NAC

Common Name: NAC

Clinical Name: N-acetyl Cysteine

Summary

N-acetyl Cysteine (NAC)

chemical name: N-acetyl Cysteine

overview of interactions:
• nutrient affecting drug performance: Acetaminophen

• nutrient affecting drug toxicity: Nausea and Vomiting due to Chemotherapy

• nutrient affecting drug toxicity: Doxorubicin (Adriamycin®)

• nutrient affecting drug performance: Nitroglycerin

functions: N-acetyl cysteine (NAC) is synthesized by the body from dietary sources of the amino acid cysteine. NAC plays a key role in the synthesis of glutathione, an important antioxidant and detoxifier, in the liver. It is also mucolytic, that is, it functions to break down mucus.

dietary sources: NAC is not found in the diet as such but rather is derived from cysteine.

deficiency: NAC is not defined as an essential nutrient since it is created in the body from cysteine.

known or potential therapeutic uses: AIDS/HIV support, antioxidant/detoxification function, bronchitis, chronic obstructive pulmonary disease (COPD), emphysema, nausea and vomiting due to chemotherapy.

maintenance dose: None established.

therapeutic dose: No therapeutic standards have been established and appropriate dosage would inherently vary according to the individual and their medical condition(s). Researchers and practitioners experienced in nutritional therapies have used a wide range of dosages, from 250-1500 mg per day.

side effects: There have, as of yet, been no confirmed or consistent reports of side effects due to NAC. NAC may increase urinary excretion of zinc; therefore, extended use of NAC at higher dosage levels would warrant supplementation with zinc, and, in turn, copper.

toxicity: Most experts consider NAC non-toxic in commonly used dosage levels. However, based on a small study, Kleinveld et al have reported that daily doses of 1200 mg of NAC can induce oxidative damage.
(Kleinveld HA, et al. Eur J Clin Pharmacol 1992;43:639-642.)

contraindications: None known, except for use during some forms of chemotherapy and radiation where antioxidants are contraindicated due to their inhibition of the free radical formation which is an intentional part of the therapeutic mechanism.



Interactions

nutrient affecting drug performance: Acetaminophen

• research: Many studies have looked into the efficacy and appropriateness of using NAC to treat patients suffering from acute toxic effects of acetaminophen. Such treatment of acetaminophen intoxication with N-acetylcysteine (NAC), both oral and intravenous, is standard hospital protocol in many countries.
(Zed PJ, Krenzelok EP. Am J Health Syst Pharm 1999 Jun 1;56(11):1081-1091; Salgia AD, Kosnik SD. Postgrad Med. 1999 Apr;105(4):81-84, 87, 90; Montoya-Cabrera MA, et al. Gac Med Mex. 1999 May-Jun;135(3):239-243; Schmidt LE, Dalhoff KP. Ugeskr Laeger. 1999 May 3;161(18):2669-2672.)

• nutritional support: NAC is generally considered safe with relatively few side effects. However, individuals suffering from acetaminophen intoxication require emergency care and use of NAC in this capacity is only appropriate in such a setting.

nutrient affecting drug toxicity: Nausea and vomiting due to Chemotherapy

• research: At an international conference on cancer therapies in 1996 de Blasio et al presented their research findings which concluded that 1,800 mg of NAC per day may reduce nausea and vomiting due to chemotherapy.
(de Blasio F, et al. Chest 1996;110(4, Suppl):103S.)

nutrient affecting drug toxicity: Doxorubicin (Adriamycin®)

• mechanism: Antioxidant action reduces cardiac toxicity of doxorubicin.

• research: Research has found that N-acetyl cysteine (NAC) exerts a protective effect from the cardiotoxicity of doxorubicin, at least in animals; no research with human has yet confirmed these results.
(Schmitt-Graff A, et al. Pathol Res Pract. 1986 May;181(2):168-74; Martinez E, Domingo P. Lancet 1991;338:249; Doroshow JH, et al. J Clin Invest 1981;68:1053-1064; Meyers C, et al. Semin Oncol 1983;10:53-55.)

• nutritional support: The prescription of NAC for people taking doxorubicin is not a common practice among nutritionally-oriented physicians.

nutrient affecting drug performance: Nitroglycerin

• research: Researchers have found that N-acetyl cysteine (NAC), intravenously, can reverse nitroglycerine tolerance, but oral doses have either create side-effects at higher levels or failed to achieve the desired effects at lower doses. Several studies on the short-term use of intravenous (IV) NAC by individuals receiving continuous nitroglycerin reported a reverse in the normal tendency to nitroglycerin tolerance.
(Ghio S, et al. Circulation 1992 Sep;86(3):798-802; May DC, et al. N Engl J Med 1987;317:805-809; Lawson DL, et al.J Cardiovasc Pharmacol. 1996 Sep;28(3):418-24; Pizzulli L, et al. Am J Cardiol. 1997 Jan 1;79(1):28-33; Nishikawa Y, et al. J Cardiovasc Pharmacol. 1998 Jul;32(1):21-28.)

Another study, a double-blind, placebo-controlled trial, found that transdermal nitroglycerin in combination with oral NAC (600 mg three times per day) was more effective than nitroglycerin, NAC or placebo alone. However, this combination of nitroglycerin and NAC also produced severe headaches among many recipients.
(Iversen HK. Clin Pharmacol Ther 1992;52:125-133; Ardissino D, et al. J Am Coll Cardiol 1997;29:941-947.)

