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PubMed2005

Controlled release of dexamethasone from microcapsules produced by polyelectrolyte layer-by-layer nanoassembly.

PURPOSE: In an effort to expand the application of core-shell structures fabricated by electrostatic layer-by-layer (LbL) self-assembling for drug delivery, this study reports the controlled release of dexamethasone from microcrystals encapsulated with a polyelectrolyte shell. METHODS: The LbL self-assembly process was used to produce dexamethasone particles encapsulated with up to five double layers formed by alternating the adsorption of positively charged poly(dimethyldiallyl ammonium chloride), negatively charged sodium poly(styrenesulfonate) and depending on the pH positively or negatively charged gelatin A or B onto the surface of the negatively charged dexamethasone particles. The nano-thin shells were characterized by quartz crystal microbalance measurements, microelectrophoresis, microcalorimetry, confocal microscopy, and scanning electron microscopy. In vitro release of dexamethasone from the microcapsules suspended in water or carboxymethylcellulose gels were measured using vertical Franz-type diffusion cells. RESULTS: Sonication of a suspension of negatively charged dexamethasone microcrystals in a solution of PDDA not only reduced aggregation but also reduced the size of the sub-micrometer particles. Assembly of multiple polyelectrolyte layers around these monodispersed cores produced a polyelectrolyte multilayer shell around the drug microcrystals that allowed for controlled release depending on the composition and the number of layers. CONCLUSIONS: Direct surface modification of dexamethasone microcrystals via the LbL process produced monodispersed suspensions with diffusion-controlled sustained drug release via the polyelectrolyte multilayer shell.

Capsules↗
PubMed1976

The effects of dexamethasone on plasma free androgens during the normal menstrual cycle.

In order to evaluate the ovarian and adrenal contribution to peripheral plasma concentrations of total testosterone (TTe), indixes of the plasma concentrations of free testosterone (FTeI), free 17 beta-hydroxysteroid androgens (FHSI), and testosterone-binding globulin (TeBG) during the menstrual cycle, women were examined during three normal cycles and three other cycles under dexamethasone (0.5 mg., four times a day) suppression. All study cycles were apparently ovulatory. The mean TTe and FTeI during the midcycle period were significantly higher than during the early follicular (P less than 0.005) and the midluteal periods (P less than 0.01 and P less than 0.001, respectively). During the menstrual cycles under dexamethasone suppression only the difference in TTe and FTeI between the midcycle (37 +/- 12.4 (S.D.) ng. per 100 ml. and 10.5 +/- 4.0 (S.D.), respectively) and the midluteal (26.0 +/- 10.1 (S.D.) ng. per 100 ml and 7.2 +/- 3.2 (S.D.), respectively) periods was significant statistically (P less than 0.05). No significant differences in the mean levels of FHSI and TeBG between three periods within the cycle were noted in either the control or the dexamethasone-treated cycle. When each phase was compared, the mean levels of TTe, FTel, and FSHI were significantly lower in the dexamethasone-treated cycles than in the normal cycles. The data suggest that the level of TeBG is not perceptibly affected by physiologic fluctuation of estrogen levels during the menstrual cycle, and the FHSI levels are stable throughout the ovulatory cycle. Decrease in levels of TTe, FTeI, and FHSI during dexamethasone suppression seems to be due to reduction of androgen production as TeBG, a major determinant of the metabolic clearance rate of androgens, was not affected by dexamethasone.

Adult↗
PubMed1983

Circadian patterns and dexamethasone-induced changes in uterine activity in pregnant rhesus monkeys.

Five monkeys with amniotic pressure catheters were placed in restraining chairs on days 127 to 131 of gestation (term = 167 days) for examination of circadian patterns in uterine activity. Uterine activity (total area under the contraction curve) was recorded continuously for 3- to 9-day intervals while the animals were exposed to a 16-hour:8-hour light:dark photoperiod. A ratio of hourly contraction area to mean hourly contraction area was established for each individual, and a circadian pattern was observed, with the occurrence of peak uterine activity between 2200 and 0200 hours (analysis of variance, P less than 0.01). An unrestrained animal equipped with a telemetry device and monitored for 23 days demonstrated a similar pattern. Four other catheterized, chair-restrained, pregnant monkeys were used to examine the effects of dexamethasone on uterine activity rhythms. After a 48-hour control period, dexamethasone (0.1 mg/hr) was infused via a maternal venous catheter for 48 hours. Fetal and maternal estrone and estradiol levels and total uterine activity were significantly reduced during dexamethasone infusion (P less than 0.05). In the 48 hours after dexamethasone infusion, mean uterine activity returned to preinfusion levels but the nocturnal peak remained ablated. Therefore, dexamethasone, alters the magnitude, as well as the circadian pattern, of uterine activity in association with reduced estrogen biosynthesis by the fetoplacental unit. Since the effect on uterine activity is biphasic, dexamethasone probably acts by more than one mechanism.

