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Biomedical subjects

J K Ma

Publications and source records attributed to J K Ma.

90 records · Page 5Linked to original sources
PubMed1975

Drug-biomolecule interactions: fluorescence studies on interaction of aminonaphthalenesulfonic acid derivatives with serum albumins.

The binding of the three aminonaphthalenesulfonic acid derivatives to human and bovine serum albumins was studied by measuring the fluorescence enhancement of the compounds. The number of binding sites of human and bovine serum albumins for these compounds appears to be one and two, respectively, under the experimental conditions. As the molar ratio of the fluorescent compounds to bovine serum albumin increased, the binding sites appeared to increase for the compounds. The quenching of the native fluorescence of albumin was examined by the successive addition of methanolic solutions of these compounds. 1-Anilinonaphthalene-8-sulfonate quenched the protein fluorescence to a greater extent than the other compounds studied, indicating that 1-anilinonaphthalene-8-sulfonate molecules are bound more closely to the tryptophan residues of albumin. The finding that the three compounds did not quench the fluorescence of tryptophan dissolved in water indicates no direct molecular interaction between tryptophan and the three fluorescent probes. The driving force for binding may be due to the structural characteristics of the amino acid sequence surrounding the tryptophan residues.

Anilino Naphthalenesulfonates↗
PubMedDate not supplied

A cell-based drug delivery system for lung targeting: I. Preparation and pharmacokinetics.

A drug-loaded tumor cell (DLTC) system has been developed for lung metastasis-targeting drug delivery. Doxorubicin was loaded into B16-F10 murine melanoma cells (96 microg/10(6) cells). The loading process led to the death of all the carrier cells. The diameter of DLTC was 15.03+/-2.36 microm (mean +/- SD). The amount and rate of doxorubicin being released from the DLTC mainly depended on the drug loading and carrier cell concentration. Over a 6-month storage in phosphate buffered saline (PBS) at 4 degrees C, the decrease in intracellular drug concentration and the carrier cell number were less than 25% and 5%, respectively. After a bolus injection of 30 microg doxorubicin in either DLTC form or free solution into the mice tail veins, drug deposit in the lung from DLTC was 3.6-fold of that achieved by free drug solution. The latter resulted in higher drug content in liver and spleen. Extensive trypsinization of DLTC reduced its lung targeting effect by 30%, and the density of surface adhesion molecule GM3 on DLTC surface by 25%. In conclusion, this DLTC system demonstrated a lung-targeting activity that may be partially attributed to its specific surface characteristics.

Animals↗
PubMedDate not supplied

A cell-based drug delivery system for lung targeting: II. Therapeutic activities on B16-F10 melanoma in mouse lungs.

The in vitro and in vivo anticancer activities of doxorubicin-loaded B16-F10 murine melanoma cells (DLTC) were evaluated. DLTC showed similar growth-inhibitory effects against live B16-F10 cells with doxorubicin solution in cell culture system, with the IC50 of 0.11 microM and 0.17 microM, respectively. However, DLTC demonstrated higher effectiveness than the free solution in treating mouse lung cancer caused by live B16-F10 cells. Syngeneic C57BL mice were inoculated intravenously with live B16-F10 cells first, and then received daily treatment of intravenous injections of doxorubicin in either DLTC or free solution form. Compared with the control group treated with phosphate-buffered saline, DLTC eradicated almost all the lung cancer colonies (>99%), while the free solution form reduced the colonies by 61%, when the treatment was given at an early stage. If the treatment started after the establishment of micrometastatic colonies in the mouse lungs, DLTC and free solution treatment resulted in 85% and 30% cancer reduction, respectively. Additional experiments demonstrated that the reduction of lung cancer colonies by DLTC was related to the initial treatment time: the earlier the treatment, the greater the effect. In conclusion, DLTC showed better therapeutic outcomes than free solution form in treating lung cancer of our animal model.

Animals↗
PubMedDate not supplied

Binding of bisbenzylisoquinoline alkaloids to phosphatidylcholine vesicles and alveolar macrophages: relationship between binding affinity and antifibrogenic potential of these drugs.

