- Glutathione is an endogenous tripeptide which regulates numerous enzymatic reactions.
- Reduced glutathione can be administered intramuscularly or intravenously at a dosage of 300 to 600 milligrams (mg) once or twice daily. Parenteral total doses of up to 5000 mg have been used as a chemoprotectant for cisplatin-based regimens.
- Following intravenous administration of reduced glutathione, an apparent volume of distribution of 15 liters (L), elimination half-life of 7 minutes (min), and clearance of 850 milliliters/minute/square meter (mL/min/m(2)) have been reported for reduced glutathione.
- No serious adverse effect attributable to glutathione has been reported in available studies.
- Glutathione has been used for the treatment of liver disorders and idiopathic pulmonary fibrosis, and as a chemoprotectant to mitigate adverse effects of antineoplastic therapy.
Doses of 600 milligrams (mg) of aerosolized reduced glutathione twice daily have been used in idiopathic PULMONARY FIBROSIS (Borok et al, 1991), chronic inflammatory upper respiratory tract disease (Testa et al, 1995), and HIV INFECTION (Holroyd et al, 1993).
For chemoprotection against cisplatin toxicity in patients with advanced gastric cancer, glutathione 1500 milligrams/square meter (mg/m(2)) was given intravenously prior to cisplatin, followed by 600 mg/m(2) intramuscularly on days 2 to 5. Patients in this study received a weekly regimen of cisplatin (40 mg/m(2)), epirubicin, 5-fluorouracil, 6S-leucovorin and granulocyte colony-stimulating factor (Cascinu et al, 1995).
Different dose regimens of intravenous reduced glutathione have been used in the treatment of hepatic, cardiovascular, urologic and neoplastic disease.
Intravenous doses of 1.5 grams/square meter (g/m(2)) have been given as chemoprotection against cisplatin toxicity in weekly cisplatin-based regimens for the treatment of gastric carcinoma (Cascinu et al, 1997; Graziano et al, 1998). Glutathione was administered as a 15-minute infusion in normal saline immediately prior to cisplatin infusion.
In ovarian carcinoma, doses of 2500 to 5000 mg or 1500 mg/m(2) have been given immediately prior to cisplatin doses in cisplatin-alone or cisplatin-based regimens (Locatelli et al, 1993; Di Re et al, 1990; Bogliun et al, 1996; Bohm et al, 1999; Bohm et al, 1991; Colombo et al, 1995).
Prior hypersensitivity to glutathione
No serious adverse effect attributable to glutathione has been reported. Cutaneous eruptions have occurred in some patients.
Place In Therapy
A. ACUTE MYOCARDIAL INFARCTION
Sixty-seven patients with acute MYOCARDIAL INFARCTION (AMI) treated with alteplase and 29 with AMI but not eligible for alteplase, were randomized to receive adjunctive treatment with reduced glutathione (1800 milligrams (mg) as an intravenous bolus followed by an infusion of 20 mg/kg/min for 24 hours) or placebo. Patients receiving glutathione in addition to alteplase demonstrated a significant decrease in plasma malondialdehyde (MDA), a faster ST recovery, a lower CPK maximum peak, an earlier CPK peak, and a lower incidence of arrhythmias (Altomare et al, 1996).
B. ALCOHOLIC LIVER CIRRHOSIS
The effects of high doses of reduced glutathione (2400 milligrams (mg) daily intravenously for 15 days) on hepatic function and fibrogenetic activity was investigated in 10 patients with chronic alcoholic liver disease in an open study (Bardellini et al, 1992). After therapy, total bilirubin decreased significantly; clearance values, elimination, and the 90-minute retention coefficient of galactose significantly improved.
