Modulation of neutrophil and inflammation markers in chronic obstructive pulmonary disease by short-term azithromycin treatment

The anti-inflammatory potential of azithromycin in chronic obstructive pulmonary disease (COPD) patients was explored following a standard oral dosing regimen. Patients with moderate and severe COPD were treated with azithromycin (500 mg, n=16) or placebo (n=8) once daily for 3 days in a randomized, double blind design, to compare effects on inflammation markers with those seen in a previous study in healthy volunteers. A battery of tests was made on serum, blood neutrophils and sputum on days 1 (baseline), 3, 4, 11, 18 and 32. In comparison to placebo, azithromycin resulted in an early transient increase in serum nitrites plus nitrates (day 3), associated with a tendency towards an increase in the blood neutrophil oxidative burst to phorbol myristic acetate. Subsequently, prolonged decreases in blood leukocyte and platelet counts, serum acute phase protein (including C reactive protein) and soluble E-selectin and blood neutrophil lactoferrin concentrations and a transient decrease in serum interleukin-8 were observed. Blood neutrophil glutathione peroxidase activity showed a prolonged increase after azithromycin treatment. The biphasic facilitatory-then-inhibitory response to azithromycin seen in healthy volunteers is not so clearly detectable in COPD patients, only potential anti-inflammatory effects. Treatment for longer periods may give therapeutic anti-inflammatory benefit in these patients.     

Pharmacokinetics of azithromycin in serum and sinus fluid after administration of extended-release and immediate-release formulations in patients with acute bacterial sinusitis

As high drug levels at the infection site are desirable for optimal activity, this study explored whether one dose of azithromycin extended release (AZ-ER) achieved higher azithromycin exposure in sinus fluid than azithromycin immediate release (AZ-IR) in adults with acute bacterial sinusitis. Subjects received AZ-ER (2g single dose; n=5) or AZ-IR (500mg daily for 3 days; n=4) and blood and sinus aspirates were collected until 120 h after initial dosing. Within 24 h, exposure was four- and three-fold higher with AZ-ER than with AZ-IR in serum and sinus fluid, respectively. Sinus fluid exposure was five- and three-fold higher than serum for AZ-IR and AZ-ER, respectively. Azithromycin concentrations in sinus fluid were maintained up to 120 h.     

PHARMACOKINETICS OF AZITHROMYCIN IN LUNG TISSUE, BRONCHIAL WASHING, AND PLASMA IN PATIENTS GIVEN MULTIPLE ORAL DOSES OF 500 AND 1000 MG DAILY

The present study compares the pharmacokinetics of azithromycin in plasma, lung tissue, and bronchial washing after oral administration of 500 mg (standard dose) versus 1000 mg daily for 3 days. Samples were taken during surgery for lung resection at various time points up to 204 h after the last drug dose, and azithromycin levels were analyzed by HPLC method. Azithromycin was widely distributed within the lower respiratory tract; sustained concentrations of the drug were detectable at the last sampling time (204 h) in lung tissue and bronchial washing, with long terminal half-lives of 132.86 and 74.32 h at 500 mg daily and 133.32 and 70.5 h at 1000 mg daily, respectively. Doubling the drug dose resulted in a remarkable increase in lung area under the curve (AUC, 1318 hx microg g(-1) vs 2502 hx microg g(-1)) and peak tissue concentration (9.13+/-0.53 microg g(-1) vs 17.85+/-2.4 microg g(-1)). In addition to this, enhanced azithromycin penetration from plasma into bronchial secretion and lung tissue was evidenced by the increase in the ratio of AUC(bronchial washing) versus AUC(plasma) (2.96 vs 5.27 at 500 and 1000 mg, respectively) and AUC(lung) versus AUC(plasma) (64.35 vs 97.73 at 500 and 1000 mg, respectively). In conclusion, the exposure of lung and bronchial washing to azithromycin is increased by doubling the dose, which results in favorable pharmacokinetic profile of the drug in the lower respiratory tract.     

