Evaluation of in vitro Penetration of Fluticasone Propionate from MP-AzeFlu and Fluticasone Propionate Nasal Spray Through EpiAirway™606 Tissues Using Vertical Diffusion Cells.

PURPOSE: Most patients with allergic rhinitis (AR) have moderate-to-severe disease, requiring complete and prompt relief when symptoms occur. The time course of fluticasone propionate (FP) penetration into nasal tissues after intranasal administration is not well characterized. The goal of this proof-of-concept study was to evaluate the mucosal penetration of FP from fixed-combination FP-azelastine nasal spray (MP-AzeFlu) compared with an FP-only nasal spray in an in vitro, 3-dimensional human bronchial tissue model. MATERIALS AND METHODS: Absorption of FP from MP-AzeFlu and FP nasal spray was modeled using EpiAirway™606 (MatTek Corporation; Ashland, MA, USA) tissue cultured in vertical diffusion cells. The dosing amount of MP-AzeFlu was optimized in a pilot study. Based on the results of the pilot study, 10 µL of MP-AzeFlu (3.65 µg; n = 8) and 10 µL of FP nasal spray (5.00 µg; n = 8) were evaluated for penetration of tissue. Tissue integrity was monitored with Lucifer yellow. FP in the receiving media was quantified for each sample using liquid chromatography with tandem mass spectrometry. RESULTS: MP-AzeFlu and FP nasal spray were associated with similar FP accumulation profiles in the receiving media, but the permeability of FP was greater for MP-AzeFlu during hours 0 to 6, suggesting faster absorption for MP-AzeFlu. No indications of compromised tissue integrity were found in any of the tested cells. CONCLUSION: The higher and more rapid penetration of FP from MP-AzeFlu supports the use of MP-AzeFlu for patients with AR, particularly when prioritizing fast and pronounced symptom relief.

Deposition characteristics of a novel intranasal formulation of azelastine hydrochloride plus fluticasone propionate in an anatomic model of the human nasal cavity.

Background: Intranasal antihistamines and steroids should be delivered in a volume and with a technique that allow for optimal drug retention within the entire nasal cavity, maximize local absorption by the nasal mucosa, and, subsequently, increase the potential for the most desirable local availability and therapeutic effect. Objective: This in vitro evaluation simulated nasal medication deposition and evaluated the extent of runoff. MP-AzeFlu, a novel intranasal formulation of azelastine hydrochloride (AZE) plus fluticasone propionate (FP), was compared with sequential sprays of available commercial products with the individual medication components. Methods: A model of a normal adult human nasal cavity was used to visualize deposition of nasal spray products. A single spray of MP-AzeFlu (0.137 mL [137 µg of AZE/50 µg of FP]) or single sequential sprays of AZE nasal spray (0.137 mL [137 µg]) followed by brand name or generic FP nasal spray (0.100 mL [50 µg]) were manually actuated into the model. The interior was coated with a water-sensitive dye that changes to magenta when exposed to aqueous-based formulations. A slight vacuum was applied during spray delivery to simulate sniffing. The results were photographed by using anterior and lateral views. Results: Three replicates of MP-AzeFlu showed no dripping from the front of the nostril or backflow from the nasal cavity. However, three replicates of AZE nasal spray, followed by a brand name or generic FP nasal spray, showed significant dripping from the front of the nostril and backflow from the nasal cavity. Conclusion: A single spray of MP-AzeFlu resulted in no runoff compared with sequential dosing of the two other therapeutic products. Product runoff is likely due to the volume exceeding the capacity of the nasal cavity model. Furthermore, the common clinical dosing regimen of two sprays per nostril of each of the individual components would promote even greater increased undesirable flooding and leakage.

A retrospective database analysis on persistence with inhaled corticosteroid therapy: comparison of two dry powder inhalers during asthma treatment in Germany.

