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[Micromedex][01] acetylcysteine 適應症整理

[Micromedex][02]Acetylcysteine適應症整理

[Micromedex][03]Acetylcysteine適應症整理

第13～第21

13

Cystinosis

1) Overview

FDA Approval: Adult, no; Pediatric, no

Efficacy: Adult, Evidence is inconclusive

Recommendation: Adult, Class IIb

Strength of Evidence: Adult, Category C

2) Summary:

Acetylcysteine has been used successfully in patients with cystinosis (Mulvaney et al, 1975).

3) Adult:

a) Six patients with cysteine stones improved after treatment with oral acetylcysteine (Mulvaney et al, 1975). The doses utilized were 20 to 500 milligrams/kilogram/day in divided doses. The usual adult dose was 0.7 gram 4 times a day. All 6 patients improved (passed fewer and/or smaller stones). The authors speculated that acetylcysteine is effective in reducing cysteine to cystine disulfide which is more soluble. No systemic side effects were reported in these patients.

14

Cytotoxicity; Treatment and Prophylaxis

1) Overview

FDA Approval: Adult, no; Pediatric, no

Efficacy: Adult, Evidence is inconclusive

Recommendation: Adult, Class IIb

Strength of Evidence: Adult, Category B

2) Summary:

Acetylcysteine has been demonstrated to exert a protective effect against cytotoxic agents in animal models and some patients (Dresdale et al, 1982).
Administration of glutathione (GSH) and N-acetylcysteine (NAC) to patients with early septic shock reduced indicators of free radical activity more effectively than did GSH alone (Ortolani et al, 2000).
Acetylcysteine was used successfully to treat sulfasalazine toxicity (Gabay et al, 1993).
Preliminary human and animal reports suggest that acetylcysteine may have a cytoprotective effect in patients with severe sepsis and associated systemic inflammatory response syndrome (SIRS) (Henderson & Hayes, 1994a; Bakker et al, 1994a; Dinarello et al, 1993a; Bone, 1992a; Jepsen et al, 1992a; Welbourn & Young, 1992a; Repine & Beehler, 1991a; Rackow & Astiz, 1991a; Glauser et al, 1991a; Ellenhorn & Barceloux, 1988a; Braganza et al, 1986; Keller et al, 1985a; Borozotta & Polk, 1983a).

3) Adult:

