(REFERENCE 1 OF 19)
Ruffmann R Wendel A
GSH rescue by N-acetylcysteine.
In: Klin Wochenschr (1991 Nov 15) 69(18):857-62
Reduced glutathione (GSH) is the main intracellular low molecular weight thiol. GSH acts as a nucleophilic scavenger and as an enzyme-catalyzed antioxidant in the event of electrophilic/oxidative tissue injury. Therefore, GSH has a major role as a protector of biological structures and functions. GSH depletion has been recognized as a hazardous condition during paracetamol intoxication. Conversely, GSH rescue, meaning recovery of the protective potential of GSH by early administration of N-acetylcysteine (NAC), has been found to be life-saving. Lack of GSH and electrophilic/oxidative injury have been identified among the causes of the adult respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), and the acquired immunodeficiency syndrome (AIDS). Experimental and early clinical data (in ARDS) point to the role of NAC in the treatment of these conditions. Recently, orally given NAC has been shown to enhance the levels of GSH in the liver, in plasma, and notably in the bronchoalveolar lavage fluid. Rescue of GSH through NAC needs to be appreciated as an independent treatment modality for an array of different disease, all of which have one feature in common: pathogenetically relevant loss of GSH.
(REFERENCE 2 OF 19)
Bridgeman MM Marsden M MacNee W Flenley DC Ryle AP
Cysteine and glutathione concentrations in plasma and bronchoalveolar lavage fluid after treatment with N-acetylcysteine.
In: Thorax (1991 Jan) 46(1):39-42
N-acetylcysteine (600 mg/day) was given to patients by mouth for five days before bronchoscopy and bronchoalveolar lavage to determine whether N-acetylcysteine could increase the concentrations of the antioxidant reduced glutathione in plasma and bronchoalveolar lavage fluid. Bronchoalveolar lavage was performed 1-3 hours (group 2, n = 9) and 16-20 hours (group 3, n = 10) after the last dose of N-acetylcysteine and the values were compared with those in a control group receiving no N-acetylcysteine (group 1, n = 8). N-Acetylcysteine was not detected in plasma or lavage fluid. Plasma concentrations of cysteine, the main metabolite of N-acetylcysteine and a precursor of reduced glutathione, were greater in the groups receiving treatment (groups 2 and 3) than in group 1. Cysteine concentrations in lavage fluid were similar in the three groups. Concentrations of reduced glutathione were greater in both plasma and lavage fluid in group 2 than in group 1. These data suggest that N-acetylcysteine given by mouth is rapidly deacetylated to cysteine, with resulting increases in the concentrations of cysteine in plasma and of reduced glutathione in plasma and the airways, which thus temporarily increase the antioxidant capacity of the lung.
(REFERENCE 2A of 19)
Deepmala, Slattery J, Kumar N, Delhey L, Berk M, Dean O, Spielholz C, Frye R
Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review.
In: Neurosci Biobehav Rev. 2015 Aug;55:294-321. doi: 10.1016/j.neubiorev.2015.04.015. Epub 2015 May 6.
N-acetylcysteine (NAC) is recognized for its role in acetaminophen overdose and as a mucolytic. Over the past decade, there has been growing evidence for the use of NAC in treating psychiatric and neurological disorders, considering its role in attenuating pathophysiological processes associated with these disorders, including oxidative stress, apoptosis, mitochondrial dysfunction, neuroinflammation and glutamate and dopamine dysregulation. In this systematic review we find favorable evidence for the use of NAC in several psychiatric and neurological disorders, particularly autism, Alzheimer's disease, cocaine and cannabis addiction, bipolar disorder, depression, trichotillomania, nail biting, skin picking, obsessive-compulsive disorder, schizophrenia, drug-induced neuropathy and progressive myoclonic epilepsy. Disorders such as anxiety, attention deficit hyperactivity disorder and mild traumatic brain injury have preliminary evidence and require larger confirmatory studies while current evidence does not support the use of NAC in gambling, methamphetamine and nicotine addictions and amyotrophic lateral sclerosis. Overall, NAC treatment appears to be safe and tolerable. Further well designed, larger controlled trials are needed for specific psychiatric and neurological disorders where the evidence is favorable.