On the other hand, in patients with angina, initial evidence from two double-blind, randomized trials indicates that lower doses of oral NAC (200 mg or 400 mg three times per day) combined with transdermal nitroglycerin did not adequately prevent nitroglycerin tolerance.
(Hogan JC, et al. Br J Clin Pharmacol 1989;28:421-426; Hogan JC, et al. Br J Clin Pharmacol 1990;30:573-577.)

• nutritional support: No clear and convincing pattern of evidence has emerged in the research literature to provide adequate support for any particular use of N-acetyl cysteine (NAC) by individuals using nitroglycerine on a long-term basis. There is also dispute among researchers as to which forms of NAC are potentially effective. There is strong evidence to indicate that the oral form of NAC most accessible to patients is more likely to result in side-effects such as headaches than to produce any predictable benefits. Before initiating use of NAC, individuals using long-acting nitroglycerin should discuss the issue of NAC supplementation in relation to nitroglycerin tolerance with their prescribing physician.
(Horowitz JD, et al. Circulation 1988 Apr;77(4):787-794.)


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Do not rely solely on the information in this article.

The information presented in Interactions is for informational and educational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, case reports, and/or traditional usage with sources as cited in each topic. The results reported may not necessarily occur in all individuals and different individuals with the same medical conditions with the same symptoms will often require differing treatments. For many of the conditions discussed, treatment with conventional medical therapies, including prescription drugs or over-the-counter medications, is also available. Consult your physician, an appropriately trained healthcare practitioner, and/or pharmacist for any health concern or medical problem before using any herbal products or nutritional supplements or before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using supplements, herbs, remedies, or other forms of self-care.



References

Albini A, D'Agostini F, Giunciuglio D, Paglieri I, Balansky R, De Flora S. Inhibition of invasion, gelatinase activity, tumor take and metastasis of malignant cells by N-acetylcysteine. Int J Cancer 1995 Mar 29;61(1):121-129.
Abstract: 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.

Ardissino D, Merlini PA, Savonitto S, et al. Effect of transdermal nitroglycerin or N-acetyl cysteine, or both, in the long-term treatment of unstable angina pectoris. J Am Coll Cardiol 1997;29:941-947.

Bodemann T, Langescheid C, Hochrein H. [Nitrate tolerance and its management by N-acetylcysteine]. Z Kardiol 1989 May;78(5):328-334. [Article in German]
Abstract: The mechanisms responsible for the development of nitrate tolerance are not completely clear, and their clinical importance remains controversial. This study examined the possible development of nitrate tolerance under the continuous infusion of high doses (10 mg/h) of nitroglycerine (NTG) and the effect of an additional N-acetylcysteine (NAC) injection in respect of hemodynamic changes. Eighteen patients with severe chronic heart failure (NYHA stages III-IV) were investigated. In 16 patients, NTG produced a marked improvement of the hemodynamic parameters; in two patients it caused a moderate amelioration only. In 13 patients there was a complete loss of the initial hemodynamic effect of NTG within 12 to 36 h. NAC reversed the NTG tolerance in 11 out of the 13 patients. In the two patients who showed a milder response to NTG and who did not develop a tolerance, NAC improved the effectiveness of NTG significantly. There was no additional NAC effect in the three patients without NTG tolerance. NAC itself produced no hemodynamic changes. These results confirm the relevance of the depletion of sulfhydryl-groups for the development of nitrate tolerance under the continuous infusion of NTG.

Brumas V, Hacht B, Filella M, Berthon G. Can N-acetyl-L-cysteine affect zinc metabolism when used as a paracetamol antidote? Agents Actions 1992;36:278-288.

de Blasio F, Forgione L, Marrazzo R. N-acetyl cysteine (NAC) in preventing nausea and vomiting induced by chemotherapy in patients suffering from inoperable non small cell lung cancer (NSCLC). Chest 1996;110(4, Suppl):103S.
Abstract: Among therapeutic strategies for inoperable NSCLC chemotherapy is still considered as the first choice even if with its controversies and debates. In fact, several studies demonstrated the effectiveness of chemotherapy vs best supportive care either in terms of survival, cost and quality of life. Nevertheless, the limiting factor of chemotherapy is represented by side effects among which nausea and vomiting. Several and effective new drugs have been proposed to solve this problem but at very high cost. AIM: The aim of the study is to evaluate the possible therapeutic role of NAC in the prevention of chemotherapy induced nausea and vomiting in patients suffering from inoperable NSCLC. METHODS: Twentytwo consecutive patients (17 male; mean age 63.2 yrs + 2.5) affected by inoperable NSCLC treated with chemotherapy were evaluated. The chemotherapy regimen (cyclophosphamide 400mg/m2; epirubicin 40 mg/m2; carboplatin 200 mg/m2 q8 days) was administered iv. in one day for six courses. Seventeen of these patients were randomly selected to further receive an oral daily dosage of 1800 mg (three tablets) of NAC. Furthermore, each of the patients received granisetron 3mg/iv on the day of the therapy, and chemotherapy induced nausea and vomiting data collected according to WHO, for five days after each course. RESULTS: At the end of the treatment patients receiving both chemotherapy and NAC showed a lower incidence of nausea and vomiting (13% vs 28%) and a low WHO intensity grade (0.8 + 0.3 vs 1.7 + 0.6) since the first day after the therapy when compared to patients receiving chemotherapy alone. CONCLUSIONS: In addition to antiemetic drugs, NAC oral administration of 1.800 mg demonstrates to prevent the incidence and the intensity of chemotherapy induced gastrointestinal side effects in patients suffering from inoperable NSCLC.