C. CANCER CHEMOPROTECTION
- Glutathione was effective in preventing oxaliplatin-induced neurotoxicity in patients receiving chemotherapy for COLORECTAL CANCER without reducing the efficacy of the chemotherapeutic regimen. In a randomized, double-blind, placebo-controlled trial, 52 patients with advanced colorectal cancer were treated with a chemotherapeutic regimen (OXALIPLATIN 100 milligrams/square meter (mg/m(2)) concurrently with leucovorin 250 mg/m(2) in a 2-hour infusion, followed by a 24-hour infusion of 5-fluorouracil 1500 mg/m(2)/day for 2 days), with reduced glutathione (GSH) 1500 mg/m(2) or normal saline given immediately before the administration of oxaliplatin. This therapy was repeated every 2 weeks. Toxicity was evaluated after every 2-week cycle with the National Cancer Institute’s (NCI) common toxicity criteria (CTC); response was evaluated after 4 cycles. After 4 cycles, 27% of patients in the GSH group and 42% in the placebo group had grade 1 or grade 2 neuropathy. Of those who completed 8 cycles, 9 of 21 (43%) in the GSH group and 15 of 19 (79%) in the placebo group had clinical neuropathy (p=0.04). Among those, 58% in the placebo group and 9.5% in the GSH group had moderate to severe neuropathy (grades 2 through 4 NCI CTC) (p=0.003). No patients in the GSH group and 5 in the placebo group had grade 3 or 4 neurotoxicity (p=0.004). No complete responses were observed in either group. Partial responses occurred in 27% of the GSH group and 23% of the placebo group. Median progression-free times were 7 months for both groups, and median survival times were 16 and 17 months for the GSH group and placebo group, respectively (Cascinu et al, 2002).
- Experimental data (Meister, 1991) have suggested that reduced glutathione could prevent or minimize platinum analog-related toxicity (particularly nephrotoxicity and neurotoxicity) without limiting antitumor activity. Phase II studies have evaluated this experimental evidence in dacarbazine resistant malignant melanoma patients treated with high-dose cisplatin (Bajetta et al, 1998), advanced head and neck cancer patients treated with 5-fluorouracil and folinic acid weekly plus escalating doses of cisplatin (Gebbia et al, 1992), advanced colorectal cancer patients treated with high-dose cisplatin and 5-fluorouracil (Cozzaglio et al, 1990), and endometrial cancer patients receiving adjuvant radiotherapy of the pelvis (De Maria et al, 1992). No effect of intravenous glutathione in limiting cisplatin related neurotoxicity was demonstrated in the study involving patients with malignant melanoma resistant to dacarbazine (Bajetta et al, 1998). In all other studies, patients treated with intravenous reduced glutathione prior to cisplatin infusion or radiotherapy showed a partial reduction of cisplatin toxicity, permitting the delivery of higher doses of chemotherapeutic agents.
- In the randomized double-blind, placebo-controlled trial (Cascinu et al, 1995), 50 patients with advanced GASTRIC CANCER treated with a weekly regimen of CISPLATIN (40 milligrams/square meter (mg/m(2)), epirubicin, fluorouracil, 6S-leucovorin and granulocyte colony-stimulating factor were randomized to receive either glutathione or placebo. Reduced glutathione 1500 mg/m(2) was given intravenously prior to cisplatin, followed by 600 mg/m(2) intramuscularly on days 2 to 5. At 9 and 15 weeks, patients treated with glutathione showed a statistically significantly lower rate of neurotoxicity than those in the placebo group. This effect did not reduce the clinical activity of chemotherapy (response rate of 76% in the glutathione group and 52% in the placebo arm).
- Glutathione showed a protective effect against cisplatin toxicity, without any interference of cisplatin efficacy, in 2 randomized studies in patients with OVARIAN CANCER. In one study (Colombo et al, 1995), 33 patients with relapsed ovarian cancer after a disease-free interval of at least 1 year and a cumulative dose of prior cisplatin ranging from 450 to 650 milligrams/square meter (mg/m(2)) received cisplatin 50 mg/m(2) weekly with or without glutathione (GSH) 2500 mg/m(2) intravenously for 9 weeks. In the other study (Bogluin et al, 1996) 54 patients with epithelial ovarian carcinoma received cisplatin (total dose 450 mg/m(2)) alone or with GSH 2500 mg intravenously immediately prior to cisplatin infusion.