BACKGROUND: Asthma is one of the most common chronic diseases worldwide. Patient persistence with treatment is essential to achieve sufficient outcomes, in particular to avoid exacerbations. OBJECTIVE: To investigate inhaled corticosteroid (ICS) therapy with two different inhalers (Novolizer® and Turbuhaler®) by comparing persistence, concomitant use of additional asthma medication and occurrence of exacerbations in real life. STUDY DESIGN: A retrospective analysis of prescription data from outpatient treatment was performed using the IMS Disease Analyzer. It provides longitudinal anonymized patient data from ~ 3,000 office-based physicians in Germany. Treatment persistence of asthma patients (ICD 10 code: J45) using 200 µg budesonide either via Novopulmon®/Budecort® (Novolizer group = NOV) or Pulmicort® (Turbuhaler group = TUR) was compared. Eligible patients hadthe first prescription of ICS medication (index day) between June 2001 and September 2007 and a data history available for at least twelve months before and after the index day. RESULTS: Analysis of 1,780 NOV and 664 TUR patients revealed that 1 year after index day, 89% NOV patients remained on their ICS compared to 85% TUR patients. NOV patients changed significantly less often and later to another ICS (p = 0.0108; log-rank test). Significantly fewer NOV patients switched temporarily or permanently to another ICS during the observation time (NOV group: 14.7%; TUR group: 20.8%; p = 0.0002, log-rank test). On average, NOV and TUR patients received comparable prescriptions of short acting medication (NOV more SABA, TUR more formoterol). There was a trend towards fewer prescriptions of systemic corticosteroids in NOV patients. CONCLUSIONS: Our results suggest better therapy persistence with NOV compared to TUR during asthma treatment in Germany. This can be a marker of better compliance and may contribute to prevent exacerbations. However, the number of exacerbations per patient year in the NOV group (0.12) compared to the TUR group (0.18) was not statically significantly lower (p = 0.4096).

Bioavailability and disposition of azelastine and fluticasone propionate when delivered by MP29-02, a novel aqueous nasal spray.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • The topical second generation anti-histamine azelastine hydrochloride (AZE) and the potent corticosteroid fluticasone propionate (FP) are well established first-line treatments in allergic rhinitis (AR). • MP29-02, a novel intranasal AZE and FP formulation, has been shown to control AR symptoms faster and better than standard intranasal AZE or FP. • The systemic bioavailabilities of marketed AZE and FP nasal spray products have been established at about 40% and 1% only, respectively. • For new combination medicinal products such as MP29-02, the determination of possible pharmacokinetic (PK) drug-drug interactions between both active components and formulation-based bioavailability alterations is essential. WHAT THIS STUDY ADDS: • This paper provides for the first time information on potential drug-drug interactions, AZE and FP bioavailability and disposition characteristics of each component administered by the novel nasal spray formulation MP29-02. • The studies employed highly sensitive FP and AZE LC-MS/MS assays and could therefore be conducted with recommended therapeutic doses, thereby circumventing previously recognized draw-backs that required nasal bioavailability studies to be conducted using supra-therapeutic doses. • No significant PK drug-drug interaction between the active components AZE and FP was noted for MP29-02. • AZE bioavailabilty was equivalent when MP29-02 data were compared with MP29-02-AZE-mono and Astelin®. • Increased FP exposure was observed with MP29-02-based products compared with FP-BI. FP serum concentrations were generally very low with all investigational products suggesting no clinically meaningful pharmacodynamic differences in terms of systemic safety. AIM(S): To determine azelastine hydrochloride (AZE) and fluticasone propionate (FP) bioavailabilities of the novel nasal spray combination product MP 29-02, compared with MP29-02-based products containing only AZE (MP29-02-AZE-mono), FP (MP29-02-FP-mono), marketed AZE and FP single entity products (Astelin® and FP Boehringer-Ingelheim; FP-BI). METHODS: Two randomized, three period, six sequence, three treatment crossover studies were conducted in healthy subjects. Study 1 administered 200 µg FP as MP29-02, MP29-02-FP-mono or FP-BI. Study 2 administered 548 µg AZE as MP29-02, MP29-02-AZE-mono or Astelin®. Each dose consisted of two sprays/nostril. Serum FP and plasma AZE were followed over 24 (FP) and 120 h (AZE) and quantified by LC-MS/MS. Peak (C(max) ) and total exposures AUC(0,t(last) ) were compared between the treatments by anova. RESULTS: Study 1: Average FP C(max) was very low with all products (≤ 10 pg ml(-1) ). FP AUC(0,t(last) ) point estimates (90% CIs) for MP29-02 : MP29-02-FP-mono and MP29-02 : FP-BI ratios (%) were 93.6 (83.6, 104.7) and 161.1 (137.1, 189.3). Corresponding ratios for C(max) were 91.0 (82.5, 100.4) and 157.4 (132.5, 187.1). Study 2: AZE AUC(0,t(last) ) point estimates (90% CIs) for MP29-02 : MP29-02-AZE-mono and MP29-02 : Astelin® ratios (%) were 98.8 (91.0, 107.4) and 105.5 (95.6, 116.4). Corresponding outcomes for C(max) were 102.7 (92.1, 114.4) and 107.3 (92.6, 124.3). CONCLUSIONS: No interactions of AZE and FP were found with the MP29-02 formulation. Azelastine bioavailability was similar for MP29-02 and Astelin®. Maximum and total FP exposure was higher for MP29-02-based products compared with FP-BI. FP concentrations were generally very low with all investigational products and did not suggest clinically meaningful differences concerning systemic safety.

Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial.

OBJECTIVE: To evaluate the efficacy and safety of α-lipoic acid (ALA) over 4 years in mild-to-moderate diabetic distal symmetric sensorimotor polyneuropathy (DSPN). RESEARCH DESIGN AND METHODS In a multicenter randomized double-blind parallel-group trial, 460 diabetic patients with mild-to-moderate DSPN were randomly assigned to oral treatment with 600 mg ALA once daily (n = 233) or placebo (n = 227) for 4 years. Primary end point was a composite score (Neuropathy Impairment Score [NIS]-Lower Limbs [NIS-LL] and seven neurophysiologic tests). Secondary outcome measures included NIS, NIS-LL, nerve conduction, and quantitative sensory tests (QSTs). RESULTS: Change in primary end point from baseline to 4 years showed no significant difference between treatment groups (P = 0.105). Change from baseline was significantly better with ALA than placebo for NIS (P = 0.028), NIS-LL (P = 0.05), and NIS-LL muscular weakness subscore (P = 0.045). More patients showed a clinically meaningful improvement and fewer showed progression of NIS (P = 0.013) and NIS-LL (P = 0.025) with ALA than with placebo. Nerve conduction and QST results did not significantly worsen with placebo. Global assessment of treatment tolerability and discontinuations due to lack of tolerability did not differ between the groups. The rates of serious adverse events were higher on ALA (38.1%) than on placebo (28.0%). CONCLUSIONS: Four-year treatment with ALA in mild-to-moderate DSPN did not influence the primary composite end point but resulted in a clinically meaningful improvement and prevention of progression of neuropathic impairments and was well tolerated. Because the primary composite end point did not deteriorate significantly in placebo-treated subjects, secondary prevention of its progression by ALA according to the trial design was not feasible.

Treatment of multiple, multiform actinic keratoses on the head with imiquimod 5% cream.

The objective of this non-controlled interventional clinical study was to evaluate the efficacy of imiquimod in the treatment of fields with multiple, multiform AK. 180 office-based dermatological practices in Germany participated. Patients with clinically typical, visible AK lesions on the head were treated with 5% imiquimod cream 3 times per week for 4 weeks followed by a 4 week treatment pause. If lesions were still present, a second treatment course of treatment (COT) was given. Complete clearance rate, i.e. no clinically visible AK lesions in the treatment area, was the main outcome measure. 829 patients were enrolled. The complete clearance rate was 40.5% after the first COT and 68.9% overall. Altogether, 85.4% of the 7,427 baseline lesions were cleared. Patients with hyperkeratotic/hypertrophic lesions showed comparable responses. Local skin reactions were the most commonly reported adverse effects, causing discontinuation in only 4 patients. Severity of the local skin reactions was a strong predictor of the outcome. Patients with multiple multiform AK on the head can be successfully and safely treated with topical imiquimod in daily practice. Assurance of patient understanding that treatment success is closely correlated to proper drug administration is important.

Recurrence rate of superficial basal cell carcinoma following treatment with imiquimod 5% cream: conclusion of a 5-year long-term follow-up study in Europe.

Imiquimod 5% cream is an immune response modifier approved for the treatment of superficial basal cell carcinoma (sBCC) once daily, 5 x per week for 6 weeks. This report reveals the final results of a 5-year follow-up study to evaluate the recurrence rate of sBCCs treated with imiquimod. As previously reported, 182 patients were enrolled in the study and 163 (89.6%) had no clinical evidence of their target sBCC at the 12-week post-treatment assessment; these 163 were followed for up to 5 years. During the follow-up period, 18 clinical recurrences occurred at the target tumour site, 8 and 10 of which occurred during the first 6 and 12 months of follow-up, respectively. The 5-year Kaplan-Meier and life-table estimates for sustained clinical clearance of those patients initially cleared were 84.5% and 86.9%, respectively, and 90.3% considering histology. The estimate of overall treatment success for all treated patients at the end of follow-up was 77.9% (80.9% considering histology). The data support clinical assessment of initial response as predictive of long-term outcome. Most of the recurrences occurred early, indicating that careful follow-up is important during the first year after treatment.