Delneste Y, Jeannin P, Potier L, Romero P, Bonnefoy JY. N-acetyl-L-cysteine exhibits antitumoral activity by increasing tumor necrosis factor alpha-dependent T-cell cytotoxicity. Blood 1997 Aug 1;90(3):1124-1132.
Abstract: Because of its anticarcinogenic and antimutagenic properties, N-acetyl-L-cysteine (NAC) has been proposed for cancer treatment. Here we present a mechanism of action for NAC in cancer. Our data show that NAC (1) induces an early and sustained increase of membrane tumor necrosis factor alpha (TNF alpha) expression on human stimulated-peripheral blood (PB) T cells and (2) increases membrane TNF-RI and TNF-RII on tumoral cell lines and on T cells after stimulation. These effects result from an early inhibition of both TNF alpha and TNF-R shedding, as well as a later increase of the respective mRNA expression. Consequently, NAC confers cytotoxic properties to human PB T cells through a membrane TNF alpha-dependent pathway. In vivo, NAC given orally inhibits tumor appearance in more than a third (18 out of 50) B6D2F1 mice injected with L1210 lymphoma cells. Spleen cells from protected mice killed L1210 lymphoma cells in vitro in a membrane TNF alpha-dependent manner. Furthermore these mice were resistant to a second inoculation of L1210 cells without further treatment with NAC. Thus, NAC exhibits a potent antitumoral activity by modulating TNF alpha and TNF-R processing without showing any in vitro and in vivo toxicity.

de Quay B, Malinverni R, Lauterburg BH. Glutathione depletion in HIV-infected patients: role of cysteine deficiency and effect of oral N-acetylcysteine. AIDS 1992;6:815-819.

Domenighetti G, Quattropani C, Schaller MD. [Therapeutic use of N-acetylcysteine in acute lung diseases]. Rev Mal Respir 1999 Feb;16(1):29-37. [Article in French]
Abstract: Oxidants play a key role in disease processes, particularly in the detrimental mechanisms leading to tissue damage in certain forms of acute lung injury. A number of mediators contribute to the pathologic response in ARDS, SIRS or hyperoxia-induced pulmonary damage. One of the most important detrimental factors is the generation and activation of highly reactive oxygen species which are leading factors implicated in the process of tissue damage. N-acetylcysteine (NAC) is a free radical scavenger and might access the endothelial cell thus increasing intracellular glutathione (GSH) stores. Different studies have demonstrated that NAC might be a promising compound either for the prevention or the treatment of acute lung damages such as ARDS. However, the true beneficial effect so far reported in several clinical and experimental studies contrasts with some contradictory and intriguing aspects, probably because the significance of a direct in vivo antioxidative effect of this compound remains to be established in humans. Thus, the mode of action of NAC may not be the same in different pathologies and clinical situations. More research into the mechanisms of action of this unique xenobiotic substance may offer a clue for elucidating these controversies.

Doroshow JH, Locker GY, Ifrim I, Myers CE. Prevention of doxorubicin cardiac toxicity in the mouse by N-acetylcysteine. J Clin Invest 1981 Oct;68(4):1053-1064.
Abstract: This study was undertaken to investigate the effect of exogenous sulfhydryl compound administration on the toxicity of doxorubicin in mice. Pretreatment of CDF1 mice with a pharmacologic dose (2,000 mg/kg) of n-acetyl-l-cysteine 1 h before doxorubicin (20 mg/kg, i.p.) decreased lethality from 100% (n = 44) to 37.7% (n = 53), P less than 0.001. Variation in the timing and dose of n-acetylcysteine significantly diminished its protective activity. Pretreatment with n-acetylcysteine also significantly reduced long-term mortality in animals receiving multiple doses of doxorubicin; 10 wk after the third of three doxorubicin doses (5 mg/kg, i.p.) administered at 2-wk intervals, survival in the n-acetylcysteine pretreated group was 51.4% (n = 35) compared with 16.7% (n = 30) for animals receiving saline before doxorubicin, P less than 0.01. In this experiment, n-acetylcysteine pretreatment also diminished doxorubicin-related losses in total body weight and heart wet weight by 55.2% (P less than 0.05), and 60.9% (P less than 0.02), respectively, compared with animals pretreated with saline. N-acetylcysteine pretreatment also ablated electron microscopic evidence of doxorubicin cardiomyopathy without alleviating morphological features of its toxic effects on the liver or small intestinal mucosa. The cardioprotective action of n-acetylcysteine may be partially explained by the 429 +/- 60% increase in cardiac nonprotein sulfhydryl content (P less than 0.01) that was measured one hour after n-acetylcysteine administration; nonprotein sulfhydryl concentration in the liver at the same time was insignificantly different from control levels. Treatment with n-acetylcysteine also increased the nonprotein sulfhydryl content of P388 leukemia cells nearly threefold; however, it did not after the chemotherapeutic activity of doxorubicin against this murine tumor. Whereas n-acetylcysteine blocked doxorubicin cardiac toxicity, it did not affect the uptake or metabolism of doxorubicin in the heart or liver. These results suggest that the concentration of free sulfhydryl groups in the heart may play a role in the development of doxorubicin cardiac toxicity and that augmenting cardiac nonprotein sulfhydryl group content with n-acetylcysteine may provide a means to enhance the chemotherapeutic index of doxorubicin.

