Comparison between Colistin Sulfate Dry Powder and Solution for Pulmonary Delivery

To assess the difference in the fate of the antibiotic colistin (COLI) after its pulmonary delivery as a powder or a solution, we developed a COLI powder and evaluated the COLI pharmacokinetic properties in rats after pulmonary administration of the powder or the solution. The amorphous COLI powder prepared by spray drying was characterized by a mass median aerodynamic diameter and fine particle fraction of 2.68 ± 0.07 µm and 59.5 ± 5.4%, respectively, when emitted from a Handihaler®. After intratracheal administration, the average pulmonary epithelial lining fluid (ELF): plasma area under the concentration versus time curves (AUC) ratios were 570 and 95 for the COLI solution and powder, respectively. However, the same COLI plasma concentration profiles were obtained with the two formulations. According to our pharmacokinetic model, this difference in ELF COLI concentration could be due to faster systemic absorption of COLI after the powder inhalation than for the solution. In addition, the COLI apparent permeability (Papp) across a Calu-3 epithelium model increased 10-fold when its concentration changed from 100 to 4000 mg/L. Based on this last result, we propose that the difference observed in vivo between the COLI solution and powder could be due to a high local ELF COLI concentration being obtained at the site where the dry particles impact the lung. This high local COLI concentration can lead to a local increase in COLI Papp, which is associated with a high concentration gradient and could produce a high local transfer of COLI across the epithelium and a consequent increase in the overall absorption rate of COLI.

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Facile Preparation of Liposomes-encapsulated Zn-DTPA from Soy Lecithin for Decorporation of Radioactive Actinides

Canadian Journal of Chemistry ◽

10.1139/cjc-2020-0340 ◽

2021 ◽

Author(s):

Manal Almalki ◽

Edward Lai ◽

Raymond Ko ◽

Chunsheng Li

Keyword(s):

Pulmonary Delivery ◽

Spherical Shape ◽

Hydrodynamic Diameter ◽

Cytotoxicity Test ◽

Soy Lecithin ◽

Short Period ◽

Pharmacokinetic Properties ◽

Facile Preparation ◽

In Vivo Cytotoxicity

Diethylenetriaminepentaacetic acid (DTPA) is an attractive decorporation agent that can enhance the excretion of radioactive actinides such as plutonium, americium, and curium after a radiological incident. However, DTPA is excreted in a short period of time after administration. Several formulations have been developed to improve DTPA pharmacokinetic properties. In this project, liposomes were prepared facilely from soy lecithin as a nanocarrier for pulmonary delivery of Zn-DTPA. Lipid hydration, reverse phase evaporation, and mechanical sonication were three methods evaluated for the preparation of liposomes-encapsulated Zn-DTPA. Mechanical sonication was the method of choice due to simple apparatus and facile preparation. Liposomes-encapsulated Zn-DTPA (lipo-Zn-DTPA) exhibited a hydrodynamic diameter of 178(±2) nm and a spherical shape. The loading capacity and encapsulation efficiency of Zn-DTPA were 41(±5) mg/g and 10(±1)%, respectively. Lyophilization of lipo-Zn-DTPA for extended storage did not affect the amount of encapsulated drug or damage the structure of liposomes. An in vivo cytotoxicity test confirmed no serious adverse effect of Zn-DTPA encapsulated lecithin liposomes in rats.

