Inhibition of development of tolerance to nitroglycerin by preventive administration of N-acetylcysteine in rats

The efficacy of N-acetylcysteine in reversing nitrate tolerance has been controversial. This study examined whether continuous administration of N-acetylcysteine, a sulfhydryl compound, can prevent the development of tolerance to nitroglycerin; its acute effects on developed tolerance were also assessed. Rats were treated with subcutaneous injections of 1) 100 mg/kg nitroglycerin, 2) 100 mg/kg nitroglycerin and 700 mg/kg N-acetylcysteine, 3 times a day for 3 days. The sensitivity to nitroglycerin was studied in aortic preparations. The degree of developed tolerance to nitroglycerin was partially inhibited by simultaneous injection of N-acetylcysteine. Subsequent in vitro preincubation of aortic strips with nitroglycerin (10(-5) M) reduced the subsequent nitroglycerin sensitivity of vessels from rats treated with nitroglycerin and N-acetylcysteine; sensitivity returned to the initial control level after in vitro preincubation with N-acetylcysteine. The nitroglycerin sensitivity of vessels from rats treated only with nitroglycerin, though, was not affected by in vitro preincubation with N-acetylcysteine. In conclusion, N-acetylcysteine is not effective in reversing the high degree of tolerance developed to nitroglycerin. However, continuous administration of N-acetylcysteine is effective in preventing the development of nitroglycerin tolerance.     

Nitrate tolerance in epicardial arteries or in the venous system is not reversed by N-acetylcysteine in vivo, but tolerance-independent interactions exist

N-acetylcysteine is assumed to reverse nitrate tolerance by replenishing depleted intracellular sulfhydryl groups, but data on interactions of N-acetylcysteine and nitrates in patients with stable angina are controversial and disappointing. Therefore, we studied the effect of N-acetylcysteine on nitrate responsiveness of epicardial arteries and of the venous system (assessed as changes in effective vascular compliance) in dogs (n = 12) during long-term nitroglycerin treatment (1.5 micrograms/kg/min i.v. for 5-6 days). In dogs with nitroglycerin-specific tolerance (shift of venous or epicardial artery dilation to 15-17-fold higher dosages), N-acetylcysteine (100 mg/kg i.v.) had no dilator effect and did not alter the dose-response relations of nitroglycerin. Yet, in nontolerant dogs (n = 17), N-acetylcysteine augmented (1.5-2.0-fold) the dilation of epicardial arteries and the reduction of peripheral vascular resistance induced by 0.5-1.5 micrograms/kg/min nitroglycerin. In vitro, the augmentation of purified guanylate cyclase activity by nitroglycerin (10-100 microM) was potentiated by N-acetylcysteine (0.01-1.0 mM) in saline or in canine plasma, but N-acetylcysteine alone was ineffective. We conclude that 1) N-acetylcysteine does not restore nitroglycerin responsiveness in tolerant epicardial arteries or veins in vivo, 2) a small, tolerance-independent augmentation of nitroglycerin-induced dilation may result from N-acetylcysteine-induced extracellular formation of a stimulant of guanylate cyclase from nitroglycerin.     

Cimetidine in the treatment of acetaminophen overdose

Acetaminophen overdose is generally treated with oral N-acetylcysteine. While N-acetylcysteine is protective, an additional effective mode of treatment is desirable in large overdoses. A growing body of evidence suggests that cimetidine significantly reduces the hepatotoxicity of an acetaminophen overdose and that its hepatoprotective action may be additive to that of N-acetylcysteine. We report a case of acetaminophen overdose treated with oral N-acetylcysteine in conjunction with cimetidine by continuous i.v. infusion. The 4-h acetaminophen level was 410 micrograms/ml, and the highest measured level of serum glutamic oxaloacetic transaminase was 83 IU/L on day 3, indicating minimal hepatic toxicity.     

Glutathione depletion in HIV-infected patients: role of cysteine deficiency and effect of oral N-acetylcysteine.