(REFERENCE 3 OF 19)
Yim CY Hibbs JB Jr McGregor JR Galinsky RE Samlowski WE
Use of N-acetylcysteine to increase intracellular glutathione during the induction of antitumor responses by IL-2.
In: J Immunol (1994 Jun 15) 152(12):5796-805
IL-2 therapy can induce marked oxidative stress via reactive oxygen and nitrogen intermediates. Glutathione, the major intracellular reductant, may become rate limiting to cytotoxic lymphocyte activation and proliferation under these circumstances. N-Acetylcysteine (NAC-cys) was used to increase intracellular glutathione levels during lymphokine-activated killer (LAK) cell activation by IL-2. Incubation of splenocytes with NAC-cys (0.6 to 1.0 mM) resulted in significant changes in intracellular reduced and total glutathione (92% and 58% increase, respectively) at 96 h. These levels correlated with markedly enhanced cell proliferation (threefold) and cytolytic effector cell generation (> fivefold increase in LU/10(6) cells) induced by the combination of NAC-cys with IL-2. IL-2 exposure by itself unexpectedly increased intracellular reduced glutathione by 43%. IL-2 and NAC-cys were synergistic in increasing glutathione levels (reduced glutathione: 292% increase; total: 251% increase). Inhibition of glutathione synthesis, using L-buthionine-(S,R)-sulfoximine reversed the effects of NAC-cys on intracellular glutathione, as well as cellular proliferation and cytotoxicity. This experiment established that the effects of NAC-cys required de novo glutathione synthesis. In conjunction with IL-2/LAK treatment, oral NAC-cys administration (260 to 900 mg/kg/day for 7 days) significantly decreased tumor progression in a refractory s.c. tumor model. A small fraction of mice (11 to 17%) had complete tumor regressions. NAC-cys may be useful as an adjunct to increase the antitumor activity of IL-2/LAK therapy.
(REFERENCE 3B OF 19)
Zhang L1, Zhu Z, Liu J, Zhu Z, Hu Z.
Protective effect of N-acetylcysteine (NAC) on renal ischemia/reperfusion injury through Nrf2 signaling pathway.
In: J Recept Signal Transduct Res. 2014 Oct;34(5):396-400. doi: 10.3109/10799893.2014.908916. Epub 2014 Apr 15.
The aim of this study was to investigate whether N-acetylcysteine (NAC), a known antioxidant, can protect kidney against ischemic injury through regulating Nrf2 signaling pathway. The expression of Nrf2, HO-1 and cleaved caspase 3 were analyzed by Western blot analysis. Apoptosis of renal tubular epithelial cells was assessed by the TUNEL method. Malondialdehyde (MDA) levels were measured by the thiobarbituric acid reaction. Blood serum creatinine and blood urea nitrogen levels were measured with an Olympus automatic multi-analyzer. We found that NAC significantly increased Nrf2 and downstream HO-1 expression. Furthermore, NAC significantly decreased cleaved caspase 3, p53 and renal epithelial tubular cell apoptosis. In addition, NAC reduced the MDA level. These findings suggest that the protective action of NAC on ischemia renal injury is associated closely with Nrf2 signaling pathway.
(REFERENCE 4 OF 19)
De Flora S
Inhibition of invasion, gelatinase activity, tumor take and metastasis of malignant cells by N-acetylcysteine.
In: Int J Cancer (1995 Mar 29) 61(1):121-9
The thiol N-acetylcysteine (NAC) is currently considered one of the most promising cancer chemopreventive agents by virtue of its multiple and coordinated mechanisms affecting the process of chemical carcinogenesis. Recent studies have shown that an unpaired cysteine residue in the propeptide plays a key role in inactivation of latent metastasis-associated metalloproteinases: the present study was designed to assess whether NAC could also affect tumor take, invasion and metastasis of malignant cells. As assessed by zymographic analysis, NAC completely inhibited the gelatinolytic activity of type-IV collagenases in the cells tested (gelatinases A and B). Moreover, NAC was efficient in inhibiting the chemotactic and invasive activities of tumor cells of human (A2058 melanoma) and murine origin (K1735 and B16-F10 melanoma cells as well as C87 Lewis lung carcinoma cells) in Boyden-chamber assays, which are predictive of the invasive and metastatic properties. Reduced glutathione (GSH) had a similar, although less effective activity. The number of lung metastases decreased sharply when B16-F10 murine melanoma cells, injected i.v. into nude mice, were pre-treated with NAC and resuspended in medium supplemented with 10 mM NAC. In other experiments NAC was given in drinking water, starting 48-72 hr before subcutaneous inoculation of either B16-F10 cells or of their highly metastatic variant B16-BL6, or intramuscular injection of LLC cells. In all experiments NAC treatment decreased the weight of the locally formed primary tumor and produced a dose-related delay in tumor formation. Spontaneous metastasis formation by B16-F10 and B16-BL6 tumors was slightly yet significantly reduced by oral administration of NAC. However, this was not observed for Lewis lung tumors. These data indicate that NAC affects the process of tumor-cell invasion and metastasis, probably due to inhibition of gelatinases by its sulfhydryl group, with the possible contribution of other mechanisms, including the potent antioxidant activity of this thiol.
