in the glucose-lowering effect of CaSR agonist peptides. Thus, activation of gut CaSR by dietary peptides reduces glycemic responses so that gut CaSR may be a potential target for the improvement of postprandial glycemia.

  9. Galantamine is a novel post-exposure therapeutic against lethal VX challenge

    SciTech Connect

    Hilmas, Corey J. Poole, Melissa J.; Finneran, Kathryn; Clark, Matthew G.; Williams, Patrick T.

    2009-10-15

    The ability of galantamine hydrobromide (GAL HBr) treatment to antagonize O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX)-induced lethality, impairment of muscle tension, and electroencephalographic (EEG) changes was assessed in guinea pigs. Guinea pigs were challenged with 16.8 {mu}g/kg VX (2LD50). One min after challenge, animals were administered 0.5 mg/kg atropine sulfate (ATR) and 25 mg/kg pyridine-2-aldoxime methochloride (2-PAM). In addition, guinea pigs were given 0, 1, 2, 4, 8 or 10 mg/kg GAL as a post-exposure treatment immediately prior to ATR and 2-PAM. Animals were either monitored for 24-h survival, scheduled for electroencephalography (EEG) recording, or euthanized 60 min later for measurement of indirectly-elicited muscle tension in the hemidiaphragm. Post-exposure GAL therapy produced a dose-dependent increase in survival from lethal VX challenge. Optimal clinical benefits were observed in the presence of 10 mg/kg GAL, which led to 100% survival of VX-challenged guinea pigs. Based on muscle physiology studies, GAL post-exposure treatment protected the guinea pig diaphragm, the major effector muscle of respiration, from fatigue, tetanic fade, and muscular paralysis. Protection against the paralyzing effects of VX was dose-dependent. In EEG studies, GAL did not alter seizure onset for all doses tested. At the highest dose tested (10 mg/kg), GAL decreased seizure duration when administered as a post-exposure treatment 1 min after VX. GAL also reduced the high correlation associated between seizure activity and lethality after 2LD50 VX challenge. GAL may have additional benefits both centrally and peripherally that are unrelated to its established mechanism as a reversible acetylcholinesterase inhibitor (AChEI)

  10. Effect of Sarizotan, a 5-HT1a and D2-Like Receptor Agonist, on Respiration in Three Mouse Models of Rett Syndrome

    PubMed Central

    Abdala, Ana P.; Lioy, Daniel T.; Garg, Saurabh K.; Knopp, Sharon J.; Paton, Julian F. R.

    2014-01-01

    Disturbances in respiration are common and debilitating features of Rett syndrome (RTT). A previous study showed that the 5-HT1a receptor agonist (R)-(+)-8-hydroxy-dipropyl-2-aminotetralin hydrobromide (8-OH-DPAT) significantly reduced the incidence of apnea and the irregular breathing pattern in a mouse model of the disorder. 8-OH-DPAT, however, is not available for clinical practice. Sarizotan, a full 5-HT1a agonist and a dopamine D2–like agonist/partial agonist, has been used in clinical trials for the treatment of l-dopa–induced dyskinesia. The purpose of this study was to evaluate the effects of sarizotan on respiration and locomotion in mouse models of RTT. Studies were performed in Bird and Jaenisch strains of methyl-CpG–binding protein 2-–deficient heterozygous female and Jaenisch strain Mecp2 null male mice and in knock-in heterozygous female mice of a common nonsense mutation (R168X). Respiratory pattern was determined with body plethysmography, and locomotion was determined with open-field recording. Sarizotan or vehicle was administered 20 minutes before a 30-minute recording of respiratory pattern or motor behavior. In separate studies, a crossover design was used to administer the drug for 7 and for 14 days. Sarizotan reduced the incidence of apnea in all three RTT mouse models to approximately 15% of their pretreatment levels. The irregular breathing pattern was corrected to that of wild-type littermates. When administered for 7 or 14 days, apnea decreased to 25 to 33% of the incidence seen with vehicle. This study indicates that the clinically approved drug sarizotan is an effective treatment for respiratory disorders in mouse models of RTT. PMID:24351104

  11. Protective Role of Ashwagandha Leaf Extract and Its Component Withanone on Scopolamine-Induced Changes in the Brain and Brain-Derived Cells

    PubMed Central

    Singh, Rumani; Saxena, Nishant; Kaul, Sunil C.; Wadhwa, Renu; Thakur, Mahendra K.