OBJECTIVE: To determine whether a single oral dose of N-acetylcysteine corrects the deficiency of cysteine and glutathione in plasma and mononuclear cells of HIV-infected patients. DESIGN: Pharmacokinetic and pharmacodynamic study. METHODS: Cysteine and glutathione were measured in plasma and peripheral blood mononuclear cells of patients at different stages of HIV infection before and after a single oral dose of N-acetylcysteine. RESULTS: At baseline, the plasma concentrations of glutathione and cysteine were significantly lower in HIV-infected patients than in healthy controls. The intracellular concentration of glutathione correlated with the absolute CD4 lymphocyte counts: the concentration of glutathione in mononuclear cells was significantly lower in patients with more advanced immunodeficiency. A single oral dose of N-acetylcysteine increased the concentration of cysteine in plasma and mononuclear cells of HIV-infected patients. Four hours after N-acetylcysteine administration, intracellular glutathione concentrations in the patients were moderately higher than at baseline and at 2 h. CONCLUSIONS: Oral N-acetylcysteine transiently increases the concentrations of cysteine and glutathione in mononuclear cells of patients with HIV infection. A sustained increase in intracellular cysteine may be necessary to normalize intracellular glutathione. This may be accomplished by repeat administration of N-acetylcysteine.     

Effects of N-acetylcysteine on oxidant-antioxidant balance in oleic acid-induced lung injury

The antioxidant and anti-inflammatory properties of N-acetylcysteine has been documented in many experimental lung injury models. Because intravenous injection of oleic acid induces histopathologic changes similar to those seen in human acute lung injury or acute respiratory distress syndrome, the authors evaluated the effects of N-acetylcysteine (NAC) on oxidative stress and lung damage in an oleic acid (OA)-induced lung injury model. Thirty-five rats were divided into 5 groups as sham, NAC, OA, pre-OA-NAC, and post-OA-NAC. Lung damage was induced by intravenous administration of oleic acid. Pre-OA-NACgroup received intravenous (IV) N-acetylcysteine 15 minutes before oleic acid infusion and post-OA-NAC group received IV N-acetylcysteine 2 hours after oleic acid infusion. In both of the N-acetylcysteine treatment groups, blood and tissue samples were collected 4 hours after oleic acid infusion, independent from the time of N-acetylcysteine infusion. In other groups, blood and tissue samples were collected 4 hours after ethanol, NAC, or OA infusions. Serum myeloperoxidase activity, total antioxidant capacity, malondialdehyde levels, and lung tissue Na+ - K+ ATPase activity were measured and light microscopic analyses of lung specimens were performed. The administration of N-acetylcysteine significantly restored Na+ - K+ ATPase activity and total antioxidant capacity levels and ameliorated lung architecture. N-acetylcysteine has been shown to have some attenuating effects in experimental animal studies. However, further investigations are necessary to suggest N-acetylcysteine as a treatment agent in critically ill patients with lung injury.     

Role of N-acetylcysteine in prevention of contrast-induced nephropathy after cardiovascular procedures: a meta-analysis

BACKGROUND: Contrast-induced nephropathy is one of the common causes of acute renal insufficiency after cardiovascular procedures. HYPOTHESIS: The objective of this paper was to analyze the published data on the usefulness of N-acetylcysteine in the prevention of contrast-induced nephropathy after these procedures. METHODS: Trials were selected if they were prospective, randomized, controlled, had selected patients with impaired renal function, used low-osmolality, nonionic contrast media intra-arterially, administered a total of four doses of N-acetylcysteine in addition to intravenous saline hydration, and had contrast-induced nephropathy as their primary outcome. Contrast-induced nephropathy was defined as an increase in serum creatinine concentration by >0.5 mg/dl or a 25% increase above baseline at or within 48 h post procedure. Meta-analysis was performed using the Fisher's Combined Test with a measure of effect size. The magnitude of the N-acetylcysteine effect was estimated using random-effects models. Homogeneity was evaluated using the chi-square test of homogeneity and standard Q statistic. Reporting bias was explored by the Rosenthal method. RESULTS: The Fisher's Combined Test was significant at p < 0.005 in favor of N-acetylcysteine. The size of the N-acetylcysteine effect was to reduce contrast-induced nephropathy by 20%. There was a 62% relative risk reduction in contrast-induced nephropathy with N-acetylcysteine using a fixed-effects model, and a 70% relative risk reduction using the random-effects model. In addition, we found that 27 unpublished trials showing no effects of N-acetylcysteine would exist to overturn the combined significance of p < 0.005 of the five trials in our meta-analysis. CONCLUSION: Oral administration of N-acetylcysteine in addition to intravenous saline hydration has a beneficial effect in the prevention of contrast-induced nephropathy after cardiovascular procedures in patients with impaired renal function.     

