Role of benzyl alcohol in the unfolding and aggregation of interferon α-2a.


:Benzyl alcohol (BA) is the most widely used antimicrobial preservative in multidose protein formulations, and has been shown to cause protein aggregation. Our previous work on a model protein cytochrome c demonstrated that this phenomenon occurs via partial unfolding. Here, we examine the validity of these results by investigating the effect of BA on a pharmaceutically relevant protein, interferon α-2a (IFNA2). IFNA2 therapeutic formulations available on the pharmaceutical market contain BA as a preservative. Isothermal aggregation kinetics and temperature scanning demonstrated that BA induced IFNA2 aggregation in a concentration-dependent manner. With increasing concentration of BA, the apparent aggregation temperature of IFNA2 linearly decreased. Denaturant melts measured using protein intrinsic fluorescence and that of the 1-anilinonaphthalene-8-sulfonic acid dye indicated that IFNA2 stability decreased with increasing BA concentration, populating a partially unfolded intermediate. Changes in nuclear magnetic resonance chemical shifts and hydrogen exchange rates identified the structural nature of this intermediate, which correlated with an aggregation "hot-spot" predicted by computational methods. These results indicate that BA induces IFNA2 aggregation by partial unfolding rather than global unfolding of the entire protein, and is consistent with our earlier conclusions from model protein studies.


J Pharm Sci


Bis RL,Singh SM,Cabello-Villegas J,Mallela KM




Has Abstract


2015-02-01 00:00:00














  • Stabilization of human papillomavirus virus-like particles by non-ionic surfactants.

    abstract::Human papillomavirus (HPV) virus-like-particles (VLPs) produced by recombinant expression systems are promising vaccine candidates for prevention of cervical cancers as well as genital warts. At high protein concentrations, HPV VLPs, comprised of the viral capsid protein L1 and expressed and purified from yeast, are p...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Shi L,Sanyal G,Ni A,Luo Z,Doshna S,Wang B,Graham TL,Wang N,Volkin DB

    更新日期:2005-07-01 00:00:00

  • Modeling of transmitted X-ray intensity variation with sample thickness and solid fraction in glycine compacts.

    abstract::The previous paper in this series introduced an X-ray diffraction quantitation method for the polymorphic content in tablets made of pure components. Before the method could be transferred, further studies were required to explain the commonly observed X-ray intensity variation in analyzing compacts. The literature ty...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Cao W,Mullarney MP,Hancock BC,Bates S,Morris KR

    更新日期:2003-12-01 00:00:00

  • Relationship between the crystallization rates of amorphous nifedipine, phenobarbital, and flopropione, and their molecular mobility as measured by their enthalpy relaxation and (1)H NMR relaxation times.

    abstract::Isothermal crystallization of amorphous nifedipine, phenobarbital, and flopropione was studied at temperatures above and below their glass transition temperatures (T(g)). A sharp decrease in the crystallization rate with decreasing temperature was observed for phenobarbital and flopropione, such that no crystallizatio...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Aso Y,Yoshioka S,Kojima S

    更新日期:2000-03-01 00:00:00

  • GLC determination of lidocaine in human plasma.

    abstract::A specific, sensitive, rapid, and reproducible analytical GLC method for lidocaine in human plasma, including pharmacokinetic parameters, is described. Aminopyrine is the internal standard. The method was used to study pharmacokinetics in four healthy volunteers following the administration of a lidocaine bolus at a d...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Caille G,Lelorier J,Latour Y,Besner JG

    更新日期:1977-10-01 00:00:00

  • Protein Aggregation in Frozen Trehalose Formulations: Effects of Composition, Cooling Rate, and Storage Temperature.

    abstract::This study was designed to assess the effects of cooling rate, storage temperature, and formulation composition on trehalose phase distribution and protein stability in frozen solutions. The data demonstrate that faster cooling rates (>100°C/min) result in trehalose crystallization and protein aggregation as determine...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Connolly BD,Le L,Patapoff TW,Cromwell MEM,Moore JMR,Lam P

    更新日期:2015-12-01 00:00:00

  • Presentation of HIV-1 Envelope Trimers on the Surface of Silica Nanoparticles.

