Increased susceptibility of Pseudomonas aeruginosa to macrolides and ketolides in eukaryotic cell culture media and biological fluids due to decreased expression of oprM and increased outer-membrane permeability.

BACKGROUND: Macrolides show high minimum inhibitory concentrations (MICs) against Pseudomonas aeruginosa when tested in recommended media (cation-adjusted Muller-Hinton broth [CA-MHB]). Nevertheless, azithromycin is successfully used in cystic fibrosis patients, supposedly because of "nonantibiotic effects." METHODS: CA-MHB and Roswell Park Memorial Institute (RPMI) 1640 medium (used for growing eukaryotic cells) were compared for measuring azithromycin MICs (with or without Phe-Arg-ß-naphthylamide [PAßN], an efflux inhibitor), [(14)C]-clarithromycin accumulation, azithromycin-induced protein synthesis inhibition, oprM (encoding the outer-membrane protein coupled with MexAB and MexXY efflux systems) expression, outer-membrane permeability (tested with 1-N-phenylnaphthylamine and nitrocefin), and synergy (determined by checkerboard assay) between azithromycin and outer-membrane disrupting agents. Key experiments were repeated with CA-MHB supplemented with serum, mouse bronchoalveolar lavage fluid, other macrolides, and other gram-negative bacteria. RESULTS: Azithromycin MICs were ≥128 mg/L in CA-MHB, compared with 1-16 mg/L in RPMI 1640 medium, CA-MHB supplemented with serum, or bronchoalveolar lavage fluid (repeated for RPMI 1640 medium with clarithromycin, other macrolides, and other gram-negative bacteria). [(14)C]-clarithromycin accumulation was 2.2-fold higher in RPMI 1640 medium, compared with CA-MHB. Inhibition of >95% of protein synthesis was obtained with azithromycin at 16 mg/L in RPMI 1640 medium, compared with >512 mg/L in CA-MHB. Strains not expressing oprM showed an MIC of 4 mg/L in CA-MHB. PAßN decreased MICs in CA-MHB but not in RPMI 1640 medium. Real-time polymerase chain reaction showed downregulation of oprM by azithromycin in RPMI 1640 medium. Outer-membrane permeability was 3-4.5 times higher in RPMI 1640 medium or bronchoalveolar lavage fluid, compared with CA-MHB. Azithromycin combined with outer-membrane disrupting agents were synergistic in CA-MHB but indifferent in RPMI 1640 medium. CONCLUSIONS: Macrolides show antimicrobial activity against P. aeruginosa in eukaryotic media through increased uptake and reduced efflux. These data may help explain the clinical efficacy of macrolides against pseudomonal infections.

The effect of combined tobramycin-clarithromycin on Mycobacterium tuberculosis isolates.

This study investigated the susceptibility of 25 Mycobacterium tuberculosis clinical isolates to tobramycin (TBM) and clarithromycin (CLM). The effect of the drugs administered together was examined for possible synergistic effect. The median minimum inhibitory concentration (MIC) for both drugs was 8 mug/ml. In 36% of the isolates, a decrease of the CLM MIC by a single or two-fold dilution was observed when a sub-inhibitory concentration of TBM was added. The results suggest that both drugs should be investigated further as potential adjuncts to the treatment of resistant tuberculosis, in particular through new drug delivery systems such as the dry powder inhaler allowing high lung deposition.

Significance of the biopharmaceutical properties of tramadol sustained-release formulations for chrono-pharmacologically optimized treatment of pain from various sources.

UNLABELLED: Tramadol is currently one of the most frequently used opioid analgesics in the world. OBJECTIVE: The objective of this study was to investigate the rate and extent of tramadol bioavailability following evening versus morning intake of an extended-release pellet system designed for once daily administration. Moreover, the suitability of the preparation for chrono-adjusted pharmacotherapy was to be investigated. METHODS: 18 male and female volunteers were enrolled in the study and treated with 200 mg tramadol extended-release capsules, which were to be taken in the fasted state between 7:30 and 8:00 a.m. or p.m., respectively. The parent compound and its O-desmethyl-metabolite were analyzed in plasma samples using a LC-MS/MS procedure. RESULTS: Maximum exposure of tramadol (geometric means of C(max)-values) was determined as 289.3 ng/ml after morning and 283.1 ng/ml after evening administration. Extent of tramadol exposure (geometric means of AUC(0-48)-values) was calculated as 4,802.5 ng x h/ml after morning and 4,767.0 ng x h/ml after evening administration. Also tmax-values were comparable after morning and evening administration (9.00 vs. 9.50 hours). Statistical analyses, based on conventional bioequivalence approach, revealed no evidence of any impact of the time-point of administration on the biopharmaceutical performance of the dosage form investigated here. CONCLUSIONS: Bioavailability of the extended-release tramadol capsules for once daily administration is not affected by the time-point of administration. Total and maximum exposure of the product was bioequivalent after intake in the morning and at night. Thus, the time-point of administration may be adjusted to the patient's needs without any significant change in the in-vivo performance.