Animals↗
PubMed1985

Effect of dexamethasone treatment on sex steroid-binding protein, corticosteroid-binding globulin, and steroid hormones in cycling rhesus macaques.

We tested the hypothesis that dexamethasone lowers sex steroid-binding protein levels and observed the effect of dexamethasone on corticosteroid-binding globulin and specific steroid hormones in plasma. Four cycling rhesus macaques were studied during three consecutive menstrual cycles (first and third cycles served as controls). In the second cycle, each animal received 0.5 mg of dexamethasone intramuscularly at 8:00 AM and 8:00 PM daily for 21 consecutive days. Blood samples were taken at 1- to 3-day intervals during each cycle. Concentrations of sex steroid-binding protein, corticosteroid-binding globulin, cortisol, testosterone, progesterone, and estradiol were measured in plasma. The percentage and plasma concentration of free testosterone were also determined. Within 2 days of treatment, dexamethasone suppressed cortisol to 5% of baseline values, which returned in the third cycle. All cycles were ovulatory. Dexamethasone significantly lowered plasma levels of all the compounds except progesterone: sex steroid-binding protein, -30%; corticosteroid-binding globulin, -14%; testosterone, -36%; and estradiol, -45%. The percentage of free testosterone was significantly elevated, but free testosterone concentrations were unchanged. Although our data conclusively show that dexamethasone suppresses plasma sex steroid-binding protein levels in the rhesus macaque, it remains to be established whether this suppressive effect leads to an increase in the metabolic clearance rate of testosterone.

Animals↗
PubMed1983

Cooperative effect of 1 alpha,25-dihydroxyvitamin D3 and dexamethasone in inducing differentiation of mouse myeloid leukemia cells.

Murine myeloid leukemia cells (MI) are induced to differentiate into macrophages by the metabolically active form of vitamin D3,1 alpha,25-dihydroxyvitamin D3[1 alpha,25(OH)2D3] (E. Abe et al., (1981) Proc. Natl. Acad. Sci. USA 78, 4990-4994). At 0.12-120 nM, 1 alpha,25(OH)2D3 suppressed cell growth in a dose-dependent manner and markedly induced phagocytic activity, lysozyme activity, and C3-receptor formation. The potency of 1 alpha,25(OH)2D3, at 0.12-120 nM, in inducing differentiation was nearly equivalent to that of 10-10,000 nM of dexamethasone, one of the most potent stimulators of Ml cells. Simultaneous treatment with low physiological plasma concentrations of 1 alpha,25(OH)2D3 (0.12 nM) and dexamethasone (10 nM) induced differentiation of Ml cells equivalent to the responses obtained only by using much higher concentrations of the respective steroids when used separately. In addition, two variant clones of Ml cells resistant to either 1 alpha,25(OH)2D3 or dexamethasone were isolated. One was resistant to 120 nM of 1 alpha,25(OH)2D3 but sensitive to 10-1000 nM of dexamethasone. The other was resistant to 1000 nM of dexamethasone but sensitive to 12 nM of 1 alpha,25(OH)2D3. This suggests that the mechanism of action of 1 alpha,25(OH)2D3 in inducing differentiation of Ml cells is different at least in part from that of dexamethasone, and that combination therapy by both steroids may be useful in reducing leukemogenicity of Ml cells in vivo.

Animals↗
PubMed1984

Regulation of guinea pig macrophage collagenase production by dexamethasone and colchicine.