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The centriolar complex isolated from starfish spermatozoa

Journal of Cell Science ◽

10.1242/jcs.49.1.33 ◽

1981 ◽

Vol 49 (1) ◽

pp. 33-49 ◽

Cited By ~ 1

Author(s):

R. Kuriyama ◽

H. Kanatani

Keyword(s):

Gradient Centrifugation ◽

Sucrose Density Gradient ◽

Microtubule Assembly ◽

High Concentration ◽

Microtubule Organization ◽

Sucrose Density Gradient Centrifugation ◽

The Difference ◽

Distal Centriole

Centrioles from spermatozoa of the starfish, Asterina pectinifera, were isolated and partially purified by solubilization of chromatin followed by sucrose density-gradient centrifugation. The ultrastructure of the isolated centriolar complex was investigated in whole mount preparations by electron microscopy. The complex unit was composed of a pair of centrioles and a pericentriolar structure, which associated with the distal end of the distal centriole by 9 spoke-like satellites extending radially to a marginal ring. Each satellite bifurcated at a dense node forming 2 fan-like shapes with a periodic striated pattern. The tubular structure of the centrioles easily disintegrated, leaving the pericentriolar structure or axonemal microtubules intact. The distal centriole in a spermatozoon served as an initiating site for flagellar microtubule assembly; that is, a number of “9 + 2′ axonemal tubules were observed adhering just beneath the distal end of the basal body. In experiments in vitro, polymerization of microtubule proteins purified from porcine brain was initiated by the structure at the ends of both proximal and distal centrioles, but not from the satellites or the marginal ring. Also, few if any microtubules were formed from the sides of each centriole, even in the presence of a high concentration of exogenous tubulin. On the other hand, centrioles of spermatozoa, when they were in mature ooplasm, could initiate the formation of sperm asters by microtubules. Therefore, centrioles in spermatozoa seem to be able to initiate microtubules in a 2 ways. A possible explanation of the difference between the 2 types of microtubule organization in vivo, i.e. in the sperm cell itself and in the ooplasm, it discussed.

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β1 Tubulin Rather Than β2 Tubulin Is the Preferred Binding Target for Carbendazim in Fusarium graminearum

Phytopathology ◽

10.1094/phyto-09-15-0235-r ◽

2016 ◽

Vol 106 (9) ◽

pp. 978-985 ◽

Cited By ~ 14

Author(s):

Yujun Zhou ◽

Yuanye Zhu ◽

Yanjun Li ◽

Yabing Duan ◽

Rongsheng Zhang ◽

...

Keyword(s):

Amino Acid ◽

Fusarium Graminearum ◽

Amino Acid Sequence Identity ◽

Deletion Strain ◽

Protein Accumulation ◽

High Concentration ◽

Sequence Identity ◽

Increased Sensitivity ◽

The Difference

Tubulins are the proposed target of anticancer drugs, anthelminthics, and fungicides. In Fusarium graminearum, β2 tubulin has been reported to be the binding target of methyl benzimidazole carbamate (MBC) fungicides. However, the function of F. graminearum β1 tubulin, which shares 76% amino acid sequence identity with β2 tubulin, in MBC sensitivity has been unclear. In this study, MBC sensitivity relative to that of a parental strain (2021) was significantly reduced in a β1 tubulin deletion strain but increased in a β2 tubulin deletion strain, suggesting that β1 tubulin was involved in the MBC sensitivity of F. graminearum. When strain 2021 was grown in a medium with a low or high concentration of the MBC fungicide carbendazim (0.5 or 1.4 μg/ml), the protein accumulation levels were reduced by 47 and 87%, respectively, for β1 tubulin but only by 6 and 24%, respectively, for β2 tubulin. This result was consistent with observations that MBC fungicides are more likely to disrupt β1 tubulin microtubules rather than β2 tubulin microtubules in GFP-β tubulin fusion mutants in vivo. Furthermore, sequence analysis indicated that a difference in tubulin amino acid 240 (240L in β1 versus 240F in β2) may explain the difference in MBC binding affinity; this result was consistent with the result that an F240L mutation in β2 tubulin greatly increased sensitivity to carbendazim in F. graminearum. We suggest that β1 tubulin rather than β2 tubulin is the preferred binding target for MBC fungicides in F. graminearum.

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Pharmacokinetic Properties of Moracin C in Mice

Planta Medica ◽

10.1055/a-1321-1519 ◽

2021 ◽

Author(s):

Byoung Hoon You ◽

Melanayakanakatte Kuberappa BasavanaGowda ◽

Jae Un Lee ◽

Young-Won Chin ◽

Won Jun Choi ◽

...