a) Acetylcysteine has been demonstrated to exert a protective effect against cytotoxic agents in animal models and some patients. Acetylcysteine inactivates acrolein, the cause of hemorrhagic cystitis during cyclophosphamide and ifosfamide therapy. Acetylcysteine may also protect against cardiotoxicity from doxorubicin and adriamycin, lung damage from bleomycin, and hepatotoxicity from nitrogen mustards. Acetylcysteine does not appear to be effective in reversing advanced left ventricular dysfunction from doxorubicin-induced cardiomyopathy. However, acetylcysteine may protect against doxorubicin cardiomyopathy when administered prior to or during chemotherapy (Dresdale et al, 1982). Protection against chloramphenicol-induced bone-marrow toxicity has also been demonstrated (Yunis et al, 1986).
b) Administration of glutathione (GSH) and N-acetylcysteine (NAC) to patients with early septic shock reduced indicators of free radical activity more effectively than did GSH alone. Thirty patients in septic shock were treated with conventional therapy and randomly assigned to receive no additional treatment, intravenous GSH 70 milligrams/kilogram/day (mg/kg/day), or GSH 70 mg/kg/day plus NAC 75 mg/kg/day, for 5 days. By day 5, patients in both groups receiving GSH showed a significant decrease in lipoperoxidative indexes (expired ethane, plasma malondialdehyde) relative to basal values (p less than 0.01) and relative to those of the control group (p less than 0.01). Furthermore, values for the group receiving both GSH and NAC were significantly more improved than those of the group receiving GSH only (p less than 0.01). At day 5, mortality of the three groups was similar, but by day 10, the mortality rate in the control group was double that of the other two (p less than 0.01). There were no adverse events associated with the high doses of GSH and NAC (Ortolani et al, 2000).
c) Acetylcysteine was used successfully to treat sulfasalazine toxicity (Gabay et al, 1993). The patient developed severe hepatitis, disseminated intravascular coagulation, high spiking fever, a mononucleosis-like syndrome and a diffuse cutaneous rash. Symptoms resolved following discontinuation of sulfasalazine and IV administration of N-acetylcysteine.
d) Preliminary human and animal reports suggest that acetylcysteine may have a cytoprotective effect in patients with severe sepsis and associated systemic inflammatory response syndrome (SIRS). SIRS is an acute illness characterized by generalized activation of the endothelium which leads to multiorgan failure and carries a high mortality rate. The cellular damage associated with SIRS is mediated by the formation of large quantities of active free radicals by inflamed cells that overwhelm and deplete endogenous antioxidants (eg, glutathione). Acetylcysteine is a glutathione precursor capable of replenishing depleted intracellular glutathione and in theory augment antioxidant defenses. A bolus dose of 150 mg/kg in dextrose 5% infused over 30 minutes followed by 15 mg/kg/h for 4 days has been used in humans. Initial reports appear to indicate that acetylcysteine may improve renal function, reduce fluid requirements, and lessen tissue edema. Acetylcysteine may be a useful adjuvant therapy for SIRS associated with severe sepsis (Henderson & Hayes, 1994a; Bakker et al, 1994a; Dinarello et al, 1993a; Bone, 1992a; Jepsen et al, 1992a; Welbourn & Young, 1992a; Repine & Beehler, 1991a; Rackow & Astiz, 1991a; Glauser et al, 1991a; Ellenhorn & Barceloux, 1988a; Braganza et al, 1986; Keller et al, 1985a; Borozotta & Polk, 1983a).
e) In animals and humans, acetylcysteine has been shown to diminish the extent of reperfusion injury following acute myocardial infarction by reducing myocardial stunning, reducing infarct size by 32% to 49%, increasing left ventricular ejection fraction, and reducing the severity of ventricular arrhythmias during reperfusion (Sochman et al, 1996; Arstall et al, 1995; Grech et al, 1993a; Young et al, 1993a; Davies et al, 1993a; Farb et al, 1993a; Kirshenbaum et al, 1992a; Ferrari et al, 1990a; Sochman et al, 1990a; Blaustein et al, 1989a; Singh et al, 1989a; Aruoma et al, 1989a; Forman et al, 1988a; Ceconi et al, 1988a; Westlin & Mullane, 1988a).
f) Acetylcysteine was not effective treatment for patients with amyotrophic lateral sclerosis (ALS). In a randomized, double-blind, placebo-controlled study involving 110 patients with ALS, treatment with acetylcysteine (50 mg/kg subcutaneously) for 12 months did not increase survival or reduce disease progression. Although free radicals are thought to play a role in the pathogenesis of ALS, treatment with acetylcysteine was no more effective than placebo in this study (Louwerse et al, 1995).

15

Diagnostic procedure on lower respiratory tract

FDA Labeled Indication
1) Overview

FDA Approval: Adult, yes; Pediatric, yes

Efficacy: Adult, Effective; Pediatric, Effective

Recommendation: Adult, Class IIa; Pediatric, Class IIa

Strength of Evidence: Adult, Category B; Pediatric, Category B

2) Summary:

Acetylcysteine inhalation solution is indicated as adjuvant therapy in diagnostic bronchial studies such as bronchograms, bronchospirometry, and bronchial wedge catheterization, for patients with abnormal, viscid, or inspissated mucous secretions (Prod Info acetylcysteine inhalation solution, 2004).

