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Effect of N-Acetyl Cysteine on the Concentrations of Thiols in Plasma

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Effect of N-Acetyl Cysteine on the Concentrations of Thiols in Plasma 670 Thorax 1994;49:670-675 Effect of N-acetyl cysteine on the concentrations of thiols in plasma, bronchoalveolar lavage fluid, and lung tissue Thorax: first published as 10.1136/thx.49.7.670 on 1 July 1994. Downloaded from Myrtle M E Bridgeman, Mark Marsden, Colin Selby, Douglas Morrison, William MacNee Abstract going lung resection those treated with Background - Oxidant/antioxidant im- N-acetyl cysteine (600 mg thrice daily for balance may occur in the lungs of five days) had similar concentrations of patients with chronic obstructive pul- cysteine and glutathione in both plasma monary disease (COPD). Glutathione is and lung tissue when compared with a an important extracellular and intracel- control untreated group. lular thiol oxidant in the lungs. These Conclusions - These data suggest that, studies were carried out to determine the even when given in high oral doses, effect of N-acetyl cysteine on thiol con- N-acetyl cysteine does not produce a centrations in plasma, bronchoalveolar sustained increase in glutathione levels lavage fluid, and lung tissue. sufficient to increase the antioxidant Methods - Studies were carried out on capacity of the lungs. normal subjects, patients with COPD, and those undergoing lung resection. In (Thorax 1994;49:670-675) the first study N-acetyl cysteine was given to three groups; healthy subjects (600 mg once daily by mouth) and two There is increasing interest in the hypothesis groups of patients with COPD. In the that an imbalance between oxidants and first group of patients with COPD the antioxidants may be involved in the patho- dose was 600 mg once daily and in the genesis of emphysema.'2 Oxidants such as re- second 600 mg thrice daily, all for five active oxygen intermediates are produced by days. The latter dosage regimen was also airspace phagocytes during lung inflammation given to six patients before bronchoscopy or inhaled directly from the environment dur- http://thorax.bmj.com/ and to 11 patients before lung resection. ing cigarette smoking or as a result of air Lung glutathione (GSH) levels in bron- pollutants such as ozone.'-3 Such oxidants can choalveolar lavage fluid or lung tissue damage lung connective tissue and epithelial were compared with the same numbers cells directly by the process of lipid peroxida- of patients who did not receive N-acetyl tion.4 It has also been suggested that during cysteine. cigarette smoking5 or ozone inhalation6 oxid- Results - N-acetyl cysteine was detected ants may reach and affect cells in the intravas- in a plasma after single 600 mg dose in cular space. Moreover, a strong relation has on September 25, 2021 by guest. Protected copyright. normal subjects and patients with COPD been shown between a deficiency in the anti- up to 15 hours after the drug was oxidant capacity of plasma and the presence of given. Plasma cysteine concentrations a family history of lung disease.7 The plasma of increased in normal subjects on both patients with chronic obstructive pulmonary days 1 and 5, and in patients with COPD disease (COPD) has also been shown to have a Department of on day 5. Glutathione concentrations in reduced capacity to prevent elastolysis which Biochemistry, plasma increased on day 1 in normal may be compounded by an abnormal anti- University of subjects but not in patients with COPD oxidant capacity in the plasma of these Edinburgh Medical School given 600 mg N-acetyl cysteine daily. patients.8 Thus, one therapeutic option in M M E Bridgeman With the higher dose of 600 mg thrice patients with COPD would be to increase the M Marsden daily, however, there was a sustained ele- antioxidant capacity, not only of the plasma, vation of GSH concentrations in Unit of Respiratory plasma but of the epithelial lining fluid and the lung Medicine, in patients with COPD. In patients cells in such patients. Department of undergoing routine diagnostic broncho- N-acetyl cysteine is a drug which has been Medicine (RIE), scopy and bronchoalveolar lavage those in treatment of City Hospital used for the past 20 years the C Selby who were given N-acetyl cysteine patients with COPD.9 Some long term studies D Morrison (600 mg) thrice daily for five days had have shown that oral administration of N- W MacNee higher concentrations of cysteine in the acetyl cysteine reduces the number of acute Edinburgh EH10 SSB, plasma, but no significant differences in exacerbations in patients with chronic bron- UK cysteine concentrations in bronchoalveo- chitis,0"11 although others have not.'2 The lar or fluid com- in these stud- Reprint requests to: lavage epithelial lining doses of N-acetyl cysteine used Dr W MacNee. pared with a control group; nor were ies'>-2 were 200mg and 300 mg twice daily, Received 7 January 1993 there any differences in reduced gluta- and 200 mg thrice daily respectively. However, Returned to authors is 7 July 1993 thione concentrations in plasma, bron- whether the efficacy of N-acetyl cysteine Revised version received choalveolar lavage or epithelial lining mediated through its antioxidant action re- 8 February 1994 Accepted for publication fluids between the control and treated mains uncertain. 