Previous studies have demonstrated that exposure of guinea pig macrophages to a primary signal, such as lipopolysaccharide (LPS), stimulates the synthesis of prostaglandin E2 (PGE2) which, in turn, elevates cAMP levels resulting in the production of the enzyme, collagenase. The potential of regulating the biochemical events in this activation sequence was examined with the anti-inflammatory agents dexamethasone and colchicine, which suppress the destructive sequelae in chronic inflammatory lesions associated with the degradation of connective tissue. The addition of dexamethasone with LPS to macrophage cultures resulted in a dose-dependent inhibition of PGE2 and collagenase production, which was reversed by the exogenous addition of phospholipase A2. Collagenase production was also restored in dexamethasone-treated cultures by the addition of products normally produced as a result of phospholipase action, such as arachidonic acid, PGE2 or dibutyryl-cAMP. Since the effect of dexamethasone was thus linked to phospholipase A2 inhibition, mepacrine, a phospholipase inhibitor, was also tested. Mepacrine, like dexamethasone, caused a dose-dependent inhibition of PGE2 and collagenase. In addition to corticosteroid inhibition, colchicine was also found to block collagenase production. However, this anti-inflammatory agent had no effect on PGE2 synthesis. Colchicine was effective only when added at the onset of culture and not 24 h later, implicating a role for microtubules in the transmission of the activation signal rather than enzyme secretion. The failure of lumicolchicine to inhibit collagenase activity provided additional evidence that microtubules are involved in the activation of macrophages. These findings demonstrate that dexamethasone and colchicine act at specific steps in the activation sequence of guinea pig macrophages to regulate collagenase production.

Animals↗
PubMed1988

Induction of alcohol dehydrogenase activity and mRNA in hepatoma cells by dexamethasone.

Liver alcohol dehydrogenase activity was present in rat H4IIE hepatoma cells. Dexamethasone increased the enzyme activity two- to fourfold in these cells, but not in HepG2 cells. Enzyme induction was observed at dexamethasone concentrations as low as 10(-9) M, and the induction was maximal at 3 days. The increase in enzyme activity was accompanied by an increase in alcohol dehydrogenase mRNA on Northern blots and a two- to fourfold increase in alcohol dehydrogenase mRNA levels as estimated from cytoplasmic dot blots. There was no effect of dexamethasone on alpha-tubulin mRNA levels. Insulin, triiodothyronine, and growth hormone had no effect on alcohol dehydrogenase activity or mRNA levels. The induction of alcohol dehydrogenase mRNA by dexamethasone could be blocked by actinomycin D, but not by protein synthesis inhibitors. Superinduction of the mRNA (approximately twofold) was observed with dexamethasone in the presence of cycloheximide. Southern blots of genomic DNA from rat liver and H4IIE cells revealed no differences in alcohol dehydrogenase gene structure. The induction of alcohol dehydrogenase activity and mRNA levels by dexamethasone may be due to an increase in the rate of transcription of the alcohol dehydrogenase gene.

Alcohol Dehydrogenase↗
PubMed1980

Fetal lung disaturated phosphatidylcholine. Ostensible increase following exposure to dexamethasone.

Fetal rat lung removed at 15 days gestation and placed in organ culture incorporates choline into phosphatidylcholine. Addition of 10(-9) M dexamethasone resulted in increased rates of choline incorporation per micrograms protein after both 6 and 12 days culture. This concentration of dexamethasone did not increase tissue phosphatidylcholine or disaturated phosphatidylcholine. Thus, at a culture time when dexamethasone had a significant effect on choline incorporation, there was no change in either the total phospholipid or disaturated phosphatidylcholine content of the lung tissue. The transplacental administration of dexamethasone decreased fetal lung DNA and phospholipid content. At the mid-range dosage tested (400 micrograms), dexamethasone depressed DNA (51%) appreciably more than total phosphatidylcholine (28%) and disaturated phosphatidylcholine (33%). These results show that the hormone does not increase the total amount of surfactant per lung. The increased disaturated phosphatidylcholine per mg DNA results in an ostensible beneficial effect of dexamethasone on surfactant and may reflect an increased proportion of Type II cells in fetal lung both in vitro and in vivo following hormone exposure. Disaturated phosphatidylcholine per Type II alveolar cell is no doubt increased but the trade-off is fewer total cells in the lung.

Animals↗
PubMed1981

Effect of dexamethasone upon surfactant phosphatidylcholine and phosphatidylglycerol synthesis in organotypic cultures of type II cells.