Fujiwaki R, Iida K, Ohnishi Y, Watanabe Y, Ryuko K, Takahashi K, Miyazaki K. Intra-arterial neoadjuvant chemotherapy followed by radical surgery and radiotherapy for stage IIb cervical carcinoma. Anticancer Res 1997 Sep-Oct;17(5B):3751-3755.
Abstract: BACKGROUND: The role of intra-arterial neoadjuvant chemotherapy (NAC) in the management of cervical carcinoma has not been established. The aim of this study was to determine whether pre-operative intra-arterial NAC is effective or not in patients with stage IIb cervical carcinoma. PATIENTS AND METHODS: A total of 28 patients with stage IIb cervical carcinoma (diameter > 4 cm) were treated with one cycle of intra-arterial NAC (cisplatin 70 mg/m2, and peplomycin sulfate 30 mg/m2 or doxorubicin 30 mg/m2) followed by radical surgery and post-operative radiotherapy. Immediate response, toxicity, survival, and prognostic factors for survival were evaluated. RESULTS: The overall clinical response rate was 79% (22/28) with a complete response in 1 patient (4%). Radical hysterectomy with pelvic lymphadenectomy was feasible in 25 patients (89%) 4 weeks after chemotherapy. Toxicity were generally mild, and there were no intraoperative complications related to intra-arterial NAC. The estimated 2- and 5-year survival rates for the entire group were 93% and 80%, respectively, with a median followup time in survivors of 62 months. Univariate analysis showed the following to be significantly related to survival: histologic type, PCNA index, clinical response to intraarterial NAC, and lymph node metastasis. Survival was not significantly related to age, grade of differentiation, serum level of squamous cell carcinoma antigen, p53 protein expression, or residual parametrial involvement. Multivariate Cox's proportional hazard analysis showed that only the histologic type significantly influenced survival (p = 0.0007). The estimated 2- and 5-year survival rates were 100% and 94% for patients with squamous cell carcinoma, and 75% and 50% for those with adenocarcinoma. CONCLUSIONS: Intra-arterial NAC followed by surgery and radiotherapy appeared to be effective in treating patients with stage IIb cervical squamous cell carcinoma, but was not as effective in patients with stage IIb cervical adenocarcinoma.

Ghio S, de Servi S, Perotti R, Eleuteri E, Montemartini C, Specchia G. Different susceptibility to the development of nitroglycerin tolerance in the arterial and venous circulation in humans. Effects of N-acetylcysteine administration. Circulation 1992 Sep;86(3):798-802.
Abstract: BACKGROUND. Tolerance to the effects of organic nitrates develops rapidly during continuous exposure to these drugs; its main mechanism seems to be an intracellular sulfhydryl group depletion. However, the relative susceptibility to the development of nitroglycerin tolerance of the arterial or venous circulation in humans is still a matter of dispute. METHODS AND RESULTS. Twenty patients with coronary artery disease underwent a continuous 24-hour nitroglycerin infusion followed by a bolus administration of N-acetylcysteine. Forearm blood flow (ml/100 ml/min) and venous volume (ml/100 ml) were measured by strain gauge plethysmography under control conditions, at the end of nitroglycerin titration, after 24-hour infusion, and after N-acetylcysteine; vascular resistance was calculated as mean cuff blood pressure divided by flow. After 24 hours of nitroglycerin infusion, the initial increase in venous volume was reduced 48% (p less than 0.01), whereas the acute effects on vascular resistance were not attenuated in the whole group. N-Acetylcysteine completely restored nitroglycerin venodilator effects in all 10 patients in whom attenuation of the venous effects was observed during the infusion period. CONCLUSIONS. The data indicate that the susceptibility to the development of nitrate tolerance in humans is higher in the venous than in the arterial circulation, and that the sulfhydryl group donor N-acetylcysteine is extremely effective in reversing nitroglycerin tolerance in the venous circulation in humans.

Ghio S, De Servi S, Perotti R, Eleuteri E, Montemartini C, Specchia G. [Different susceptibilities to the development of nitroglycerin tolerance in the human peripheral venous and arterial circulations]. Cardiology 1994;84 Suppl 1:64-70. [Article in Italian]
Abstract: Aim of the study was to assess the relative susceptibility to the development of nitroglycerin tolerance in the arterial and venous circulation in man and to evaluate the interactions between nitroglycerin and N-acetylcysteine. Twenty patients with coronary artery disease underwent a continuous 24-h nitroglycerin infusion followed by a bolus administration of N-acetylcysteine. Forearm blood flow (ml/100 ml/min) and venous volume (ml/100 ml) were measured by strain gauge plethysmography under control conditions, at the end of nitroglycerin titration, after 24 h of infusion and after N-acetylcysteine; vascular resistance was calculated as mean cuff blood pressure/flow. After 24 h of nitroglycerin infusion, the initial increase in venous volume was reduced by 48% (p < 0.01), while the acute effects on vascular resistance were not attenuated in the whole group. N-acetylcysteine restored nitroglycerin venodilator effects in all 10 patients who developed venous tolerance but did not change significantly vascular resistance in 5 patients in whom attenuation of the arterial effects was observed during the infusion period. In conclusion, the results indicate that the susceptibility to the development of nitrate tolerance in man is higher in the venous than in the arterial circulation and that the sulphydryl group donor N-acetylcysteine is more effective in reversing nitroglycerin tolerance in the venous than in the arterial circulation.