D. CHRONIC RENAL FAILURE
- The effect of intravenous reduced glutathione (1200 milligrams (mg)) at the end of each HEMODIALYSIS session was evaluated in a placebo-controlled study in 20 chronic RENAL FAILURE patients. During the 120 days of therapy, there was an increase in levels of red blood cells, reduced glutathione, hematocrit, and hemoglobin, with a concomitant decrease in plasma oxidized glutathione and reticulocytes. No changes in these parameters was reported in the placebo group. The maximum effect was observed after 120 day of therapy (Costagliola et al, 1992).
- Similar results were observed in an open study in which 28 hemodialysis patients were treated with reduced glutathione (1200 mg intravenously at the end of each hemodialysis session for at least nine months) to improve anemia. After the first three months of therapy the levels of red blood cells, hemoglobin, hematocrit, and reticulocytes improved significantly in 17 (60%) patients (Usberti et al, 1997).
E. HIV INFECTION
In an open study, 14 HIV seropositive subjects were treated with aerosolized reduced glutathione (600 milligrams (mg) twice daily) to assess the possibility of increasing glutathione levels in the epithelial lining fluid (ELF). After three days of treatment glutathione ELF increased and persisted in the normal range for at least three hours (Holroyd et al, 1993).
F. IDIOPATHIC PULMONARY FIBROSIS
Aerosolized glutathione (600 milligrams (mg) twice daily for three days) was reported to reverse oxidant-antioxidant imbalance in 10 patients with idiopathic PULMONARY FIBROSIS. Total epithelial lining fluid (ELF) glutathione rose transiently, but not significantly; ELF oxidized glutathione increased significantly, and there was a decrease in spontaneous superoxide anion release by alveolar macrophages (Borok et al, 1991).
G. ISCHEMIC HEART DISEASE
The effect of intracoronary infusion of reduced glutathione (50 milligrams/minute (mg/min) at a rate of 2 milliliters (mL)/min for 6 minutes) was evaluated in 26 consecutive subjects undergoing cardiac catheterization for atypical chest pain. Glutathione did not significantly change epicardial coronary diameters or blood flow, but suppressed the constrictor response of epicardial diameter to acetylcholine (ACh) intracoronary infusion, increased blood flow in response to ACh, and potentiated the coronary dilator effect of nitroglycerin. Saline infusion did not shown any effect (Kugiyama et al, 1998)..
H. MALE INFERTILITY
In a placebo-controlled, double-blind, crossover trial of 20 infertile patients with dyspermia associated with unilateral varicocele or genital tract inflammation, intramuscular glutathione (600 milligrams (mg) daily) showed a statistically significant positive effect on sperm motility, particularly forward motility and kinetic parameters, and on sperm morphology (Lenzi et al, 1993).
I. PERIOPERATIVE RENAL DYSFUNCTION
The effect of perioperative administration of intravenous glutathione (200 milligrams/kilogram (mg/kg) in 100 milliliters (mL) saline) on renal function was assessed in 19 consecutive patients undergoing CORONARY ARTERY BYPASS GRAFTING (CABG). Patients were randomly assigned to receive glutathione or no treatment. Mean arterial pressure and systemic vascular resistance were lower in the treated group. Urine volume, creatinine clearance, renal excretory index, fractional excretion of sodium, and plasma osmolarity were significantly improved in patients treated with glutathione. No significant difference between groups was observed in plasma renin activity and angiotensin II (Amano et al, 1994).
