scholarly journals Drug Exchange between Albumin Nanoparticles and Erythrocyte Membranes

Nanomaterials ◽  
2018 ◽  
Vol 9 (1) ◽  
pp. 47 ◽  
Author(s):  
Bilyana Tacheva ◽  
Boyana Paarvanova ◽  
Ivan Ivanov ◽  
Boris Tenchov ◽  
Radostina Georgieva ◽  
...  
Keyword(s):  
Critical Concentration ◽  
Erythrocyte Membranes ◽  
Erythrocyte Suspension ◽  
Physiological Conditions ◽  
Critical Concentrations ◽  
Albumin Nanoparticles ◽  
Drug Substances ◽  
Drug Concentrations ◽  
Low Concentrations ◽  
Biphasic Effect

The effects of thioridazine (TDZ) and chlorpromazine (CPZ) and bovine serum albumin nanoparticles (BSA-NPs) on erythrocyte membranes have been investigated. Two kinds of hemolytic assays were used; hemolysis under hypotonic conditions and hemolysis in physiological conditions. Under hypotonic conditions for 50% hemolysis, both TDZ and CPZ have a biphasic effect on membranes; namely, stabilization at low concentrations and destabilization after reaching a critical concentration. In physiological conditions, there are other critical concentrations above which both drugs hemolyse the erythrocites. In each case, the critical concentrations of TDZ are lower than those of CPZ, which is consistent with the ratio of their partition coefficients. When BSA-NPs are added to the erythrocyte suspension simultaneously with the drugs, the critical concentrations increase for both drugs. The effect is due to the incorporation of a portion of drug substances into the BSA-nanoparticles, which consequently leads to the decrease of the active drug concentrations in the erythrocyte suspension medium. Similar values of the critical concentrations are found when the BSA-NPs are loaded with the drugs before their addition to the erythrocyte suspension in which case the events of the partition are: desorption of the drug from BSA-NPs, diffusion through the medium, and adsorption on erythrocyte membranes. This result suggests that the drugs are not influenced by the processes of adsorption and desorption onto and out of the BSA-NPs, and that the use of BSA-NPs as drug transporters would allow intravenous administration of higher doses of the drug without the risk of erythrocyte hemolysis.

scholarly journals Bidirectional polymerization of G-actin on the human erythrocyte membrane.

1984 ◽  
Vol 98 (3) ◽  
pp. 1102-1110 ◽  
Author(s):  
S Tsukita ◽  
S Tsukita ◽  
H Ishikawa
Keyword(s):  
Erythrocyte Membrane ◽  
Actin Filaments ◽  
Critical Concentration ◽  
Experimental System ◽  
Opposite Polarity ◽  
Erythrocyte Membranes ◽  
Low Concentrations ◽  
Thin Section Electron Microscopy ◽  
Section Electron ◽  
Almost All

The directional polymerization of actin on the erythrocyte membrane has been examined at various concentrations of G-actin by thin-section electron microscopy. For this purpose, a new experimental system using single-layered erythrocyte membranes with the cytoplasmic surfaces freely exposed was developed. The preformed actin filaments did not bind with the cytoplasmic surface of the erythrocyte membranes. When the erythrocyte membranes were incubated at low concentrations (0.3 and 0.5 microM) of G-actin, greater than 80% of polymerized actin filaments pointed toward the membranes mainly in an end-on fashion, as judged by arrowhead formation with heavy meromyosin. At higher concentrations (2 and 4 microM) of G-actin, about half of the polymerized actin filaments were directed with arrowheads pointing toward the membranes, while the rest of the filaments showed the opposite polarity pointing away from the membranes. The majority of polymerized actin filaments formed loops at the points of attachment to the membranes. In contrast, when G-actin (2 and 4 microM) in the presence of cytochalasin B was polymerized into filaments, approximately 70% showed the polarity pointing away from the membrane mainly in an end-on fashion. To check the treadmilling phenomena, the erythrocyte membranes with bidirectionally polymerized actin filaments were further incubated with G-actin at the overall critical concentration. In this case, almost all (90%) of actin filaments showed the polarity with arrowheads pointing toward the membranes. The results obtained are discussed with special reference to the mode of association of actin filaments with the plasma membrane in general.

scholarly journals Aggregation of p-Nitrophenyl Alkanoates in Aqueous Solution. Limitations on Their Use as Substrates in Enzyme Model Studies