Differential surface expression of CD18 and CD44 by neutrophils in bone marrow and spleen contributed to the neutrophilia in thalidomide-treated female B6C3F1 mice

Previously, we have reported that thalidomide (Thd) can enhance neutrophil function in female B6C3F1 mice. The present study was intended to evaluate the mechanisms underlying the enhanced neutrophil responses following Thd treatment intraperitoneally (100 mg/kg) for 14 or 28 days. Treatment with Thd increased the numbers of neutrophils in the spleen, peripheral blood, bone marrow, peritoneal cavity and lungs of female B6C3F1 mice when compared to the vehicle control mice. Thd treatment for 14 days increased the percentage and the number of neutrophils in the spleen in the first 8 h (peaking at 2 h) after the last Thd treatment, and it returned to the baseline after 24 h. However, Thd treatment for 28 days increased the percentage and number of neutrophils in the spleen even at the 24-h time point after the last Thd treatment. These neutrophils were demonstrated to be functional by the myeloperoxidase activity assay. Further studies have ruled out the possibility of an increased bone marrow granulopoiesis following Thd treatment. Flow cytometric analysis of the surface expression of adhesion molecules suggested that Thd treatment for either 14 or 28 days decreased the surface expression of either CD18 or CD44 by bone marrow neutrophils. On the other hand, the surface expression of both CD18 and CD44 by splenic neutrophils was increased following Thd treatment for 28 days but not for 14 days. No effect was produced for other cell surface molecules such as CD62L and CD11a. It was possible that decreased surface expressions of CD18 and CD44 facilitated neutrophils' release from the bone marrow; increased surface expressions of CD44 and CD18 by splenic neutrophils after 28 days of Thd treatment increased their ability to remain in the periphery. Taken together, Thd treatment increased neutrophils in female B6C3F1 mice, at least partially, through differentially modulating the surface expression of CD18 and CD44 by the neutrophils in the bone marrow and spleen.     

Steady-state pharmacokinetics of rufloxacin in elderly patients with lower respiratory tract infections.

The pharmacokinetics of rufloxacin, after repeated doses, was evaluated in 12 elderly patients with lower respiratory tract infections. Patients were given a single loading dose of 400 mg on the first day of treatment and single daily maintenance doses of 200 mg for the next 6-9 days. Serum concentrations of the drug were determined by high-performance liquid chromatography (HPLC) at regular intervals during treatment and fitted to a one-compartment open model for repeated doses. The maximum serum concentration after the first dose was 6.46 +/- 1.06 (mean +/- SEM) micrograms/ml and was reached in 4.3 +/- 0.8 h after the first administration. The elimination half-life was 28.7 +/- 4.1 h. The area under the serum levels-time curve from 0 to 24 h was 103 +/- 14 micrograms/h/ml after the first dose. On the last day of observation it increased to 155 +/- 28 micrograms/h/ml, with a mean extent of accumulation of 2.3 +/- 0.3 times. The elimination half-life was comparable to those in other studies in healthy young subjects, while plasma levels were about 80% higher. These results suggest that in elderly patients elevated drug concentrations may be reached in the serum. Although no untoward reactions related either to the drug concentration in serum or the dose have been noted with rufloxacin, this patient population should nevertheless be monitored carefully for adverse effects.     

Improved tonsillar disposition of azithromycin following a 3-day oral treatment with 20 mg kg(-1) in paediatric patients.

The present study was performed in order to compare azithromycin concentrations in tonsils of paediatric patients treated with different dose regimens of this antibiotic. Sixty-four children, scheduled to undergo surgical removal of tonsils, were treated with azithromycin 10 or 20 mgkg(-1) daily as oral suspension for 3 days. Samples of blood and tonsil were collected during surgery at days 0.5, 2.5, 4.5, 6.5 or 8.5 after the last dose. Azithromycin concentrations were measured by reversed phase high-performance liquid chromatography. In patients treated with 10 mgkg(-1), the highest concentrations of azithromycin were detected in plasma and tonsils at day 0.5 and 2.5, respectively. Consistent drug levels could be measured in tonsils up to 8.5 days. After administration of 20 mgkg(-1), azithromycin tonsillar concentrations were higher than those obtained with 10 mgkg(-1) up to day 6.5, whereas plasma levels did not differ significantly. The present results indicate that an improved tonsillar distribution of azithromycin can be achieved when this antibiotic is administered for 3 days at doses higher than 10 mgkg(-1) daily. These findings give pharmacokinetic support to the suggestion that increments of azithromycin dosing might ensure enhanced therapeutic levels at infective sites of the upper respiratory tract.     