    abstract::Inducing immune responses protecting from HIV infection or at least controlling replication poses a huge challenge to modern vaccinology. An increasingly discussed strategy to elicit a potent and broad neutralizing antibody response is the immobilization of HIV's trimeric envelope (Env) surface receptor on a nanoparti...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Thalhauser S,Peterhoff D,Wagner R,Breunig M

    更新日期:2020-01-01 00:00:00

  • Dissolution of theophylline monohydrate and anhydrous theophylline in buffer solutions.

    abstract::The dissolution kinetics of theophylline monohydrate and anhydrous theophylline were investigated with a rotating-disk apparatus in buffer solutions at 298 K under sink conditions. The observed dissolution rate of theophylline monohydrate under various conditions agreed well with predictions based on the Extended Simu...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: de Smidt JH,Fokkens JG,Grijseels H,Crommelin DJ

    更新日期:1986-05-01 00:00:00

  • High-performance frontal analysis-high-performance liquid chromatographic system for stereoselective determination of unbound ketoprofen enantiomers in plasma after direct sample injection.

    abstract::An on-line, high-performance frontal analysis (HPFA)-high-performance liquid chromatographic system was developed for the enantioselective determination of a low level of unbound ketoprofen (KP) that is in equilibrium with KP that is bound to protein. The system consists of three subsystems (HPFA system, preconcentrat...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Shibukawa A,Terakita A,He JY,Nakagawa T

    更新日期:1992-07-01 00:00:00

  • Pharmacokinetics of methylphenidate in the rat using single-ion monitoring GLC-mass spectrometry.

    abstract::A GLC-mass spectrometric assay for methylphenidate in biological fluids was developed using the ethyl ester homolog of the drug as the internal standard. The procedure has a lower level of sensitivity of 1.2 ng/ml and is based on GLC-mass spectrometic monitoring of the m/e 180 ion common to the mass spectra of the N-t...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Gal J,Hodshon BJ,Pintauro C,Flamm BL,Cho AK

    更新日期:1977-06-01 00:00:00

  • Prediction of xanthine solubilities using statistical techniques.

    abstract::Mixture response-surface methodology can be used as a technique to predict solubility in mixed solvent systems. The present report shows that if the intent is to predict solubility in nonideal solutions, mixture response-surface methodology is a better technique than one which assumes a particular mechanism to hold tr...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Ochsner AB,Belloto RJ Jr,Sokoloski TD

    更新日期:1985-02-01 00:00:00

  • Effects of phenobarbital on the distribution pharmacokinetics and biological half-lives of model nonmicrosomal enzyme metabolizable sulfonamides in rats.

    abstract::The pharmacokinetics of sulfisoxazole and sulfanilamide were studied in control rats and in rats treated for 5 days with a daily 100 mg/kg ip dose of phenobarbital. These drugs represent the organic anionic and nonionized drugs, respectively, whose nonmicrosomal enzymatic metabolisms were unstimulated by phenobarbital...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Nagwekar JB,Kundu S

    更新日期:1982-04-01 00:00:00

  • Effect of certain drugs in perfused human placenta XII: autacoid antagonism by phenothiazines.

    abstract::The effects of chlorpromazine, prochlorperazine, and trifluoperazine on the pressor actions of serotonin, angiotensin, and bradykinin in the perfused vessels of full-term human placentas were investigated. A significant inhibition of the effect of serotonin was observed with trifluoperazine and chlorpromazine but not ...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Wolstenholme WW,Gautieri RF

    更新日期:1976-10-01 00:00:00

  • Molecular Dynamics of Amorphous Sulfamethazine With Structurally Related Sulfonamide Impurities Evaluated Using Thermal Analysis.

    abstract::In this study, the effects of structurally related organic impurities on the molecular dynamics of amorphous sulfamethazine were evaluated using thermal analysis. Sulfanilamide (SNA), sulfamerazine (SMR), and sulfadimethoxine were used as virtual impurities of sulfamethazine. The amorphous state was prepared in situ i...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Hamada Y,Ono M,Ohara M,Yonemochi E

    更新日期:2017-04-01 00:00:00

  • Determination of diphenoxylate hydrochloride and atropine sulfate in solutions and tablets.