A group of bisbenzylisoquinoline alkaloids has been shown to exhibit various degrees of effectiveness in preventing silica-induced fibrosis in animal models. The objective of the present study was to characterize the binding of several of these alkaloids to phosphatidylcholine vesicles and rat alveolar macrophages using fluorometric and equilibrium dialysis methods, respectively. The lipid binding affinity of these alkaloids was found to depend upon several structural factors including hydrophobic substitutions, chiral configurations, and double oxygen bridge-restricted confirmation of the benzylisoquinoline moieties. Tetrandrine, which is a highly effective agent in preventing fibrosis, showed strong binding to both lipid vesicles and alveolar macrophages. In contrast, certain analogues of tetrandrine such as curine and tubocurine, which have little or no effect on silicosis, exhibited only weak binding to lipid vesicles and almost no binding to cells. The moderate binding affinity of fangchinoline to vesicles and cells corresponded to a moderate effectiveness of the compound as an antifibrogenic agent. Methoxyadiantifoline, an alkaloid of unknown antifibrogenic potential, also exhibited high binding affinities for lipid and cells. In conclusion, the results of these studies indicate that alveolar macrophages exhibit large binding capacities for certain members of this class of bisbenzylisoquinoline alkaloids. A positive correlation was observed between binding affinity to alveolar macrophages and the reported antifibrotic potency of these compounds. These data also suggest that the ability of these drugs to interact with alveolar macrophages may be a key step in inhibition of the progression of silica-induced pulmonary disease.

1,2-Dipalmitoylphosphatidylcholine↗
PubMedDate not supplied

Inhibitory action of tetrandrine on macrophage production of interleukin-1 (IL-1)-like activity and thymocyte proliferation.

Tetrandrine is a bisbenzylisoquinoline alkaloid which has been shown to exhibit antifibrotic activity against silicosis. Tetrandrine is characterized by its strong binding to alveolar macrophages and inhibition of particle-induced respiratory burst activity in these phagocytes. In contrast, tubocurine and tubocurarine are structurally similar to tetrandrine but exhibit little effect on fibrosis or activation of alveolar macrophages. The objective of the present study was to test the effect of tetrandrine on macrophage production of monokines in response to occupational dusts, and to determine tetrandrine's effect on monokine-medicated cell growth using a mouse thymocyte proliferation assay and lipopolysaccharide (LPS) as a positive control. Stimulation of alveolar macrophages by respirable silica dust resulted in a release of monokines which caused a fourfold increase in thymocyte proliferation. Coal dust, on the other hand, had no effect on macrophage production of this cytokine. Tetrandrine was found to exhibit a dose-dependent inhibition of monokine release from both silica and LPS-stimulated alveolar macrophages. In experiments where thymocytes were directly treated with tetrandrine, a dose-dependent inhibition of thymocyte proliferation was noted with both interleukin-1-(IL-1) specific and nonspecific mitogenic (concanavalin A) actions. In contrast to the inhibitory potency of tetrandrine, tubocurarine was found to have no effect on either the production of monokines by LPS-stimulated alveolar macrophages or IL-1-mediated thymocyte proliferation. These results provide a correlation between the antifibrotic effect of tetrandrine and inhibition of macrophage activation.

Alkaloids↗
PubMedDate not supplied

Inhibition of respiratory burst activity in alveolar macrophages by bisbenzylisoquinoline alkaloids: characterization of drug-cell interaction.

The objective of this study was to investigate the effects of various bisbenzylisoquinoline (BBIQ) alkaloids on respiratory burst activity of alveolar macrophages and to characterize the interaction of these drugs with alveolar phagocytes. BBIQ alkaloids were chosen for study because they exhibit a wide range of antifibrotic potencies in a rat model, with tetrandrine being very effective and tubocurarine being ineffective. These drugs inhibited zymosan-stimulated oxygen consumption with a potency sequence of tetrandrine (TT) approximately fangchinoline (FA) > berbamine (BE) approximately cepharanthine (CE) approximately cycleanine (CY) >> tubocurarine (TU). This inhibition of respiratory burst activity could not be attributed to a drug-induced decline in the ATP content of these pneumocytes. Drug binding to alveolar macrophages was directly dependent on temperature and drug concentration. The sequence for binding capacity was FA > TT approximately BE approximately CY > CE >> TU. Therefore, there was no simple relationship between binding capacity and inhibitory potency. Binding capacity was not related to lipophilicity of these alkaloids. In addition, tetrandrine failed to bind to metabolically dead cells or sonicated macrophage preparations. These data suggest that the interaction of BBIQ alkaloids with phagocytes is not simply nonspecific binding to membrane lipids. Alteration of the cytoskeletal system with vinblastine, taxol, or cytochalasin B decreased tetrandrine binding by approximately 33% when added separately and by 93% when added jointly. Pre-exposure of alveolar macrophages to stimulants increased the ability of BBIQ alkaloids to inhibit both oxygen consumption and superoxide release. These data suggest that the mechanism by which BBIQ alkaloids inhibit activation of phagocytes involves microtubules and bules and microfilaments. Pre-exposure of macrophages to stimulants would change the conformation of cytoskeletal components and may make these structures more susceptible to drug interaction.

