Stability profiling and degradation products of dihydromyricetin in Dulbecco's modified eagle's medium.

Dihydromyricetin has shown many bioactivities in cell level. However, dihydromyricetin was found to be highly instable in cell culture medium DMEM. Here, the underlying degradation mechanism was investigated via UPLC-MS/MS analysis. Dihydromyricetin was mainly converted into its dimers and oxidized products. At lower temperature, dihydromyricetin in DMEM showed higher stability. Vitamin C increased the stability of dihydromyricetin in DMEM probably due to its high antioxidant potential.

Dietary polyphenols and type 2 diabetes: current insights and future perspectives.

Significant evidence suggests that polyphenol-rich diets have the ability to protect against diabetes. Since several previous reviews focused on the nutrition and health effects including type 2 diabetes of polyphenols in 2007-2008, a number of related original publications have been pulished in this field. This review summarizes important advances related to influence of dietary polyphenols and polyphenol-rich diets on preventing and managing type 2 diabetes, as well as diabetes-mediated changes in bioactivities of dietary polyphenols. It appears that anthocyanins or anthocyanin-rich food intake is related to the risk of type 2 diabetes, but there is no association for other polyphenol subclasses. It is discussed that procyanidins are more active when administered individually than when mixed with food. The benefits of dietary polyphenols for type 2 diabetes can be summarized as: protection of pancreatic ß-cells against glucose toxicity, anti-inflammatory and antioxidant effects, inhibition of α-amylases or α- glucosidases and thus decrease of starch digestion, and inhibition of advanced glycation end products formation. Moreover, type 2 diabetes also significantly influences the benefits of dietary polyphenols, although there are very limited studies have been conducted so far. How type 2 diabetes impacts the pharmacology of dietary polyphenols is not well understood. Comprehension of type 2 diabetes-mediated changes in pharmacokinetics and bioactivity of dietary polyphenols might lead to improve the benefits of these phytochemicals and subsequent clinical outcomes for type 2 diabetics.

[Mechanism of action of nasal glucocorticosteroids in the treatment of allergic rhinitis. Part 1: Pathophysiology, molecular basis]. / Wirkmechanismen nasaler Glukokortikosteroide in der Therapie der allergischen Rhinitis. Teil 1: Pathophysiologie, molekulare Grundlagen.

Allergic rhinitis (AR) is a common airway disease characterized by mucosal swelling leading to congestion, mucosal hyperreactivity and increased secretions. Inflammatory processes in the mucosa are responsible for most symptoms and are characterized by mucosal remodeling after longer time periods. The early phase response, which is characterized by sneezing, rhinorrhea and nasal congestion, is the response of the sensory nerve terminals and blood vessels in the nasal mucosa to chemical mediators such as histamine, prostaglandins and leukotrienes. Nasal exposure to allergens leads to infiltration of inflammatory cells, such as activated eosinophils and T helper type 2 (TH2) cells, into the nasal mucosa by chemoattractant factors such as cytokines including interleukin 5 (IL-5), chemical mediators including cysLTs and chemokines including eotaxin. Edema of the nasal mucosa develops as a secondary reaction with inflammatory cells. This inflammation, referred to as the late-phase response, develops 6-10 h after allergen challenge and causes prolonged nasal congestion. In addition, a neurogenic mechanism is activated after liberation of substance P and others. Therefore, allergic rhinitis is a complex immunogenic disease that also activates mechanisms of the immune system in general. Antiallergic and antiinflammatory medications such as nasal glucocorticosteroids (nGCS) are thought to be the most effective treatment for controlling the symptoms and inflammatory mechanisms of AR. The antiinflammatory action of nGCS depends on at least two different mechanisms: transactivation and transrepression. Moreover, they regulate immune functions by inducing regulatory cytokines and forkhead box P3 (Foxp3). Foxp3 is of upmost importance as a transcription factor of regulatory t-cells, allowing the inhibition of effector function and proliferation of other CD4+ cells.

[Mechanism of action of nasal glucocorticosteroids in the treatment of allergic rhinitis. Part 2: Practical aspects of application]. / Wirkmechanismen nasaler Glukokortikosteroide in der Therapie der allergischen Rhinitis. Teil 2: Praxisorientierte Aspekte der Anwendung.