    abstract::Methods for the determination of diphenoxylate hydrochloride and atropine sulfate combinations in solutions and powdered tablet composites are presented. A semiautomated assay for diphenoxylate hydrochloride in individual tablets (content uniformity) also is presented. The USP XIX assays for these products are cumbers...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Ballbach RL,Brown DJ,Walters SM

    更新日期:1977-11-01 00:00:00

  • Non-invasive systemic drug delivery: developability considerations for alternate routes of administration.

    abstract::Over the past few decades alternate routes of administration have gained significant momentum and attention, to complement approved drug products, or enable those that cannot be delivered by the oral or parenteral route. Intranasal, buccal/sublingual, pulmonary, and transdermal routes being the most promising non-inva...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章,评审


    authors: Mathias NR,Hussain MA

    更新日期:2010-01-01 00:00:00

  • Nonadditive Effects of Repetitive Administration of Lipoplexes in Immunocompetent Mice.

    abstract::Repetitive administration is routinely used to maintain therapeutic drug levels, but previous studies have documented an accelerated blood clearance of some lipid-based delivery systems under these conditions. To assess the effect of repetitive administration, non-PEGylated lipoplexes (+/-0.5) were administered 4 time...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Betker JL,Anchordoquy TJ

    更新日期:2017-03-01 00:00:00

  • Sensitive radioimmunoassay and enzyme-linked immunosorbent assay for the simultaneous determination of chloroquine and its metabolites in biological fluids.

    abstract::Two new methods for the simultaneous determination of chloroquine and its two main metabolites (monodesethylchloroquine and bisdesethylchloroquine) in biological samples, radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA), are described. Antiserum is produced in rabbits immunized with N-(2-carboxyeth...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Escande C,Chevalier P,Verdier F,Bourdon R

    更新日期:1990-01-01 00:00:00

  • Isolation of cannabisativine, an alkaloid, from Cannabis sativa L. root.

    abstract::An ethanol extract of the root of a Mexican variant of Cannabis sativa L.(marijuana) afforded, after partitioning and chromatography, the new spermidine alkaloid cannabisativine. ...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Turner CE,Hsu MH,Knapp JE,Schiff PL Jr,Slatkin DJ

    更新日期:1976-07-01 00:00:00

  • Effect of food on the bioavailability of lisinopril, a nonsulfhydryl angiotensin-converting enzyme inhibitor.

    abstract::A randomized, two-way, crossover study was performed on 18 normal volunteers to assess the influence of food on the bioavailability of lisinopril, (1-[N2-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl]-L-proline), a long-acting nonsulfhydryl angiotensin converting enzyme inhibitor. A single, 20-mg oral dose of lisinopril was ...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Mojaverian P,Rocci ML Jr,Vlasses PH,Hoholick C,Clementi RA,Ferguson RK

    更新日期:1986-04-01 00:00:00

  • Coloaded Nanoparticles of Paclitaxel and Piperlongumine for Enhancing Synergistic Antitumor Activities and Reducing Toxicity.

    abstract::The purpose of this study was to develop a nanocarrier system for codelivery of paclitaxel (PTX) and piperlongumine (PL) and investigate the therapeutic potential of improving efficacy and reducing toxicity. PTX and PL were formulated into poly lactic-co-glycolic acid and D-α-tocopheryl polyethylene glycol succinate v...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Liu Q,Zhao D,Zhu X,Chen H,Yang Y,Xu J,Zhang Q,Fan A,Li N,Guo C,Kong Y,Lu Y,Chen X

    更新日期:2017-10-01 00:00:00

  • Reevaluation of the absorption of carbenoxolone using an in situ rat intestinal technique.

    abstract::The absorption of the model drug carbenoxolone was reevaluated using an in situ rat intestinal perfusion technique in which disappearance from the intestinal lumen, binding to the perfused jejunal segment, and appearance in the mesenteric (jejunal) vein were measured. The effect of the degree of ionization on these pr...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Blanchard J,Tang LM,Earle ME

    更新日期:1990-05-01 00:00:00

  • Bulk Dynamic Spray Freeze-Drying Part 2: Model-Based Parametric Study for Spray-Freezing Process Characterization.

    abstract::Spray freeze-drying is an evolving technology that combines the benefits of spray-drying and conventional lyophilization techniques to produce drug substance and drug product as free-flowing powders. The high surface-to-volume ratio associated to the submillimeter spray-frozen particles contributes to shorter drying a...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Sebastião IB,Bhatnagar B,Tchessalov S,Ohtake S,Plitzko M,Luy B,Alexeenko A