Effect of Transdermal Nitroglycerin or N-Acetylcysteine,or Both,in the Long-Term Treatment of Unstable Angina Pectoris

Objectives. This study was designed to evaluate whether the addition of transdermal nitroglycerin or oral N-acetylcysteine, or both, to conventional medical therapy improves the natural history of unstable angina pectoris.Background. Transdermal nitroglycerin is widely used to treat angina pectoris, but the development of tolerance is a major problem that may reduce its clinical efficacy. It has been suggested that the addition of N-acetylcysteine to nitroglycerin reverses the development of tolerance, potentiates the hemodynamic response to nitroglycerin and may improve in-hospital prognosis in unstable angina.Methods. We assessed the efficacy of adding transdermal nitroglycerin or oral N-acetylcysteine, or both, to conventional medical therapy in a randomized, double-blind, placebo-controlled trial involving 200 patients with unstable angina who were followed up for 4 months.Results. Outcome events—death, myocardial infarction or refractory angina requiring revascularization—occurred in 31% of patients receiving nitroglycerin, 42% of those receiving N-acetylcysteine, 13% of those receiving nitroglycerin plus N-acetylcysteine and 39% of those receiving placebo (p = 0.0052). Kaplan-Meier curves showed a higher probability (p < 0.01) of no failure of medical treatment in the group receiving both nitroglycerin and N-acetylcysteine than in those receiving placebo, N-acetylcysteine or nitroglycerin alone. The combination of nitroglycerin and N-acetylcysteine was associated with a high incidence of side effects (35%), mainly intolerable headache, which was almost twice as frequent as in patients receiving nitroglycerin alone.Conclusions. The combination of nitroglycerin and N-acetylcysteine, associated with conventional medical therapy in the long-term treatment of patients with unstable angina, reduces the occurrence of outcome events. However, the high incidence of side effects limits the clinical applicability of this therapeutic strategy at least at the dosage used in the present study.(J Am Coll Cardiol 1997;29:941–7)© 1997 by the American College of Cardiology     

Portal and systemic haemodynamic action of N-acetylcysteine in patients with stable cirrhosis.

The effects of intravenous N-acetylcysteine on hepatic and systemic haemodynamics were investigated in 11 patients with stable cirrhosis (eight alcohol; two primary biliary cirrhosis; one cryptogenic). N-acetylcysteine administration had no effect on the mean heart rate or mean arterial blood pressure despite a significant fall in systemic and pulmonary vascular resistance. Cardiac index increased but estimated liver blood flow and portal venous pressure did not change significantly. Administration of N-acetylcysteine resulted in increased oxygen delivery to the tissues because of the increased cardiac index but this was not accompanied by a rise in either arteriovenous oxygen extraction ratio or mean tissue oxygen consumption. Therefore N-acetylcysteine administration seems to confer no haemodynamic benefit to patients with cirrhosis.     

N-acetylcysteine and clotrimazole inhibit sickle erythrocyte dehydration induced by 1-chloro-2,4-dinitrobenzene.

Clotrimazole, a specific inhibitor of the Ca(2+) activated potassium (Gardos) channel, and the antioxidant N-acetylcysteine were found to inhibit the in vitro formation of high-density sickle cells induced by treatment with 1-chloro-2,4-dinitrobenzene (CDNB). The CDNB induced leakage of K(+) can be inhibited by treatment of SS erythrocytes with 20 mM N-acetylcysteine. We conclude that the effect of N-acetylcysteine in preventing K(+) efflux and formation of high-density sickle cells is related to its ability to protect the Gardos channel from oxidative damage caused by diminished levels of reduced glutathione. This effect is due to the ability of N-acetylcysteine to maintain an appropriate level of reduced glutathione and its direct antioxidant activity.     