Evolution of a new drug formulation: the rationale for high-dose, short-course therapy with azithromycin

The rationale for the use of high-dose, short-course azithromycin treatment regimens is based on the pharmacokinetic properties of azithromycin. Its long elimination half-life (approximately 60 h) and antibacterial potency make short-course (1-day) regimens feasible. Azithromycin is concentrated within phagocytic cells, which deliver it in a targeted manner to sites of infection. In vitro and in vivo models demonstrate that azithromycin is taken up, transported and released at the sites of infection by polymorphonuclear neutrophils and macrophages. Uptake is not saturable, so delivery of the total azithromycin therapeutic regimen as a single dose of azithromycin microspheres should lead to increased uptake and delivery of the drug to sites of infection. By achieving higher drug concentrations at the site of infection, a single, high dose of azithromycin microspheres should maximize efficacy. The new microsphere formulation allows for 'front loading' of the dose to achieve the highest drug levels early in the course of infection while maintaining favorable tolerability.     

Effects of depletion of neutrophils or macrophages on the inflammatory response induced by metalloelastase (MMP-12) in mice airways

Macrophage elastase (recombinant human matrix metalloproteinase-12, rhMMP-12), was instilled in mouse airways, inducing an early inflammatory response characterized by neutrophil recruitment and cytokine release in the bronchoalveolar lavage (BAL) fluids, followed by a delayed macrophage recruitment. We investigated the role played by alveolar macrophages and neutrophils in the delayed macrophage influx induced by rhMMP-12 (8 x 10(-3) U/mouse) in A/J mice. Mice depleted of circulating neutrophils, using a cytotoxic antibody, did not present an increase in neutrophil numbers in bronchoalveolar lavage fluids, 4 h and 24 h after rhMMP-12 instillation but the macrophage recruitment was not modified as compared to control mice at 7 days. Similar results were obtained using mice when the gene for neutrophil elastase was knocked out. Intranasal instillation of clodronate liposomes, 72 h prior to rhMMP-12 instillation, induced macrophage depletion which did not modify the macrophage recruitment at 7 days. Moreover, the stimulation of mouse macrophages by rhMMP-12 did not elicit the release of cytokines in culture supernatants. These results indicate that resident alveolar macrophages and recruited neutrophils do not play a role in the delayed macrophage recruitment induced by rhMMP-12.     

Effects of acute and long-term diazepam administrations on neutrophil activity: a flow cytometric study

This study analyzed the effects of acute and long-term diazepam treatments on rat peripheral blood neutrophil activity and cortisol serum levels. Rats were acutely and long-term (21 days, once daily) treated with diazepam (10 mg/kg) or its vehicle (1.0 ml/kg). Blood was collected 1 h after treatments for flow cytometric analysis of neutrophil oxidative burst and phagocytosis. Corticosterone and diazepam concentrations were also determined. Results showed that: (1) both diazepam treatments increased lipopolysaccharide (LPS) and phorbol myristate acetate (PMA)-induced neutrophil oxidative burst; (2) the increase in oxidative burst after Staphylococcus aureus induction in acutely treated animals was higher than that observed after long-term treatment; (3) phagocytosis is increased by acute diazepam treatment and decreased by a long-term regimen; (4) acute, but not long-term, diazepam treatment increased corticosterone levels; (5) diazepam plasmatic levels after acute and long-term treatments were not different. These results indicate the development of tolerance to diazepam effects on corticosterone serum levels but not on neutrophil activity.     

Targeting neutrophils using novel drug delivery systems in chronic respiratory diseases

Neutrophils are essential effector cells of immune system for clearing the extracellular pathogens during inflammation and immune reactions. Neutrophils play a major role in chronic respiratory diseases. In respiratory diseases such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, lung cancer and others, there occurs extreme infiltration and activation of neutrophils followed by a cascade of events like oxidative stress and dysregulated cellular proteins that eventually result in apoptosis and tissue damage. Dysregulation of neutrophil effector functions including delayed neutropil apoptosis, increased neutrophil extracellular traps in the pathogenesis of asthma, and chronic obstructive pulmonary disease enable neutrophils as a potential therapeutic target. Accounting to their role in pathogenesis, neutrophils present as an excellent therapeutic target for the treatment of chronic respiratory diseases. This review highlights the current status and the emerging trends in novel drug delivery systems such as nanoparticles, liposomes, microspheres, and other newer nanosystems that can target neutrophils and their molecular pathways, in the airways against infections, inflammation, and cancer. These drug delivery systems are promising in providing sustained drug delivery, reduced therapeutic dose, improved patient compliance, and reduced drug toxicity. In addition, the review also discusses emerging strategies and the future perspectives in neutrophil-based therapy.     