Keyword(s):

Plasma Concentration ◽

Plasma Concentrations ◽

Disease Model ◽

Pharmacokinetic Parameters ◽

High Concentration ◽

In Vivo Evaluation ◽

Dosage Regimens ◽

Pharmacokinetic Properties ◽

Multiple Treatments

AbstractMoracin C from Morus alba fruits, also known as the mulberry, has been proven to exhibit inhibitory activities against lipoxygenase enzymes, TNF-α and interleukin-1β secretion, and proprotein convertase subtilisin/kexin type 9 expression. Despite the various pharmacological activities of moracin C, its pharmacokinetic characteristics have yet to be reported. Here, the pharmacokinetic parameters and tissue distribution of moracin C have been investigated in mice, and the plasma concentration of moracin C with multiple dosage regimens was simulated via pharmacokinetic modeling. Our results showed that moracin C was rapidly and well absorbed in the intestinal tract, and was highly distributed in the gastrointestinal tract, liver, kidneys, and lungs. Moracin C was distributed in the ileum, cecum, colon, and liver at a relatively high concentration compared with its plasma concentration. It was extensively metabolized in the liver and intestine, and its glucuronidated metabolites were proposed. In addition, the simulated plasma concentrations of moracin C upon multiple treatments (i.e., every 12 and 24 h) were suggested. We suggest that the pharmacokinetic characteristics of moracin C would be helpful to select a disease model for in vivo evaluation. The simulated moracin C concentrations under various dosage regimens also provide helpful knowledge to support its pharmacological effect.

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Albumin-binding Aptamer Chimeras for Improved siRNA Bioavailability

10.1101/2021.04.15.440012 ◽

2021 ◽

Author(s):

Jonah Rosch ◽

Ella Hoogenboezem ◽

Alexander Sorets ◽

Craig Duvall ◽

Ethan Lippmann

Keyword(s):

Rna Aptamers ◽

Albumin Binding ◽

High Concentration ◽

Biologic Drugs ◽

Pharmacokinetic Properties ◽

Target Disease ◽

Extended Circulation ◽

Exponential Enrichment

Short interfering RNAs (siRNAs) are potent nucleic acid-based drugs designed to target disease driving genes that may otherwise be undruggable with small molecules. However, the potential of administering therapeutic siRNA in vivo is limited by poor pharmacokinetic properties, including rapid renal clearance and nuclease degradation. Nanocarriers have traditionally been explored as means to overcome these challenges, but they have intrinsic downsides such as dose-limiting toxicity and synthetic complexity. Backpacking on natural carriers such as albumin, which is present at high concentration and has a long half-life in serum, is an effective way to modify pharmacokinetics of biologic drugs that otherwise have poor bioavailability. In this work, we sought to develop albumin-binding aptamer-siRNA chimeras to improve the bioavailability of siRNA. We used a Systematic Evolution of Ligands through Exponential Enrichment (SELEX) approach to obtain RNA aptamers with modified bases that bind albumin with high affinity. We then fused the aptamers directly to an siRNA to generate the chimera structure. These aptamer-siRNA chimeras are stable in serum, exhibit potent gene knockdown capabilities in vitro, and display extended circulation time in vivo. We suggest that this albumin-binding aptamer-siRNA chimera approach is a promising strategy for drug delivery applications.