J. PERIPHERAL OCCLUSIVE DISEASE
Pain free walking distance (PFWD) improved after glutathione treatment in subjects with Fontaine stage II stable obstructive peripheral artery disease in a randomized, double-blind, placebo- controlled trial. Twenty patients were administered glutathione 0.646 gram/250 milliliters (mL) sodium chloride intravenously and 20 patients were administered sodium chloride 250 mL intravenously twice a day for 5 days. PFWD increased in glutathione-treated patients at the end of the infusion period (221 plus/minus 15 versus 113 plus/minus 11 meters; p less than 0.04) compared to controls (119 plus/minus 18 versus 159 plus/minus 26 meters). The time to blood flow motion, measured by doppler flowmetry, after ischemia was decreased by glutathione treatment (32 plus/minus 4 versus 48 plus/minus 11 seconds; p less than 0.05) (Arosio et al, 2002).
K. SUBARACHNOID HEMORRHAGE
The effect of intravenous glutathione (2400 milligrams (mg) daily for 14 days) on delayed vasospasm and the outcome of subarachnoid hemorrhage (SAH) was assessed in an open, nonrandomized study; 77 SAH patients treated with glutathione were compared to an untreated control group of 70 patients. There were no statistically significant demographic differences between groups. Patient outcome parameters (recovery, disability, survival) were significantly better in the glutathione group. Symptomatic vasospasm was significantly lower in patients treated with glutathione (Okamoto et al, 1998). Further well designed randomized clinical trials should
MECHANISM OF ACTION/PHARMACOLOGY
A. MECHANISM OF ACTION
- Glutathione (GSH) is a cysteine-containing tripeptide found in all eukaryotic cells. Intracellular GSH is synthesized within the cytosol from the amino acids glutamate, cysteine, and glycine by a two step enzymatic process utilizing ATP as the energy source. Ninety percent of the GSH that is synthesized within the cell is stored in the cytosol; a small amount (10%) is stored in mitochondria.
- GSH plays an important role in the regulation of many enzymatic reactions and is the most important scavenger molecule, participating in several detoxification reactions. Its cellular functions include amino acid transport, acting as a cofactor in various enzymatic reactions, and maintenance of sulfhydryl redox status. GSH represents a defense against electrophilic xenobiotics and intracellular oxidants (ie, free radicals).
- All eukaryotic cells are capable of synthesizing GSH, and the liver is the major site of glutathione synthesis in humans and animals. Once synthesized by hepatic cells, GSH is either translocated to plasma or excreted in the bile. The bulk of plasma GSH is in the reduced form (85%), while the reminder is oxidized (15%). GSH is cleared in the kidney through direct glomerular filtration and a nonfiltration mechanism using the gamma-glutamyl transpeptidation reaction.
- GSH deficiency may be inherited or acquired. Hereditary deficiency is rare and due to a deficiency in an enzyme required to synthesize GSH in reduced form. In acquired deficiency, it is not known whether reduction in GSH is an effect or cause of the disease process (Meister, 1991; White et al, 1994).
B. DEFICIENCY STATES
- GSH is present in the epithelial lining fluid (ELF) of the normal respiratory tract and participates in the prevention of parenchymal oxidant injury. A deficiency of GSH in ELF has been reported in idiopathic pulmonary fibrosis and in adult respiratory distress syndrome (ARDS), diseases in which reactive oxygen species could have a pathogenic role (White et al, 1994). GSH aerosol was reported to restore respiratory epithelial surface (RES) oxidant-antioxidant balance in cystic fibrosis (Roum et al, 1999) and in chronic disease of the upper respiratory tract (Testa et al, 1995).
- Adequate GSH levels seem to be necessary for both T and B lymphocyte function and immune function in general, and may affect HIV replication on a molecular level (Staal et al, 1992; White et al, 1994).
- Studies performed in patients with cirrhosis showed that hepatocyte GSH levels are low, which could exacerbate hepatic injury. Ethanol-exposed hepatocytes showed increased susceptibility to oxidant injury and were protected by preincubation with a GSH ester (White et al, 1994).
- In animals and humans, exogenous administration of high-dose reduced GSH has been reported to protect against cisplatin nephrotoxicity and from oxazaphosphorine (cyclophosphamide, ifosfamide) urotoxicity, without interfering with antitumor efficacy (Meister, 1991; Aebi et al, 1991; White et al, 1994; Links & Lewis, 1999).
