Glutathione

Glutathione

PEP Topic 
Peripheral Neuropathy
Description 

Glutathione is a peptide that contains one amino acid residue each of glutamic acid, cysteine, and glycine that occurs widely in plant and animal tissues and plays an important role in biologic oxidation-reduction processes and as a coenzyme. Glutathione is used in metabolic and biochemical reactions such as DNA synthesis and repair, as well as synthesis of a variety of other proteins and operation of multiple body systems. Glutathione is synthesized by the body and is also present naturally in many foods. It is also available as an oral dietary supplement, although not well absorbed when taken by mouth. Since the body synthesizes glutathione, increased intake of its amino acid precursors is an approach to increase glutathione.

Effectiveness Not Established

Research Evidence Summaries

Cascinu, S., Catalano, V., Cordella, L., Labiance, R., Giordani, P., Baldelli, A.M., . . . Catalano, G. (2002). Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: A randomized, double-blind, placebo-controlled trial. Journal of Clinical Oncology, 20– 3478–3483.

doi: 10.1200/JCO.2002.07.061
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Intervention Characteristics/Basic Study Process:

Fifty-two patients with advanced colorectal cancer who were treated with a bimonthly oxaliplatin-based regimen were randomized to receive glutathione (GSH) (1,500 mg/m² over a 15-minute infusion period before oxaliplatin) or normal saline solution. Chemotherapy regimen was given as follows: oxaliplatin 100 mg/m² on day 1 concurrent with leucovorin 250 mg/m² followed by 5-FU 1,500 mg/m² per day for two consecutive days every two weeks. GSH was administered at a dose of 1,500 mg/m² in 100 ml of normal saline over 15 minutes immediately before each oxaliplatin administration. The placebo-randomized patients received normal saline. Disease response was assessed after four cycles of therapy. Those with responsive or stable disease received four additional cycles of treatment.

Sample Characteristics:

  • Fifty-two patients with histologically verified advanced colorectal carcinoma were randomized to receive combination chemotherapy; 26 with and 26 without GSH.
  • Patients were excluded if they had established clinical neuropathy, diabetes, alcoholic disease, other neurologic disease or brain involvement.
  • Those who received vitamin B1, B6, or B12 supplements also were excluded.

Study Design:

The study had a randomized, double-blind, placebo-controlled trial design.

Measurement Instruments/Methods:

  • A neurologic examination, including measures of strength and reflexes, assessment of neurologic symptoms, position and vibratory sensation, and neurophysiologic evaluations of sural nerves were conducted at baseline, 4, 8, and 12 cycles of chemotherapy.
  • The presence of signs and symptoms of peripheral nervous system involvement and the assessment of position and vibratory sensations also was performed.
  • Neurotoxicity was expressed according to National Cancer Institute Common Terminology Criteria for Adverse Events.
  • Neurophysiologic evaluation of sensory nerve conduction in the sural nerves was performed by the same examiners who were blinded to the group affiliation.

Results:

At baseline, no patients suffered from clinical neuropathy in either arm. At the time of second the neurologic exam (four cycles) seven patients had clinical neuropathy in the GSH arm and 11 in the placebo arm. After eight cycles of chemotherapy, nine patients had clinical neuropathy in the GSH arm compared with 15 patients in the placebo arm with an incidence of moderate to severe (grade 2–4) clinical neurotoxicity present in 11 of 19 assessable patients in the placebo arm, as compared to 2 of 21 assessable patients in GSH arm. No grade 3–4 neurotoxicity was present in GSH arm while grade 3–4 neurotoxicity was reported in five patients in placebo arm. Only 18 patients received 12 cycles of chemotherapy, 10 in the GSH arm and 8 in the placebo arm. Grade 2–3 neurotoxicity was observed in three patients in GSH arm and eight patients in the placebo arm.

Limitations:

The study was performed on patients who had received preliminary date on a small number of patients with no true control group.

Cascinu, S., Cordella, L., Del Ferro, E., Fronzoni, M., & Catalana, G. (1995). Neuroprotective effect of reduced glutathione on cisplatin-based chemotherapy in advanced gastric cancer: A randomized double-blind placebo-controlled trial. Journal of Clinical Oncology, 13, 26–32.

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Intervention Characteristics/Basic Study Process:

Fifty patients with advanced gastric cancer were randomized to receive either 1.5 g/m² GSH in 1 L of normal saline or normal saline 1 L as a placebo infusion given over 15 minutes before cisplatin-based chemotherapy. GSH also was given by intramuscular injection on days 2 and 5. One cycle consisted of nine weekly treatments. Patients who showed responsive or stable disease received an additional six weeks of therapy.