Pharmacoscintigraphic and pharmacokinetic evaluation on healthy human volunteers of sustained-release floating minitablets containing levodopa and carbidopa.

In this study, scintigraphic and pharmacokinetic studies were conducted on 10 healthy, fed volunteers. Two concepts of sustained-release floating minitablets--Levo-Form 1 (matrix) and 2 (coated)--were evaluated and compared to the marketed product Prolopa HBS 125. All the floating forms were radiolabelled with (111)In in order to evaluate their gastric residence time using gamma-scintigraphy. It was shown that the three formulations offered almost the same mean gastric residence time, which was about 240 min. Prolopa HBS 125 and Levo-Form 2 presented intragastric disintegration, which can lead to a more pronounced "peak & valley" effect on the plasma concentration-time profile of levodopa. In contrast, the plasma concentration-time profile of levodopa following the administration of Levo-Form 1 was more evenly distributed. Moreover, Levo-Form 1 provided the lowest variations between men and women in terms of AUC and C(max) values. Finally, when the same amount of inhibitors of extracerebral dopa decarboxylase--carbidopa and benserazide--had been administrated, the mean AUC, C(max) and T(max) values obtained for benserazide were lower than those obtained for carbidopa.

Evaluation and floating enhancement of levodopa sustained release floating minitablets coated with insoluble acrylic polymer.

This article describes the in vitro evaluation and the enhancement of the floating properties of coated sustained release (SR) minitablets (MTs). The evaluated system consisted of a 3-mm drug-containing gas-generating core prepared by melt granulation and subsequent compression, which was then coated with a flexible polymeric membrane. Eudragit RL30D and acetyl triethylcitrate were used as a film former and a plasticizer, respectively. The coating level was fixed at 20% (wt/wt). The optimally coated floating MTs floated within 10 min and remained buoyant for more than 13 h, regardless of the pH of the test medium. By evaluating the dissolution profiles of levodopa at different pH, it was found that the release of levodopa was sustained for more than 12 h regardless of the pH, even if the coating did not cancel the effect of the pH-dependent solubility of the active drug. Finally, the robustness of the coated floating MTs was assessed by testing the drug release variability in function of the stirring conditions during dissolution tests.

[Importance of the formulation for a chronopharmacologically optimised way of pain therapy. Results of a comparative bioavailability study of tramadol extended-release capsules after single-dose evening versus morning administration]. / Bedeutung der Galenik in der "chrono- adjustierten" Schmerzbehandlung. Ergebnisse einervergleichenden Bioverfügbarkeitsuntersuchung mit einem Tramadol- Retardpräparat nach Einmalgabe am Abend und am Morgen.

UNLABELLED: Objective of this study was to investigate the rate and extent of tramadol bioavailability following evening versus morning administration. METHODS: The study was performed following an open, randomised, cross-over study-design. 18 male and female volunteers were enrolled into the study and treated with 200 mg tramadol extended-release capsules (T-long), which were to be taken either in the morning or in the evening. RESULTS: Plasma concentration versus time profiles obtained after morning and evening administration were almost superimposable for both, tramadol and its active metabolite. Maximum exposure of tramadol and O-desmethyltramadol (geometric means of c(max)-values) as well as extent of exposure (geometric means of AUC(0-48)-values) were comparable after morning and eveningadministration. CONCLUSIONS: Time-point of administration does not have any relevant impact on the rate and extent of absorption in the investigated dosage form. Thus, time-point of administration may be adjusted to the patient's need in a chronopharmacologically optimised way for pain therapy.

New levodopa sustained-release floating minitablets coated with insoluble acrylic polymer.