Prevention of exercise-induced asthma by a fixed combination of disodium cromoglycate plus reproterol compared with montelukast in young patients.

BACKGROUND: The leukotriene inhibitor montelukast has been recommended against exercise-induced asthma (EIA), however, single-dose agents might be favourable in several aspects. OBJECTIVE: To compare the protective effects against EIA of a single inhalation of the combination disodium cromoglycate (DSCG, CAS 16110-51-3) and reproterol (REP, CAS 54063-54-6) with 3 days oral treatment of montelukast (MON, CAS 158966-92-8). METHODS: Open-label, cross-over, single-centre trial. Twenty-four 6 to 18-year-old children and adolescents, with reversible and stable airway obstruction, baseline FEV1 > or = 70%, predicted and proven EIA (i.e. a maximum decrease of FEV1 by > or = 20% compared with baseline) were treated with MON, orally for 3 days in the evening, or one single inhalation of DSCG/REP 20 min before the exercise challenge. The treatment sequence was randomised. The exercise test on a treadmill was performed under standardised conditions. RESULTS: 24 patients completed both periods. Both treatments clearly provided protection against EIA; however, protection of DSCG/REP was more pronounced than that of MON. This difference was statistically significant even if the data were adjusted for the increase in FEV1 between inhalation of DSCG/REP and challenge (DSCG/REP(adjusted). The nadir FEV1 level after exercise following prophylaxis with DSCG/REP was even higher than the pre-inhalation FEV1 value. From these data, protection indices of 66%, 81%, and 113% for MON, DSCG/REP(adjusted), and DSCG/REP(unadjusted), respectively, were estimated. CONCLUSIONS: Inhalation of DSCG/REP before exercise provides significantly better protection against EIA than three days treatment with MON.

Single-dose pharmacokinetics and safety pharmacodynamics of formoterol delivered by two different dry powder inhalers.

The present study aimed at assessing the pharmacokinetics (PK) and safety pharmacodynamics (PD) of 24 microg formoterol delivered via a Novolizer and via an Aerolizer in healthy subjects. This was a randomized, open-label, crossover study. Beside PK, serum potassium, and glucose profiles, vital signs, and ECG were recorded. Twenty-nine subjects (15 males) were enrolled. The inhalation maneuver had to be repeated by 19 subjects using the Aerolizer and 1 subject using a Novolizer. While eight (28%) subjects completely failed to inhale correctly via the Aerolizer (four were identified by the investigators immediately after inhalation, another four by bioanalytics later), all did it correctly via the Novolizer. The bioanalytical evaluation indicated two distinct serum peaks. The shapes of serum concentration-time profiles were more homogeneous after inhaling via the Novolizer than via the Aerolizer. After adjusting for the delivered dose the Cmax of formoterol predicting pulmonary absorption was higher after the Novolizer than after the Aerolizer, while the average AUC0-infinity levels indicating total systemic exposure were equivalent. There was no evidence for different pharmacodynamic behavior with respect to serum potassium and glucose profiles, vital signs, and ECG. The Novolizer yields higher pulmonary absorption of formoterol than the Aerolizer and equivalent safety profiles. Considering the lower variability of PK profiles and the higher proportion of correct inhalations, formoterol is more reliably inhaled via Novolizer.

Effect of azelastine, montelukast, and their combination on allergen-induced bronchoconstriction in asthma.

OBJECTIVES: Histamine and cysteinyl leukotrienes play an important role in early (EAR) and late (LAR) allergen reactions. Although protection by anti-histamines and anti-leukotrienes has been studied extensively, little is known about the effect of their combination. We, therefore, assessed the effect of clinically recommended doses of azelastine and montelukast alone and in combination on EAR and LAR. METHODS: Seventeen patients (mean age 31 years, 14 m/3 f) with asthma and proven EAR and LAR received an oral dose of 4 mg azelastine twice daily, or 10mg montelukast once daily, or both for 1 week, in a double-blind, double-dummy, cross-over fashion. FEV(1) was measured after single-dose allergen challenges during EAR (0-2h) and LAR (2-9h). RESULTS: Azelastine, montelukast and their combination protected against both EAR and LAR (p<0.004, each) by 46% and 43%, 76% and 59%, and 89% and 78%, respectively. Azelastine was not as effective during EAR but equally effective to montelukast during LAR. The combination was superior to each drug alone during both EAR and LAR (p<0.05, each). CONCLUSION: The combination of azelastine and montelukast in clinically recommended doses has a greater effect in suppressing early and late allergen reactions than each drug alone.