Gillissen A, Nowak D. Characterization of N-acetylcysteine and ambroxol in anti-oxidant therapy. Respir Med 1998 Apr;92(4):609-623. (Review)

Henry PJ, Horowitz JD, Louis WJ. Determinants of in vitro nitroglycerin tolerance induction and reversal: influence of dose regimen, nitrate-free period, and sulfhydryl supplementation. J Cardiovasc Pharmacol 1989 Jul;14(1):31-37 .
Abstract: The influence of dose regimen on the induction and reversal of tolerance to nitroglycerin (NTG) is not well understood despite the current widespread clinical use of both sustained and intermittent modes of NTG administration. In an isolated coronary artery preparation both the NTG preexposure concentration and the duration of the NTG preexposure period were positive and independent determinants of the extent of NTG tolerance induction. During a "nitrate-free" or washout period, NTG tolerance was at least partially reversible. The apparent rate of NTG tolerance reversal during a "nitrate-free" period was not dependent on the absolute degree of NTG tolerance induced or on the dose regimen used to induce NTG tolerance. In this isolated vascular preparation, sulfhydryl (SH) supplementation with 1 mM N-acetylcysteine produced no significant augmentation of NTG-induced relaxations in either NTG tolerant or non tolerant tissues. N-acetylcysteine was ineffectual in attenuating the development of NTG tolerance in coronary artery preparations incubated in either Krebs bicarbonate buffer or in 10% human plasma. We conclude that in this model the NTG preexposure concentration, the duration of the NTG preexposure period, and the duration of the "nitrate-free" period are critical and independent determinants of the extent of NTG tolerance but that NTG tolerance is not significantly attenuated by SH supplementation.

Hogan JC, Lewis MJ, Henderson AH. Chronic administration of N-acetylcysteine fails to prevent nitrate tolerance in patients with stable angina pectoris. Br J Clin Pharmacol 1990;30:573-577.

Hogan JC, Lewis MJ, Henderson AH. N-acetylcysteine fails to attenuate haemodynamic tolerance to glycerol trinitrate in healthy volunteers. Br J Clin Pharmacol 1989;28:421-426.
Abstract: 1. The effects of chronic dosing with N-acetylcysteine (NAC), on nitrate-induced haemodynamic changes during the acute and chronic treatment of healthy volunteers with glyceryl trinitrate (GTN) patches (Transiderm nitro) has been investigated. 2. Seven volunteers were treated in a double-blind randomised crossover manner for two periods of 4 days with 20 mg of transdermal GTN/24 h together with NAC (200 mg three times daily) or matching placebo. There was a washout period of greater than 3 days between treatment periods. 3. Haemodynamic measurements (blood pressure (BP); heart rate (HR] at rest and following maximal treadmill exercise were performed before treatment and 4 h after starting treatment on days 1 and 4. 4. Significant haemodynamic changes as evidenced by a fall in BP and rise in HR, were seen on day 1 in both the NAC and placebo phases. By day 4 the haemodynamic changes had returned towards the pre-treatment values during both the NAC and placebo phases suggesting the development of tolerance in both treatment groups. 5. These findings suggest that concurrent administration of NAC fails to prevent the development of tolerance to GTN.

Horowitz JD, Henry CA, Syrjanen ML, Louis WJ, Fish RD, Smith TW, Antman EM. Combined use of nitroglycerin and N-acetylcysteine in the management of unstable angina pectoris. Circulation 1988 Apr;77(4):787-794.
Abstract: The vasodilator effects of nitroglycerin (NTG) are mediated via activation of guanylate cyclase; this process is believed to require the availability of free sulfhydryl groups. Previous studies in man have shown that the sulfhydryl donor N-acetylcysteine (NAC) potentiates the systemic and coronary vasodilator effects of NTG. Furthermore, interaction of NTG and NAC may lead to the formation of S-nitroso-NAC, which strongly inhibits platelet aggregation. The effects of intravenous NTG combined with intravenous NAC (5 g 6 hourly) were compared with those of intravenous NTG alone in a double-blind trial in 46 patients with severe unstable angina pectoris unresponsive to conventional treatment, which included calcium antagonists and cutaneous nitrates in all but one patient. Treatment with NTG/NAC (24 patients) and that with NTG alone (22 patients) was associated with a similar frequency of episodes of chest pain and of increments in NTG infusion rate for pain control (10 vs 17; p = NS). The NTG/NAC group had a significantly lower incidence of acute myocardial infarction than the NTG/placebo group (three vs 10 patients; p = .013). Symptomatic hypotension occurred frequently in the NTG/NAC group (seven vs 0 patients; p = .006). Lactate-pyruvate ratios and venous NTG concentrations were not significantly affected by NAC. Subsequently, another 20 consecutive patients were treated with intravenous NTG and continuously infused NAC (10 g/day). Seven remained pain free during the first 24 hr of NTG infusion; 11 required increments in NTG infusion rate for pain control. Acute myocardial infarction occurred in one patient, while none developed symptomatic hypotension.