    2011-01-01

    Background Scopolamine is a well-known cholinergic antagonist that causes amnesia in human and animal models. Scopolamine-induced amnesia in rodent models has been widely used to understand the molecular, biochemical, behavioral changes, and to delineate therapeutic targets of memory impairment. Although this has been linked to the decrease in central cholinergic neuronal activity following the blockade of muscarinic receptors, the underlying molecular and cellular mechanism(s) particularly the effect on neuroplasticity remains elusive. In the present study, we have investigated (i) the effects of scopolamine on the molecules involved in neuronal and glial plasticity both in vivo and in vitro and (ii) their recovery by alcoholic extract of Ashwagandha leaves (i-Extract). Methodology/Principal Findings As a drug model, scopolamine hydrobromide was administered intraperitoneally to mice and its effect on the brain function was determined by molecular analyses. The results showed that the scopolamine caused downregulation of the expression of BDNF and GFAP in dose and time dependent manner, and these effects were markedly attenuated in response to i-Extract treatment. Similar to our observations in animal model system, we found that the scopolamine induced cytotoxicity in IMR32 neuronal and C6 glioma cells. It was associated with downregulation of neuronal cell markers NF-H, MAP2, PSD-95, GAP-43 and glial cell marker GFAP and with upregulation of DNA damage- γH2AX and oxidative stress- ROS markers. Furthermore, these molecules showed recovery when cells were treated with i-Extract or its purified component, withanone. Conclusion Our study suggested that besides cholinergic blockade, scopolamine-induced memory loss may be associated with oxidative stress and Ashwagandha i-Extract, and withanone may serve as potential preventive and therapeutic agents for neurodegenerative disorders and hence warrant further molecular analyses. PMID:22096544

  12. Elevated expression of periostin in human osteoarthritic cartilage and its potential role in matrix degradation via matrix metalloproteinase-13

    PubMed Central

    Attur, Mukundan; Yang, Qing; Shimada, Kohei; Tachida, Yuki; Nagase, Hiroyuki; Mignatti, Paolo; Statman, Lauren; Palmer, Glyn; Kirsch, Thorsten; Beier, Frank; Abramson, Steven B.

    2015-01-01

    We investigated the role of periostin, an extracellular matrix protein, in the pathophysiology of osteoarthritis (OA). In OA, dysregulated gene expression and phenotypic changes in articular chondrocytes culminate in progressive loss of cartilage from the joint surface. The molecular mechanisms underlying this process are poorly understood. We examined periostin expression by immunohistochemical analysis of lesional and nonlesional cartilage from human and rodent OA knee cartilage. In addition, we used small interfering (si)RNA and adenovirus transduction of chondrocytes to knock down and up-regulate periostin levels, respectively, and analyzed its effect on matrix metalloproteinase (MMP)-13, a disintegrin and MMP with thrombospondin motifs (ADAMTS)-4, and type II collagen expression. We found high periostin levels in human and rodent OA cartilage. Periostin increased MMP-13 expression dose [1–10 µg/ml (EC50 0.5–1 μg/ml)] and time (24–72 h) dependently, significantly enhanced expression of ADAMTS4 mRNA, and promoted cartilage degeneration through collagen and proteoglycan degradation. Periostin induction of MMP-13 expression was inhibited by CCT031374 hydrobromide, an inhibitor of the canonical Wnt/β-catenin signaling pathway. In addition, siRNA-mediated knockdown of endogenous periostin blocked constitutive MMP-13 expression. These findings implicate periostin as a catabolic protein that promotes cartilage degeneration in OA by up-regulating MMP-13 through canonical Wnt signaling.—Attur, M., Yang, Q., Shimada, K., Tachida, Y., Nagase, H., Mignatti, P., Statman, L., Palmer, G., Kirsch, T., Beier, F., Abramson, A. B. Elevated expression of periostin in human osteoarthritic cartilage and its potential role in matrix degradation via matrix metalloproteinase-13. PMID:26092928