Peak inspiratory flow rates generated through the Novolizer and the Turbuhaler dry powder inhaler devices by children with stable asthma.

We compared the peak inspiratory flows (PIF) generated through a novel dry powder inhaler device, the Novolizer (PIF-N), and the Turbuhaler (PIF-T). Forty-six pediatric patients with stable bronchial asthma were randomized in an open-label, multicenter, crossover trial. No drug was administered during the inhalation maneuvers that were spaced by 10 min. There was neither a carryover nor a sequence effect. The patients were characterized by mean age of 8.5 years, mean FEV(1) of 1.79 L, and mean PIF without any device (baseline, PIF-B) of 185 L/min. Through the devices mean PIF-N of 94 L/min and mean PIF-T of 69 L/min were achieved, calculated from the maxima of three inhalations. This resulted in p < 0.0001 for the difference. The median PIFN/PIF-T ratio was estimated as 1.39. Each child achieved a higher PIF-N than PIF-T and was able to release the feedback mechanisms of the Novolizer indicating sufficient inhalation performance. We conclude that the PIF through the Novolizer is higher than the PIF through the Turbuhaler in stable asthmatic children. The flow rates achieved through the Novolizer allow for sufficient lung deposition even in children as young as 6 years.

Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial.

OBJECTIVE: The aim of this trial was to evaluate the effects of alpha-lipoic acid (ALA) on positive sensory symptoms and neuropathic deficits in diabetic patients with distal symmetric polyneuropathy (DSP). RESEARCH DESIGN AND METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, 181 diabetic patients in Russia and Israel received once-daily oral doses of 600 mg (n = 45) (ALA600), 1,200 mg (n = 47) (ALA1200), and 1,800 mg (ALA1800) of ALA (n = 46) or placebo (n = 43) for 5 weeks after a 1-week placebo run-in period. The primary outcome measure was the change from baseline of the Total Symptom Score (TSS), including stabbing pain, burning pain, paresthesia, and asleep numbness of the feet. Secondary end points included individual symptoms of TSS, Neuropathy Symptoms and Change (NSC) score, Neuropathy Impairment Score (NIS), and patients' global assessment of efficacy. RESULTS: Mean TSS did not differ significantly at baseline among the treatment groups and on average decreased by 4.9 points (51%) in ALA600, 4.5 (48%) in ALA1200, and 4.7 (52%) in ALA1800 compared with 2.9 points (32%) in the placebo group (all P < 0.05 vs. placebo). The corresponding response rates (>/=50% reduction in TSS) were 62, 50, 56, and 26%, respectively. Significant improvements favoring all three ALA groups were also noted for stabbing and burning pain, the NSC score, and the patients' global assessment of efficacy. The NIS was numerically reduced. Safety analysis showed a dose-dependent increase in nausea, vomiting, and vertigo. CONCLUSIONS: Oral treatment with ALA for 5 weeks improved neuropathic symptoms and deficits in patients with DSP. An oral dose of 600 mg once daily appears to provide the optimum risk-to-benefit ratio.

Synergistic effects of the anti-cholinergic R,R-glycopyrrolate with anti-inflammatory drugs.

Currently, much effort is geared towards developing therapies that impact on the inflammation in respiratory diseases such as asthma and COPD, assuming that this will improve disease pathology. R,R-Glycopyrrolate, a quaternary ammonium compound, is a muscarinic receptor antagonist with the potential to be used as a long-acting bronchodilator in patients with asthma and COPD. In this study we evaluated whether the combination of R,R-glycopyrrolate with known anti-inflammatory drugs results in synergistic effects. Human primary monocytes were used as an in vitro model system. M3, M4, M1 and M2 receptors were expressed in these cells in descending order. The combinatory effects of the drugs on the release of TNF-alpha after lipopolysaccharide stimulation were analyzed. R,R-Glycopyrrolate alone did not affect LPS induced TNF-alpha release. The PDE4 inhibitor rolipram dose dependently inhibited the TNF-alpha release. Maximum inhibition was around 70%. The IC(35) for rolipram was 68.9+/-15.2 nM. The simultaneous administration of 10 microM R,R-glycopyrrolate reduced the IC(35) to 1.70+/-1.18 nM. The anti-histamine azelastine inhibited TNF-alpha release dose dependently. The simultaneous administration of R,R-glycopyrrolate did not influence the action of azelastine. The corticosteroid budesonide inhibited the TNF-alpha release dose dependently with an IC(50) of 0.55+/-0.13 nM. The simultaneous administration of 10 microM R,R-glycopyrrolate reduced the IC(50) to 0.13+/-0.03 nM. Finally, R,R-glycopyrrolate was most effective in the triple combination with budesonide and rolipram in the reduction of TNF-alpha release. In conclusion, R,R-glycopyrrolate acts synergistically with the PDE4 inhibitor rolipram and the steroid budesonide in inhibiting inflammatory mediators.