Allergic rhinitis (AR) is the single most common allergic disease and one of the most common chronic diseases. It affects approximately 25-30% of the population, and can substantially worsen patients' medical conditions, reduce quality of life, and contribute to absenteeism from work or school. It is also responsible for substantial direct and indirect economic burdens on the health care system. The medical management of allergic rhinitis includes several available pharmacotherapies, such as α-sympathomimetics, anticholinergic drugs, natural saline or other nasal rinses, mast cell-stabilizing agents, topical and systemic antihistamines, topical and systemic glucocorticosteroids, leukotriene-receptor antagonists and the new monoclonal antibodies following a stepwise approach. Allergen-specific immunotherapy is the only treatment option that interferes with the natural course of the disease and, besides allergen elimination, is thought to be the only causative treatment option. Nasal glucocorticosteroids (nGCS) are thought to be the most effective treatment choice for controlling the symptoms of AR. Double-blind, randomized clinical trials have demonstrated greater efficacy of nGCSs versus placebo, antihistamines or montelukast for relief of all nasal symptoms, especially congestion. Therefore, especially in the management of AR-related nasal inflammation and congestion, nGCSs are considered the most appropriate treatment. Patients should be informed that symptom improvement can be expected after 2-4 days for intermittent rhinitis and after up to 2-3 weeks for persistent rhinitis. The medication has to be taken regularly and not as "on-demand" treatment. Adherence to treatment also affects outcomes, and this may be influenced by patient preferences for the sensory attributes of an individual drug and the awareness of possible side effects. More recently, safety studies have shown that the newer nGCS agents have improved safety profiles compared with older nGCS agents. The newer nGCS drugs have been found to have minimal adverse effects on growth and hypothalamic-pituitary-adrenal-axis function in children. This review will discuss the pathophysiology of allergic inflammation in the nasal mucosa and the mechanism of action of nGCSs; also the efficacy and safety of nGCSs will be discussed by focusing on clinical evidence.

Dissolution in nasal fluid, retention and anti-inflammatory activity of fluticasone furoate in human nasal tissue ex vivo.

BACKGROUND: Intranasal glucocorticoids represent the most effective pharmacologic treatment of allergic rhinitis. So far, no clinical data are available that compare fluticasone furoate (FF) with other intranasally applied glucocorticoids. OBJECTIVE: Because the pharmacokinetic behaviour of drugs governs their presence at the therapeutic target site we analysed selected in vitro properties of FF in comparison with triamcinolone acetonide (TCA), budesonide (Bud), fluticasone propionate (FP) and mometasone furoate (MF). Additionally, we determined the anti-inflammatory activity of the glucocorticoid fraction residing in human nasal tissue samples after washing. METHODS: We analysed the solubility of the compounds in artificial human nasal fluid and the retention in human nasal tissue as well as typical spray volumes of commercially available drug preparations. As an anti-inflammatory measure, we evaluated the inhibition of IL-8 release from epithelial cells. RESULTS: FF is delivered in the smallest application volume per spray. Despite the low aqueous solubility of glucocorticoids, a fraction of the compounds is already dissolved in the aqueous supernatants of drug preparations (Bud>TCA>FP>MF>FF). The dissolution of FP, MF and FF was significantly enhanced in artificial nasal fluid and FF displayed the most pronounced enhancement of solubility in the presence of proteins. Consistent with this result, the highest retention in nasal tissue was observed for FF, followed by FP>MF>Bud>TCA. After washing of the nasal tissue samples, all compounds inhibited IL-8 release, with FF displaying the highest activity. CONCLUSION: FF displayed beneficial properties for nasal application. Its low application volume per spray is a prerequisite for effective drug utilization by avoiding immediate loss by nose runoff or drip down the throat. Sustained dissolution and high tissue binding of FF should contribute towards an extended presence of compounds in nasal tissue as a basis for a prolonged pharmacologic activity.

Elevated levels of soluble CD163 in sera and fluids from rheumatoid arthritis patients and inhibition of the shedding of CD163 by TIMP-3.

The aim of the present study was to evaluate levels of soluble CD 163 in sera and fluids from rheumatoid arthritis (RA) patients and elucidate the mechanism that regulates the shedding of CD163. Levels of soluble CD163 in sera and fluids from RA patients were examined by a sandwich enzyme immunoassay and Western blotting. To determine the effects of tissue inhibitors of metalloproteinase (TIMPs) on the shedding of CD163 from monocytes/macrophages, levels of soluble CD163 in cultures of monocytes/macrophages and the expression of CD163 on monocytes/macrophages in the presence or absence of TIMPs were examined by a sandwich enzyme immunoassay and flow cytometry, respectively. The clinical marker that was most associated with serum levels of soluble CD163 was levels of CRP. TIMP-3, but not TIMP-1 or TIMP-2, inhibited the shedding of CD163 from monocytes/macrophages. It was shown that serum levels of soluble CD163 are a sensitive and reliable marker to monitor activated macrophages in synovitis from RA patients and the results imply that the responsible proteinase for the shedding of CD163 is not a member of the matrix metalloproteinases, but is likely to be a member of ADAMs.