The aim of this study was to develop a new coated multiple-unit sustained-release floating system that is able to float over an extended period of time. Levodopa was used as a model drug. The system consisted of a 3mm drug-containing gas-generating core, prepared by melt granulation and subsequent compression, and coated with a flexible polymeric membrane. Eudragit RL30D and ATEC were used as a film former and a plasticizer, respectively. The coating level was fixed at 20% (w/w). The floating lag time decreased as the proportion of effervescent agents increased. The optimized coated floating minitablets could float within 20min and remained buoyant for more than 13h. In addition, a sustained release of levodopa for more than 20h was observed.

Development and evaluation of new multiple-unit levodopa sustained-release floating dosage forms.

This work relates to the development and the in vitro evaluation of sustained-release minitablets (MT), prepared by melt granulation and subsequent compression, which are designed to float over an extended period of time. Levodopa was used as a model drug. The importance of the composition and manufacturing parameters of the MT on their floating and dissolution properties was then examined. The investigation showed that MT composition and MT diameter had the greatest influence on drug release, which was sustained for more than 8h. By using the same formulation, the best floating properties were obtained with 3mm MT prepared at low compression forces ranging between 50 and 100N. Their resultant-weight (RW) values were always higher than those obtained with a marketed HBS dosage form within 13h. When they were filled into gelatin capsules, no sticking was observed. By evaluating the dissolution profiles of levodopa at different pH values, it was found that dissolution profiles depend more on the prolonged-release ability of Methocel K15M than on the pH-dependent solubility of levodopa. Finally, the robustness of the floating MT was assessed by testing the drug release variability in function of the stirring conditions during dissolution tests.

Treatment of alcoholic polyneuropathy with vitamin B complex: a randomised controlled trial.

AIMS: To evaluate the therapeutic efficacy and safety of BEFACT Forte 'new formulation' and BEFACT Forte 'old formulation' in the treatment of sensory symptoms of alcoholic polyneuropathy. METHODS: A multi-centre, randomised, double-blind, placebo-controlled study was conducted on 325 patients with sensory symptoms and signs of alcoholic polyneuropathy. Patients were randomised to the 'old formulation' (i.e. vitamins B1, B2, B6, and B12), 'new formulation' [i.e. identical to the 'old formulation' with additional folic acid (vitamin B9)], or placebo in a 1:1:1 ratio. One tablet of the study medication ('new formulation' or 'old formulation') or placebo was taken orally, three times a day, over a 12-week treatment period. RESULTS: Therapeutic efficacy was assessed in 253 patients by measuring vibration perception threshold (biothesiometry), intensity of pain, sensory function, co-ordination, and reflex responses. Patients treated with the 'new formulation' or 'old formulation' showed significant improvement in the primary efficacy endpoint (vibration perception threshold at the big toe) and secondary efficacy endpoints in comparison to placebo. The active treatment groups were comparable to placebo in terms of safety. CONCLUSIONS: A specific vitamin B complex (with and without folic acid) significantly improved symptoms of alcoholic polyneuropathy over a 12-week treatment period.

Long-term tolerability of tramadol LP, a new once-daily formulation, in patients with osteoarthritis or low back pain.

INTRODUCTION: Tramadol hydrochloride is a centrally acting analgesic, which possesses opioid agonist properties and activates monoaminergic spinal inhibition of pain. An oral, once a day, sustained release formulation of tramadol is thought to be advantageous compared with immediate release preparations as it prevents plasma peaks associated with increased side-effects of the drug. It may also improve compliance. The purpose of the study was to assess the long-term safety of a new sustained-release formulation of tramadol (tramadol LP) in patients with knee or hip osteoarthritis and in patients with refractory low back pain. STUDY DESIGN: The design was a phase III, open, multicentre, international, tolerability study with tramadol LP at a dose titrated by the patient between 100 and 400 mg once daily, according to the intensity of pain. The treatment was administered for a continuous period of 4 weeks followed by an intermittent intake of 5 months in 204 patients. The safety criteria for evaluation were recording of adverse events, laboratory tests, electrocardiogram, radiography, global tolerability assessed by the patient and the investigators. RESULTS: Long-term use of tramadol LP was reasonably well tolerated. Most of the reported adverse events were expected and occurred within the first month of treatment. Roughly half of the patients (49%) reported adverse events, of which 66% were related to treatment. Gastrointestinal events (nausea and vomiting) were the most frequent. Serious adverse events were reported in 6.4% of patients, from which only two cases were related to treatment. There was no sign of tolerance development and the percentage of patients presenting withdrawal symptoms after the end of treatment was low (6%). CONCLUSION: Long-term treatment with tramadol LP once daily is generally safe in patients with osteoarthritis or refractory low back pain.