N-acetylcysteine and glycyrrhizin combination: Benefit outcome in a murine model of acetaminophen-induced liver failure

BACKGROUND Acetaminophen overdose is the most frequent cause of drug-induced liver failure in developed countries. Substantial progress has been made in understanding the mechanism of hepatocellular injury, but N-acetylcysteine remains the only effective treatment despite its short therapeutic window. Thus, other hepatoprotective drugs are needed for the delayed treatment of acetaminopheninduced hepatotoxicity. Our interest focused on glycyrrhizin for its role as an inhibitor of high mobility group box 1(HMGB1) protein, a member of the family of damage-associated molecular pattern, known to play an important pathological role in various diseases.AIM To investigate the efficacy of the N-acetylcysteine/glycyrrhizin combination compared to N-acetylcysteine alone in the prevention of liver toxicity.METHODSEight-week-old C57 BL/6 J wild-type female mice were used for all our experiments. Mice fasted for 15 h were treated with acetaminophen(500 mg/kg) or vehicle(phosphate-buffered saline) by intraperitoneal injection and separated into the following groups: Glycyrrhizin(200 mg/kg); N-acetylcysteine(150 mg/kg); and N-acetylcysteine/glycyrrhizin. In all groups, mice were sacrificed 12 h following acetaminophen administration. The assessment of hepatotoxicity was performed by measuring plasma levels of alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase. Hepatotoxicity was also evaluated by histological examination of hematoxylin and eosin-stained tissues sections. Survival rates were compared between various groups using Kaplan-Meier curves.RESULTS Consistent with data published in the literature, we confirmed that intraperitoneal administration of acetaminophen(500 mg/kg) in mice induced severe liver injury as evidenced by increases in alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase but also by liver necrosis score. Glycyrrhizin administration was shown to reduce the release of HMGB1 and significantly decreased the severity of liver injury. Thus, the co-administration of glycyrrhizin and N-acetylcysteine was investigated. Administered concomitantly with acetaminophen, the combination significantly reduced the severity of liver injury. Delayed administration of the combination of drugs, 2 h or 6 h after acetaminophen, also induced a significant decrease in hepatocyte necrosis compared to mice treated with N-acetylcysteine alone. In addition, administration of N-acetylcysteine/glycyrrhizin combination was associated with an improved survival rate compared to mice treated with only N-acetylcysteine.CONCLUSION We demonstrate that, compared to N-acetylcysteine alone, co-administration of glycyrrhizin decreases the liver necrosis score and improves survival in a murine model of acetaminophen-induced liver injury. Our study opens a potential new therapeutic pathway in the prevention of acetaminophen hepatotoxicity.     

N-acetylcysteine infusion in viral myocarditis:: A case report

N-acetylcysteine improves survival in established acute liver failure following paracetamol overdose by reducing the incidence of multiorgan failure. These benefits are thought to be related to decreased tissue hypoxia by the enhancement of both oxygen delivery and oxygen extraction. Similar findings have been recorded in critically ill patients from an alternative aetiology. The cardiovascular properties of N-acetylcysteine are to increase stroke volume index, and thus cardiac output, although there is no effect on cardiac output in normal subjects. N-acetylcysteine is known to improve myocardial contraction in a hamster model of chronic myocardial ischaemia, but such effects have not previously been described in humans. We report the beneficial circulatory effect of N-acetylcysteine in a patient with marked left ventricular dysfunction secondary to acute viral myocarditis.     