Hyperresponsive airways correlate with lung tissue inflammatory cell changes in ozone-exposed rats

The role of inflammatory cell infiltration in the development of hyperresponsiveness of the airways to muscarinic challenge remains poorly understood. Unlike previous investigations that only examined conducting airway inflammation, the present study utilized both bronchoalveolar lavage (BAL) and lung tissue digestion to determine rat lung inflammatory cell contents following a 4-h exposure to 2 ppm ozone. Immediately following ozone exposure, neutrophil content of the lung tissue was significantly increased and reached a value that was fourfold higher than air-exposed controls by 3 h postexposure. Although lavage-recovered neutrophils were elevated at 24 h, tissue neutrophil numbers had returned to control values. This transient elevation of tissue neutrophils directly correlated with an elevation and subsequent decline of airway hyperresponsiveness, measured as a decrease in the intravenous dose of methacholine provoking a 200% increase in airway resistance (PD(200)R). Animals rendered neutropenic with a rabbit anti-rat neutrophil serum prior to exposure were protected from ozone-induced hyperresponsive airways, further demonstrating an association between neutrophil infiltration into the lung and altered airway physiology. Although BAL-recovered neutrophils demonstrated no adverse effects as a result of ozone exposure, macrophages were not only found to be necrotic but also displayed altered oxidative metabolism when challenged with phorbol myristate acetate. Thus, changes in the microenvironment of the airways smooth muscle were shown to be associated with transient accumulation of neutrophils within the lung tissue and abnormalities of bronchoalveolar lavage-recovered macrophages.     

Hyperresponsive Airways Correlate with Lung Tissue Inflammatory Cell Changes in Ozone-Exposed Rats

The role of inflammatory cell infiltration in the development of hyperresponsiveness of the airways to muscarinic challenge remains poorly understood. Unlike previous investigations that only examined conducting airway inflammation, the present study utilized both bronchoalveolar lavage (BAL) and lung tissue digestion to determine rat lung inflammatory cell contents following a 4-h exposure to 2 ppm ozone. Immediately following ozone exposure, neutrophil content of the lung tissue was significantly increased and reached a value that was fourfold higher than air-exposed controls by 3 h postexposure. Although lavage-recovered neutrophils were elevated at 24 h, tissue neutrophil numbers had returned to control values. This transient elevation of tissue neutrophils directly correlated with an elevation and subsequent decline of airway hyperresponsiveness, measured as a decrease in the intravenous dose of methacholine provoking a 200% increase in airway resistance (PD 200 R). Animals rendered neutropenic with a rabbit anti-rat neutrophil serum prior to exposure were protected from ozone-induced hyperresponsive airways, further demonstrating an association between neutrophil infiltration into the lung and altered airway physiology. Although BAL-recovered neutrophils demonstrated no adverse effects as a result of ozone exposure, macrophages were not only found to be necrotic but also displayed altered oxidative metabolism when challenged with phorbol myristate acetate. Thus, changes in the microenvironment of the airways smooth muscle were shown to be associated with transient accumulation of neutrophils within the lung tissue and abnormalities of bronchoalveolar lavage-recovered macrophages.     

Acute functional enhancement of circulatory neutrophils after intratracheal instillation with diesel exhaust particles in rats

We have previously demonstrated that intratracheal instillation (IT) with diesel exhaust particles (DEP) exacerbates myocardial ischemia/reperfusion-induced arrhythmia in rats. Since activated neutrophils play a pivotal role in ischemia/reperfusion arrhythmia, in the present study we investigated the effects of DEP on peripheral neutrophil count and on the oxyradical production (ORP) of neutrophils in rats. We also determined the production of cytokines for better understanding of the relationship between pulmonary inflammation and neutrophil function. Instillation with 5 mg DEP elevated circulatory neutrophil counts (CNC) at 12 and 24 h post-instillation to levels approximately 2.1- and 2.3-fold those in the vehicle-treated animals, respectively. On the other hand, 1-mg DEP caused an approximately 0.4-fold increase in CNC at 6 h. 12-O-Tetradecanoylphorbol 13-acetate-induced ORP in the isolated neutrophil was enhanced at 12 and 24 h after instillation with 5 mg DEP. Cytokine-induced neutrophil chemoattractant-1 (CINC-1), tumor necrosis factor-alpha (TNFalpha) and macrophage inflammatory protein-2 (MIP-2) levels were increased in the bronchoalveolar lavage fluid (BALF) collected from animals that received 5 mg DEP. In serum, a marked elevation of CINC-1 and a slight elevation of MIP-2 were also observed, while TNFalpha was not detected. Granulocyte-macrophage colony-stimulating factor (GM-CSF) was detected in neither BALF nor serum for 24 h after the instillation. These results suggest that IT instillation of DEP enhances systemic oxidative stress by increasing neutrophil count and ORP in the acute period.     