Sample Characteristics:

  • Fifty patients with advanced gastric cancer; 25 received GSH treatment and 25 received placebo infusions of normal saline.
  • Sample size was determined to detect a 40% difference in the occurrence of grade 1–4 (World Health Organization [WHO] scale) neurotoxicity between the two treatment arms.
  • Exclusion criteria includes previous chemotherapy, established clinical neuropathy, diabetes, alcoholic disease, brain involvement, or use of vitamins B1, B6, or B12.

Study Design:

The study had a randomized, placebo-controlled clinical trial design.

Measurement Instruments/Methods:

  • Complete neurologic examination (strength, deep tendon reflexes, symptoms of peripheral nervous system involvement, position, and vibratory sensation); neurophysiologic assessment of the medial, ulnar; and sural nerves also were performed.
  • Toxicity scores (using the WHO criteria) were evaluated weekly by the same examiner who was blinded to treatment group assignment.

Results:

Seven patients in the placebo group were unable to complete the study (six with progressive disease and one from grade 3 neurotoxicity). Only one patient in the GSH group was not able to complete the study. At nine weeks, no patients who received GSH had clinical evidence of neuropathy, compared to16 patients (66%) in the placebo-control group. After 15 weeks, 4 of 24 (17%) patients in the GSH arm showed clinical evidence of neurotoxicity compared to 16 (88%) in the placebo-control group. Most common symptoms included distal parasthesias and numbness in legs, decreased sense of vibration, and reduced or absent deep reflexes. No changes in mean latency and sensory amplitude potentials were noted in the group that received GSH but were significantly affected at 9 and 15 weeks in the control group. No patients reported ototoxicity.

Limitations:

  • The study is almost 20 years old.
  • Well-described methods and measures recorded higher than expected levels of neurotoxicity in the control arm, but could be from specific attention to the symptom.
  • This study did not examine potential delayed toxicity. This could lead to an inaccurate conclusion about the benefits of GSH if it delays rather than prevents toxicity.

Smyth, J.F., Bowman, A., Perren, T., Wilkinson, P., Prescott, R.J., Quinn, K.J., & Tedeschi, M. (1997). Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: Results of a double-blind, randomized trial. Annals of Oncology, 8, 569–573.

doi: 10.1023/A:1008211226339
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Study Purpose:

GSH has high affinity for heavy metals, so the researchers postulated that it may reduce the toxic effects of cisplatin. Early clinical studies suggest that GSH provides neuroprotection.

Intervention Characteristics/Basic Study Process:

151 women with advanced ovarian cancer were randomized to receive cisplatin with or without GSH 3 g/m² in 200 cc of normal saline or cisplatin and a placebo-infusion of 200 cc of normal saline administered over 20 minutes immediately before cisplatin administration. Randomized in double-blind fashion to cisplatin 100 mg/m² plus 3 g/m² GSH in 200 cc normal saline or a placebo infusion of 200 cc normal saline every three weeks for six cycles. Seventy-seven women received the placebo infusion and 74 received GSH.

Sample Characteristics:

151 women with ovarian cancer

Setting:

Multicenter

Study Design:

The study had a randomized, placebo-controlled, clinical trial with parallel group design.

Measurement Instruments/Methods:

  • Audiograms and neurologic examinations were conducted at baseline and after three and six cycles of chemotherapy.
  • Four of 10 centers measured quality of life with the Hospital Anxiety and Depression Scale.
  • Anemia, leukopenia, thrombocytopenia, neurohearing, nephrotoxicity, peripheral neuropathy, and nausea and vomiting were assessed using the National Cancer Institute's Common Terminology Criteria for Adverse Events and World Health Organization toxicity scales.

Results:

The addition of GSH to cisplatin chemotherapy allowed the full six cycles to be administered to more patients (58%) as compared to those who received cisplatin alone (39%). Women in the GSH arm had a statistically significant rise in weight of 2 kg over the study period (p = 0.01). Women in the study who received GSH reported an improvement in quality of life during cisplatin chemotherapy. Significant difference in the reduction of creatinine clearance for GSH treated group as compared to the control group (74% versus 62%). Significant improvement in depression, emesis, peripheral neurotoxicity, hair loss, shortness of breath, and difficulty concentrating as measured by the Hospital Anxiety and Depression scale. Those who received GSH were significantly more able to undertake housekeeping and shopping. The trend was toward a better outcome in GSH-treated group (p = 0.25).

Limitations:

  • The study did not clearly identify what the neurologic examination involved.
  • The study has substantial between-center differences which may make findings less interpretable.

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