Soluble CD163 inhibits phorbol ester-induced lymphocyte proliferation.

CD163 is a member of the scavenger receptor cysteine-rich family which is expressed exclusively on human monocytes and macrophages. Upon an inflammatory stimulus the protein is shed rapidly from the membranes' surface. CD163 expression is significantly upregulated by glucocorticoids and IL-10. While the membrane-bound form of CD163 was recently identified as scavenger receptor for hemoglobin-haptoglobin complexes, there is no information about a possible role of the shed soluble CD163. It has been suggested earlier that CD163 plays a pivotal role in the downregulatory phase of inflammation. However, it has remained elusive so far as to how this protein might influence the inflammatory process. We have now identified a potential direct anti-inflammatory effect mediated by soluble CD163. The highly purified protein statistically significantly inhibits phorbol ester-induced human T-lymphocyte activation, thus attenuating the immune response to the inflammatory mediator.

Comparison of the tissue affinity of glucocorticoids to human lung, nasal and skin tissue in vitro.

High affinity binding of topically applied glucocorticoids to their target tissues is the basis for prolonged action of the drug and reduces efflux into the systemic circulation that might account for adverse effects. Since little information on the accumulation and depletion of glucocorticoids to tissues of therapeutic interest is available the binding behavior of different glucocorticoids to human lung, nasal and skin tissue is now evaluated and drug concentrations in different tissues are compared. Furthermore, the role of tissue lipids and proteins in glucocorticoid binding is investigated. Therefore, sliced human lung, nasal and skin tissues are incubated with glucocorticoid containing buffers and time course of adsorption and desorption is monitored. Two model glucocorticoids, the highly lipophilic fluticasone propionate (CAS 80474-14-2) and the rather hydrophilic hydrocortisone (CAS 50-23-7) are compared respecting their binding to native and lipid-depleted tissues. While total adsorption rates to different tissues were highly comparable for each glucocorticoid the observed initial desorption was clearly different. Highest initial depletion was seen for lung tissue, lowest for skin tissue. After initial depletion a prolonged desorption of very low concentrations is observed for all tissues. Lipid depletion of tissues did neither change accumulation not depletion behavior except that about twice as high concentrations were bound and depleted, probably due to protein denaturation. It is concluded that glucocorticoids primarily bind to protein components of human lung, nasal and skin tissues. Connective tissue proteins are discussed to bind glucocorticoids with higher affinity than other protein components, thus preventing high initial release rates. While total amounts of adsorption to different tissues are equivalent and initial desorption of glucocorticoids from saturated tissues varies, highest total remaining concentrations should be observed in skin tissue followed by nasal and lung tissue. Although tissue lipids seem to play no role in total glucocorticoid binding they are suggested to influence the rate constant of uptake and depletion.

Adverse effects of opioid analgesic treatment are correlated with a significant elevation in plasma epinephrine in healthy humans.

OBJECTIVE: The purpose of this study was to elucidate the relationship of plasma catecholamine concentrations with experienced pain intensity and analgesic effects in the setting of an experimental pain study with human volunteers. METHODS: Plasma norepinephrine and epinephrine concentrations of 12 healthy human volunteers were analysed before and during painful electrical tooth-pulp stimulation under medication using the highly potent opioid analgesic tilidine in a fixed tilidine/naloxone combination and with the non-steroidal anti-inflammatory agent bromfenac. Catecholamine levels were compared with pharmacodynamic effects and reported adverse effects. RESULTS: Catecholamine levels revealed a statistically significant increase in plasma epinephrine concentrations (but not norepinephrine concentrations) 60-90 min after administration of tilidine/naloxone. This was correlated with the onset of adverse effects involving vertigo episodes in all reported cases. In contrast, there was no obvious correspondence of epinephrine or norepinephrine plasma concentrations to the experience of pain and analgesia. For comparison, under medication with the non-opioid analgesic bromfenac, only one mild adverse effects were noted, and no changes in plasma epinephrine or norepinephrine could be determined during the experimental sessions. CONCLUSIONS: It is proposed that elevated plasma epinephrine concentrations are a newly determined response to opioid-induced vertigo; this has possible clinical implications.