Effect of intravenous N-acetylcysteine infusion on haemostatic parameters in healthy subjects

BACKGROUND AND AIMS: N-acetylcysteine is used to treat paracetamol overdose but depresses the activity of plasma coagulation factors II, VII, and X, which are often used to assess liver injury. The aim of this study was to investigate the effect of N-acetylcysteine on haemostasis in normal volunteers. METHODS: Haemostatic parameters in 10 healthy subjects were analysed before and following intravenous infusion of therapeutic doses of N-acetylcysteine, as well as in vitro. RESULTS: N-acetylcysteine induced significant decreases in plasma levels of vitamin K dependent haemostatic proteins in vivo, being maximal at one hour following the start of infusion, with maximal decreases from 1.00 to 0.73 (0.67-0.79) (mean (95% confidence interval)), 0.66 (0.58-0.73), 0.81 (0.73-0.90), 0.64 (0.57-0.70), 0.74 (0.65-0.82), and 0.61 (0.54-0.67) for factor II, VII, IX, and X activities, protein C activity, and free protein S reactivity, respectively. These data suggest that N-acetylcysteine induces protein modifications affecting activity. Five subjects developed an adverse reaction to infusion of N-acetylcysteine and these were associated with a rapid increase in levels of factor VIII and its carrier protein von Willebrand factor (vWf) from 1.0 to 1.85 (1.08-2.62) and 1.77 (0.83-2.71), respectively, which suggests that the allergic reaction induced release of vWf from endothelial cells. N-acetylcysteine did not affect factor VIII or vWf in subjects without adverse reactions, and nor did it affect factor V or antithrombin in any of the subjects. CONCLUSION: Therapeutic doses of N-acetylcysteine cause abnormal haemostatic activity, and this should be taken into account when using haemostatic function tests as an indicator of hepatic injury.     

N-acetylcysteine and exacerbations of chronic obstructive pulmonary disease

Oxidative stress may play a role in chronic obstructive pulmonary disease (COPD) exacerbations. There is heterogeneity in the literature with regard to the impact of antioxidant therapy on COPD exacerbation frequency. Clinical trials of N-acetylcysteine in COPD were identified in unrestricted searches of MEDLINE, CINAHL, International Pharmaceutical Abstracts and the Cochrane Register. Randomized, controlled trials which reported exacerbations over a treatment period > or =3 months were selected. Two observers independently extracted data regarding exacerbation number over the treatment period in subjects allocated to either N-acetylcysteine or placebo. Data were analyzed using inverse-variance weighted random effects meta-analysis methodology. Meta-analysis of data from 8 trials (randomized n = 2,214) indicated that N-acetylcysteine significantly reduced the odds of experiencing one or more exacerbations over the treatment period (odds ratio = 0.49, 95% confidence interval [0.32-0.74], p = 0.001). Treatment effect was not reduced in studies which enrolled >50% active smokers (odds ratio = 0.36 [0.24-0.55], p < 0.001), although a greater effect was observed with exclusion of subjects using concurrent inhaled corticosteroids (odds ratio = 0.42 [0.32-0.54], p < 0.0001), suggesting that inhaled steroids attenuate the effect of N-acetylcysteine. The use of N-acetylcysteine significantly reduces the odds of exacerbation in patients with COPD, an effect possibly attenuated by inhaled steroids but not smoking. This analysis suggests treatment with N-acetylcysteine may be beneficial in a subset of patients with COPD.     

What is the rate of adverse events after oral N-acetylcysteine administered by the intravenous route to patients with suspected acetaminophen poisoning?

STUDY OBJECTIVE: We conduct a study to determine the rate of adverse events (anaphylactoid and cardiorespiratory) associated with the use of oral N-acetylcysteine by the intravenous route for the treatment of suspected acetaminophen poisoning and to examine specific variables that may be associated with adverse events. METHODS: We conducted a retrospective medical record review with explicit criteria. All patients who received oral N-acetylcysteine by the intravenous route from September 1995 to September 2001 were included. Patients were identified by cross-matching 3 databases. Adverse events were divided into categories of cutaneous, systemic, or life threatening. Five reviewers abstracted charts by using a standardized data collection form. Interrater reliability was calculated by using 24 medical records abstracted by all 5 reviewers. RESULTS: There were 7 adverse events identified in 187 patients (3.7%; 95% confidence interval 1.0% to 6.5%). Six adverse events were cutaneous and responded rapidly to antihistamines. One adverse event was life threatening but not clearly related to N-acetylcysteine. A high rate of antihistamine exposure (53%) was identified before the administration of N-acetylcysteine. Interrater agreement was higher than 95%. CONCLUSION: Intravenous administration of an oral solution of N-acetylcysteine is associated with a low rate of adverse events and should be considered for selected patients with suspected acetaminophen poisoning.     