Effect of gefarnate on acute gastric mucosal lesion progression in rats treated with compound 48/80, a mast cell degranulator, in comparison with that of teprenone

We have reported that teprenone (geranylgeranylacetone), an anti-ulcer drug, prevents acute gastric mucosal lesion progression in rats treated once with compound 48/80 (C48/80), a mast cell degranulator, possibly by suppressing mucus depletion, neutrophil infiltration, and oxidative stress in the gastric mucosa. Herein, we examined the preventive effect of gefarnate (geranyl farnesylacetate), an anti-ulcer drug, on acute gastric mucosal lesion progression in rats treated once with C48/80 (0.75 mg/kg, i.p.) in comparison with that of teprenone, because the chemical structure and anti-ulcer action of gefarnate are similar to those of teprenone. Gefarnate (50, 100 or 200 mg/kg) administered orally at 0.5 h after C48/80 treatment, at which time gastric mucosal lesions appeared, reduced progressive gastric mucosal lesions at 3 h dose-dependently. At 3 h after C48/80 treatment, the gastric mucosa had decreased adherent mucus and hexosamine contents and increased myeloperoxdiase (an index of neutrophil infiltration) and xanthine oxidase activities and thiobarbituric acid reactive substances (an index of lipid peroxidation) content. Post-administered gefarnate attenuated all these changes dose-dependently. These preventive effects of gefarnate were similar to those of teprenone at a dose of 200 mg/kg. Post-administered gefarnate did not affect the increases in serum serotonin and histamine concentrations and the decrease in gastric mucosal blood flow at 3 h after C48/80 treatment like teprenone. These results indicate that orally administered gefarnate prevents acute gastric mucosal lesion progression in C48/80-treated rats possibly by suppressing mucus depletion, neutrophil infiltration, and oxidative stress in the gastric mucosa like teprenone.     

The effects of an antacid or cimetidine on the serum concentrations of azithromycin.

The effects of an antacid and of cimetidine on the serum concentrations of azithromycin were examined in volunteers. Ten subjects were given 500 mg azithromycin alone and immediately after being given 30 mL Maalox (Rorer, Fort Washington, PA) in a crossover design. There were no statistically significant differences in Tmax or AUC0-48 after administration of azithromycin alone or with antacid, but mean values of Cmax were reduced by 24% (P = .015). Thus, although Cmax was decreased, the extent of absorption of azithromycin was not affected by coadministration with an antacid. Two groups of six volunteers were given 500 mg azithromycin on day 1. On day 8, one group was given 800 mg cimetidine 2 hours before a dose of azithromycin; the remaining group received placebo before azithromycin. There were no differences in the pharmacokinetic parameters produced by administration with cimetidine or placebo, relative to those on day 1. Thus, cimetidine administered 2 hours before a dose of azithromycin had no apparent effect on the serum concentrations of azithromycin.     

Pharmacokinetics of Oral Azithromycin in Serum, Urine, Polymorphonuclear Leucocytes and Inflammatory vs Non-Inflammatory Skin Blisters in Healthy Volunteers