  13. Methamphetamine neurotoxicity in dopamine nerve endings of the striatum is associated with microglial activation.

    PubMed

    Thomas, David M; Walker, Paul D; Benjamins, Joyce A; Geddes, Timothy J; Kuhn, Donald M

    2004-10-01

    Methamphetamine intoxication causes long-lasting damage to dopamine nerve endings in the striatum. The mechanisms underlying this neurotoxicity are not known but oxidative stress has been implicated. Microglia are the major antigen-presenting cells in brain and when activated, they secrete an array of factors that cause neuronal damage. Surprisingly, very little work has been directed at the study of microglial activation as part of the methamphetamine neurotoxic cascade. We report here that methamphetamine activates microglia in a dose-related manner and along a time course that is coincident with dopamine nerve ending damage. Prevention of methamphetamine toxicity by maintaining treated mice at low ambient temperature prevents drug-induced microglial activation. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), which damages dopamine nerve endings and cell bodies, causes extensive microglial activation in striatum as well as in the substantia nigra. In contrast, methamphetamine causes neither microglial activation in the substantia nigra nor dopamine cell body damage. Dopamine transporter antagonists (cocaine, WIN 35,428 [(-)-2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane 1,5-naphthalenedisulfonate], and nomifensine), selective D1 (SKF 82958 [(+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide]), D2 (quinpirole), or mixed D1/D2 receptor agonists (apomorphine) do not mimic the effect of methamphetamine on microglia. Hyperthermia, a prominent and dangerous clinical response to methamphetamine intoxication, was also ruled out as the cause of microglial activation. Together, these data suggest that microglial activation represents an early step in methamphetamine-induced neurotoxicity. Other neurochemical effects resulting from methamphetamine-induced overflow of DA into the synapse, but which are not neurotoxic, do not play a role in this response.

  14. [Study of acetylsalicylic acid role in the potentiation of antiamnesic and neuroprotective properties of piracetam in rats with alloxan diabetes].

    PubMed

    Zhiliuk, V I; Levykh, A E; Mamchur, V I

    2013-01-01

    It has been established that prolonged alloxan-induced hyperglycemia in rats potentiates amnesic properties of scopolamine hydrobromide. It was characterized by shortening of the latent period by 44% (p<0,01) and by 47,7% (p<0,05) after 24 hours and on the 20th day of conditioned passive avoidance test. This effect was accompanied by increase in oxidative modification of proteins and nitric oxide synthesis in the cerebral cortex. Along with this, a significant enhancement of ADP- and collagen-induced platelet aggregation was observed. These processes may play the leading role in the development of cognitive deficit in diabetes. Meanwhile, co-administration of piracetam with acetylsalicylic acid was accompanied by an expressed antiamnetic potential - the reduction of early markers of proteins degradation (aldehydephenylhydrazones, APH) by 21,7% (p<0,05) and late markers of proteins degradation (ketonephenylhydrazones, KPH) by 23,8% (p<0,001) was noted. This combination was 15,7% (p<0,05) more active than piracetam according to the effect upon KPH. NO2-/NO3- level was also decreased by 30,3% (p<0,05) in comparison with alloxan-diabetic rats. The significant anti-platelet effect was observed: degree of collagen-induced platelet aggregation was reduced by 56,8% (p<0,01), ADP (5 μmol/l)-induced - by 31,7% (p<0,01), ADP (20 μmol/l)-induced - by 47,3% (p<0,01) as compared to the hyperglycemic rats. Such an increase in nootropic activity of piracetam may be assumed to be directly related to the ability of acetylsalicylic acid to improve microcirculation in the ischemic areas of the brain in diabetes and probably to its neuroprotective potential.