1973 ◽  
Vol 51 (21) ◽  
pp. 3494-3498 ◽  
Author(s):  
J. Peter Guthrie
Keyword(s):  
Aqueous Solution ◽  
Rate Constants ◽  
Critical Concentration ◽  
Solubility Limit ◽  
Modest Increase ◽  
Model Studies ◽  
Critical Concentrations ◽  
Low Concentrations ◽  
Enzyme Model ◽  
Hydrolysis Of

p-Nitrophenyl alkanoates are aggregated at extremely low concentrations in aqueous solution. Second-order rate constants for imidazole or hydroxide catalyzed hydrolysis are independent of ester concentration up to a critical concentration of ester, and then decrease with increasing ester concentration. The critical concentrations at 25 °C are: p-nitrophenyl hexanoate, 1 × 10−4 M; octanoate, 9.6 × 10−6 M; decanoate, 1.2 × 10−6 M. For the dodecanoate ester, the critical concentration was estimated as ca. 10−7 M. Addition of 10% methanol causes only a modest increase in the critical concentration. The critical concentration probably represents the solubility limit of the ester. The rate constants for the hydrolysis of the longer chain esters evaluated here are significantly larger than those in the literature, suggesting that the earlier work was done using conditions where the esters were aggregated.

scholarly journals In Vitro Synergistic Interactions of Isavuconazole and Echinocandins against Candida auris

Antibiotics ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 355
Author(s):  
Unai Caballero ◽  
Sarah Kim ◽  
Elena Eraso ◽  
Guillermo Quindós ◽  
Valvanera Vozmediano ◽  
...  
Keyword(s):  
Interaction Model ◽  
Antifungal Drugs ◽  
Health Concern ◽  
Candida Auris ◽  
Fungistatic Activity ◽  
Drug Concentrations ◽  
Low Concentrations ◽  
Wide Range ◽  
Time Kill

Candida auris is an emergent fungal pathogen that causes severe infectious outbreaks globally. The public health concern when dealing with this pathogen is mainly due to reduced susceptibility to current antifungal drugs. A valuable alternative to overcome this problem is to investigate the efficacy of combination therapy. The aim of this study was to determine the in vitro interactions of isavuconazole with echinocandins against C. auris. Interactions were determined using a checkerboard method, and absorbance data were analyzed with different approaches: the fractional inhibitory concentration index (FICI), Greco universal response surface approach, and Bliss interaction model. All models were in accordance and showed that combinations of isavuconazole with echinocandins resulted in an overall synergistic interaction. A wide range of concentrations within the therapeutic range were selected to perform time-kill curves. These confirmed that isavuconazole–echinocandin combinations were more effective than monotherapy regimens. Synergism and fungistatic activity were achieved with combinations that included isavuconazole in low concentrations (≥0.125 mg/L) and ≥1 mg/L of echinocandin. Time-kill curves revealed that once synergy was achieved, combinations of higher drug concentrations did not improve the antifungal activity. This work launches promising results regarding the combination of isavuconazole with echinocandins for the treatment of C. auris infections.

scholarly journals The conjugation of nonsteroidal anti-inflammatory drugs (NSAID) to small peptides for generating multifunctional supramolecular nanofibers/hydrogels

2013 ◽  
Vol 9 ◽  
pp. 908-917 ◽  
Author(s):  
Jiayang Li ◽  
Yi Kuang ◽  
Junfeng Shi ◽  
Yuan Gao ◽  
Jie Zhou ◽  
...  
Keyword(s):  
Amino Acids ◽  
Critical Concentration ◽  
Therapeutic Agents ◽  
Multiple Roles ◽  
Small Peptides ◽  
Covalent Linkage ◽  
Physiological Conditions ◽  
Racemic Ibuprofen ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