Adenosine Triphosphate↗
PubMedDate not supplied

Modification of alveolar macrophage function with bis-basic ethers of fluorene and fluoren-9-substituted derivatives.

Bis-basic ethers of fluorene and fluoren-9-substituted derivatives such as tilorone have been reported to inhibit silica-induced fibrosis in rats. The potential antifibrotic potency of 2,7-bis(diethylamino)ethoxy fluorene (F-9-H,H), fluorenone (F-9-one), fluorenoxime (F-9-oxime), and fluorenol (F-9-ol) was F-9-oxime > F-9-one approximately F-9-H,H >> F-9-ol. Since the release of reactive oxygen species and growth factors from alveolar macrophages (AM) in response to silica exposure has been linked to the development of pulmonary fibrosis, the present study was carried out to determine the inhibitory effects of these compounds on rat AM activity in vitro. The following parameters were monitored: (1) cellular viability; (2) zymosan-induced respiratory burst activity (superoxide and hydrogen peroxide release, chemiluminescence, and oxygen consumption) of AM; (3) drug binding to AM; and (4) lipopolysaccharide (LPS)-stimulated interleukin-1 (IL-1) release from AM. The bis-basic ethers, at 40 microM, did not affect cell viability when incubated with AM for 30 min, but significantly inhibited zymosan-induced macrophage respiratory burst activity. The inhibitory effect of these agents was F-9-oxime > F-9-one approximately F-9-H,H >> F-9-ol. Binding of these drugs to AM was time and dose dependent, and exhibited the following binding affinity: F-9-oxime > F-9-one > F-9-H,H > F-9-ol. F-9-oxime was shown to inhibit LPS-stimulated IL-1 release by AM in a dose-dependent manner. This inhibition of IL-1 release by AM cannot be explained as a decrease in viability. In addition, these drugs were also shown to impair human fibroblast proliferation in response to serum stimuli without impairing cell viability. These results indicate a positive correlation between drug binding to AM or other cell types and their inhibitory effects on cellular activities including oxygen consumption, superoxide release, hydrogen peroxide secretion, chemiluminescence, IL-1 release, and proliferation. The ability of these bis-basic ethers to modify AM and fibroblast functions in vitro suggests that further investigation of their reported antifibrotic potency in vivo is warranted.

Animals↗
PubMedDate not supplied

Effects of diesel exhaust particles on the release of interleukin-1 and tumor necrosis factor-alpha from rat alveolar macrophages.

The effects of diesel exhaust particles (DEP) and their components (washed dust and methanol extracts) on the release of proinflammatory cytokines, interleukin-I (IL-1), and tumor necrosis factor-alpha (TNF-alpha) by alveolar macrophages (AM) were investigated. Rat AM were incubated with 0, 5, 10, 20, 50, or 100 micrograms/10(6) AM/mL of DEP, methanol-washed DEP, or equivalent concentrations of DEP methanol extracts at 37 degrees C for 24 h. AM-conditioned supernatants were collected and assayed for the activities of IL-1 and TNF-alpha. At high concentrations both DEP and DEP methanol extracts were shown to increase IL-I-like activity secreted by AM, whereas methanol-washed DEP had no effect. Neither DEP, methanol-washed DEP, nor DEP methanol extracts was found to stimulate the secretion of TNF-alpha. The effects of DEP on the release of IL-I and TNF-alpha by lipopolysaccharide (LPS)- or interferon-gamma (IFN-gamma)-primed AM were also studied. AM were preincubated with various concentrations of DEP for 2 h, then challenged with either 0.1 microgram/mL of LPS or 5 units/mL of IFN-gamma. DEP inhibited LPS-stimulated production of H-I and TNF-alpha. These inhibitory effects were attributed to the organic extracts of DEP. In contrast, stimulation of AM production of TNF-alpha by IFN-gamma was not affected by DEP exposure. In summary, evidence that DEP enhanced the production of IL-1 by AM in vitro suggests that this proinflammatory cytokine may play a role in the pulmonary response to DEP inhalation. The suppressive response of DEP-pretreated AM to LPS stimulation may be a contributing factor to the impairment of pulmonary defense system after prolonged DEP exposure.

Animals↗
PubMedDate not supplied

Kinetics of drug release from polylactic acid-hydrocortisone microcapsules.