(REFERENCE 5 OF 19)
Cysteine and glutathione deficiency in AIDS patients: a rationale for the treatment with N-acetyl-cysteine.
In: Pharmacology (1993) 46(2):61-5
A series of clinical studies and laboratory investigations suggests that the acquired immunodeficiency syndrome (AIDS) may be the consequence of a virus-induced cysteine deficiency. HIV-infected persons at all stages of the disease were found to have decreased plasma cystine and cysteine concentrations and decreased intracellular glutathione levels. HIV-infected persons and SIV-infected rhesus macaques have also, on the average, substantially increased plasma glutamate levels. Increased glutamate levels aggravate the cysteine deficiency by inhibiting the membrane transport of cystine. Even moderately elevated extracellular glutamate levels as they occur in HIV-infected persons cause a substantial decrease of intracellular cysteine levels. Clinical studies revealed that individual cystine and glutamate levels are correlated with the individual lymphocyte reactivity and T4+ cell counts but not T8+ cell counts. This phenomenon was demonstrated not only in HIV-infected persons but also in healthy human individuals. The cellular cysteine supply affects amongst others the intracellular glutathione level and IL-2-dependent proliferation of T cells and (inversely) also the activation of the transcription factor NF-kappa B. The cysteine deficiency of HIV-infected persons is, therefore, possibly responsible not only for the cellular dysfunction but also for the overexpression of tumor necrosis factor-alpha (TNF-alpha), interleukin-2 receptor alpha-chain, and and beta 2-microglobulin.
(REFERENCE 6 OF 19)
Roederer M Staal FJ Ela SW Herzenberg LA Herzenberg LA
N-acetylcysteine: potential for AIDS therapy.
In: Pharmacology (1993) 46(3):121-9
The observations that people infected with HIV suffer not only from an inflammatory stress but also from depleted glutathione levels have led to a general hypothesis that these two are causally related, and that treatment of AIDS should include thiol-replenishment therapy. In particular, inflammatory stimulations are dependent on intracellular thiol levels, as they are potentiated at low glutathione levels (oxidative stress) and inhibited at high glutathione levels. Inflammatory stress may itself lead to decreased levels of glutathione. HIV has taken advantage of inflammatory signals to regulate its own replication; thus, the HIV infection is exacerbated by low levels of glutathione. We have shown that N-acetylcysteine can inhibit inflammatory stimulations, including that of HIV replication. Since N-acetylcysteine can replenish depleted glutathione levels in vivo, we suggest that it be used as an adjunct in the treatment of AIDS.
(REFERENCE 7 OF 19)
Focaccia R Cattapan A Conceicao O Buainain R Salaroli A Focaccia MT
Response to N-acetyl-L-cysteine on the CD4-CD8 system.
In: Int Conf AIDS (1994 Aug 7-12) 10(1):222 (abstract no. PB0319)
We report the first results of a clinical trial conducted to test the response of CD4-CD8 lymphocyte system to the administration of N-Acetyl-L-Cysteine (NAC). HIV-positive patients bearing CD4 counts < 500 cells/mm3 measured by flow cytometry were studied. Patients were divided in 2 groups that received doses every 12 Hs during 1 mo., 8 cases Parenteral, 400 mg. 7 cases Oral, 600 mg. Five of the patients were being treated with AZT without significant change of CD4 counts. RESULTS: Two of the 8 successful cases became serum p24 antigen negative. The 6 cases of the parenteral group ceased to develop opportunistic infections so far. No side effects were reported in both groups. CONCLUSION: NAC associated to antiviral therapy can be a powerful immunotherapy drug. Current research effort is aimed to determine the clinical meaning of CD4-CD8 enhancement and the determination of a suitable maintenance schedule.