Here we report supramolecular hydrogelators made of nonsteroidal anti-inflammatory drugs (NSAID) and small peptides. The covalent linkage of Phe–Phe and NSAIDs results in conjugates that self-assemble in water to form molecular nanofibers as the matrices of hydrogels. When the NSAID is naproxen (1), the resultant hydrogelator 1a forms a hydrogel at a critical concentration (cgc) of 0.2 wt % at pH 7.0. Hydrogelator 1a, also acting as a general motif, enables enzymatic hydrogelation in which the precursor turns into a hydrogelator upon hydrolysis catalyzed by a phosphatase at physiological conditions. The conjugates of Phe–Phe with other NSAIDs, such as (R)-flurbiprofen (2), racemic flurbiprofen (3), and racemic ibuprofen (4), are able to form molecular hydrogels, except in the case of aspirin (5). After the conjugation with the small peptides, NSAIDs exhibit improved selectivity to their targets. In addition, the peptides made of D-amino acids help preserve the activities of NSAIDs. Besides demonstrating that common NSAIDs are excellent candidates to promote aromatic–aromatic interaction in water to form hydrogels, this work contributes to the development of functional molecules that have dual or multiple roles and ultimately may lead to new molecular hydrogels of therapeutic agents for topical use.

scholarly journals Combination Treatment with Hepatitis C Virus Protease and NS5A Inhibitors Is Effective against Recombinant Genotype 1a, 2a, and 3a Viruses

2012 ◽  
Vol 57 (3) ◽  
pp. 1291-1303 ◽  
Author(s):  
Judith M. Gottwein ◽  
Sanne B. Jensen ◽  
Yi-Ping Li ◽  
Lubna Ghanem ◽  
Troels K. H. Scheel ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Combination Therapy ◽  
Combination Treatment ◽  
Resistance Mutations ◽  
Adaptive Mutations ◽  
Genotype 1A ◽  
Drug Concentrations ◽  
Low Concentrations ◽  
Ns3 Protease

ABSTRACTWith the development of directly acting antivirals, hepatitis C virus (HCV) therapy entered a new era. However, rapid selection of resistance mutations necessitates combination therapy. To study combination therapy in infectious culture systems, we aimed at developing HCV semi-full-length (semi-FL) recombinants relying only on the JFH1 NS3 helicase, NS5B, and the 3′ untranslated region. With identified adaptive mutations, semi-FL recombinants of genotypes(isolates) 1a(TN) and 3a(S52) produced supernatant infectivity titers of ∼4 log10focus-forming units/ml in Huh7.5 cells. Genotype 1a(TN) adaptive mutations allowed generation of 1a(H77) semi-FL virus. Concentration-response profiles revealed the higher efficacy of the NS3 protease inhibitor asunaprevir (BMS-650032) and the NS5A inhibitor daclatasvir (BMS-790052) against 1a(TN and H77) than 3a(S52) viruses. Asunaprevir had intermediate efficacy against previously developed 2a recombinants J6/JFH1 and J6cc. Daclatasvir had intermediate efficacy against J6/JFH1, while low sensitivity was confirmed against J6cc. Using a cross-titration scheme, infected cultures were treated until viral escape or on-treatment virologic suppression occurred. Compared to single-drug treatment, combination treatment with relatively low concentrations of asunaprevir and daclatasvir suppressed infection with all five recombinants. Escaped viruses primarily had substitutions at amino acids in the NS3 protease and NS5A domain I reported to be genotype 1 resistance mutations. Inhibitors showed synergism at drug concentrations reportedin vivo. In summary, semi-FL HCV recombinants, including the most advanced reported genotype 3a infectious culture system, permitted genotype-specific analysis of combination treatment in the context of the complete viral life cycle. Despite differential sensitivity to lead compound NS3 protease and NS5A inhibitors, genotype 1a, 2a, and 3a viruses were suppressed by combination treatment with relatively low concentrations.

Electrical and Rheological Properties of Double Percolated Poly(methyl methacrylate)/Multiwalled Carbon Nanotube Nanocomposites

2007 ◽  
Vol 7 (11) ◽  
pp. 3847-3851 ◽  
Author(s):  
Sung-Hun Jin ◽  
Dai-Soo Lee
Keyword(s):  
Carbon Nanotube ◽  
Methyl Methacrylate ◽  
Rheological Properties ◽  
Critical Concentration ◽  
Threshold Concentration ◽  
Multiwalled Carbon Nanotube ◽  
Multiwalled Carbon ◽  
Poly Methyl Methacrylate ◽  
Critical Concentrations ◽  
Double Percolation