Human monocytes express CD163, which is upregulated by IL-10 and identical to p155.

CD163 is a glucocorticoid-inducible member of the scavenger receptor cysteine-rich family of proteins. Previous reports have indicated that CD163 is highly expressed on human macrophages, but found on less than 50% of peripheral blood monocytes. We now show that >99% of all CD14 positive monocytes express CD163 and that monocyte derived dendritic cells express low levels of CD163. We also show that IL-10, like glucocorticoids, induces high CD163 expression on cultured human monocytes. Glucocorticoid induced CD163 expression was not inhibited by anti-IL-10 and was additive with IL-10 treatment, suggesting that glucocorticoids increase CD163 expression by an IL-10 independent mechanism. Other anti-inflammatory cytokines (IL-4 and IL-13) did not increase CD163 expression. In addition, we show that p155 (a previously identified monocyte/macrophage marker of unknown function) shares identity with CD163. Western blots and flow cytometric analysis of HEK 293 cells transfected with the cDNA for CD163 were positive when probed with either mAb RM3/1 (which recognizes CD163) or Mac 2-48 (which defines p155).

Binding of glucocorticoids to human nasal tissue in vitro.

BACKGROUND: Intranasal application of glucocorticoids is an efficacious treatment of allergic rhinitis and some cases of nonallergic rhinitis. However, no data on binding of glucocorticoids to nasal tissue are available. Pronounced binding of the compound to the target tissue is favorable as it might serve as a local deposit delivering the glucocorticoid to specific receptors and it slows down the efflux of the compound into systemic circulation. METHODS: Human nasal tissue was incubated with fluticasone propionate, budesonide, flunisolide and beclomethasone-17-monopropionate. Kinetics of binding and redistribution of the tissue-bound fraction into human plasma was monitored. RESULTS: Binding of glucocorticoids to human nasal tissue was fast and highest for the lipophilic fluticasone propionate, followed by beclomethasone-17-monopropionate. Also, highest concentrations of these lipophilic glucocorticoids remained in nasal tissue after equilibration of drug-saturated tissue with plasma. CONCLUSIONS: Lipophilic compounds exhibit a high tissue binding and retention which is an important property of topically applied glucocorticoids. It is the basis for prolonged action and low concentration of the compound in systemic circulation.

Molecular modeling of G-protein coupled receptor kinase 2: docking and biochemical evaluation of inhibitors.

G-protein coupled receptor kinase 2 (GRK2) regulates the activity of many receptors. Because potent inhibitors of GRK2 are thus far limited to polyanionic compounds like heparin, we searched for new inhibitors with the aid of a molecular model of GRK2. We used the available crystal structure of cAMP dependent protein kinase (cAPK) as a template to construct a 3D homology model of GRK2. Known cAPK and GRK2 inhibitors were docked into the active sites of GRK2 and cAPK using DOCK v3.5. H8 docked into the hydrophobic pocket of the adenosine 5'-triphosphate (ATP) binding site of cAPK, consistent with its known competitive cAPK inhibition relative to ATP. Similarly, 3 of 4 known GRK2 inhibitors docked into the ATP binding pocket of GRK2 with good scores. Screening the Fine Chemicals Directory (FCD, containing the 3D structures of 13,000 compounds) for docking into the active sites of GRK2 identified H8 and the known GRK2 inhibitor trifluoperazine as candidates. Whereas H8 indeed inhibited light-dependent phosphorylation of rhodopsin by GRK2, but with low potency, 3 additional FCD compounds with promising GRK2 scores failed to inhibit GRK2. This result demonstrates limitations of the GRK2 model in predicting activity among diverse chemical structures. Docking suramin, an inhibitor of protein kinase C (not present in FCD) yielded a good fit into the ATP binding site of GRK2 over cAPK. Suramin did inhibit GRK2 with IC50 32 microM (pA26.39 for competitive inhibition of ATP). Suramin congeners with fewer sulfonic acid residues (NF062, NF503 [IC50 14 microM]) or representing half of the suramin molecule (NF520) also inhibited GRK2 as predicted by docking. In conclusion, suramin and analogues are lead compounds in the development of more potent and selective inhibitors of GRK2.