Two open-label studies were conducted to assess the serum, urine, polymorphonuclear (PMN) and red blood cell (RBC) pharmacokinetics of a 5-day course (1500mg total) of oral azithromycin. Inflammatory and non-inflammatory blisters were also induced to study the propensity of azithromycin to preferentially concentrate at a model infection site. 14 subjects participated in the two studies and tolerated azithromycin and the study methods well. Comodelling of the serum and urine data demonstrated very extensive distribution into peripheral compartments, low renal clearance (7% of total oral clearance) and an extended terminal half-life (79 hours). PMN leucocyte concentrations peaked at 119 mg/L following the final dose and remained above 60 mg/L 7 days after the final dose. The ratio of blister to serum AUCs was significantly higher in inflammatory (2.2) vs non-inflammatory (1.2) blisters (p < 0.02). The extensive uptake of azithromycin into PMNs coupled with the accumulation of azithromycin into an inflammatory compartment (e.g. infection site) support the hypothesis that PMN leucocytes laden with azithromycin migrate to sites of inflammation, thereby enhancing local concentrations. These studies further demonstrate the unique pharmacokinetic properties of azithromycin and its preferential delivery by phagocytes to the site of infection.     

Effect of doxycycline on oxygen-dependent killing mechanisms of human neutrophils

The effects of doxycycline on neutrophil adhesivity, ingestion rate, and oxidative burst by particle and soluble compounds have been analyzed. The rate of bacterial ingestion by neutrophils as well as its subsequently particle-induced oxidative burst comprising oxygen uptake, hydrogen peroxide and superoxide anion productions, and iodination were all inversely correlated to doxycycline concentration included in the assay medium. The neutrophil oxidative burst induced by phorbol myristate (a soluble stimulant) was also inversely correlated to doxycycline concentration. Drug effect was observed at lower concentrations when the neutrophil stimulant was a soluble compound than when it was particles. In contrast doxycycline did not affect neutrophil adhesivity to either nylon fibers or Petri dishes. Further studies are needed to assess whether the activity of the drug on the neutrophil is due only to its ability to chelate calcium and magnesium or to other properties.     

Acute Functional Enhancement of Circulatory Neutrophils After Intratracheal Instillation with Diesel Exhaust Particles in Rats

Abstract

We have previously demonstrated that intratracheal instillation (IT) with diesel exhaust particles (DEP) exacerbates myocardial ischemia/reperfusion-induced arrhythmia in rats. Since activated neutrophils play a pivotal role in ischemia/reperfusion arrhythmia, in the present study we investigated the effects of DEP on peripheral neutrophil count and on the oxyradical production (ORP) of neutrophils in rats. We also determined the production of cytokines for better understanding of the relationship between pulmonary inflammation and neutrophil function. Instillation with 5 mg DEP elevated circulatory neutrophil counts (CNC) at 12 and 24 h post-instillation to levels approximately 2.1- and 2.3-fold those in the vehicle-treated animals, respectively. On the other hand, 1-mg DEP caused an approximately 0.4-fold increase in CNC at 6 h. 12-O-Tetradecanoylphorbol 13-acetate-induced ORP in the isolated neutrophil was enhanced at 12 and 24 h after instillation with 5 mg DEP. Cytokine-induced neutrophil chemoattractant-1 (CINC-1), tumor necrosis factor-α (TNFα) and macrophage inflammatory protein-2 (MIP-2) levels were increased in the bronchoalveolar lavage fluid (BALF) collected from animals that received 5 mg DEP. In serum, a marked elevation of CINC-1 and a slight elevation of MIP-2 were also observed, while TNFα was not detected. Granulocyte–macrophage colony-stimulating factor (GM-CSF) was detected in neither BALF nor serum for 24 h after the instillation. These results suggest that IT instillation of DEP enhances systemic oxidative stress by increasing neutrophil count and ORP in the acute period.     

Pharmacokinetics of single and multiple ascending doses of the antiallergic agent tiacrilast in man

Five groups of six healthy subjects received single oral doses of 150, 300, 450, 600 or 750 mg tiacrilast 150 mg capsules, followed 24 h later by the same dose given every 6 h for 7 days, in a study designed to assess the pharmacokinetics of single and multiple doses of tiacrilast. Plasma samples were obtained at specified times after the initial dose, after 4 days of multiple dosing and after the last dose of tiacrilast. Samples were assayed for unchanged drug by a specific HPLC method. Wide variability was seen in the plasma concentration-time data. Plasma concentrations and pharmacokinetic parameters were nearly proportional to dose over the 150 to 750 mg dose range studied. Moreover, there was no evidence of unexpected accumulation of the drug in the plasma during multiple dosing and food did not appear to alter the bioavailability of tiacrilast to any clinically significant extent. The apparent elimination half-life was similar after single and multiple doses and ranged from 1 to 3 h.