(REFERENCE 8 OF 19)
Boman G Backer U Larsson S Melander B Wahlander L
Oral acetylcysteine reduces exacerbation rate in chronic bronchitis: report of a trial organized by the Swedish Society for Pulmonary Diseases.
In: Eur J Respir Dis (1983 Aug) 64(6):405-15
This multicentre trial was undertaken to confirm previous results indicating that long-term treatment with oral acetylcysteine reduces the exacerbation rate in patients with chronic bronchitis. Two hundred and eighty-five patients, smokers or ex-smokers, with chronic bronchitis started a pre-trial placebo-period of 1 month. After this run-in period 259 patients were included in the trial and randomized into two parallel groups. The patients were treated in a double-blind way either with acetylcysteine 200 mg b.i.d. or placebo b.i.d. for 6 months. The trial was completed by 98 patients in the acetylcysteine group and by 105 patients in the placebo group. Initially, there were no significant differences between the groups. Twice weekly, the patients filled in a diary card concerning symptoms. The number of exacerbations was assessed from these cards and at visits 2, 4 and 6 months after institution of therapy. The exacerbation rate was significantly lower in the acetylcysteine group in which 40% of the patients remained free from exacerbations compared to 19% in the placebo group. Sick-leave due to acute exacerbation was significantly less common in the acetylcysteine group. The drug was well tolerated.
(REFERENCE 9 OF 19)
Riise GC Larsson S Larsson P Jeansson S Andersson BA
The intrabronchial microbial flora in chronic bronchitis patients: a target for N-acetylcysteine therapy?
In: Eur Respir J (1994 Jan) 7(1):94-101
Chronic bronchitis is common among smokers, often together with recurrent infectious exacerbations. Streptococcus pneumoniae and Haemophilus influenzae are the pathogens traditionally considered most important. N-Acetylcysteine (NAC) treatment has been shown to reduce the number of infectious exacerbations in patients with chronic bronchitis. We attempted to characterize the intrabronchial bacterial flora in patients with chronic bronchitis in an infection-free interval, and to determine whether pharmacological and immunological factors effected the bacterial occurrence. Twenty two smokers with non-obstructive chronic bronchitis, 19 smokers with chronic bronchitis and chronic obstructive pulmonary disease (COPD) and 14 healthy nonsmokers underwent bronchoscopy. Quantitative bacterial cultures and virus isolations were performed. S. pneumoniae and H. influenzae were found in five patients, and only in the patients without NAC treatment. The most common bacterium was alpha-haemolytic streptococcus. Negative cultures were more common in the healthy controls. Of the various factors examined, only NAC medication had an influence on bacterial numbers. Significantly fewer patients with NAC medication had positive cultures (3 out of 16) than in the group of patients without NAC therapy (15 out of 21).
(REFERENCE 10 OF 19)
Rasmussen JB Glennow C
Reduction in days of illness after long-term treatment with N- acetylcysteine controlled-release tablets in patients with chronic bronchitis.
In: Eur Respir J (1988 Apr) 1(4):351-5
The clinical effect of N-acetylcysteine (NAC) controlled-release tablets, 300 mg b.i.d., and placebo, in chronic bronchitis was investigated. The study was performed as a double-blind six month comparison between active drug and placebo in two parallel groups with statistical evaluation after four and six months. The patients were chosen from nine centres. One hundred and sixteen out-patients were included and ninety one of them completed the six month study. The acetylcysteine-treated group had a significantly reduced number of sick-leave days caused by exacerbations of chronic bronchitis after the four winter months December-March compared with the control group (NAC 173, placebo 456). The number of exacerbation days was also very much reduced, however, not significantly (NAC 204, placebo 399). At the end of the six month trial, including also two spring months, the absolute numbers of sick-leave days and exacerbation days were still fewer in the acetylcysteine-treated group, (NAC 260, placebo 739) and (NAC 378, placebo 557) respectively. This study demonstrates a significant reduction in sick-leave days after four months of NAC-treatment. A constant tendency to reduction in the number of exacerbations and exacerbation days was also registered after four and six months. The differences in these parameters were, however, not statistically significant. This was probably due to the small number of patients participating.