Regulation of CD 163 on human macrophages: cross-linking of CD163 induces signaling and activation.

CD163 is a member of the group B scavenger receptor cysteine-rich (SRCR) superfamily. This study describes aspects of the tissue distribution, the regulation of expression, and signal transduction after cross-linking of this receptor at the cell surface of macrophages. CD163 showed an exclusive expression on resident macrophages (e.g., red pulp macrophages, alveolar macrophages). The expression was inducible on monocyte-derived macrophages by glucocorticoids but not by interleukin-4 (IL-4), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma. The combination of IL-4 or GM-CSF with glucocorticoids resulted in a further increase. Subcellular analysis of alveolar macrophages by immunoelectron microscopy showed a plasma membrane localization of the antigen. Cross-linking of CD163 with monoclonal antibody induced a protein tyrosine kinase-dependent signal that resulted in (1) slow-type calcium mobilization, (2) inositol triphosphate production, and (3) secretion of IL-6 and GM-CSF. The data suggest a function for the SRCR-superfamily receptor CD163 in the regulation of inflammatory processes by macrophages.

Comparison of tilidine/naloxone, tramadol and bromfenac in experimental pain: a double-blind randomized crossover study in healthy human volunteers.

AIM: The analgesic efficacy and safety of single oral doses of two centrally acting compounds, the combination of 50 mg tilidine and 4 mg naloxone (Valoron N) and 50 mg tramadol (Tramal), were compared to 25, 50 and 75 mg of the non-steroidal antiinflammatory bromfenac in experimental pain. SUBJECTS AND METHODS: It was a placebo-controlled double-blind 6-way crossover study design with 12 human volunteers. Acute pain was generated by electrical tooth pulp stimulation. Treatment effects were determined by recording somatosensory-evoked potentials and by subjective pain rating. RESULTS: The tilidine/naloxone combination clearly was the most potent medication in this study, followed by bromfenac 75 mg, which produced an early pain relief. Tramadol produced poor analgesia, as did bromfenac 25 and 50 mg. There was no dose-response relationship for bromfenac. Control of plasma levels revealed pronounced interindividual differences in peak plasma concentrations for bromfenac, but not for tramadol. Tilidine/naloxone exerted adverse effects in 9, tramadol in 3 volunteers. Under medication with 25 and 50 mg bromfenac, respectively, only one subject reported adverse effects. No adverse effects were experienced with 75 mg bromfenac or placebo. CONCLUSION: The results support previous conclusions about the analgesic efficacy of tilidine/naloxone and tramadol in experimental pain. Moreover, the findings suggest that 75 mg bromfenac might be suitable for fast but short relief of pain of non-inflammatory genesis.

Shedding of CD163, a novel regulatory mechanism for a member of the scavenger receptor cysteine-rich family.

The glucocorticoid-inducible transmembrane protein CD163 is a member of the scavenger receptor cysteine-rich (SRCR) family which is expressed exclusively on human monocytes and macrophages. The expression of the protein is significantly downregulated in response to phorbol 12-myristate 13-acetate (PMA) by a yet unknown mechanism. We now demonstrate that PMA induces shedding of a soluble form of CD163 rather than internalization, revealing a novel regulatory mechanism for a member of the SRCR family. Bisindolylmaleimide I was shown to inhibit phorbol ester-induced shedding, thus implying an involvement of protein kinase C (PKC). Furthermore, cleavage could be prevented by protease inhibitors. Therefore, we suggest that PMA-induced activation of PKC leads to protease-mediated shedding of CD163. These results indicate a specific release mechanism of soluble CD163 by human monocytes which could play an important role in modulating inflammatory processes.

Binding kinetics of budesonide to the human glucocorticoid receptor.

Glucocorticoid receptor-ligand binding kinetics of budesonide, a glucocorticoid used for inhalation therapy, were determined and compared with dexamethasone and fluticasone propionate using glucocorticoid receptors from human lung tissue. From the association constant of 18.9 x 10(5)l mol-1 min-1 and the dissociation constant of 25.0 x 10(-4) min-1 resulted the equilibrium dissociation constant KD of 1.32 nmol/l and a relative receptor affinity of 855 with dexamethasone as reference (100). The half-life of the budesonide-receptor complex was 4.6 h. Results agree with data derived from competition tests we performed earlier.

Identification of the integral membrane protein RM3/1 on human monocytes as a glucocorticoid-inducible member of the scavenger receptor cysteine-rich family (CD163).