Iversen HK. N-acetylcysteine enhances nitroglycerin-induced headache and cranial artery response. Clin Pharmacol Ther 1992;52:125-133.

Kleinveld HA, Demacker PNM Stalenhoef AFH. Failure of N-acetylcysteine to reduce low-density lipoprotein oxidizability in healthy subjects. Eur J Clin Pharmacol 1992;43:639-642.

Lawson DL, Haught WH, Mehta P, Mehta JL. Studies of vascular tolerance to nitroglycerin: effects of N-acetylcysteine, NG-monomethyl, L-arginine, and endothelin-1. J Cardiovasc Pharmacol. 1996 Sep;28(3):418-24.
Abstract: Development of vascular tolerance to nitroglycerin (NTG) has been attributed to sulfhydryl (SH) depletion, guanylate cyclase desensitization, or both. Controversy regarding the precise contribution of these mechanisms may be due to variations in experimental design. To examine further the biochemical basis of NTG tolerance, norepinephrine (NE)-precontracted rat aortic rings were exposed to NTG (10(-5)M), which resulted in 84 +/- 6% relaxation. Other rings were first superfused with NTG (10(-6)M) and then contracted with NE. These rings showed a marked tolerance to the vasorelaxant effects of NTG (maximal relaxation 20 +/- 5%, n = 15, p < 0.001 vs. control rings). Similar tolerance to NTG was observed when the vascular rings were first superfused with acetylcholine (ACh 10(-6)M), indicating cross-tolerance between ACh and NTG. Treatment of NTG-tolerant rings with N-acetylcysteine (NAC) (10(-5)M) did not restore vascular smooth muscle (VSM) relaxation in response to NTG (maximal relaxation 23 +/- 5%, n = 8), suggesting that SH depletion may not be the basis of NTG tolerance in these experiments. Parallel sets of NTG-tolerant aortic rings were contracted with endothelin-1 (ET-1, n = 5) or the endothelium-derived relaxing factor (EDRF) synthase inhibitor NG-monomethyl L-arginine (L-NMMA, 10(-4)M, n = 8). In both ET-1- and L-NMMA-contracted rings, vascular relaxation in response to NTG was preserved (80 +/- 6 and 88 +/- 8% relaxation, respectively). Measurement of cyclic GMP in aortic rings showed marked accumulation on initial exposure of tissues to NTG (310 +/- 10 fmol/mg), whereas the NTG-tolerant rings showed much less cyclic GMP accumulation (48 +/- 29 fmol/mg). Rings contracted with L-NMMA or ET-1, but not NE, accumulated cyclic GMP when exposed to NTG (280 +/- 20 fmol/mg). These data indicate that NTG tolerance develops on exposure of vascular rings superfused with NTG or ACh and is probably not related to tissue SH depletion. Contraction of NTG-tolerant rings with ET-1 or L-NMMA restores NTG-mediated relaxation.

Martinez, E, Domingo, P. N-acetylcysteine as chemoprotectant in cancer chemotherapy. Lancet 1991 Jul 27;338(8761):249. (Letter)

May DC, Popma JJ, Black WH, et al. In vivo induction and reversal of nitroglycerin tolerance in human coronary arteries. N Engl J Med 1987;317:805-809.

Montoya-Cabrera MA, Escalante-Galindo P, Nava-Juarez A, Terroba-Larios VM, Teran-Hernandez JA. [Evaluation of the efficacy of N-acetylcysteine administered alone or in combination with activated charcoal in the treatment of acetaminophen overdoses]. Gac Med Mex. 1999 May-Jun;135(3):239-243. [Article in Spanish]
Abstract: STUDY OBJECTIVE: To evaluate the efficacy of N-acetylcysteine (N-AC) alone or combined with multiple-dose activated charcoal (AC) in the treatment of acetaminophen (ACT) overdose. DESIGN: Prospective observational case series of 14 consecutive pediatric patients. Group A (n = 7) were treated only with N-AC and group B (n = 7) with N-AC combined with AC. Plasma ACT concentrations were measured at 0.0, 24 and 48 h. As a measure of ACT disappearance, half-life of elimination (t1/2 beta) and exogenous body clearance (ClB) were calculated. RESULTS: Group A, Initial and final mean ACT plasmatic levels were 27 micrograms/mL and 4 micrograms/mL; t1/2 beta of 17 h and ClB 0.640 mL.kg.min. Group B, 27 micrograms/mL and 0.66 microgram/mL; t1/2 beta of 10 h and ClB 1.092 mL.kg.min. For both t1/2 beta and ClB differences, p < 0.05 (SS). CONCLUSION: N-AC significantly decreased the plasma ACT levels in both treatments; however, there were several advantages with the combined therapy: AC enhanced the efficacy of N-AC according with the higher elimination of the overdosed drug (97.6% vs. 85.2%), the t1/2 beta decreased 42%, and the ClB increased 70% in relation to the group A. Data of this study suggested that N-AC plus AC is more effective than N-AC alone in enhancing ACT elimination in overdosed patients and that it provided additional hepatoprotective benefit.

Myers C, Bonow R, Palmeri S, Jenkins J, Corden B, Locker G, Doroshow J, Epstein S. A randomized controlled trial assessing the prevention of doxorubicin cardiomyopathy by N-acetylcysteine. Semin Oncol 1983 Mar;10(1 Suppl 1):53-55.