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Platelet Reactivity In Vitro in Relation to Thromboxane in Healthy Pregnancy

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650272 ◽

1996 ◽

Vol 75 (02) ◽

pp. 346-351 ◽

Cited By ~ 3

Author(s):

E H Horn ◽

E Hardy ◽

J Cooper ◽

S Heptinstall ◽

P C Rubin

Keyword(s):

Arachidonic Acid ◽

Pregnant Women ◽

Biosynthetic Pathway ◽

Platelet Reactivity ◽

Platelet Rich Plasma ◽

High Concentration ◽

Increased Sensitivity ◽

The Difference

SummaryThere is substantial evidence of increased platelet reactivity in vivo and in vitro during pregnancy. Previous in vitro studies suggest that platelets from pregnant women show increased sensitivity to agonists, the response to which has a thromboxane dependent component. The aim of this study was to determine whether this is due to increased activity of the thromboxane biosynthetic pathway or to increased platelet sensitivity to the effects of thromboxane. During pregnancy, platelets were more sensitive to the pro-aggregatory effects in vitro of the thromboxane mimetic U46619, in whole blood and in platelet rich plasma, compared to those from non-pregnant controls. The difference in extent of U46619-induced platelet aggregation between groups was abolished in the presence of a high concentration of the specific thromboxane antagonist ICI 192605, but not by prior incubation of blood with aspirin. Platelets from pregnant women were significantly less sensitive to inhibition of arachidonic acid induced activation by the thromboxane synthetase inhibitor dazmegrel, but there was no change in platelet cyclic AMP accumulation under these conditions. Arachidonic acid induced platelet thromboxane B2 production was similar in pregnant and non-pregnant subjects. In conclusion, platelets are more sensitive to the activating effects of thromboxane during pregnancy, but there is no change in the intrinsic reactivity of the thromboxane biosynthetic pathway.

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Biological Obstacles for Identifying In Vitro-In Vivo Correlations of Orally Inhaled Formulations

Pharmaceutics ◽

10.3390/pharmaceutics11070316 ◽

2019 ◽

Vol 11 (7) ◽

pp. 316 ◽

Cited By ~ 6

Author(s):

Eleonore Fröhlich

Keyword(s):

Predictive Models ◽

Lung Diseases ◽

Pulmonary Delivery ◽

Oral Route ◽

In Vitro Models ◽

Epithelial Lining Fluid ◽

Oral Inhalation ◽

Inhaler Performance

Oral inhalation of drugs is the classic therapy of obstructive lung diseases. In contrast to the oral route, the link between in vitro and in vivo findings is less well defined and predictive models and parameters for in vitro-in vivo correlations are missing. Frequently used in vitro models and problems in obtaining in vivo values to establish such models and to identify the action of formulations in vivo are discussed. It may be concluded that major obstacles to link in vitro parameters on in vivo action include lack of treatment adherence and incorrect use of inhalers by patients, variation in inhaler performance, changes by humidity, uncertainties about lung deposition, and difficulties to measure drug levels in epithelial lining fluid and tissue. Physiologically more relevant in vitro models, improvement in inhaler performance, and better techniques for in vivo measurements may help to better understand importance and interactions between individual in vitro parameters in pulmonary delivery.

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Tem analysis of multiple-energy arsenic implanted and Rta'd silicon

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100126135 ◽

1987 ◽

Vol 45 ◽

pp. 246-247

Author(s):

R.A. Herring

Keyword(s):

Device Fabrication ◽

High Concentration ◽

Tem Analysis ◽

Defect Clusters ◽

High Fluences ◽

Small Defect ◽

Before And After ◽

The Matrix ◽

The Difference ◽

Factor Type

Rapid thermal annealing (RTA) of ion-implanted Si is important for device fabrication. The defect structures of 2.5, 4.0, and 6.0 MeV As-implanted silicon irradiated to fluences of 2E14, 4E14, and 6E14, respectively, have been analyzed by electron diffraction both before and after RTA at 1100°C for 10 seconds. At such high fluences and energies the implanted As ions change the Si from crystalline to amorphous. Three distinct amorphous regions emerge due to the three implantation energies used (Fig. 1). The amorphous regions are separated from each other by crystalline Si (marked L1, L2, and L3 in Fig. 1) which contains a high concentration of small defect clusters. The small defect clusters were similar to what had been determined earlier as being amorphous zones since their contrast was principally of the structure-factor type that arises due to the difference in extinction distance between the matrix and damage regions.