16

Disease of liver

1) Overview

FDA Approval: Adult, no; Pediatric, no

Efficacy: Adult, Evidence is inconclusive

Recommendation: Adult, Class IIb

Strength of Evidence: Adult, Category B

2) Summary:

N-acetylcysteine (NAC) induced significant increases in liver blood flow (hepatosplanchnic) index, cardiac index, and liver function in patients experiencing the early stage of septic shock (Rank et al, 2000a).
Acetylcysteine appears to improve hepatic circulation and oxygen delivery and consumption in patients with severe liver dysfunction (liver failure, alcoholic or autoimmune hepatitis, and liver transplantation) (Devlin et al, 1997).
Three patients who developed hepatic veno-occlusive disease after allogeneic stem cell transplantation (ASCT) were successfully treated with acetylcysteine (Ringden et al, 2000).
Infusion of acetylcysteine (AC) into stabilized patients with fulminant hepatic failure did not improve oxygen uptake or tissue oxygen extraction (Walsh et al, 1998).

3) Adult:

a) N-acetylcysteine (NAC) induced significant increases in liver blood flow (hepatosplanchnic) index, cardiac index, and liver function in patients experiencing the early stage of septic shock. In a randomized, double-blind study, patients experiencing the onset of septic shock within the past 24 hours were assigned to receive either placebo (n=30) or intravenous NAC 150 milligrams/kilogram (mg/kg) given as a loading dose, followed by a continuous infusion of NAC 12.5 mg/kg/hour given over 90 minutes (n=30). All patients were hemodynamically stable after conventional resuscitation, and maintained on mechanical ventilation. Hepatosplanchnic (HSp) perfusion was measured by indocyanine green dye technique, and microsomal liver function was assessed by the degree of metabolism imposed upon lignocaine given as a single 1 mg/kg infusion. Patients receiving NAC experienced significant increases in HSp blood flow index and cardiac index, compared with patients receiving placebo (p=0.01 and 0.02, respectively). NAC-group patients also experienced significant increases in serum concentrations of monoethylglycinexylidide (MEGX), the primary metabolite of lignocaine, compared with the placebo group (p=0.04); a significant correlation was found between MEGX and the liver blood flow index (p less than or equal to 0.01). A significant decrease was seen in the difference between arterial and gastric mucosal carbon dioxide tension (p=0.05), indirectly reflective of the improvement in splanchnic perfusion sustained by patients receiving NAC. There were no serious adverse events observed with the infusion of NAC; however, patients receiving NAC experienced a significant decline in pulmonary oxygenation after the NAC infusion (Rank et al, 2000a).
b) Acetylcysteine appears to improve hepatic circulation and oxygen delivery and consumption in patients with severe liver dysfunction (liver failure, alcoholic or autoimmune hepatitis, and liver transplantation). Fifteen hemodynamically stable patients with hepatic impairment and other critical illness and requiring mechanical ventilation were infused with acetylcysteine 150 mg/kg in 250 mL of dextrose 5% in water (D5W) over 15 minutes followed by 50 mg/kg in D5W 250 mL over 45 minutes at an infusion rate of 62.5 mL/hr. Improved indocyanine green clearance in 13 of the 15 patients suggested improved hepatic circulation. Also, oxygen delivery (Do2) and oxygen consumption (Vo2) were found to increase significantly in 13 of 15 subjects. These investigators concluded that circulatory and hemodynamic benefits associated with acetylcysteine infusion may be useful in patients with liver disorders or other critical illnesses where systemic or regional circulation is compromised (Devlin et al, 1997).
c) Three patients who developed hepatic veno-occlusive disease after allogeneic stem cell transplantation (ASCT) were successfully treated with acetylcysteine. All three patients manifested elevated bilirubin before day 21 after ASCT, hepatomegaly, ascites, and unexpected weight gain of more than 5%. Acetylcysteine was administered intravenously, typically as 100 to 150 milligrams/kilogram per day for 12 to 31 days, depending on the severity of the condition. Bilirubin, serum liver enzymes, and elevated cytokines returned to normal Acetylcysteine may be an effective treatment option for this often fatal disease (Ringden et al, 2000).
d) Infusion of acetylcysteine (AC) into stabilized patients with fulminant hepatic failure did not improve oxygen uptake or tissue oxygen extraction. Eleven patients received a loading dose of AC 150 milligrams/kilogram (mg/kg) in 200 milliliters (mL) 5% dextrose over 15 minutes, followed by 50 mg/kg in 500 mL 5% dextrose over 4 hours, and then 100 mg/kg in 1 L over 16 hours. Seven patients received volume-matched infusions of 5% dextrose alone. Oxygen consumption (VO2) and oxygen delivery (DO2) were measured independently. With respect to cardiac output, there were responders and nonresponders, but there were no significant differences between the 2 groups. In all but 3 cases, there was no relationship between VO2 and DO2. There also were no correlations between AC concentrations and mean arterial pressure, cardiac output, or systemic vascular resistance. These results differ from those of other studies, perhaps because of the independent determinations of VO2 and DO2 and because of the degree of illness of the patients (Walsh et al, 1998).