(REFERENCE 11 OF 19)
Volkl KP Schneider B
Therapy of respiratory tract diseases with N-acetylcysteine. An open therapeutic observation study of 2,512 patients
In: Fortschr Med (1992 Jun 30) 110(18):346-50 (Published in German)
STUDY DESIGN: Open therapeutic observational study. PATIENTS: 2,510 patients with acute and chronic bronchitis, bronchial asthma, and emphysema. TREATMENT: 4-week treatment with N-acetylcystein administered three times a day 200 mg dissolved (n = 1734) or undissolved (n = 608) or at some other, usually lower, dosage (n = 173). During the f-week treatment phase, any other drugs being taken were neither discontinued nor changed. TARGET PARAMETERS: In addition to 1-sec capacity (FEV1), various, mainly subjective, parameters were noted, in particular coughing, amount and nature of expectorate. RESULTS: for the evaluation, the patients were assigned either to the acute bronchitis or the chronic bronchitis group; the latter group also contained patients with other diseases, such as asthma and emphysema, since such conditions often presented simultaneously. All selected parameters clearly improved under treatment, equally in the acute and chronic bronchitis groups. As expected, the mucolytic effect was very pronounced, the 1-sec capacity increased significantly. No major difference was to be found in the results observed in patients on and those not on other additional medication.
(REFERENCE 12 OF 19)
MacNee W Bridgeman MM Marsden M Drost E Lannan S Selby C Donaldson K
The effects of N-acetylcysteine and glutathione on smoke-induced changes in lung phagocytes and epithelial cells.
In: Am J Med (1991 Sep 30) 91(3C):60S-66S
We studied the mechanism of the delay in neutrophil traffic in pulmonary microvasculature previously observed during cigarette smoking, the effect of cigarette smoke on lung phagocytes and epithelial cell function, and augmentation of the glutathione (GSH) antioxidant system using the thiol drug N-acetylcysteine. Using a micropore membrane system to mimic the dimensions of the average pulmonary capillary, we showed that cigarette smoke reduces cell deformability, increasing the difficulty experienced by the larger neutrophils in negotiating the smaller capillary segments, so delaying their passage during smoking. This effect is both diminished and recoverable by the addition of plasma, and by GSH in concentrations found in plasma. Cigarette smoke induces oxidative changes in both the cell membrane and the cell cytoskeleton, and diminishes the ability of neutrophils to release reactive oxygen intermediates. The injurious effect of oxidants can be measured in vitro by the detachment of 51Cr-radiolabeled alveolar epithelial cells grown in monolayers, an effect also diminished by the addition of GSH. Such epithelial cell detachment in vitro may be reflected as the epithelial permeability that occurs at an early stage in asymptomatic smokers. N-Acetylcysteine given orally (600 mg/day) increases both plasma and bronchoalveolar lavage GSH in normal subjects, but a sustained increase in plasma GSH requires higher dosage regimens in patients with chronic obstructive pulmonary disease (600 mg three times daily). Thus, the potential exists to enhance the antioxidant status of both plasma and the airspaces of the lungs against oxidant-induced injury.
(REFERENCE 13 OF 19)
Linden M Wieslander E Eklund A Larsson K Brattsand R
Effects of oral N-acetylcysteine on cell content and macrophage function in bronchoalveolar lavage from healthy smokers.
In: Eur Respir J (1988 Jul) 1(7):645-50
Bronchoalveolar lavage (BAL) was performed in fourteen healthy non-smokers and eleven healthy smokers. In smokers BAL was performed before and after eight weeks' treatment with N-acetylcysteine (NAC; 200 mg t.i.d.). Cell number, composition and viability were determined in the BAL fluid. Alveolar macrophages (AMs) were cultured before examination of their phagocytic capacity and their ability to produce leukotriene B4 (LTB4). BAL fluid from smokers contained more cells than that from non-smokers (p less than 0.001). This was mainly attributable to increases in both proportion and absolute number of AMs (p less than 0.001) and to an increase in absolute number of neutrophils (p less than 0.05). However, there was a decrease in proportion of lymphocytes in BAL fluid from smokers (p less than 0.001). Phagocytic capacity of adherent cells and capacity of AMs to generate LTB4 after stimulation with opsonized zymosan (OZy) were decreased in smokers (p less than 0.05 and p less than 0.01 respectively). NAC treatment of smokers did not affect cell number but resulted in an increased proportion of lymphocytes in BAL fluid (p less than 0.05). The phagocytic capacity of AMs was not significantly altered but was improved in five of eleven smokers after NAC treatment. NAC also enhanced the decreased LTB4 secretion by smokers' AMs (p less than 0.05). We conclude that smoking leads to reduced phagocytic capacity and LTB4 secretion of AMs and that oral NAC treatment may improve the function of AMs.