Polylactic acid microcapsules of similar particle size distribution containing various drug loadings of hydrocortisone were prepared. The microcapsules, which contained randomly dispensed drug particles, showed a dissolution pattern which consists of a fast first-stage and a slow second-stage drug release. Our studies showed that the kinetics of drug release from the microcapsules can be adequately described by a spherical matrix model based on a flux mechanism involving the diffusion of dissolved drug at the penetrating front of the dissolution medium. Drug loading played an important role in the control of drug release rate. An empirical relationship between drug loading and drug diffusibility through the polymeric matrix was developed and showed that the rate of drug release increased exponentially with the increase in drug loading. The microcapsules were further shown to exhibit increased rate of drug release in dissolution medium containing either cetylpyridium chloride or aerosol OT. The effect of the surfactants was attributed to surface tension lowering and improved wetting of the microcapsule particles.

Acetates↗
PubMedDate not supplied

Preparation and in vitro evaluation of polylactic acid-mitomycin C microcapsules.

An emulsion method was developed for the incorporation of water-soluble mitomycin C into polylactic acid biodegradable microcapsules. With an average particle size of about 95 microns, microcapsules with a desired loading of from 3.65 to 13.80 per cent were prepared. These microcapsules, which contained both crystalline and finely dispersed drug particles, showed a dose-dependent drug release pattern with microcapsules of higher drug loading having a faster release rate than those of lower drug loading. Effective sterilization of the microcapsules for parenteral use was achieved by 60Co gamma-ray irradiation, which did not affect the microcapsule structure, release rate or drug stability. Mitomycin C showed dose-dependent antiproliferative activity against the growth of the K562 human erythroleukaemia cells. The microencapsulated dosage form of mitomycin C was found to enhance the drug's activity through sustained drug release. In experiments where drug concentrations in the cell medium were reduced according to the drug's biological half-life, the microcapsule systems showed a distinct advantage over the non-capsulated dose for the kinetic inhibition of K562 cell growth.

Acetates↗
PubMedDate not supplied

Effect of surface active agents on drug release from polylactic acid-hydrocortisone microcapsules.

Polylactic acid microcapsules containing randomly distributed hydrocortisone particles were prepared. The rate of release of hydrocortisone from the microcapsules in pH 7.4 phosphate buffer was found to be largely increased by the presence of polysorbate 80, cetylpyridinium chloride, or aerosol OT in the dissolution medium. The surfactant effect was attributed to the ability of the surface active agent to improve solvent penetration into the microcapsules by lowering the surface tension at the solid-liquid interface. The effect of the cationic surfactant, cetylpyridinium chloride on the rate of drug release is similar in magnitude to that of the nonionic surfactant, polysorbate 80. In these systems, the rate of drug release from the microcapsules was found to be linearly related to the surface tension of the dissolution medium in the range of 40-60 dyn/cm (x 10(-3) N/m). In the same surface tension range, the effect of aerosol OT on rate increase was found to be much less than those of the cationic and nonionic surfactants. This suggests that the anionic surfactant is not well adsorbed at the interface due to the negative charge characteristics of the surface of the polylactic acid microcapsules. However, at nearly the critical micelle concentration of aerosol OT, where the corresponding surface tension is much lower than those of the cationic and nonionic surfactants, the microcapsules exhibited the highest rate of drug release.

Capsules↗
PubMedDate not supplied

A method for the preparation of polylactic acid microcapsules of controlled particle size and drug loading.

A solvent partition technique for the microencapsulation of hydrocortisone-polylactic acid has been developed for the preparation of microcapsules of controlled particle size distribution and drug loading. The method involves continuous injection of a drug-polymer solution with a syringe infusion pump into flowing mineral oil where microcapsules are formed as the solvent of the drug-polymer is partitioned into the mineral oil. Using preselected syringe needle size and mechanical control of the mineral oil flow rate at the needle tip, microcapsules of consistent particle sizes and desired drug loadings were prepared. Microcapsules of different internal structures were also prepared by varying the solvent system for the drug-polymer preparation. Dissolution studies showed that at the same drug loading, the rate of the percentage drug release increased with decreasing particle size, and that at similar particle size distributions, the rate increased with increasing drug loading. These results indicate that both the particle size distribution, and the drug loading must be controlled in a microencapsulation process to produce microcapsules of controlled drug release rate.

Capsules↗
PubMedDate not supplied

Strategies for the treatment of pneumoconiosis.

Regulatory control of dust in the workplace has greatly reduced the development of pneumoconiosis, yet the prevention of silicosis and coal workers' pneumoconiosis has not been accomplished. Cases of pneumoconiosis continue to occur, and there is no proven way to affect the natural history of these progressive inflammatory and fibrotic processes. Although pneumoconiosis and silicosis are considered untreatable in Western countries, in China an aggressive search has been underway for therapeutic agents and clinical procedures to treat these diseases. The important aspects are reviewed for the tried therapies, including corticosteroids, aluminum citrate complex, PVNO, tetrandrine, xinin, and whole lung lavage.

Adrenal Cortex Hormones↗