High-dose N-acetylcysteine for the Prevention of Contrast-induced Nephropathy

Background

Whether N-acetylcysteine is beneficial for the prevention of contrast-induced nephropathy is uncertain.

Methods

We conducted a meta-analysis to evaluate the efficacy of high-dose N-acetylcysteine for the prevention of contrast-induced nephropathy. Our prespecified inclusion criteria were as follows: adult subjects; English language literature; administration of high-dose N-acetylcysteine a priori defined as a daily dose greater than 1200 mg or a single periprocedural dose (within 4 hours of contrast exposure) greater than 600 mg; prospective trials of individuals randomized to N-acetylcysteine, administered orally or intravenously, versus a control group; and trials that included the end point of the incidence of contrast-induced nephropathy. Trials that compared N-acetylcysteine with another active treatment were excluded.

Results

Sixteen comparisons of patients randomized to high-dose N-acetylcysteine versus controls met our prespecified inclusion criteria with a total sample size of 1677 subjects (842 assigned to high-dose N-acetylcysteine and 835 assigned to the control arm). The average population age was 68 years, 38.7% were diabetic, and the majority was male (67.8% of reported instances). The weighted mean baseline creatinine of the overall population was 1.58 mg/dL. No significant heterogeneity was detected (P = .09; I² = 34%). The overall effect size assuming a common odds ratio revealed an odds ratio of 0.46 (95% confidence interval [CI], 0.33-0.63) for the occurrence of contrast-induced nephropathy with the use of high-dose N-acetylcysteine. The results of the more conservative random effects approach were similar (odds ratio = 0.52; 95% CI, 0.34-0.78). There was no evidence of publication bias (P = .34).

Conclusion

Our results suggest that high-dose N-acetylcysteine decreases the incidence of contrast-induced nephropathy.     

N-Acetylcysteine improves renal dysfunction, ameliorates kidney damage and decreases blood pressure in salt-sensitive hypertension

BACKGROUND: Salt-sensitive hypertension in humans and experimental animals causes progressive increases in renal damage and dysfunction. The Dahl salt-sensitive (S) rat closely mimics human salt-sensitive hypertension. AIM: Our goal was to test the hypothesis that enhancing the glutathione system with dietary N-acetylcysteine administration in Dahl S rats on a high sodium intake for 5 weeks will attenuate the increases in arterial pressure, the decreases in renal hemodynamics and the increases in renal damage that normally occur in S rats on high sodium. METHODS: Forty-four 7- to 8-week-old Dahl S/Rapp strain rats were maintained on a high sodium (8%), high sodium + N-acetylcysteine (4 g/kg per day), or low sodium (0.3%) diet for 5 weeks. Rats had arterial and venous catheters implanted at day 21. RESULTS: By day 35 in the high-sodium rats, N-acetylcysteine treatment significantly increased the renal reduced-to-oxidized glutathione ratio, glomerular filtration rate, and renal plasma flow, and decreased renal cortical and medullary O2 release, urinary protein excretion, renal tubulointerstitial damage and glomerular necrosis. At this time, mean arterial pressure increased to 183 +/- 1 mmHg, and N-acetylcysteine reduced this arterial pressure to 121 +/- 4 mmHg. By day 35 in S high-sodium rats, N-acetylcysteine had caused a 91% decrease in glomerular necrosis and an 83% decrease in tubulointerstitial damage. CONCLUSIONS: In Dahl S rats on high sodium intake, arterial pressure increases significantly and renal injury is pronounced. Treatment with N-acetylcysteine enhances the renal glutathione system, improves renal dysfunction and markedly decreases arterial pressure and renal injury in Dahl salt-sensitive hypertension.     