  15. Echinococcus granulosus infection in dogs in Sidi Kacem Province (North-West Morocco).

    PubMed

    Dakkak, A; El Berbri, I; Petavy, A F; Boué, F; Bouslikhane, M; Fassi Fihri, O; Welburn, S; Ducrotoy, M J

    2017-01-01

    This study was undertaken in the Province of Sidi Kacem in northwest Morocco between April 2010 and March 2011. The main objective of the study was to determine the prevalence of Echinococcus granulosus (Eg) infection in owned dogs. This province was selected as a case study because of the social conditions, geographic and climatic diversity making it a model representative of many parts of Morocco. The survey was carried out in 23 rural communes and in the 5 municipalities (urban districts) of the Province and sampling was undertaken in randomly selected households. A total of 273 owned dogs comprising 232 from the 23 rural communes (rural dogs) and 41 from the 5 municipalities (urban dogs) were tested. Arecoline hydrobromide purgation was selected as the diagnostic method of choice to enable visualisation of expelled worms by dog owners, thereby imparting messages on the transmission mode of Eg to humans and farm animals. Of the 273 dogs tested, purgation was effective in a total of 224 dogs (82.1%). The overall estimated prevalence of Eg infection was 35.3% (79/224, 95% CI 22.3-47.0%). Dogs inhabiting rural communes were at greater risk of infection (38.0%, 95% CI 31.1-45.3%) than dogs roaming in municipalities or urban areas (18.8%, 95% CI 7.2-36.4%) and the prevalence of infection was higher in those inhabiting rural communes with slaughterhouses (62.7%, 95% CI 48.1-75.9%) than in communes without (29.1%, 95% CI 21.7-37.2%). This first assessment of Eg infection in Sidi Kacem Province indicates a key role of rural slaughterhouses in parasite transmission to dogs.

  16. The injury of serotonin on intestinal epithelium cell renewal of weaned diarrhoea mice.

    PubMed

    Dong, Y; Yang, C; Wang, Z; Qin, Z; Cao, J; Chen, Y

    2016-12-28

    Diarrhoea is a common cause of death in children and weaned animals. Recent research has found that serotonin (5-HT) in the gastrointestinal tract plays an important role in regulating growth and the maintenance of mucosa, which protect against diarrhoea. To determine the influence of 5-HT on intestinal epithelium cell renewal under weaned stress diarrhoea, a weaned-stress diarrhoea mouse model was established with senna infusion (15 mL/Kg) via intragastric administration and stress restraint (SR). Mice with an increase in 5-HT were induced by intraperitoneal injection with citalopram hydrobromide (CH, 10 mg/Kg). The results demonstrated that compared with the control animals, diarrhoea appeared in weaned stress mice and the 5-HT content in the small intestine was significantly increased (P<0.05). Further, the caspase-3 cells and cells undergoing apoptosis in the small intestine were significantly increased, but the VH (villus height), V/C (villus height /crypt depth), and PCNA-positive rate significantly decreased. Compared with the control animals, CH increased the intestinal 5-HT content, caspase-3 cells and cells undergoing apoptosis but decreased the VH and V/C. Compared with both control and weaned stress animals, weaned stress animals that were pre-treated with CH showed higher 5-HT concentrations, positive caspase-3 cells and cells undergoing apoptosis but lower VH, V/C and PCNA-positive rate. In vitro, a low concentration of 5-HT inhibit, IEC-6 cell line apoptosis but a higher concentration of 5-HT promoted it. Therefore, weaned stress diarrhoea mice were accompanied by a 5-HT increase in the small intestine and vice versa, and the increase in 5-HT induced by CH caused diarrhoea. In brief, 5-HT and diarrhoea slowed the intestinal epithelium cell renewal and injured the abortion function and mucosal barrier by decreasing VH, V/C and proliferation and increasing epithelium cell apoptosis.