17

Disease of respiratory system, chronic, With abnormal, viscid, or inspissated mucous secretions

FDA Labeled Indication
1) Overview

FDA Approval: Adult, yes; Pediatric, yes

Efficacy: Adult, Effective; Pediatric, Effective

Recommendation: Adult, Class IIa; Pediatric, Class IIa

Strength of Evidence: Adult, Category B; Pediatric, Category B

2) Summary:

Acetylcysteine inhalation solution is indicated as an adjuvant therapy for patients with abnormal, viscid, or inspissated mucous secretions in several conditions including chronic bronchopulmonary disease (chronic emphysema, emphysema with bronchitis, tuberculosis, bronchiectasis, and primary amyloidosis of the lung) (Prod Info acetylcysteine inhalation solution, 2004).
Once-per-day N-acetylcysteine (NAC) reduced the exacerbation rate in patients with chronic obstructive pulmonary disease (COPD) during an open, 6-month trial (Pela et al, 1998).

3) Adult:

a) Chronic Obstructive Pulmonary Disease

1) Once-per-day N-acetylcysteine (NAC) reduced the exacerbation rate in patients with chronic obstructive pulmonary disease (COPD) during an open, 6-month trial. One-hundred sixty nine patients received either standard therapy for COPD (beta2-agonists, anticholinergics, theophylline, and inhaled and/or oral corticosteroids) or standard therapy plus NAC 600 milligrams per day orally in a single dose. The rate of occurrence of exacerbations over 6 months was 41% less in the NAC group than in the standard-treatment-only group (p less than 0.003). Lung function was not different for the 2 groups, either at the beginning or the end of the study. There were no differences between the groups in the number of side effects reported (Pela et al, 1998).
2) Acetylcysteine did not contribute to improvement in chronic obstructive pulmonary disease (COPD) patients in a controlled study. One hundred eighty-one patients with chronic bronchitis and severe airway obstruction received either acetylcysteine (200 milligrams 3 times a day) or placebo orally for five months in a double-blind, parallel-group study. Patients kept detailed daily symptom-diaries and were assessed monthly. No statistical differences were noted in mean number of exacerbations between groups (Anon, 1985).
3) The reports of use of acetylcysteine (NAC) in chronic obstructive pulmonary disease (COPD) have, in general, been unsatisfactory. The only beneficial response attributable to NAC has been a decrease in sputum consistency (Hirsch et al, 1970b; Hirsch & Kory, 1967a), with no improvement in pulmonary function tests or subjective response. NAC has been shown to produce hypoxemia and hypercarbia with a decrease in vital capacity and increase in airway resistance in these patients (Rao et al, 1970a).

4) Pediatric:

a) Intratracheal administration of NAC to liquefy airway mucus neither improves the clinical condition nor hastens recovery in premature infants with chronic lung disease and its administration may lead to increased total airway resistance and cyanotic spells (Bibi et al, 1992).

18

Drug allergy

1) Overview

FDA Approval: Adult, no; Pediatric, no

Efficacy: Adult, Ineffective

Recommendation: Adult, Class III

Strength of Evidence: Adult, Category B

2) Summary:

Acetylcysteine (NAC) at a dose of 3 grams twice daily was not effective in HIV patients for preventing hypersensitivity reactions to trimethoprim-sulfamethoxazole (TMP-SMX), a prophylactic treatment against Pneumocystis carinii pneumonia (Walmsley et al, 1998).
Acetylcysteine has been used to treat phenytoin-induced hypersensitivity (Redondo et al, 1997).