Organotypic cultures of pulmonary type II epithelial cells were treated with dexamethasone at concentrations between 10(-10) and 10(-5) M for 48 h followed by a 3 h incubation in 5.6 mM [U-14C]glucose. A surfactant and a residual fraction was isolated from the cultures by discontinuous sucrose gradient centrifugation. Phosphatidylcholine and phosphatidylglycerol were purified from each fraction and analyzed for total content. The specific activity of each phospholipid was measured as an index of the rate of synthesis. Dexamethasone treatment produced a dose-dependent increase in synthesis and content of surfactant phosphatidylcholine, with a maximum response occurring at 10(-6) M dexamethasone. At concentrations of 10(-5) M, dexamethasone ceased to produce a significant stimulation. Dexamethasone produced an increase in surfactant phosphatidylglycerol synthesis only at a concentration of 10(-8) M and higher. There was not a significant effect upon the content or rate of synthesis of phosphatidylcholine or phosphatidylglycerol in the residual fraction at any of the dexamethasone concentrations tested.

Animals↗
PubMed1982

Effect of dexamethasone on 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity and cholesterol synthesis in rat liver.

Dexamethasone increases reductase activity in cultured liver cells after a lag period of 2 h. The increases of activity are linear from 10(-9) to 10(-5) M dexamethasone, the maximum responses ranging from 2- to 4-fold. The increased reductase activity after dexamethasone treatment is not due to a change of the state of phosphorylation/dephosphorylation of the enzyme nor to an increase of cytosolic activating factor(s) for the reductase. Cholesterol synthesis, measured by incorporation of either [14C]acetate or 3H2O, increases 3-fold after dexamethasone (10(-6) M) treatment, as does the hydroxymethylglutaryl-CoA reductase activity, confirming that this enzyme is rate-controlling for cholesterol synthesis in cultured liver cells as it is in vivo. Dexamethasone (10 micrograms/100 g rat), given after onset of the light cycle, increases reductase activity over control rats at the nadir of the circadian cycle of this enzyme. When given after onset of the dark cycle, dexamethasone does not increase reductase activity over controls at the peak of their circadian cycle. Thus, physiologic doses of glucocorticoids partially reverse the decline in reductase activity due to the circadian rhythm.

Acetates↗
PubMed1991

Effect of cell density on induction of growth hormone receptors by dexamethasone in primary cultured rat hepatocytes.

The effect of cell density on the regulation of growth hormone (GH) receptors was studied by measuring specific binding of [125I]hGH to primary cultured hepatocytes with or without dexamethasone, which induces GH receptors. In cell cultures without dexamethasone, the cell density did not affect the level of binding of labeled GH appreciably. On the other hand, in the presence of dexamethasone, which induced an increase in the level of GH receptors on the cells, GH-binding by cultured cells at low cell density (3.3 x 10(4) cells/cm2) was about one-third of that of cells at high cell density (10(5) cells/cm2). Scatchard plot analysis showed that the cell-density dependent change in induction of GH binding, by dexamethasone was due to change in the number of binding sites without significant change in their affinity. The binding capacity of glucocorticoid receptors, measured as specific binding of [3H]dexamethasone to the hepatocytes, was not significantly affected by cell density. These results suggest that cell density modulates GH receptor induction by dexamethasone via events after glucocorticoid receptor binding.

Animals↗
PubMed1987

Plasma dexamethasone kinetics during the DST after oral and intravenous administration of the test drug.

We compared early biophase kinetics of dexamethasone in 33 patients with a major depression who received a DST either by an oral (n = 20) or an intravenous (n = 13) route. After an oral DST, the dexamethasone kinetics between 14 suppressors and 6 nonsuppressors were indistinguishable during the early distribution phase. However, elimination of dexamethasone from the circulation was significantly enhanced in DST nonsuppressors, resulting in an association of decreased plasma dexamethasone with elevated post-DST cortisol levels. Following intravenous DST administration, we identified 5 nonsuppressors and 8 suppressors whose plasma dexamethasone kinetics were indistinguishable, and during the elimination phase, were in the same order of magnitude as those of nonsuppressors after an oral DST. We suggest that the actual plasma concentration at the conventional post-DST sampling times does not reflect the biopotency of the test drug to suppress the pituitary adrenocortical activity. Plasma dexamethasone concentrations after an oral DST that were associated with nonsuppressed cortisol seem to be coherent phenomena of the underlying endocrine disturbance, the precise nature of which deserves further study.

Administration, Oral↗
PubMed1996

Depressive psychomotor disturbance, cortisol, and dexamethasone.