Glycopyrrolate causes prolonged bronchoprotection and bronchodilatation in patients with asthma.

INTRODUCTION: Inhaled anticholinergic drugs are effective bronchodilators in the treatment of COPD, and tiotropium bromide has recently been introduced as a once-daily bronchodilator for use as a maintenance treatment. Racemic glycopyrrolate is an anticholinergic drug that has been used orally to control gastric acidity, parenterally as an antisialogogue and to reverse neuromuscular blockade, and has been studied by inhalation for asthma and COPD. DESIGN AND OBJECTIVE: We investigated the duration of protection against the constrictor effects of inhaled methacholine of a single dose of inhaled nebulized racemic glycopyrrolate (0.5, 1.0, and 2.0 mg) compared with ipratropium bromide (0.5 mg) and placebo in 10 atopic asthmatic volunteers in a double-blind, five-way, crossover study. RESULTS: Protection against methacholine-induced bronchospasm after administering glycopyrrolate was maintained to 30 h, the last time point measured. Both bronchodilatation and bronchoprotection were significantly longer with glycopyrrolate than after ipratropium bromide, and bronchoprotection was significant at all time points from 2 to 30 h compared to placebo. Dryness of the mouth and nose was described in 18% of patients after the highest dose of glycopyrrolate. CONCLUSIONS: The prolonged bronchodilator response and the protection against methacholine-induced bronchospasm demonstrated in asthma suggests that inhaled racemic glycopyrrolate would be superior to ipratropium bromide for treatment of stable COPD.

Tramadol SR Formulations : Pharmacokinetic Comparison of a Multiple-Units Dose (Capsule) versus a Single-Unit Dose (Tablet).

INTRODUCTION: Different oral sustained-release (SR) formulations of tramadol have been introduced in pain treatment in order to prolong the dosage interval to improve convenience for the patient. The objective of this study was to compare tramadol pharmacokinetics and intra- and intersubject variability after replicate single-dose administrations of a multiple-units SR formulation (capsule) and a single-unit formulation (tablet). METHODS: This was a randomised, single-dose, single-centre study with an open-label, four-period, two-sequence, two-formulation, replicate crossover design in healthy subjects under fed conditions. The main outcome measures were the intra- and intersubject variance of the area under the concentration-time curve from 0 to 12 hours (AUC(12)) and maximum concentration (C(max)), as well as the mean AUC(12) and C(max) for tramadol. Study drugs were a tramadol SR multiple-units formulation (capsule) and a tramadol SR single-unit formulation (tablet), each containing tramadol hydrochloride 100mg. The time interval from 0 to 12 hours of AUC(12) of the single-dose design corresponds to the recommended twice-daily dosage interval for both study drugs during long-term treatment. RESULTS: The two formulations were equivalent in the area under the curve (AUC(infinity): 2411 vs 2527 mug . h/L). However, capsules led to a lower C(max) (148.6 vs 183.2 mug/L), to a later time to reach C(max) (5.9 vs 4.9 hours), and to a longer half-value duration (13.4 vs 10.4 hours). In addition, intrasubject variability of AUC(12) was significantly smaller for capsules than for tablets (p = 0.041). Capsules also produced smaller intra- and intersubject variability in plasma concentrations during the first 2.5 and 3.0 hours after administration, respectively (p < 0.05). CONCLUSION: Although tramadol SR capsules and tramadol SR tablets led to an equivalent systemic exposure to the drug, capsules provided a smoother and more extended plasma profile. In addition, in the case of capsules, bioavailability was subjected to lower variability in terms of both rate and extent of absorption.