3) Adult:

a) Acetylcysteine (NAC) at a dose of 3 grams twice daily was not effective in HIV patients for preventing hypersensitivity reactions to trimethoprim-sulfamethoxazole (TMP-SMX), a prophylactic treatment against Pneumocystis carinii pneumonia. In a randomized trial with 198 HIV-infected patients who were being treated with trimethoprim 80 milligrams (mg) and sulfamethoxazole 400 mg orally twice daily, 96 patients also received oral NAC 3 grams (15 milliliters of a 20% solution) 1 hour before each dose of TMP-SMX for 2 months. Patients were followed for 3 additional months while continuing to take TMP-SMX without NAC. The need to discontinue TMP-SMX treatment because of fever, rash, or pruritus occurred in 25% of those receiving TMP-SMX alone and in 21% of those receiving TMP-SMX plus NAC (p=0.65). There were statistically significant differences in symptoms leading to discontinuation between the 2 groups. NAC was not well tolerated in the formulation used, even though it was administered in cola or orange juice to make it more palatable. Because of the unpleasant taste and the side effects of nausea and vomiting, compliance may have been less than reported. With the dose and formulation used, NAC cannot be recommended to prevent hypersensitivity reaction to TMP-SMX in HIV patients (Walmsley et al, 1998).

19

Drug tolerance, Nitrate

1) Overview

FDA Approval: Adult, no; Pediatric, no

Efficacy: Adult, Evidence is inconclusive

Recommendation: Adult, Class III

Strength of Evidence: Adult, Category B

2) Summary:

Concurrent administration of N-acetylcysteine attenuates loss of vasodilatory response to nitroglycerin in some angina patients with normal ventricular function (Pizzulli et al, 1997).
One study reported that N-acetylcysteine at 100 milligrams/kilogram intravenously did not reverse tolerance to the hemodynamic and antianginal effects of isosorbide dinitrate in 12 patients with chronic stable angina (Parker et al, 1987).
N-acetylcysteine (200 milligrams/kilogram orally) was at least partially effective in reversing the tolerance observed in heart failure patients receiving continuous IV infusions of nitroglycerin (Packer et al, 1987).

3) Adult:

a) Concurrent administration of NAC attenuates loss of vasodilatory response to nitroglycerin in some angina patients with normal ventricular function. In a controlled study (Pizzulli et al, 1997), patients with angina pectoris and normal left ventricle function were tested for response to nitroglycerin 0.8 milligram (mg) sublingually before and after a 48-hour continuous nitroglycerin infusion (1.5 micrograms/kilogram (kg)/minute). For 16 patients, a concomitant infusion of NAC (5 mg/kg/hour) was administered with the 48-hour nitroglycerin infusion. A group of 15 matched controls received no concurrent NAC during the 48-hour nitroglycerin infusion. Eleven of 16 in the NAC group responded to sublingual nitroglycerin after the 48-hour infusion, while only 1 in the control group responded to the second dose of sublingual nitroglycerin.
b) In contrast, one study reported that N-acetylcysteine at 100 milligrams/kilogram intravenously did not reverse tolerance to the hemodynamic and antianginal effects of isosorbide dinitrate in 12 patients with chronic stable angina (Parker et al, 1987). However, in 11 healthy volunteers, N-acetylcysteine potentiated and prolonged the headache response and nitroglycerin-induced dilation of the temporal artery at low doses of nitroglycerin (Iversen, 1992b).
c) N-acetylcysteine (200 milligrams/kilogram orally) was at least partially effective in reversing the tolerance observed in heart failure patients receiving continuous IV infusions of nitroglycerin (Packer et al, 1987). N-acetylcysteine administration resulted in restoration of hemodynamic benefits, approaching those observed at the start of the nitroglycerin infusion.

20

Hemorrhagic cystitis; Prophylaxis

1) Overview

FDA Approval: Adult, no; Pediatric, no

Efficacy: Adult, Evidence is inconclusive

Recommendation: Adult, Class III

Strength of Evidence: Adult, Category B

2) Summary:

Acetylcysteine is effective in preventing or reducing cyclophosphamide or ifosfamide induced hemorrhagic cystitis (Watson, 1984; Morgan, 1981).