  17. Nicotine Ameliorates NMDA Receptor Antagonist-Induced Deficits in Contextual Fear Conditioning through High Affinity Nicotinic Acetylcholine Receptors in the Hippocampus

    PubMed Central

    André, Jessica M.; Leach, Prescott T.; Gould, Thomas J.

    2011-01-01

    NMDA glutamate receptors (NMDARs) and nicotinic acetylcholine receptors (nAChRs) are both involved in learning and synaptic plasticity. Increasing evidence suggests processes mediated by these receptors may interact to modulate learning; however, little is known about the neural substrates involved in these interactive processes. The present studies investigated the effects of nicotine on MK-801 hydrogen maleate (MK-801) and DL-2-Amino-5-phosphonovaleric acid (APV) induced disruption of contextual fear conditioning in male C57BL/6J mice, using direct drug infusion and selective nAChR antagonists to define the brain regions and the nAChR subtypes involved. Mice treated with MK-801 showed a deficit in contextual fear conditioning that was ameliorated by nicotine. Direct drug infusion demonstrated that the NMDAR antagonists disrupted hippocampal function and that nicotine acted in the dorsal hippocampus to ameliorate the deficit in learning. The high-affinity nAChR antagonist Dihydro-β-erythroidine hydrobromide (DhβE) blocked the effects of nicotine on MK-801-induced deficits while the α7 nAChR antagonist methyllycaconitine citrate salt hydrate (MLA) did not. These results suggest that NMDARs and nAChRs may mediate similar hippocampal processes involved in contextual fear conditioning. Furthermore, these results may have implications for developing effective therapeutics for the cognitive deficits associated with schizophrenia because a large subset of patients with schizophrenia exhibit cognitive deficits that may be related to NMDAR dysfunction and smoke at much higher rates than the healthy population, which may be an attempt to ameliorate cognitive deficits. PMID:21167848

  18. Accessibility of mid-segment domain IV S6 residues of the voltage-gated Na+ channel to methanethiosulfonate reagents

    PubMed Central

    Sunami, Akihiko; Tracey, Arlene; Glaaser, Ian W; Lipkind, Gregory M; Hanck, Dorothy A; Fozzard, Harry A

    2004-01-01

    The inner pore of the voltage-gated Na+ channel is predicted by the structure of bacterial potassium channels to be lined with the four S6 α-helical segments. Our previously published model of the closed pore based on the KcsA structure, and our new model of the open pore based on the MthK structure predict which residues in the mid-portion of S6 face the pore. We produced cysteine mutants of the mid-portion of domain IV-S6 (Ile-1575–Leu-1591) in NaV 1.4 and tested their accessibility to intracellularly and extracellularly placed positively charged methanethiosulfonate (MTS) reagents. We found that only two mutants, F1579C and V1583C, were accessible to both outside and inside 2-(aminoethyl)-methanethiosulfonate hydrobromide (MTSEA) Further study of those mutants showed that efficient closure of the fast inactivation gate prevented block by inside [2-(trimethylammonium)ethyl]methanethiosulfonate bromide (MTSET) at slow stimulation rates. When fast inactivation was inhibited by exposure to anthropleurin B (ApB), increasing channel open time, both mutants were blocked by inside MTSET at a rate that depended on the amount of time the channel was open. Consistent with the fast inactivation gate limiting access to the pore, in the absence of ApB, inside MTSET produced block when the cells were stimulated at 5 or 20 Hz. We therefore suggest that the middle of IV-S6 is an α-helix, and we propose a model of the open channel, based on MthK, in which Phe-1579 and Val-1583 face the pore. PMID:15579536