(REFERENCE 14 OF 19)
Olivieri D Marsico SA Del Donno M
Improvement of mucociliary transport in smokers by mucolytics.
In: Eur J Respir Dis Suppl (1985) 139:142-5
The purpose of the present study was to compare the effects of two mucolytic drugs with different mechanism of action on mucociliary transport (MCT). N-Acetylcysteine (NAC-600 mg/day) and ambroxol (AMB-90 mg/day) were administered according to a double-blind cross-over scheme to 12 heavy smokers suffering from hypersecretory bronchitis and homogeneous reduction of the MCT. Placebo of both treatments was administered during an interval of ten days between the administrations of NAC and AMB. The entire treatment period was 30 days. The data were analyzed according to ANOVA for the two-period cross-over clinical trial. The results indicate that: NAC and AMB, administered both before and after placebo, produce a significant increase in MCT, NAC showed a slightly greater efficacy than AMB, but the differences are not statistically significant. The overall efficacy of NAC and AMB is consistently greater than that of placebo. The sequence of administration of the drugs does not influence their effect.
(REFERENCE 15 OF 19)
Barkworth MF Mangold B Rehm KD Schmieder G Toberich H Vinchenzo A Weber J Rubartsch C
The biological availability of cefadroxil given simultaneously with N-acetylcysteine
In: Arzneimittelforschung (1991 Aug) 41(8):839-43 (Published in German)
A preliminary study revealed that similarly to the antibiotics amoxillin, thiamphenicol, erythromycin and doxycycline, the oral cephalosporin cefadroxil (CAS 66592-87-8) can be administered simultaneously with the mucolytic N-acetylcysteine (CAS 616-91-1). In the present study 12 healthy male volunteers received in a randomised cross-over design a single oral dose of 1000 mg cefadroxil or a single oral dose of 1000 mg cefadroxil (Bidocef) plus 200 mg N-acetylcysteine. The two study days were separated by a wash-out period of one week. To determine the pharmacokinetic profile of cefadroxil, plasma and sputum were analysed by HPLC at defined intervals. Regarding the bioavailability of cefadroxil, the free combination is bioequivalent to the individual component. After administration of cefadroxil plus N-acetylcysteine, a higher cefadroxil concentration was found in the sputum compared to an administration of cefadroxil alone. However, the difference was not statistically significant. According to the results, simultaneous administration of the oral cephalosporin cefadroxil and the mucolytic N-acetylcysteine is possible without changes in the bioavailability of cefadroxil being observed.
(REFERENCE 16 OF 19)
Fan J Shen SJ
The role of Tamm-Horsfall mucoprotein in calcium oxalate crystallization. N-Acetylcysteine--a new therapy for calcium oxalate urolithiasis.
In: Br J Urol (1994 Sep) 74(3):288-93
OBJECTIVE: To assess the role of Tamm-Horsfall mucoprotein (THM), obtained from normal subjects (nTHM) and stone-formers (sfTHM), on crystallization of calcium oxalate (CaOx) in whole urine, and to assess the effects of N-acetylcysteine (NAC) in preventing renal stone formation. MATERIALS AND METHODS: A modified rapid evaporation method was used to test the effects of THM and AC on crystallization of CaOx in vitro. Animal experiments involving 30 rats and a clinical study involving 17 patients with idiopathic CaOx urolithiasis were also performed to identify further the role of AC in preventing CaOx stone formation in vivo. RESULTS: The results showed that the volume of CaOx crystals was greatly reduced, by ultrafiltration, to 39.1% of untreated urine, but increased to 81.4% by adding nTHM (35 mg/l). sfTHM was a more potent promoter. NAC was found to inhibit the transformation of THM and lower the crystallization of CaOx both in vitro and in vivo. CONCLUSION: We believe that the transformation of THM is an important step in the formation of urolithiasis. NAC might be a new way to prevent renal stone formation and recurrence.
