Antioxidant therapy in the management of acute, chronic and post-ERCP pancreatitis: A systematic review

Table 1 Controlled clinical trials of antioxidants in patients with acute or chronic pancreatitis

Study/Ref.	Drug/supplements	Study design	Jadadscore	Participants	Treatment (intervention)		Outcome (results)		Adverse effects/events
					Case	Control	Clinical	Laboratory
Bhardwaj et al[16] 2009	Combined antioxidant (organic selenium, vitamin C, β-carotene, α-tocopherol and methionine)	Randomized; double blind; placebo-controlled	5	147 patients with CP	71 patients; combined antioxidants: 600 μg organic selenium, 0.54 g ascorbic acid, 9000 IU β-carotene, 270 IU α-tocopherol and 2 g methionine; per day; for 6 mo	76 patients; placebo	Number of painful days per month2 Numbers of oral analgesic tablets and parenteral analgesic injections per month2 Hospitalization2 Percentage of patients become pain-free2 Number of man-days lost per month2	Lipid peroxidation (TBARS)2 Serum SOD2 Total antioxidant capacity (FRAP)1 Serum vitamin A1 Serum vitamin C1 Serum vitamin E1 Erythrocyte superoxide dismutase2	Headache & constipation (all during the first month of treatment)
Xue et al[17] 2008	Glutamine	Randomized	1	80 patients with severe AP	38 patients; 100 mL/d of 20% AGD intravenous infusion; for 10 d; starting on the day 1 (Early treatment)	38 patients; 100 mL/d of 20% AGD intravenous infusion/for 10 d starting on the day 5 (Late treatment)	Infection rate2 Operation rate2 Mortality2 Hospitalization2 Duration of ARDS2 Renal failure2 Acute hepatitis2 Encephalopathy2 Enteroparalysis2 Duration of shock2 15-d APACHE II core2		-
Fuentes-Orozco et al[18] 2008	Glutamine	Randomized; double blind; controlled	4	44 patients with AP	22 patients; 0.4 g/kg per day of L-alanyl-L-Glutamine in standard TPN; 10 d	22 patients; standard TPN; 10 d	Infectious morbidity2 Hospital stay day3 Mortality3	Serum IL-101 Serum IL-62 CRP2 Ig A1 Protein1 Albumin1 Leucocyte2 Total lymphocyte1 Nitrogen balance was (+) in treated group vs (-) in control group	-
Siriwardena et al[19] 2007	Combined antioxidant (N-acetylcysteine, selenium, vitamin C)	Randomized; double blind; placebo- controlled	5	43 patients with severe AP	22 patients; N-acetylcysteine, selenium and vitamin C; for 7 d	21 patients; placebo	Organ dysfunction3 APACHE-II3 Hospitalization3 All case mortality3	Serum vitamin C3 Serum selenium3 GSH/GSSG ratio3 CRP3	-
Kirk et al[4] 2006	Combined antioxidant (selenium, β-carotene, L-methionine, vitamins C and E)	Randomized; double-blind; placebo-controlled; crossover	4	36 patients with CP	36 patients; Antox tablet: 75 mg of selenium, 3 mg β-carotene, 47 mg vitamin E, 150 mg vitamin C, and 400 mg methionon; four times per day; for 10 wk	36 patients; placebo; four times per day; for 10 wk	Quality of life1 Pain2 Physical and social functioning1 Health perception1 Emotional functioning, energy, mental health3	Plasma selenium1 Plasma vitamin C1 Plasma vitamin E1 Plasma β-carotene1	Two patients complained of nausea and one of an unpleasant taste during treatment with Antox
Durgaprasad et al[20] 2005	Curcumin	Randomized; single blind; placebo- controlled	3	20 patients of tropical pancreatitis (CP)	Eight patients; capsule: 500 mg curcumin (95%) with 5 mg of piperine; three times per day; for 6 wk	Seven patients; placebo (lactose)	Pain3	Erythrocyte MDA2 GSH level3	-