Electrical and rheological properties of nanocomposites based on poly(methyl methacrylate) (PMMA) and multiwalled carbon nanotube (MWCNT) were studied from view points of double percolation by adding crosslinked methyl methacrylate-butadiene-styrene (MBS) copolymer particles to lower percolation threshold concentration of MWCNTs. It was found that the critical concentrations of MWCNTs for the percolation in the nanocomposites decrease and then increase with increasing the MBS contents of the nanocomposites. It is postulated that the addition of MBS at low concentrations results in double percolation of MWCNT and the significant decrease of critical concentration for the percolations. However, adding MBS particles in large amounts results in limited space for the distribution of MWCNTs and less efficient dispersion of the MWCNTs and the increase of the critical concentrations of MWCNTs for the percolations. Rheological properties and change of Tgs reflect large interfacial areas in the well dispersed nanocomposite and were also interpreted to support the speculations for the effects of MBS contents and MWCNT concentrations of PMMA/MWCNT nanocomposites.

Ca2+ Uptake Coupled to Glycogen Phosphorolysis in the Glycogenolytic-Sarcoplasmic Reticulum Complex from Rat Skeletal Muscle

1996 ◽  
Vol 51 (7-8) ◽  
pp. 591-598 ◽  
Author(s):  
M. Nogues ◽  
A. Cuenda ◽  
F. Henao ◽  
C. Gutiérrez-Merino
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Glycogen Phosphorylase ◽  
Rat Skeletal Muscle ◽  
Subcellular Structure ◽  
Sequential Action ◽  
Physiological Conditions ◽  
Low Concentrations ◽  
Ischemic Muscle ◽  
Stimulation Of

Abstract The glycogenolytic-sarcoplasmic reticulum complex from rat skeletal muscle accumulates Ca2+ upon stimulation of glycogen phosphorolysis in the absence of added ATP. It is shown that an efficient Ca2+ uptake involves the sequential action of glycogen phosphorylase, phosphoglucomutase and hexokinase, which generate low concentrations of ATP (approximately 1 -2 μм) compartmentalized in the immediate vicinity of the sarcoplasmic reticulum Ca2+, Mg2+-ATPase (the Ca2+ pump). The Ca2+ uptake supported by glycogenolysis in this subcellular structure is strongly stimulated by micromolar concentrations of AMP, showing that the glycogen phosphorylase associated with this complex is in the dephosphorylated b form. The results point out that the flux through this compartmentalized metabolic pathway should be enhanced in physiological conditions leading to increased AMP concentrations in the sarcoplasm, such as long-lasting contractions and in ischemic muscle.

The Pharmacokinetics of Biologics: A Primer

2015 ◽  
Vol 33 (Suppl. 1) ◽  
pp. 61-69 ◽  
Author(s):  
Diane R. Mould
Keyword(s):  
Body Weight ◽  
Clinical Response ◽  
Half Life ◽  
Severe Disease ◽  
Concomitant Administration ◽  
European Medicines Agency ◽  
Drug Concentrations ◽  
Low Concentrations ◽  
Dose Metrics ◽  
Potential Factor

Monoclonal antibodies (MAbs) exhibit complex pharmacokinetics (PK) and pharmacodynamics (PD, response) against tumor necrosis factor (TNF). Many factors impact anti-TNF MAb PK, altering MAb clearance and therefore the half-life: albumin, weight (particularly, obesity), disease (severity, stage and co-morbidities) and concomitant administration of immunosuppressants (e.g. methotrexate). These factors can alter MAb exposure, impacting on the likelihood of clinical response. Formation of anti-drug antibodies (ADAs) is another potential factor that can affect MAb PK. Factors impacting the likelihood of developing ADA are classified as patient-related (concomitant immunosuppressants, prior ADA against other anti-TNF MAb) or product-related (structure, manufacturing process, aggregate formation, route of administration and dosing regimen). Repeated episodic exposure can induce ADAs, shortening the effective treatment interval. Avoiding intervals where anti-TNF MAbs are non-measurable is important for efficacy and may delay onset of ADAs. Thus, patients whose factors predispose them to having faster clearance (or short half-life) such as severe disease, low albumin or high body weight may need shorter dose intervals to reduce the likelihood of intermittent exposure. ADAs can have no effect or can impact efficacy through MAb binding, thus inhibiting its function or potentially causing hypersensitivity reactions (PD). ADA can also increase MAb clearance (PK). Because of their impact on MAb clearance, ADAs have been linked to lower serum drug concentrations, potentially negatively impacting clinical response. ADAs have been reported for biologics in most therapeutic areas. ADAs are well documented in clinical studies due to the Food and Drug Administration and the European Medicines Agency recommendations regarding testing and impact of immunogenicity. Lastly, the dose metrics (e.g. mg vs. mg/kg) can cause issues as well. MAbs such as infliximab are dosed on a mg/kg basis, which commonly results in low concentrations in patients with low body weight. Conversely MAbs such as adalimumab are administered as a flat (mg) dose, which can result in low concentrations in high weight patients.