(REFERENCE 17 OF 19)
In: Am J Med (1983 Nov 14) 75(5A):104-12
Acetaminophen is a remarkably safe agent when used in therapeutic doses. Most reported overdoses of acetaminophen are the result of suicide attempts. The clinical course of patients with toxic blood levels follows four distinct stages. Symptoms of nausea, vomiting, diaphoresis, and anorexia usually begin within seven to 14 hours after ingestion. After 24 to 48 hours, these symptoms may diminish, but SGOT, SGPT, bilirubin, and prothrombin time begin to rise. Peak hepatotoxicity occurs at 72 to 96 hours, and SGOT levels of 20,000 I.U. are not unusual. Oral N-acetylcysteine is the drug of choice for acetaminophen overdose. Intravenous use of N-acetylcysteine is advocated in England, Europe, and elsewhere, but it is not available in the United States. Clinical studies of oral and intravenous N-acetylcysteine clearly demonstrate that the drug has a profound effect on reducing morbidity and mortality if it is administered during the first 16 hours after the overdose. In addition, data from these studies have shown that alcohol taken simultaneously with an overdose of acetaminophen is actually hepatoprotective. Therefore, patients who have consumed alcohol at the time of overdose, or those who are chronic alcoholics, should be managed in the same way as patients with no exposure to alcohol. However, study results also reveal that overdose in children under 10 to 12 years of age follows a distinctly different pattern. These children demonstrate a lesser degree of hepatotoxicity and have only minor increases in transaminase levels.
(REFERENCE 18 OF 19)
Parker D White JP Paton D Routledge PA
Safety of late acetylcysteine treatment in paracetamol poisoning.
In: Hum Exp Toxicol (1990 Jan) 9(1):25-7
Twenty patients who had taken overdoses of paracetamol were treated with acetylcysteine between 12 and 24 hours after the incident. Although 19 patients had plasma paracetamol concentrations greater than those associated with a 90% risk of moderate to severe liver damage, this complication occurred in only seven (35%) individuals. No patient developed hepatic encephalopathy or acute renal failure and all recovered without sequelae. We conclude that acetylcysteine administration up to 24 hours following paracetamol overdose is not dangerous and may prevent further liver damage.
(REFERENCE 19 OF 19)
Clinical pharmacokinetics of N-acetylcysteine.
In: Clin Pharmacokinet (1991 Feb) 20(2):123-34
N-acetylcysteine is useful as a mucolytic agent for treatment of chronic bronchitis and other pulmonary diseases complicated by the production of viscous mucus. It is also used as an antidote to paracetamol (acetaminophen) poisoning and found to be effective for the prevention of cardiotoxicity by doxorubicin and haemorrhagic cystitis from oxazaphosphorines. After an oral dose of N-acetylcysteine 200 to 400 mg the peak plasma concentration of 0.35 to 4 mg/L is achieved within 1 to 2 hours. Although the data are conflicting, it appears that the administration of charcoal may interfere with drug absorption, with up to 96% of the drug adsorbed on to the charcoal. Information on absorption in the presence of food or other drugs is not available. The volume of distribution ranges from 0.33 to 0.47 L/kg and protein binding is significant, reaching approximately 50% 4 hours after the dose. Pharmacokinetic information is not available as to whether or not N-acetylcysteine crosses the blood-brain barrier or placenta, or into breast milk. Renal clearance has been reported as 0.190 to 0.211 L/h/kg and approximately 70% of the total body clearance is nonrenal. Following oral administration, reduced N-acetylcysteine has a terminal half-life of 6.25h. Little is known of the metabolism of this agent, although it is believed to be rapidly metabolised and incorporated on to proteins. The major excretory product is inorganic sulphate. Frequently reported side effects are nausea, vomiting and diarrhoea. Biochemical and haematological adverse effects are observed but are not clinically relevant. Drug interactions of clinical significance have been observed with paracetamol, glutathione and anticancer agents.