8 March 1994 groups. Moreover, in patients under- N-acetyl cysteine is rapidly metabolised N-Acetyl cysteine and thiol concentrations 671 during absorption to cysteine, whose thiol thiol levels of a higher dosage of N-acetyl group also possesses reducing and antioxidant cysteine, 600 mg thrice daily for five days, was properties."3 Moreover, cysteine is a precursor assessed. Blood samples were withdrawn at in the biosynthesis of glutathione, an import- 0, 6, 12 and 24 hours - that at the time the is, Thorax: first published as 10.1136/thx.49.7.670 on 1 July 1994. Downloaded from ant intracellular and extracellular anti- N-acetyl cysteine dose was due - on both oxidant.'415 We have previously shown that day 1 and day 5. N-acetyl cysteine, 600 mg/day for five days, can increase cysteine concentrations in plasma and temporarily increase the concentrations of EFFECTS OF N-ACETYL CYSTEINE ON PLASMA glutathione in plasma and bronchoalveolar AND BRONCHOALVEOLAR LAVAGE THIOL LEVELS lavage fluid.'6 This may have a therapeutic role Two groups (4 and 5, table 1) of patients who by increasing the antioxidant capacity in the were either smokers or ex-smokers, all with plasma and the lungs. However, because of the peripheral bronchial carcinomas who were low bioavailability of N-acetyl cysteine,13 undergoing diagnostic bronchoscopy and higher doses may be necessary to achieve a bronchoalveolar lavage, were studied. Group 4 sustained effect within the airspaces or in lung acted as a control group and were not given N- tissue, particularly in patients with COPD. acetyl cysteine; subjects in group 5 were given The aim of this study was to compare the N-acetyl cysteine in a dose of 600 mg thrice effects of two dose regimens of N-acetyl daily for five days. Blood and bronchoalveolar cysteine on plasma thiol concentrations in lavage samples (the latter from the lung with- patients with COPD, and to study the effect of out the tumour) were obtained from all the higher dose regimen on thiol concentra- patients. In the treated group bronchoalveolar tions in bronchoalveolar lavage fluid and lung lavage and blood samples were obtained three tissue. hours after the last dose of N-acetyl cysteine on day 5 of treatment. Methods EFFECTS OF N-ACETYL CYSTEINE ON PLASMA EFFECT OF N-ACETYL CYSTEINE ON PLASMA AND THIOL LEVELS IN NORMAL SUBJECTS AND LUNG THIOL LEVELS PATIENTS WITH COPD Two groups of patients (groups 6 and 7, table This study involved three groups: healthy, 1), 22 in total, all with peripheral bronchial normal, non-smoking subjects (group 1) and carcinomas planned for lung resection, were two groups of patients, both ex-smokers, with studied. Group 6 acted as a control group and COPD (groups 2 and 3) (table 1). The normal were not given N-acetyl cysteine; patients in subjects were given N-acetyl cysteine by group 7 were given N-acetyl cysteine 600 mg mouth one hour after meals in a single oral thrice daily for 5 days before their operation. http://thorax.bmj.com/ dose of 600 mg daily for five days. Blood Samples were obtained 12-16 hours after the samples were withdrawn from an indwelling last dose of N-acetyl cysteine. venous catheter at 0, 0 5, 1-0, 1-5, 2-0, 4 0, 6 0, Informed consent was given by all subjects and 8&0 hours after N-acetyl cysteine on days 1 and patients, and the study had the approval of and 5. Based on these results, a comparison of the local hospital ethical committee. plasma thiol levels was made in patients with COPD (group 2, table 1) at similar time points, excepting eight hours, following an oral dose METHODOLOGY on September 25, 2021 by guest. Protected copyright. of 600mg N-acetyl cysteine which was pre- Blood samples ceded by treatment with 600 mg N-acetyl cys- Venous blood, 5 ml, was withdrawn into lith- teine once daily for four days. Two blood ium heparin tubes and centrifuged at 4°C for samples separated by six hours were also with- 10 minutes at 800g to obtain plasma. drawn from both groups where no N-acetyl cysteine had been given in order to determine the stability of baseline concentrations of cys- Measurement of urea teine and glutathione. The concentrations of urea in plasma and In a further group of six patients with bronchoalveolar lavage fluid were measured COPD (group 3, table 1) the effect on plasma using a standard kit (No 66, Sigma, Poole, Table 1 Mean (SD) patient characteristics Group Type n Age (years) FEV, FVC (% predicted range) (% predicted range) 1 Normal subjects 6 30-0 (8 5) 91-110 93-114 4M:2F 2 COPD 6 69-3 (10-6) 26-50 43-81 4M:2F 3 COPD 6 65-5 (40) 27-58 28-68 2M:4F 4 Bronchial carcinoma 6 65-2 (11-9) 56-83 65-80 3M:3F 5 Bronchial carcinoma 6 71-5 (6-1) 49-74 59-89 6M 6 Bronchial carcinoma 11 62-9 (10-4) 59-100 53-98 7M:4F 7 Bronchial carcinoma 11 65-2 (6-0) 50-96 62-90 9M:2F COPD =chronic obstructive pulmonary disease; FEV, = forced expiratory volume in one second; FVC=forced vital capacity.
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