The RM3/1 Ag is a membrane glycoprotein restricted to human monocytes and macrophages that evolve in the late phase of inflammation. Peptide sequence analysis of the RM3/1 protein revealed similarity to CD163, a member of the scavenger receptor cysteine-rich family. Using specific Abs (RM3/1, Ki-M8), we demonstrate an identical cellular regulation for the RM3/1 and the CD163 protein. Most notably, we show for the first time that CD163 is significantly up-regulated by glucocorticoids. In contrast, the protein is down-regulated by the immunosuppressant cyclosporin A and by phorbol esters, while the inflammatory mediator LPS has no significant influence on the expression. We describe the first isolation of a full-length cDNA of CD163 and expression of the corresponding protein. Several splice variants of CD163 exist, and we elucidated the kinetics of induction of three major mRNA splice variants by fluticasone propionate; another splice variant was proved to be unresponsive to this glucocorticoid. Taken together with a previous result showing an involvement of RM3/1 in adhesion of monocytes to the activated endothelium, we discuss that CD163 might play an important role in inflammatory processes.

Rapid method for isolation of total RNA from eukaryotic cell lines and leukocytes.

Total RNA was isolated from human leukocytes (monocytes, granulocytes), various cell lines (COS-7, Mono-Mac-6, L-132, HaCaT, EA.hy926, HL-60), and fungal mycelium by a rapid two-step method. Cells were lysed with NaDodSO4 in a citric acid-containing buffer. This procedure was succeeded by salt precipitation to remove contaminating DNA and protein and a final alcohol precipitation of RNA. Isolated RNA was of high quality, with a reasonable yield and little or no protein or DNA contamination. We present here a fast method for preparing RNA particularly from cell lines, which limits the use of toxic compounds.

Biochemical characterization of a glucocorticoid-induced membrane protein (RM3/1) in human monocytes and its application as model system for ranking glucocorticoid potency.

PURPOSE: Upon glucocorticoid stimulation, human mononuclear leucocytes express an antigen, RM3/1, which characterizes a subpopulation of human monocytes and macrophages evolving in late phase of inflammation. We investigated biochemical properties of the RM3/1 antigen and correlations between antigen expression and glucocorticoid potency. METHODS: Biochemical properties were analyzed after solubilization by immunoaffinity methods and SDS-PAGE. RESULTS: Induction of the RM3/1 antigen is a glucocorticoid receptor mediated process, in contrast, inflammatory mediators such as LPS or TPA were not able to upregulate RM3/1 expression. After SDS-PAGE, the antigen appeared as a 130 kDa (nonreduced)/150 kDa (reduced) glycoprotein with a 25 kDa N-linked glycoportion. The interdependence between antigen density and glucocorticoid efficacy was assessed by calculation of relative antigen expression induced by dexamethasone, fluticasone propionate, budesonide, triamcinolone acetonide, flunisolide, beclomethasone, prednisolone and triamcinolone. Relative antigen expression was significantly correlated with the relative receptor affinity of the glucocorticoid. CONCLUSIONS: We described biochemical properties of the glucocorticoid-induced protein RM3/1. Though the precise role of the RM3/1 antigen in the antiinflammatory process is not fully understood yet, an useful application of the induced expression could already be demonstrated for pre-clinical screening of glucocorticoid potency.

Distribution of inhaled fluticasone propionate between human lung tissue and serum in vivo.

High retention of inhaled glucocorticoids in the airways means prolonged anti-inflammatory action and low delivery into the serum. The objective of this study was to investigate the retention in and distribution of inhaled fluticasone propionate (FP) between central and peripheral human lung tissue and serum in vivo. In 17 patients undergoing lung resection surgery, a single 1.0 mg dose of FP was inhaled at varying time-points (range 2.8-21.7 h) preoperatively. Peripheral and central lung tissue was obtained, and blood was drawn simultaneously. FP concentrations in central lung tissue were approximately three to four times higher than peripheral lung tissue concentrations, which in turn, exceeded those found in serum by 10 times. FP was detectable up to 21 and 16 h, respectively, after inhalation, with drug levels falling almost in parallel in peripheral lung tissue and in serum. The results of this study demonstrate that fluticasone propionate is retained in lung tissue for a long time. Serum concentrations after a single inhaled dose are low. Retention of high concentrations of fluticasone propionate in the airways may promote high topical anti-inflammatory activity.