Pharmacokinetic evaluation of a new oral sustained release dosage form of tramadol.

AIMS: To compare the pharmacokinetic profile of a new modified release formulation of tramadol (Tramadol LP 200 mg, SMB Technology, Marche-en-Famenne, Belgium) with that of an immediate release capsule (Topalgic) 50 mg, Grünenthal, Aachen, Germany) after single and multiple dosing and to assess the potential effect of food on its relative bioavailability. METHODS: The first study had an open, single-dose, three-treatment, three-period, six-sequence, randomised, crossover design with at least a five-day wash-out. The second study had an open, steady-state, two-treatment, two-period, two-sequence, randomised crossover design with at least a seven-day wash-out. Both studies contained 30 healthy subjects. Both enantiomers of tramadol and O-demethyl-tramadol (the only active metabolite of tramadol) were assayed in the plasma using an LC-MS/MS method. AUC infinity, AUCt, Cmax, Tmax, and T1/2 were estimated. Statistical analysis was performed using univariate anova, the Wilcoxon nonparametric method or Friedman's nonparametric anova where appropriate. RESULTS: Tramadol had a significantly lower Cmax and longer Tmax than the conventional formulation. Thus, the mean (+/- sd) Cmax of tramadol were 646 +/- 192 and 300 +/- 94 ng ml-1 for Topalgic 4 x 50mg and Tramadol LP 200 mg, respectively (95% confidence interval on the difference expressed as a percentage 42-51). AUC of tramadol from both formulations was comparable (similar AUC infinity and AUCt). Thus, the mean AUC infinity of (+/-)tramadol obtained after multiple dosing were 4611 +/- 1944 and 5105 +/- 2101 ngh ml-1 after Topalgic 4 x 50mg and Tramadol LP 200 mg, respectively (95%CI 102-123%). We also demonstrate that the pharmacokinetics of the drug are not influenced by the intake of food. Thus, the mean AUC infinity of (+/-) tramadol were 5444 +/- 1637 and 5169 +/- 1580 ngh ml-1 after Tramadol LP 200 mg given in the fasting and fed states, respectively (95%CI = 88-103%). CONCLUSIONS: The new sustained release form of tramadol exhibits adequate properties for once a day administration. Furthermore, its pharmacokinetic profile is not affected by the intake of food.

Dose-finding and 24-h monitoring for efficacy and safety of aerosolized Nacystelyn in cystic fibrosis.

The aim of the present studies was to investigate the tolerability and activity of a novel mucolytic drug, Nacystelyn (NAL), for the treatment of cystic fibrosis (CF) lung disease. In study 1, involving 10 CF patients, the main objective was to determine the tolerability and potential efficacy of a range of single doses of NAL in comparison to a placebo, in order to establish an optimal dose for further testing. On five consecutive scheduled treatment days, patients inhaled either from two (4 mg) to eight puffs (16 mg) of a single dose of NAL from the range, administered in an open-label fashion, or 12 puffs of active NAL (24 mg) versus 12 puffs of placebo, administered in a randomized double-blind fashion. Pulmonary function data were unaffected and clinically-adverse effects were limited to wheezing in some patients that inhaled 12 puffs of either placebo or active drug. Subsequent rheological analysis of their sputum showed a dose-dependent decrease in sputum viscoelasticity, accompanied by a decrease in sputum solids content and an increase in chloride and sodium concentrations. In study 2, involving 12 CF patients, the clinical safety and mucolytic activity of a single dose of NAL was monitored over 24 h. On different scheduled treatment days, 7 days apart, patients inhaled a single dose of 12 puffs of active NAL (24 mg) or 12 puffs of placebo drug in a randomized, double-blind sequence, with sputum samples taken at intervals before and after inhalation. Mucus rigidity decreased following NAL inhalation, with the maximum effect observed at 4 h; the 1-, 2- and 4-h NAL rheology results were significantly different from placebo. No adverse effects were observed. The drug was well tolerated in both studies. Sputum results were predictive of improved clearability by ciliary and cough transport mechanisms.