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Enhancement of ADP-induced Platelet Aggregation by Adrenaline in Vivo and Its Prevention

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647788 ◽

1973 ◽

Vol 29 (02) ◽

pp. 490-498 ◽

Cited By ~ 6

Author(s):

Hiroh Yamazaki ◽

Itsuro Kobayashi ◽

Tadahiro Sano ◽

Takio Shimamoto

Keyword(s):

Platelet Count ◽

Platelet Aggregation ◽

Platelet Rich Plasma ◽

The Other ◽

Endothelial Surface ◽

Important Interaction ◽

Blood Coagulability ◽

The Difference

SummaryThe authors previously reported a transient decrease in adhesive platelet count and an enhancement of blood coagulability after administration of a small amount of adrenaline (0.1-1 µg per Kg, i. v.) in man and rabbit. In such circumstances, the sensitivity of platelets to aggregation induced by ADP was studied by an optical density method. Five minutes after i. v. injection of 1 µg per Kg of adrenaline in 10 rabbits, intensity of platelet aggregation increased to 115.1 ± 4.9% (mean ± S. E.) by 10∼5 molar, 121.8 ± 7.8% by 3 × 10-6 molar and 129.4 ± 12.8% of the value before the injection by 10”6 molar ADP. The difference was statistically significant (P<0.01-0.05). The above change was not observed in each group of rabbits injected with saline, 1 µg per Kg of 1-noradrenaline or 0.1 and 10 µg per Kg of adrenaline. Also, it was prevented by oral administration of 10 mg per Kg of phenoxybenzamine or propranolol or aspirin or pyridinolcarbamate 3 hours before the challenge. On the other hand, the enhancement of ADP-induced platelet aggregation was not observed in vitro, when 10-5 or 3 × 10-6 molar and 129.4 ± 12.8% of the value before 10∼6 molar ADP was added to citrated platelet rich plasma (CPRP) of rabbit after incubation at 37°C for 30 second with 0.01, 0.1, 1, 10 or 100 µg per ml of adrenaline or noradrenaline. These results suggest an important interaction between endothelial surface and platelets in connection with the enhancement of ADP-induced platelet aggregation by adrenaline in vivo.

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Reliability of a Single β-Thromboglobulin Measurement in a Diabetic Population : Importance of PGE1 in Anticoagulant Mixture

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651094 ◽

1987 ◽

Vol 57 (02) ◽

pp. 201-204 ◽

Cited By ~ 2

Author(s):

P Y Scarabin ◽

L Strain ◽

C A Ludlam ◽

J Jones ◽

E M Kohner

Keyword(s):

In Vitro Release ◽

Mean Value ◽

Reliable Estimate ◽

Diabetic Patients ◽

Single Measurement ◽

Diabetic Population ◽

The Difference ◽

Vitro Release

SummaryDuring the collection of samples for plasma β-thromboglobulin (β-TG) determination, it is well established that artificially high values can be observed due to in-vitro release. To estimate the reliability of a single β-TG measurement, blood samples were collected simultaneously from both arms on two separate occasions in 56 diabetic patients selected for a clinical trial. From each arm, blood was taken into two tubes containing an anticoagulant mixture with (tube A) and without (tube B) PGE!. The overall mean value of B-TG in tube B was 1.14 times higher than in tube A (p <0.01). The markedly large between-arms variation accounted for the most part of within-subject variation in both tubes and was significantly greater in tube B than in tube A. Based on the difference between B-TG values from both arms, the number of subjects with artifically high B-TG values was significantly higher in tube B than in tube A on each occasion (overall rate: 28% and 14% respectively). Estimate of between-occasions variation showed that B-TG levels were relatively stable for each subject between two occasions in each tube. It is concluded that the use of PGEi decreases falsely high B-TG levels, but a single measurement of B-TG does not provide a reliable estimate of the true B-TG value in vivo.

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