3) Adult:

a) General Information

1) Limiting aspects of the use of the chemotherapeutic alkylating agents, such as cyclophosphamide and ifosfamide, have been inflammation, ulceration and fibrosis of the urinary bladder. The incidence or severity of bladder damage can be reduced by lowering or fractionating the dosage and adequate hydration; however, this is not sufficient to protect the bladder. N-acetylcysteine (NAC) has been used to prevent hemorrhagic cystitis by neutralizing these alkylating agents. Acetylcysteine provides thiol groups for the alkylator's metabolites to react with, thereby sparing the bladder (Watson, 1984).
2) Factors contributing to the limited acceptance of oral acetylcysteine as a uroprotective agent include nausea and vomiting associated with high doses, poor taste, and undesirable pharmacokinetic properties (less than 10% is excreted in the urine) (Schoenike & Dana, 1990). Comparative studies indicate that mesna (mercaptoethane sulfonate), another thiol compound capable of binding with acrolein, is more effective than acetylcysteine for hemorrhagic cystitis (Williams et al, 1990; Legha et al, 1990). However, mesna treatment has not been shown in controlled studies to be superior to hyperhydration with forced diuresis for protection against cyclophosphamide-induced hemorrhagic cystitis (Haselberger & Schwinghammer, 1995).

b) Use With Ifosfamide

1) Oral acetylcysteine was effective in preventing ifosfamide-induced hematuria in a study of ten patients (Morgan, 1981). Patients received ifosfamide 1.2 grams/square meter/day intravenously for 5 days every 28 days, while another group of 10 patients received acetylcysteine 1 gram orally four times a day on the same days ifosfamide was administered. Of the 19 patients receiving ifosfamide alone, 7 of 10 patients demonstrated hematuria while only 3 of 10 patients receiving both acetylcysteine and ifosfamide developed hematuria. In these 3 patients, hematuria developed after the patients became nauseated and refused the acetylcysteine but continued to receive ifosfamide.
2) Eleven of 18 patients who developed microscopic hematuria (4 or greater red blood cells/high power field)) with the first course of ifosfamide (1200 milligrams/square meter/day for 5 days, repeated every 28 days) received oral acetylcysteine. Acetylcysteine was administered 4 times a day (as a 20% solution) for 5 days along with ifosfamide. The first dose was started 2 hours before ifosfamide therapy. Doses of 3, 6, 9, or 12 grams/day of acetylcysteine were assessed. If lower doses were tolerated by the patient, the dose was escalated to the next level with subsequent courses of treatment. The number of patients per oral daily dose of acetylcysteine was small, but 6 grams/day appeared to be the optimum uroprotective dose and was tolerated without significant nausea or vomiting (Slavik & Saiers, 1983).

21

Hepatorenal syndrome

1) Overview

FDA Approval: Adult, no; Pediatric, no

Efficacy: Adult, Evidence is inconclusive

Recommendation: Adult, Class IIb

Strength of Evidence: Adult, Category C

2) Summary:

Acetylcysteine improved renal function in patients with hepatorenal syndrome (Holt et al, 1999).

3) Adult:

a) Renal function was improved in patients with early hepatorenal syndrome by treatment with N-acetylcysteine (NAC). Twelve patients meeting the 5 major diagnostic criteria for hepatorenal syndrome were treated with NAC (150 milligrams/kilogram (mg/kg) intravenously for 2 hours, followed by continuous infusion of 100 mg/kg for 5 days). Creatinine clearance increased (p less than 0.001), serum creatinine decreased (p less than 0.02), urine output increased (p less than 0.001), and sodium excretion increased (p less than 0.05). There were no significant changes in liver function or blood pressure. The survival rates at 1 and 3 months were 67% and 58%, respectively (including 2 patients who had received liver transplants after improvement of renal function). NAC may offer a bridging therapy, extending the time available for liver transplantation (Holt et al, 1999).