Newman CM, Warren JB, Taylor GW, Boobis AR, Davies DS. Rapid tolerance to the hypotensive effects of glyceryl trinitrate in the rat: prevention by N-acetyl-L- but not N-acetyl-D-cysteine. Br J Pharmacol 1990 Apr;99(4):825-829.
Abstract: 1. A new model of tolerance to the hypotensive effect of organic nitrates has been developed in the rat. 2. The fall in mean arterial pressure (MAP) in response to bolus doses of sodium nitroprusside (NP) (4 micrograms kg-1) and glyceryl trinitrate (GTN) (10 micrograms kg-1) was recorded both before and after a 60 min infusion of either 0.9% saline, NP (20 micrograms kg-1 min-1) or GTN (40 micrograms kg-1 min-1). 3. The hypotensive effects of NP or GTN were unchanged following saline infusion, but were reduced in both cases by approximately 40% following the infusion of NP. 4. Infusion of GTN for 60 min virtually abolished the hypotensive effect of a GTN bolus (i.e. nitrate tolerance), whilst the effect of a NP bolus was reduced only to a similar extent (30%) as after an infusion of NP. This latter effect is attributed to a degree of non-specific cross-tolerance between GTN and NP. 5. Co-treatment of a group of rats with N-acetyl-L-cysteine (L-NAC) prevented the development of nitrate tolerance, confirming the role of thiols in this phenomenon, whereas N-acetyl-D-cysteine (D-NAC) did not. 6. The stereospecificity in the effect of NAC in preventing this specific tolerance to GTN suggests that the interaction between GTN and NAC and/or cysteine involves an enzyme-dependent step. 7. NAC was unable to prevent the non-specific cross-tolerance to NP which followed infusion of GTN, suggesting that the mechanism does not directly involve NAC and/or cysteine.

Nishikawa Y, Kanki H, Ogawa S. Differential effects of N-acetylcysteine on nitroglycerin- and nicorandil-induced vasodilation in human coronary circulation. J Cardiovasc Pharmacol. 1998 Jul;32(1):21-28.
Abstract: We investigated the role of the availability of sulfhydryl groups during vasodilation of the human coronary circulation induced by nitroglycerin and nicorandil. In patients with normal coronary arteries (n = 29) or with coronary artery disease (CAD; n = 26), coronary blood flow (CBF) and epicardial coronary artery diameter after intracoronary administration of 50 microg nitroglycerin or 0.5 mg nicorandil were measured, before and after the intravenous infusion of saline or 100 mg/kg of N-acetylcysteine (NAC). In normal subjects, saline infusion did not alter the nitroglycerin- and nicorandil-induced vasodilation in large epicardial coronary artery. In contrast, NAC potentiated both nitroglycerin- and nicorandil-induced vasodilation. In patients with CAD, nitroglycerin and nicorandil induced less dilation than in normal subjects. NAC augmented the nitroglycerin- and nicorandil-induced vasodilation in the small epicardial coronary artery, but not in the large epicardial segments. In both groups, NAC potentiated the increase in CBF in response to nitroglycerin. However, NAC had no effects on the CBF response to nicorandil. Sulfhydryl availability is at least one determinant of the in vivo responsiveness to nitroglycerin of conductance and resistance vessels in normal human coronary circulation. In patients with CAD, external augmentation of sulfhydryl availability did not affect the depressed response to nitroglycerin in the large epicardial coronary artery. Although nicorandil acts as an NO donor, similar to nitroglycerin, in dilating the epicardial coronary artery, other effects, such as the opening of K(ATP) channel, play a more important role in the nicorandil-induced vasodilation of resistance vessels.

Pizzulli L, Hagendorff A, Zirbes M, Jung W, Luderitz B. Pizzulli L, et al. N-acetylcysteine attenuates nitroglycerin tolerance in patients with angina pectoris and normal left ventricular function. Am J Cardiol. 1997 Jan 1;79(1):28-33.
Abstract: The aim of this study was to assess whether N-acetylcysteine (NAC) is able to prevent tolerance to a 48-hour infusion of nitroglycerin (NTG) in the setting of normal left ventricular function. In 16 patients, the hemodynamic response to 0.8 mg sublingual (s.l.) NTG was assessed by measuring mean arterial, pulmonary artery, pulmonary capillary wedge and right atrial pressures, cardiac output, and calculation of the systemic and pulmonary vascular resistances. The parameters were obtained at baseline and 1 to 10 minutes after the s.l. NTG application (day 1). NTG was started at 1.5 microg/kg/min; concomitantly, a bolus of 2,000 mg of NAC was administered, followed by an infusion of 5 mg/kg/hour. Both infusions were continued for 48 hours, and the hemodynamic study was repeated (day 3). The same measurements were obtained in a matched control group of 15 patients with NTG infusion alone. Plasma renin activity, aldosterone, and norepinephrine were measured before and after the infusion period. The first s.l. NTG infusion (day 1) caused a significant decrease in mean arterial (p <0.01), pulmonary artery (p <0.001), and right atrial pressures (p <0.001), and in systemic (p <0.01) and pulmonary vascular resistances (p <0.001) in both groups. After the 48-hour infusion (day 3), there was a total loss of nitrate-mediated vasodilation (pressure values and vascular resistances day 3 > day 1) in 5 of 16 patients (NAC nonresponders), whereas in the other 11 of 16 patients (NAC responders), there was significant vasodilation throughout the infusion period. Tolerance had developed in 14 of 15 patients with NTG infusion alone. The same difference (responder vs nonresponder vs NTG alone) held true regarding the response to the second s.l. NTG infusion after 48 hours. The neurohormonal counter-regulation and intravascular volume expansion (increase in plasma renin activity, p <0.001, and norepinephrine, p <0.05; decrease in aldosterone, p <0.01) did not differ between responders and nonresponders. We conclude that NAC attenuates tolerance development to a continuous NTG infusion in a specific patient subgroup and that this occurs despite the same amount of neurohormonal counter-regulation and intravascular volume expansion compared with patients with tolerance development.