Du et al[21] 2003	Vitamin C	Randomized; controlled	3	84 patients with AP	40 patients; IV vitamin C; 10 g/d; for 5 d	44 patients; IV vitamin C; 1 g/d; for 5 d	Hospitalization2 Deterioration of disease2 Improvement of disease1 Cure rate1	Tnf-α2 IL-12 IL-82 CRP2 Serum interleukin-2 receptor2 Plasma vitamin C1 Plasma lipideroxide1 Plasma vitamin E1 Plasma β-carotene1 Whole blood glutathione1 Activity of erythrocyte superoxide dismutase1 Erythrocyte catalase1	-
Ockenga et al[22] 2002	Glutamine	Randomized, double blind; controlled	4	28 patients with AP	Standard TPN which contains 0.3 g/kg per day L-alanine-L-glutamine; at least 1 wk	Standard TPN	Hospitalization2 Duration of TPN2 Cost of TPN3	Cholinesterase1 Albumin1 lymphocyte count1 CRP2	-
de Beaux et al[23] 1998	Glutamine	Randomized; double-blind; controlled	5	14 patients with AP	Six patients; 0.22 g/kg per day of glycyl-glutamine in standard TPN; for 7 d	Seven patients; standard TPN	-	Lymphocytic proliferation (by DNA synthesis)1 TNF3 IL-63 IL-82	-
Banks et al[24] 1997	Allopurinol	Randomized, double-blind, two-period crossover clinical trial	4	13 patients with CP	13 patients; 300 mg/d allopurinol; 4 wk	13 patients; placebo	Pain3	Uric acid level2	-
Sharer et al[25] 1995	Glutathione precursors (S-adenosyl methionine and N-acetylcysteine)	Randomized	-	79 patients with AP	SAMe 43 mg/kg and N-acetylcysteine 300 mg/kg	-	APACHE II score reduction3 Complication rate3 Days in hospital3 Mortality3	-	-
Bilton et al[26] 1994	S-adenosyl methionine (SAMe)	Randomized; double-blind; crossover; placebo- controlled	5	20 patients with AP or CP	20 patients; SAMe 2.4g/d; 10 wk	Placebo	Attack rate and background pain3	Free radical activity2 Serum selenium2 Serum β-carotene2 Serum vitamin E23 Serum vitamin C2 Serum SAMe1	-
	Selenium and β-carotene + SAMe				20 patients; SAMe 2.4 g/d, Selenium 600 μg and β-carotene 9000 IU; 10 wk			Free radical activity2 Serum selenium2 Serum β-carotene1 Serum vitamin E13 Serum vitamin C2 Serum SAMe1
Salim[27] 1991	Allopurinol; dimethyl sulfoxide	Randomized; double-blind; placebo- controlled	4	78 patients with CP	25 patients; allopurinol; 50 mg four times per day, with analgesic regimen (IM pethidine hydrochloride; 50 mg every 4 h, and IM metoclopramide hydrochloride; 10 mg every 8 h)	27 patients; placebo with analgesic regimen	Pain2 Hospitalization2 Epigastric tenderness2	WBC count2 Serum amylase2 Serum LDH2	Allergies General malaise Headache Nausea Vomiting Dyspepsia Abdominal pain
					26 patients; dimethyl sulfoxide; 500 mg four times per day; with analgesic regimen
Uden et al[28,29] 1992, 1990	Combined antioxidant (selenium, β-carotene, vitamin C, vitamin E, methionine)	Randomized; double-blind; crossover; placebo- controlled	5	28 patients with CP	23 patients; daily doses of 600 mg organic selenium, 9000 IU β-carotene, 0.54 g vitamin C, 270 IU vitamin E and 2 g methionine; 10 wk	23 patients; placebo	Pain2	Free radical activity2 Serum selenium1 Serum β-carotene1 Serum vitamin E1 Serum SAMe2	-

¹Significant increase as compared with control;

²Significant decrease as compared with control;

³No significant difference between groups. TBARS: Thiobarbituric acid reactive substances; FRAP: Ferric reducing antioxidant power; SOD: Superoxide dismutase; AGD: Alanyl-glutamine dipeptide; CRP: C-reaction protein; MDA: Malondialdehyde; LDH: Lactate dehydrogenase; APACHE II: Acute Physiology and Chronic Health Evaluation II; GSH: Glutathione; TPN: Total parenteral nutrition; TNF-α: Tumor necrosis factor-α; IL: Interleukin.