We examine the dexamethasone suppression test as a biological correlate of melancholia as defined by the CORE system, a scale for rating objective signs of psychomotor disturbance. Postdexamethasone cortisol concentrations and rates of nonsuppression were higher in CORE, Newcastle, and DSM-III-R defined melancholic groups. These differences, however, were no longer significant after partialling out the combined effects of age, dexamethasone, and basal cortisol concentrations. There was a significant correlation between the CORE (but not the Newcastle) scale and 8:00 AM postdexamethasone cortisol levels, which persisted after partialling out those same three covariates. Dexamethasone concentrations themselves were lower in CORE- and Newcastle-defined melancholics, though these were no longer significant after covarying for cortisol concentrations. Dexamethasone levels were also significantly inversely correlated with CORE and Newcastle scales. A significant correlation between CORE (but not Newcastle) scores and dexamethasone levels at 4:00 PM persisted after partialling out the effects of age and cortisol. These findings indicate an intriguing relationship between the CORE system as a dimensional construct for rating psychomotor disturbance, and both postdexamethasone cortisol and dexamethasone concentrations.

Age Factors↗
PubMed1993

Dexamethasone reduces vascular density and plasminogen activator activity in 9L rat brain tumors.

Angiogenesis, a process dependent upon perivascular proteolysis, is required for solid tumor growth and is inhibited by certain steroids including glucocorticoids. We examined the relationship between tumor growth and vessel density in experimental rat brain 9L glial tumors following chronic treatment with the glucocorticoid dexamethasone. Tumor growth was inhibited by intraperitoneal administration of 3 mg/kg/day dexamethasone. Maximal cross-sectional areas of post-implantation day 9 tumors were 4.6 +/- 1.0 mm2 in dexamethasone-treated animals and 17.0 +/- 3.4 mm2 in controls (P < 0.01). Microvessel density assessed by laminin immunohistochemistry was 59% lower in dexamethasone-treated tumors (P < 0.01). Plasminogen activator (PA) activity, a proteolytic enzyme related to endothelial migration and vessel growth, was 4.2 +/- 0.9 IU/micrograms protein in dexamethasone-treated tumors and 9.0 +/- 1.0 IU/micrograms protein in control tumors (P < 0.01). Exposure of cultured 9L and central nervous system microvessel endothelial cells to dexamethasone concentrations comparable to those achieved in vivo had no effect on cell growth, but reduced the PA activity of culture supernatant fractions by 78% and 99%, respectively. These findings suggest that inhibition of proteolytic steps involved in vessel growth may underlie, in part, the mechanism by which glucocorticoids decrease brain tumor growth.

Animals↗
PubMed1996

Monoamine oxidase B expression is selectively regulated by dexamethasone in cultured rat astrocytes.

The influence of dexamethasone on monoamine oxidase (MAO) A and B expression and activity was investigated in primary cultures of rat type 1 astrocytes cultured under serum free, defined conditions. Dexamethasone treatment resulted in a dose- and time-dependent induction of MAO-B, but not of MAO-A, activity. The selective MAO-B increase was substantially reduced by the antagonist RU 486, thus suggesting a glucocorticoid receptor-mediated action of the hormone. Kinetic analysis showed an increase in Vmax of MAO-B with no change in apparent K(m). The dexamethasone-induced selective rise in MAO-B activity appeared to be due to enhanced enzyme synthesis, since MAO-B mRNA was markedly increased by dexamethasone treatment and the recovery of MAO-B activity after its irreversible inhibition by deprenyl was more pronounced in the presence than in the absence of the hormone. Furthermore, the dexamethasone effect was abolished by the protein synthesis inhibitors actinomycin D or cycloheximide. The present study demonstrates that dexamethasone is able to selectively induce MAO-B in type 1 astrocytes and leads to speculation of a possible role for glucocorticoids in the increase in brain MAO-B associated with neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases.

Animals↗
PubMed1996

Effect of intrahippocampal dexamethasone on the levels of amino acid transmitters and neuronal excitability.