Salgia AD, Kosnik SD. When acetaminophen use becomes toxic. Treating acute accidental and intentional overdose. Postgrad Med. 1999 Apr;105(4):81-84, 87, 90. (Review)

Schmidt LE, Dalhoff KP. [Side-effects of N-acetylcysteine treatment in patients with paracetamol poisoning]. Ugeskr Laeger. 1999 May 3;161(18):2669-2672. [Article in Danish]
Abstract: Treatment of paracetamol intoxication with N-acetylcysteine (NAC) is standard in Denmark. NAC is considered safe with relatively few side effects. It is recommended that all patients be treated irrespective of paracetamol dose or time from intoxication to treatment start. Consequently a higher number of patients will be treated with NAC than with previous regimens based on plasma concentrations of paracetamol. In this retrospective study we evaluated the incidence of side effects of NAC in 310 patients admitted to the Department of Hepatology, Rigshospitalet, Copenhagen, over a four-year period (1.1.1994-31.12.1997). Twenty-six (8.4%) patients developed side effects. Side effects were anaphylactoid, mainly from skin (25 rash, pruritus or flushing), in rare cases more serious (four bronchospasm, three angioedema, one hypotension). None were life-threatening and all patients received the full course of NAC. In all cases the recommended treatment with antihistamine or steroids against adverse effects was administered. We conclude that treatment with NAC is safe. Accordingly we find no reason to change the recommendation for treatment of paracetamol intoxication in Denmark.

Schmitt-Graff A, Scheulen ME. Prevention of adriamycin cardiotoxicity by niacin, isocitrate or N-acetyl-cysteine in mice. A morphological study. Pathol Res Pract. 1986 May;181(2):168-74.
Abstract: Adriamycin is known to produce treatment limiting cardiotoxicity. We studied the effect of niacin, isocitrate, and N-acetyl-cysteine on cumulative adriamycin-induced cardiotoxicity in NMRI mice. Pathologic grading of the hearts indicated a significant reduction in myocardial injury. In addition, according to median survival and weight changes there was a significant decrease in toxicity. As demonstrated in Ehrlich ascites tumor, coadministration of N-acetyl-cysteine may interfere with the antitumor activity of adriamycin. In contrast, niacin and isocitrate did not show significant inhibition of antineoplastic activity. Our experiments suggest a promising role of niacin and isocitrate as potential cardioprotectors in the course of chemotherapy with adriamycin.

Threlkeld DS, ed. Diuretics and Cardiovasculars, Antianginal Agents, Nitrates. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Apr 1992.

Torresi J, Horowitz JD, Dusting GJ. Prevention and reversal of tolerance to nitroglycerine with N-acetylcysteine. J Cardiovasc Pharmacol 1985 Jul-Aug;7(4):777-783.
Abstract: A recent study demonstrated that the sulfhydryl donor N-acetylcysteine (NAC) potentiated hemodynamic responsiveness to nitroglycerine (NTG) in patients with ischaemic heart disease. The interaction between NTG and NAC in rings of bovine coronary artery was examined. Vasodilator responses to NTG were determined after elevation of tone with the thromboxane mimetic U46619 [(15S)-hydroxy-11 alpha, 9 alpha-(epoxymethano) prosta-5Z, 13E-dienoic acid]. NAC (1 microM-3 mM) induced no changes in tone of the preparation, but 10 microM NAC significantly potentiated responses to NTG (EC50 reduced from 0.69 +/- 0.19 microM to 0.22 +/- 0.06 microM; p less than 0.01). Increasing degrees of tolerance to NTG were produced at pH 7.4 by preincubating coronary rings with NTG in concentrations of 4.4 and 44 microM, and 0.22 mM. With 0.22 mM NTG, EC50 for subsequently administered NTG was increased to 11.0 +/- 1.8 microM (p less than 0.001 vs. control vessels). The degree of tolerance produced with this concentration of NTG was markedly attenuated by simultaneous (EC50 = 0.50 +/- 0.30 microM; p less than 0.001 vs. tolerant vessels) or subsequent (EC50 = 1.17 +/- 0.59 microM, p less than 0.001 vs. control vessels) incubation with 10 microM NAC. These data confirm that responses to NTG are modulated by sulfhydryl (or specifically cysteine) availability and suggest that in vitro tolerance to NTG is related to sulfhydryl (or cysteine) depletion. It is therefore possible that in vivo potentiation of NTG responses by NAC will be of clinical benefit in preventing or reversing loss of hemodynamic responsiveness to NTG.

Werbach MR. Foundations of Nutritional Medicine. Tarzana, CA: Third Line Press, 1997. (Review).

Zed PJ, Krenzelok EP. Treatment of acetaminophen overdose. Am J Health Syst Pharm 1999 Jun 1;56(11):1081-1091. (Review)