Cardioprotective effects of N-acetylcysteine: the reduction in the extent of infarction and occurrence of reperfusion arrhythmias in the dog

We have studied the cardioprotective effect of N-acetylcysteine in the dog. In mongrel dogs of either sex, the left anterior descending coronary artery was ligated for a period of 2 hours behind the origin of its first diagonal branch. After this period, dogs in a treated group were administered 100 mg of N-acetylcysteine/kg body weight while a control group remained untreated. This was followed by a 2-hour period of reperfusion. The extent of necrosis was determined using the triphenyltetrazolium method. Presence or absence of collaterals was established at the same time. The incidence of ventricular arrhythmias was monitored throughout the study. Compared with 11 dogs of the control group, 10 dogs treated with N-acetylcysteine showed a decrease of 32.7% in the extent of infarction. The extent of infarction, expressed as the percentage of the left ventricular myocardium at risk, was 55.0 +/- 7.0% in the control group and 37.0 +/- 12.6% in the treated group (P less than 0.01). N-acetylcysteine also statistically significantly decreased the incidence of ventricular arrhythmias over the period of reperfusion. Compared with the control group, the difference was evident as early as the first 5-10 minutes of reperfusion, becoming most pronounced at the 60th minute (P less than 0.001). We conclude that N-acetylcysteine is effective in limiting the extent of infarction and significantly reduces the incidence of reperfusion ventricular arrhythmias.     

N-acetylcysteine improves microcirculatory flow during smoking: new effects of an old drug with possible benefits for smokers.

BACKGROUND: Cigarette smoking provokes marked acute changes in the microcirculatory vasculature, including a reduced blood flow velocity. In accordance with the hypothesis that the reduced blood flow is due to an imbalance between pro-oxidants and oxidants, we recently showed that most of the reduction could be reversed by a high dose of vitamin C. HYPOTHESIS: In the present work we tested the hypothesis that N-acetylcysteine, a mucolyticum and an antioxidant, may have an effect on the smoking-induced changes observed by vital capillary microscopy of the nailfold. METHODS: In all, 37 healthy volunteers of both genders and with varied smoking habits were treated with N-acetylcysteine 200 mg t.i.d. for 2 weeks. In vivo investigation of the microcirculation by capillaroscopy was performed before and after treatment. RESULTS: Treatment with N-acetylcysteine significantly reduced the smoking-induced relative decrease in capillary blood flow velocity in a group of volunteers with varied smoking habits (p = 0.0016). The preventive effect was clearly significant in smokers (p = 0.003). CONCLUSION: Treatment with N-acetylcysteine has a positive impact on microcirculatory flow during smoking, particularly in habitual smokers.     

Addition of N-acetylcysteine to aqueous model bile systems accelerates dissolution of cholesterol gallstones

The organic matrix of cholesterol gallstones contains a macromolecular complex of mucin and bilirubin that may inhibit stone dissolution by limiting contact of desaturated bile with crystalline cholesterol. The goal of this study was to determine if the mucolytic agent N-acetylcysteine could accelerate gallstone dissolution in vitro. Paired gallstones were dissolved in either pure taurocholate (140 mM) or ursodeoxycholate (100 mM), or in bovine bile supplemented with either taurocholate or ursodeoxycholate to achieve the same respective bile-salt concentrations. N-acetylcysteine was added to 1 stone from each pair at a concentration of 500 mM in pure bile salts and 100 mM in supplemented bile. Gallstones dissolved significantly faster in bovine bile supplemented with taurocholate or ursodeoxycholate than in pure solutions of the respective bile salts (n = 30, p less than 0.001). N-acetylcysteine significantly accelerated gallstone dissolution in pure solutions of bile acids (n = 30, p less than 0.001 for each) and in supplemented bovine biles (n = 30, p less than 0.001). N-acetylcysteine also significantly increased the frequency of complete gallstone dissolution in taurocholate-supplemented (66.6% vs. 40.0%) and ursodeoxycholate-supplemented (76.6% vs. 50.0%) bile. These results indicate that the mucolytic agent N-acetylcysteine significantly accelerates in vitro gallstone dissolution. We speculate that adjuvant therapy with an appropriate mucolytic agent may potentially increase the efficacy of clinical gallstone dissolution.