Deposition of nacystelyn from a dry powder inhaler in healthy volunteers and cystic fibrosis patients.

The aim of this study was to compare, using gamma scintigraphy, the lung deposition of a novel mucoactive agent, Nacystelyn (NAL), administered as a dry powder inhaler (DPI) in six healthy volunteers, six adult patients with cystic fibrosis (CF), and six children and adolescents patients with CF. The correlation between in vitro and in vivo results was also tested. It was first demonstrated that the method of labeling of NAL with 99mTc was reliable as tested by three in vitro methods (multistage liquid impinger, multistage cascade impactor, and 2-stage glass impinger). The deposition of unlabeled NAL, labeled NAL, and the radiolabel was similar in all stages of each device. Furthermore, the fine particle fraction (FPF) was the same on all apparatuses. The mean lung deposition obtained in volunteers was 27.5 +/- 13.5%. The results are approximately three times higher than the results obtained previously in healthy volunteers with NAL metered-dose inhalers (MDIs). As expected, the lung deposition observed in patients with CF was lower, e.g., 23.5 +/- 7.0% for adults and 16.5 +/- 5.9% for children and adolescents. A significant correlation was found between lung deposition and both the patient weight (p < 0.02) and height (p < 0.04). Surprisingly, the peripheral:central (P:C) ratio was similar for the three populations, indicating that the presence of mucus in moderately ill patients with CF does not modify the lung distribution of NAL. The FPF measured in vitro was similar to that obtained in volunteers but higher than that found in both patient populations. The DPI formulation of NAL developed will probably improve patient compliance and comfort in future clinical trials and postmarketing use of the drug.

Enantiomeric determination of tramadol and its main metabolite O-desmethyltramadol in human plasma by liquid chromatography-tandem mass spectrometry.

Pharmacokinetic studies require sensitive analytical methods to allow the determination of low concentrations of drugs and metabolites. When drugs present an asymmetric center, the enantiomeric determination of the compounds of interest should be performed. The method developed is based on on-line LC-MS-MS using atmospheric pressure chemical ionization as an interface determination of enantiomers of tramadol (T) and its active metabolite O-desmethyltramadol (ODT) in human plasma. This determination is preceded by an off-line solid-phase extraction (SPE) on disposable extraction cartridges (DECs), performed automatically by means of a sample processor equipped with a robotic arm (ASPEC system). The DEC filled with ethyl silica (50 mg) was first conditioned with methanol and water. The washing step was performed with water and the analytes were finally eluted by dispensing methanol. The collected eluate was then evaporated to dryness before being dissolved in the LC mobile phase and injected into the LC system. The enantiomeric separation of tramadol and ODT was achieved on a Chiralpak AD column containing amylose tris-(3,5-dimethylphenylcarbamate) as chiral selector. The mobile phase was isohexane-ethanol-diethylamine (97:3:0.1, v/v). The LC system was then coupled to a tandem mass spectrometry system with an APCI interface in the positive ion mode. The chromatographed analytes were detected in the selected reaction monitoring mode. The MS-MS ion transitions monitored were 264-->58 for tramadol, 250-->58 for ODT, and 278-->58 for ethyltramadol, used as internal standard. The method was validated. The recoveries were around 90% for both T and ODT. The method was found to be linear for each enantiomer of both compounds (r2>0.999). The mean RSD values for repeatability and intermediate precision were 3.5 and 6.4% for T enantiomers and 5.0 and 5.6% for ODT enantiomers, respectively. Moreover, the method was found to be selective towards other metabolites, N-desmethyltramadol and N,O-desmethyltramadol (NODT). The method developed was successfully used to investigate plasma concentration of enantiomers of T and ODT in a pharmacokinetic study.

Optimization of a dry powder inhaler formulation of nacystelyn, a new mucoactive agent.