Table 2 Controlled clinical trials of antioxidant therapy to prevent post-ERCP pancreatitis

Ref.	Drug/supplements	Study design	Jadadscore	n	Treatment (intervention)		Outcome (results)		Adverse effects/events	Other comments
					Case	Control	Primary	Other
Romagnuolo et al[30] 2008	Allopurinol	Randomized; double blind; placebo-controlled	4	586	293 patients; 300 mg oral allopurinol 60 min before ERCP	293 patients; placebo	Rate of PEP3 (5.5% vs 4.1%)	Disease-related adverse events3 Procedure-related complications3 Hospitalization3	-	In the non-high-risk group (n = 520), the crude PEP rates were 5.4% for allopurinol and 1.5% for placebo (P = 0.017), favoring placebo, indicating harm associated with allopurinol, whereas in the high-risk group (n = 66), the PEP rates were 6.3% for allopurinol and 23.5% for placebo (P = 0.050), favoring allopurinol
Milewski et al[31] 2006	N-acetylcysteine	Randomized; placebo-controlled	2	106	55 patients; 600 mg oral N-acetylcysteine 24 and 12 h before ERCP and 1200 mg IV for 2 d after the ERCP	51 patients; isotonic IV saline twice for 2 d after the ERCP	Rate of PEP3 (7.3% vs 11.8%)	Urine amylase activity3 Serum amylase activity3	-	-
Katsinelos et al[32] 2005	Allopurinol	Randomized; double blind; placebo-controlled	4	250	125 patients; 600 mg oral allopurinol 15 and 3 h before ERCP	118 patients; placebo	Rate of PEP2 (3.2% vs 17.8%)	Hospitalization2 Severity of pancreatitis2	-	-
Katsinelos et al[33] 2005	N-acetylcysteine	Randomized; double-blind; placebo-controlled	3	256	124 patients; 70 mg/kg 2 h before and 35 mg/kg at 4 h intervals for a total of 24 h after the procedure	125 patients; placebo (normal saline solution)	Rate of PEP3 Hospitalization3	-	Nausea; skin rash; diarrhea; vomiting	-
Mosler et al[34] 2005	Allopurinol	Randomized; double blind; placebo- controlled	4	701	355 patients; 600 mg 4 h and 300 mg 1 h oral allopurinol before ERCP	346 patients; placebo	Rate of PEP3 (13.0% vs 12.1%)	Severity of pancreatitis3	-	-
Lavy et al[35] 2004	Natural β-carotene	Randomized; double-blind; placebo-controlled	5	321	141 patients; 2 g oral β-carotene 12 h before ERCP	180 patients; placebo	Rate of PEP3 (10% vs 9.4%)	Severe pancreatitis2	-	-
Budzyńska et al[36] 2001	Allopurinol	Randomized; placebo-controlled	3	300	99 patients; 200 mg oral allopurinol 15 and 3 h before ERCP	101 patients; placebo	Rate of PEP3 (12.1% vs 7.9%)	Severity of pancreatitis3	-	-

¹Significant increase as compared with control;

²Significant decrease as compared with control;

³No significant difference between groups. PEP: Post endoscopic pancreatitis.

Table 3 Studies evaluating post-ERCP pancreatitis after allopurinol administration

Study	Allopurinol	Placebo
Romagnuolo et al[30] 2008	16/293	12/293
Katsinelos et al[32] 2005	4/121	21/118
Mosler et al[34] 2005	46/355	42/346
Budzyńska et al[36] 2001	12/99	8/101