  19. Dopaminergic D2-like agonists produce yawning in the myelin mutant taiep and Sprague-Dawley rats.

    PubMed

    Eguibar, Jose R; Cortes, Ma del Carmen; Lara-Lozano, Manuel; Mendiola, Diana M

    2012-07-01

    Systemic administration of D2-like dopaminergic-receptor agonists increases yawning behavior. However, only a few studies have been done in animals with pathological conditions. The taiep rat is a myelin mutant with an initial hypomyelination followed by progressive demyelination, being the brainstem one of the most affected areas. In our experiments, we analyzed the effects of systemic administration of the D2-family agonists and antagonists on yawning behavior, and correlated them with the lipid myelin content in the brainstem and other areas in the central nervous system (CNS) in 8 month old male taiep and Sprague-Dawley rats. Subjects were maintained under standard conditions in Plexiglas cages with a 12:12 light-dark cycle, lights on at 0700 and free access to rodent pellets and tap water. Drugs were freshly prepared injected ip at 0800 and subjects were observed for 60 min. When antagonists were used it was administered 15 min before the agonist. Sprague-Dawley and taiep rats significantly increased their yawning frequency after systemic injection of (-)-quinpirole hydrochloride, R(+)-7-Hydroxy-2-(dipropylamino)tetralin hydrobromide (7-OH-DPAT) or trans-(±)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano [4,3-b]-1,4-oxazin-9-ol hydrochloride ((±)-PD 128,907). Among D2-like agonists used higher effects are obtained with (-)-quinpirole. The effects caused by (-)-quinpirole can be reduced by (-)-sulpiride; and yawning caused by 7-OH-DPAT was decreased by tiapride only in taiep rats. In Sprague-Dawley only (-)-sulpiride is able to decrease (-)-quinpirole-caused yawning. In conclusion, dopaminergic D2-like agonists are still able to cause yawning despite the severe myelin loss in taiep rats. Similarly, patients with various CNS illnesses that affect myelin, such as stroke or multiple sclerosis, are able to yawn suggesting that trigger neurons are still able to command this innate behavior.

  20. Pharmacokinetic Effects of Isavuconazole Coadministration With the Cytochrome P450 Enzyme Substrates Bupropion, Repaglinide, Caffeine, Dextromethorphan, and Methadone in Healthy Subjects

    PubMed Central

    Yamazaki, Takao; Desai, Amit; Goldwater, Ronald; Han, David; Howieson, Corrie; Akhtar, Shahzad; Kowalski, Donna; Lademacher, Christopher; Pearlman, Helene; Rammelsberg, Diane

    2016-01-01

    Abstract This report describes phase 1 clinical trials performed to assess interactions of oral isavuconazole at the clinically targeted dose (200 mg, administered as isavuconazonium sulfate 372 mg, 3 times a day for 2 days; 200 mg once daily [QD] thereafter) with single oral doses of the cytochrome P450 (CYP) substrates: bupropion hydrochloride (CYP2B6; 100 mg; n = 24), repaglinide (CYP2C8/CYP3A4; 0.5 mg; n = 24), caffeine (CYP1A2; 200 mg; n = 24), dextromethorphan hydrobromide (CYP2D6/CYP3A4; 30 mg; n = 24), and methadone (CYP2B6/CYP2C19/CYP3A4; 10 mg; n = 23). Compared with each drug alone, coadministration with isavuconazole changed the area under the concentration‐time curves (AUC∞) and maximum concentrations (Cmax) as follows: bupropion, AUC∞ reduced 42%, Cmax reduced 31%; repaglinide, AUC∞ reduced 8%, Cmax reduced 14%; caffeine, AUC∞ increased 4%, Cmax reduced 1%; dextromethorphan, AUC∞ increased 18%, Cmax increased 17%; R‐methadone, AUC∞ reduced 10%, Cmax increased 3%; S‐methadone, AUC∞ reduced 35%, Cmax increased 1%. In all studies, there were no deaths, 1 serious adverse event (dextromethorphan study; perioral numbness, numbness of right arm and leg), and adverse events leading to study discontinuation were rare. Thus, isavuconazole is a mild inducer of CYP2B6 but does not appear to affect CYP1A2‐, CYP2C8‐, or CYP2D6‐mediated metabolism. PMID:27273149