- Intracellular reduced GSH has a role in protection of endothelial cells against oxygen-free radicals, and may prevent endothelial dysfunction in arteries exposed to oxidative stress (Meister, 1991).
- Although extracellular GSH is not effectively transported into cells, exogenous addition of GSH results in a substantial increase in intracellular and extracellular cysteine, an antioxidant, in cultured endothelial cells and in humans.
1. Aebi S, Assereto R & Lauterburg BH: High-dose intravenous glutathione in man. Pharmacokinetics and the effects on cysteine in plasma and urine. Eur J Clin Invest 1991; 21:103-110.
2. Altomare E, Colonna P, D’Agostino C et al: High-dose antioxidant therapy during thrombolysis in patients with acute myocardial infarction. Curr Ther Res 1996; 57(2):131-141.
3. Amano J, Suzuki A & Sunamori M: Salutary effect of reduced glutathione on renal function in coronary artery bypass operation. J Am Coll Surg 1994; 179:714-720.
4. Arosio E, DeMarchi S, Zannoni M et al: Effect of glutathione infusion on leg arterial circulation, cutaneous microcirculation, and pain-free walking distance in patients with peripheral obstructive arterial disease: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc 2002; 77(8):754-759.
5. Bajetta E, Rimassa L, Carnaghi C et al: Preliminary experience with high-dose cisplatin, reduced glutathione and natural interferon-a in dacarbazine-resistant malignant melanoma. Tumori 1998; 84:48-51.
6. Bardellini E, Bindi P, Borzone S et al: The effect of high doses of reduced glutathione on hepatic clearances and fibrogenetic activity in patients with chronic alcoholic liver disease. Adv Ther 1992; 9(2):116-122.
7. Bogliun G, Marzorati L, Marzola M et al: Neurotoxicity of cisplatin +/- reduced glutathione in the first-line treatment of advanced ovarian cancer. Int J Gynecol Cancer 1996; 6:415-419.
8. Bohm S, Oriana S, Spatti G et al: Dose intensification of platinum compounds with glutathione protection as induction chemotherapy for advanced ovarian carcinoma. Oncology 1999; 57:115-120.
9. Bohm S, Spatti GB, Di Re F et al: A feasibility study of cisplatin administration with low-volume hydration and glutathione protection in the treatment of ovarian carcinoma. Anticancer Res 1991; 11:1613-1616.
10. Borok Z, Buhl R, Grimes GJ et al: Effect of glutathione on oxidant-antioxidant imbalance in idiopathic pulmonary fibrosis. Lancet 1991; 338:215-216.
11. Cascinu S & Catalano S: Intensive weekly chemotherapy for elderly gastric cancer patients, using 5-fluorouracil, cisplatin, epi-doxorubicin, 6S-leucovorin, and glutathione with the support of G-CSF. Tumori 1995; 81:32-35.
12. Cascinu S, Catalano V, Cordella L et al: Neuroprotective effect of reduced glutathione on oxaliplatin- based chemotherapy in advanced colorectal cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2002; 20(16):3478-3483.
13. Cascinu S, Cordella L, Del Ferro E et al: Neuroprotective effect of reduced glutathione on cisplatin-based chemotherapy in advanced gastric cancer: a randomized double-blind placebo-controlled trial. J Clin Oncol 1995; 13:26-32.
14. Cascinu S, Labianca R, Alessandroni P et al: Intensive weekly chemotherapy for advanced gastric cancer using fluorouracil, cisplatin, epi-doxorubicin, 6S-leucovorin, glutathione and filgrastim: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD). J Clin Oncol 1997; 15:3313-3319.
15. Cascinu S, Labianca R, Graziano F et al: Intensive weekly chemotherapy for locally advanced gastric cancer using 5-fluorouracil, cisplatin, epidoxorubicin, 6S-leucovorin, glutathione and filgrastim: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD). Br J Cancer 1998; 78(3):390-393.