Ascorbic Acid Catalyzes Nitric Oxide Production from Nitrite Ions.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1574-1574 ◽  
Author(s):  
Nathawut Sibmooh ◽  
Barbora Piknova ◽  
Alan N. Schechter
Keyword(s):  
Nitric Oxide ◽  
Ascorbic Acid ◽  
Rate Constant ◽  
Dehydroascorbic Acid ◽  
Nitrite Reduction ◽  
Erythrocyte Membranes ◽  
No Production ◽  
Ferrous Ions ◽  
Physiological Conditions ◽  
Ferrous Heme

Abstract We have previously shown that nitrite ions can be reduced by hemoglobin to nitric oxide (NO), a ubiquitous signaling molecule and potent vasodilator. Nitrite serves as a stable tissue and vascular source for NO production; the reduction reaction is maximal at about 50% oxygen saturation values and is enhanced at low pH but little is known about other effectors of this reaction. In the current work, we studied the effect of ascorbic acid on nitrite reduction under physiological conditions using chemiluminescence to quantify NO production. In physiological buffer, this reaction has a rate constant of about 1×10−5 M−1.s−1. Thus, a significant production of NO would likely occur in plasma only at pharmacological levels of ascorbic acid (> 1 mM) although lowering pH below 7.0 markedly enhances this reaction. Loading human erythrocytes with 0.5 mM dehydroascorbic acid, which is in redox equilibrium with ascorbic acid and which can significantly raise intracellular ascorbic acid levels, increased basal levels of nitrite ions from 42±9.0 nM to 98±56 nM. Uptake of nitrite ions into erythrocytes by incubation in 10 μM nitrite was increased about 1.5 fold by dehydroascorbic acid and the half-time of nitrite loss was slowed to the same extent. Ascorbic acid also reduced free ferric heme in erythrocytes and plasma to ferrous heme which catalyzed the reduction of nitrite to NO with a rate constant of 2.3×103 M−1.s−1 under physiological conditions. However, free ferrous ions did not significantly produce NO in physiological buffer (rate constant = 1.8×10−2 M−1.s−1). The reaction of ferrous heme with nitrite was not affected by heme binding to proteins such as hemopexin and albumin, or erythrocyte membranes. These results suggest that physiological levels of ascorbic acid (20–80 μM in plasma and erythrocytes) may act to catalyze NO production in the blood by promoting the reduction of nitrite ions by free ferrous heme and by increasing intra-erythrocytic levels of nitrite ions which can be reduced to NO by deoxyhemoglobin.

Observed differences in dextran and polyvinylpyrrolidone as rouleaux-inducing agents

1980 ◽  
Vol 58 (3) ◽  
pp. 271-274 ◽  
Author(s):  
Lionel S. Sewchand ◽  
Dieter Bruckschwaiger
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Animal Species ◽  
Critical Concentration ◽  
Rbc Membrane ◽  
Low Concentrations ◽  
High Concentrations ◽  
Induced Aggregation ◽  
Do So

The effectiveness of dextran fractions (Dx-500, Dx-100, Dx-70) and polyvinylpyrrolidone (PVP-360, PVP-40) in inducing aggregation of red blood cells (RBC) was studied in a nonflowing environment. The Dx fractions, at low concentrations, induced aggregation of human RBC but failed to do so at high concentrations (concentrations greater than 70 g/L). The effect was different on RBC from animal species (cat and rabbit); aggregation increased steadily with the Dx concentration and there was no critical concentration beyond which Dx failed to induce aggregation. The PVP was found to be very effective, at all concentrations, in inducing aggregation of RBC from both human and the animal species. These results have a twofold significance: (1) they suggest that Dx and PVP, both neutral polymers, interact differently with the human RBC membrane; and (2) the association of Dx with the human RBC membrane is different from that with cat and rabbit RBC membranes.

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