    更新日期:2019-06-01 00:00:00

  • Design and optimization of self-nanoemulsifying delivery system to enhance quercetin hepatoprotective activity in paracetamol-induced hepatotoxicity.

    abstract::The present study aimed to develop optimized quercetin (QT)-loaded self-nanoemulsifying drug delivery system (SNEDDS) that offers protective effect against liver damage. Solubility study of QT in different oils, surfactants, and cosurfactants was performed. Ternary phase mixtures of the selected components were constr...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Ahmed OA,Badr-Eldin SM,Tawfik MK,Ahmed TA,El-Say KM,Badr JM

    更新日期:2014-02-01 00:00:00

  • High-performance liquid chromatographic determination of propranolol and 4-hydroxypropranolol in plasma.

    abstract::A high-performance liquid chromatographic method for the simultaneous determination of propranolol and 4-hydroxypropranolol in plasma is presented. The method involves plasma extraction at basic pH with ethyl column, and fluorescence detection. The within-run a reversed-phase column coefficient of variation were 3.0-7...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Rosseel MT,Bogaert MG

    更新日期:1981-06-01 00:00:00

  • Mechanisms of corneal drug penetration. I: In vivo and in vitro kinetics.

    abstract::Corneal penetration studies were conducted in unanesthetized albino rabbits using various organic compounds representing both polar and nonpolar species. Very low molecular weight compounds demonstrate rapid uptake into the aqueous humor despite the lipid-like barrier imposed by the corneal epithelium. Evidence that t...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Grass GM,Robinson JR

    更新日期:1988-01-01 00:00:00

  • Synthesis and characterization of surface-hydrophobic ion-exchange microspheres and the effect of coating on drug release rate.

    abstract::Biodegradable, dextran-based ion-exchange microspheres (IE-MS) have been used for localized delivery of anticancer drugs and chemosensitizers. Because of their hydrophilic nature, the IE-MS release their payload quickly. The purpose of this work was to develop an IE-MS system that could provide a broad range of releas...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Liu Z,Wu XY,Ballinger JR,Bendayan R

    更新日期:2000-06-01 00:00:00

  • Thermodynamic Evaluation of the Interaction Driven by Hydrophobic Bonding in the Aqueous Phase.

    abstract::In the present study, the interaction between phenobarbital and activated carbons which is driven by hydrophobic bonding was evaluated. The Two-Mechanism Langmuir-Like Equation was proposed to describe the isotherms for phenobarbital adsorbing to activated carbons. The parameters in the Two-Mechanism Langmuir-Like Equ...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Yu P,Wurster DE

    更新日期:2019-01-01 00:00:00

  • Graphical approach for determining whether absorption and elimination rate constants are equal in the one-compartment open model with first-order processes.

    abstract::An equation was developed which enables blood level data to be utilized for determining whether or not the first-order absorption and elimination rate constants are equal in the one-compartment open model. This equation was tested using simulated data with excellent results. ...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Macheras PE

    更新日期:1985-05-01 00:00:00

  • Liposomal subunit vaccines: effects of lipid A and aluminum hydroxide on immunogenicity.

    abstract::Protein and peptide antigens frequently are only slightly immunogenic when utilized alone in vaccines. Formulation of these antigens in a carrier vehicle, particularly when an adjuvant is included, often results in markedly enhanced immune responses. Encapsulation of peptide and protein antigens in liposomes generally...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Richards RL,Alving CR,Wassef NM

    更新日期:1996-12-01 00:00:00

  • Molecular structure and gas chromatographic retention behavior of the components of Ylang-Ylang oil.

    abstract::Using quantitative structure-retention relationships (QSRR) methodologies the Kovats gas chromatographic retention indices for both apolar (DB-1) and polar (DB-Wax) columns for 48 compounds from Ylang-Ylang essential oil were empirically predicted from calculated and experimental data on molecular structure. Topologic...

    journal_title:Journal of pharmaceutical sciences

    pub_type: 杂志文章


    authors: Olivero J,Gracia T,Payares P,Vivas R,Díaz D,Daza E,Geerlings P

    更新日期:1997-05-01 00:00:00