Direct effect of type-II corticosteroid receptor agonist dexamethasone on extracellular amino acid levels and neuronal excitability in the hippocampus was studied by simultaneous application of in vivo microdialysis and recording hippocampal evoked responses in freely moving male rats. Microdialysis probes and hippocampal recording electrodes were implanted to the CA1-CA3 regions of dorsal hippocampus. Local dexamethasone infusion via microdialysis resulted in a transient increase in glutamate level at 30 min, while glutamine decreased by 30-40% throughout the 180-min sampling period. Taurine increased by 50% and remained elevated up to 180 min. No significant changes were detected in extracellular concentration of asparagine, arginine, glycine, threonine, alanine and serine. In contrast, dexamethasone infusion to the striatum had no effect on the extracellular levels of amino acid transmitters. Effect of dexamethasone injected via microdialysis on the neural activity elicited by perforant path stimulation was a decrease in population spikes after 60 min starting dexamethasone infusion. Steroid effect on neural excitability was reversible. Our data indicate that local infusion of type-II receptor agonist dexamethasone has a complex effect in the hippocampus, starts with a change in extracellular glutamate and glutamine concentration and followed by a reduced synaptic excitability.

Adrenocorticotropic Hormone↗
PubMed1984

Autoradiographic localization of specific [3H]dexamethasone binding in fetal lung.

The cellular and subcellular localization of specific [3H]dexamethasone binding was examined in fetal mouse lung at various stages of development and in human fetal lung at 8 weeks of gestation using a rapid in vitro steroid incubation technique followed by thaw-mount autoradiography. Competition studies with unlabeled steroids demonstrate the specificity of [3H]dexamethasone labeling, and indicate that fetal lung mesenchyme is a primary glucocorticoid target during lung development. Quantitative binding studies, involving incubation of intact tissue with competing ligand and subsequent subcellular fractionation, show this to be specific, nuclear binding characteristic of glucocorticoid receptors. Autoradiographs of [3H]dexamethasone binding in lung tissue at early stages of development demonstrate that the mesenchyme directly adjacent to the more proximal portions of the bronchiolar network is heavily labeled. In contrast, the epithelium which will later differentiate into bronchi and bronchioles, is relatively unlabeled. Distal portions of the growing epithelium, destined to become alveolar ducts and alveoli, do show nuclear localization of [3H]dexamethasone. Because of the known importance of the mesenchyme in controlling lung development and the ability of glucocorticoids to stimulate lung development, these results suggest that many of the growth-promoting effects of glucocorticoids may be mediated through the mesenchyme. In addition, by utilizing a technique which allows the simultaneous examination of extracellular matrix components and [3H]dexamethasone binding, a relationship is observed between extensive mesenchymal [3H]dexamethasone binding and extensive extracellular matrix accumulation. Since glucocorticoids stimulate the synthesis of many extracellular matrix components, these results suggest a role for these hormones in affecting mesenchymal-epithelial interactions during lung morphogenesis.

Animals↗
PubMed1995

Dexamethasone and methylprednisolone affect rat peritoneal phagocyte chemiluminescence after administration in vivo.

Production of reactive oxygen compounds by peritoneal monocytes/macrophages was studied in rats exposed to dexamethasone or methylprednisolone in the drinking water. Luminol-amplified chemiluminescence was measured in preparations of peritoneal leukocytes activated ex vivo by serum opsonized zymosan, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) or phorbol 12-myristate 13-acetate (PMA). After dexamethasone administration for 1 day (approximately 0.13 mg/kg per 24 h) a significant reduction in chemiluminescence was found in cells stimulated with serum opsonized zymosan, while responses to fMLP and PMA stimulation were significantly reduced after 2 days. The maximal inhibition obtained after 5-8 days of dexamethasone administration (plasma levels < 5 nM) was 92.0 +/- 1.2%, 87.6 +/- 0.2% and 84.5 +/- 3.1% in cells stimulated with serum opsonized zymosan, fMLP and PMA, respectively. Administration of dexamethasone or methylprednisolone for 48 h gave a dose-dependent reduction of chemiluminescence. ED50 values of dexamethasone were estimated at 0.06-0.15 mg/kg for the different stimulators (plasma concentrations 5-10 nM). Estimated ED50 values for methylprednisolone were 35-36 mg/kg. Since the percentage of mononuclear phagocytes in the peritoneal cell population did not change significantly with dose or time of dexamethasone exposure, this study indicates that glucocorticoids have a depressive effect on the monocyte/macrophage 'respiratory burst' in vivo. The results are consistent with the hypothesis that these effects are mediated by glucocorticoid receptors. Although the pathway activated by serum opsonized zymosan was more rapidly inhibited than the fMLP- and PMA-activated pathways, the responses induced by the different stimulators were similarly affected, suggesting a modulation of common components in the activation pathways, possibly protein kinase C or the NADPH-oxidase complex, after administration of low pharmacological doses of glucocorticoids in vivo.

Animals↗