The aim of this study was to optimize a dry powder inhaler formulation containing a new mucoactive drug, nacystelyn. Formulations were made using three types of lactose, crystalline alpha-lactose, spray-dried lactose and a roller-dried anhydrous beta-lactose. The roller-dried anhydrous beta-lactose possessed the most adequate surface properties, resulting in a significantly higher (P < 0.05) in-vitro lung deposition of nacystelyn than the conventional crystalline alpha-lactose and spray-dried lactose. The particle size distribution of roller-dried beta-lactose was optimized also. Within the size ranges tested (63-100, 90-125 and 100-160 microm), the coarser the lactose, the higher the in-vitro deposition of the drug (up to 40%). In contrast, the in-vitro lung deposition of 100-160 microm roller-dried beta-lactose was very low (< 0.5%), so limiting the potential risk of lung irritation due to the carrier. The influence of the ratio of active ingredient/excipient (w/w) was also investigated. No difference was observed for mixtures from 1:2 to 1:4 while higher dilutions (1:5 and 1:6) showed significantly (P < 0.005) lower deposition results. Finally, the influence of the airflow rate was assessed. No dependence of the fine particle dose was observed between 40 and 80 L min(-1) while significantly higher results were obtained at 100 L min(-1). The dry powder inhaler formulation of nacystelyn using the unusual roller-dried anhydrous beta-lactose resulted in very high and reproducible in-vitro deposition results. However, the latter needs to be confirmed by in-vivo studies.

Effect of the mucoactive drug nacystelyn on the respiratory burst of human blood polymorphonuclear neutrophils.

In lung diseases such as chronic obstructive pulmonary disease (COPD) or cystic fibrosis, the activation of phagocytic cells produces high amounts of cytotoxic reactive oxygen species (ROS) that are partly implicated in the pathogenic process. In this study, the ex vivo antioxidant activity of nacystelyn (NAL), a recently developed mucoactive thiol-containing agent, was investigated using the respiratory burst of human blood polymorphonuclear neutrophils (PMNs). The ROS generation was induced by serum-opsonized zymosan and assessed with luminol- and lucigenin-enhanced chemiluminescence (ECL). The activity of NAL was compared with N-acetylcysteine (ACC) and captopril, other thiol-containing pharmacological agents having documented antioxidant properties. The three drugs significantly inhibited the ECL response of activated PMNs in the presence of luminol, a luminogenic agent which mostly reflects the production of hydroxyl and hypohalite radicals. NAL was more efficient than the other two drugs: the concentrations producing a 50% inhibition (IC50) of total luminol-ECL were 290 microM, 1580 microM and 760 microM for NAL, ACC and captopril, respectively. The inhibition of the lucigenin-ECL response of activated PMNs was less marked for all compounds suggesting a poorer reactivity with superoxide radicals. These findings demonstrate that NAL, at concentrations obtainable in vivo by inhalation, impairs the PMNs chemiluminescence response related to hydroxyl and hypohalite radicals production. As those radicals are highly cytotoxic, NAL appears as a promising agent in the prevention of oxidative lung damage caused by an active inflammatory response.

In vitro comparative assessment of the antioxidant activity of nacystelyn against three reactive oxygen species.

Thiol-containing molecules possess antioxidant properties that are of interest in the pharmacological inactivation of reactive oxygen species (ROS), particularly in the treatment of chronic inflammatory respiratory diseases. In the present study, the in vitro antioxidant activity of a new agent was examined and compared with other thiol containing molecules, N-acetylcysteine (NAC) and captopril. Nacystelyn (CAS 89344-48-9, NAL) is a L-lysine salt of NAC having demonstrated several advantages as compared to NAC. The deoxyribose assay used for assessing the scavenging effect of drugs against hydoxyl radicals (.OH) first showed a prooxidant effect for thiols at relatively low concentrations that was attributed to a reduction of Fe(III) ions added in the system. This interference could be corrected by increasing ascorbate concentration. Second order rate constants for reaction with OH were calculated by extrapolation of the linear part of competition plots. Both NAL and NAC appeared as potent .OH scavengers (Ks > 10(10) mol-1 s-1) and reacted faster than captopril. The horseradish peroxidase assay for assessing the activity of thiols against H202 could not be used because thiol derivatives were substrates for the enzyme. By using the dithio-bis-nitrobenzoic acid (DTNB) assay, first order rate constants for reaction with H2O2 were obtained showing that both NAL and NAC reacted quite slowly with this species (K approximately equal to 0.03 min-1) although faster than captopril. Finally, the elastase-alpha 1-antiproteinase assay for assessing the activity of thiols against HClO again demonstrated the superiority of NAC and NAL over captopril, but this time, NAL was more efficient in maintaining the protease/antiprotease balance than NAC. This last observation may be of importance and deserves further investigation as HClO has been implicated in lung tissue damages during inflammatory respiratory diseases.