Antioxidant therapy in acute, chronic and post-endoscopic retrograde cholangiopancreatography pancreatitis: An updated systematic review and meta-analysis

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

Ref.	Drug/supplements	Study design	Jadad score	Participants	Treatment (intervention)		Outcome (results)		Adverse effects/events
					Case	Control	Clinical	Laboratory
Bansal et al[18], 2011	Combined antioxidant (vitamin A, vitamin C, vitamin E)	Single-center, prospective randomized, open-label with blinded endpoint	4	39 patients with severe AP	19 patients; combined antioxidants: 1000 mg vitamin C in 100 mL normal saline, 200 mg vitamin E oral, and 10000 IU vitamin A intramuscularly; per day; for 14 d	20 patients; placebo	Multi-organ dysfunction1Length of hospital stay1	Serum GSH1Serum SOD1
Sateesh et al[17], 2009	Combined antioxidant (vitamin C, N-acetyl cysteine, antoxyl forte)	Randomized; placebo-controlled	3	53 patients with AP	23 patients; combined antioxidants: 500 mg vitamin C, 200 mg 8 hourly N-acetyl cysteine and 1 capsule hourly antoxyl forte); per day; for 7 d	30 patients; placebo	Length of hospital stay and complications ↓	Serum MDA1TBARS ↓SOD ↓
Xue et al[19], 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 rate ↓Operation rate ↓Mortality ↓Hospitalization ↓Duration of ARDS ↓Renal failure ↓Acute hepatitis ↓Encephalopathy ↓Enteroparalysis ↓	TAC ↓Vitamin C ↑-	-
Fuentes-Orozco et al[20], 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	Duration of shock ↓15 d APACHE II core ↓Infectious morbidity ↓Hospital stay day1Mortality1	Serum IL10 ↑Serum IL-6 ↓CRP ↓Ig A ↑Protein ↑Albumin ↑Leucocyte ↓	-
Sahin et al[21], 2007	Glutamine enriched total parenteral nutrition (TPN)	Randomized; double blind; placebo- controlled	3	40 patients with AP	20 patients; 0.3 g/kg per day glutamine; for 7-15 d	20 patients; placebo	Complication rates ↓	Total lymphocyte ↑Nitrogen balance was (+) in treated group vs (-) in control groupTransferrin level ↑Fasting blood sugar, albumin1BUN1Creatinine1Total cholesterol concentrations1AST1ALT1LDH activities1Leukocytes, CD4, CD81Serum Zn, Ca and P
Siriwardena et al[22], 2008	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 7d	21 patients; placebo	Organ dysfunction1APACHE- II1Hospitalization1 All case mortality1	Serum lipase ↓Amylase activities↓CRP ↓Serum vitamin C1Serum selenium1GSH/GSSG ratio1CRP1	-
Pearce CB et al[23], 2006	Glutamine, arginine, tributyrin and antioxidants	Randomized; double blind; placebo- controlled	5	31 patients with severe AP	15 patients; glutamine, arginine, tributyrin and antioxidants; for 3 d; If patients required further feeding the study was continued up to 15 d	16 patients; placebo isocaloric isonitrogenous control feed was undertaken		CRP ↑CAPAP↓	Diarrhea (1 patient)Vomiting (2 patients)
Du et al[24], 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	Hospitalization ↓Deterioration of disease ↓ Improvement of disease ↑ Cure rate ↑	TNF-α↓IL-1 ↓IL-8 ↓CRP ↓Serum interleukin-2 receptor ↓Plasma vitamin C ↑Plasma lipideroxide ↑Plasma vitamin E ↑Plasma β-carotene ↑Whole blood glutathione ↑Activity of erythrocyte surperoxide dismutase ↑Erythrocyte catalase ↑	Hypernatremia (2 patients)-
Ockenga et al[25], 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	Hospitalization ↓Duration of TPN ↓Cost of TPN1	Cholinesterase ↑Albumin ↑	-
de Beaux et al[26], 1998	Glutamine	Randomized; double-blind; controlled	5	14 patients with AP	6 patients; 0.22 g/kg per day of glycyl-glutamine in standard TPN; for 7 d	7 patients; standard TPN		Lymphocyte count ↑CRP ↓Lymphocytic proliferation (by DNA synthesis) ↑TNF1 IL61IL8↓	-
Sharer et al[27], 1995	Glutathione precursors (S-adenosyl methionine and N-acetylcysteine)	Randomized	2	79 patients with AP	SAMe 43 mg/kg and N-acetylcysteine 300 mg/kg	-	APACHE II score reduction1Complication rate1	-	-
Bilton et al[28], 1994	S- adenosyl methionine (SAMe)Selenium and β-carotene + SAMe	Randomized; double-blind; crossover; placebo- controlled	5	20 patients with AP or CP	20 patients; SAMe 2.4 g/d; 10 wk20 patients; SAMe 2.4 g/d, Selenium 600 μg and β-carotene 9000 IU; 10 wk	Placebo	Days in hospital1Mortality1Attack rate and background pain1	Free radical activity ↓Serum Selenium ↓Serum β-carotene ↓Serum vitamin E ↓Serum vitamin C ↓Serum SAMe ↑Free radical activity ↓Serum selenium ↓Serum β-carotene ↑Serum vitamin E ↑1Serum vitamin C ↓Serum SAMe ↑	-

¹No significant difference between groups. ↑: Significant increase as compared with control; ↓: Significant decrease as compared with control; TBARS: Thiobarbitoric 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; AST: Aspartate aminotransferase; ALT: Alanine transaminase; CAPAP: Carboxypeptidase B activation peptide; BUN: Blood urea nitrogen.

Table 2 Controlled clinical trials of antioxidants in patients with chronic pancreatitis

Ref.	Drug/supplements	Study design	Jadad score	Participants	Treatment (intervention)		Outcome (results)		Adverse effects/events
					Case	Control	Clinical	Laboratory
Dhingra et al[29], 2013	Combined antioxidant (organic selenium, vitamin C, β carotene, vitamin E, methionine)	Randomized; placebo-controlled	3	61 patients with CP	31 patients; 600 Hg of organic selenium, 0.54 g of vitamin C, 9000 IU of β carotene, 270 IU of vitamin E, and 2 g of methionine	30 patients; placebo	Number of painful days per month ↓Number of analgesic tablets per month ↓	Platelet-derived growth factor (PDGF) AA ↓Transforming growth factor β 11Thiobarbituric acid-reactive substances1Ferric-reducing ability of plasma ↑TBARS ↓FRAP ↑
Shah et al[30], 2013	Combined antioxidant (vitamin C, vitamin E, β carotene, selenium, methionine)	Randomized; double blind; placebo-controlled	5	14 patients with CP	7 patients; Antox tablet: vitamin C, vitamin E, β carotene, selenium, methionine (Pharma Nord, Morpeth, United Kingdom); 6 m	7 patients; placebo	Opiate usage1	Serum vitamin C ↑ Serum vitamin E ↑Serum b caroteneSerum vitamin A ↑WCC1Hb1CRP1Serum selenium1IL 1b, 4, 6, and 101TNF-α1
Siriwardena et al[31], 2012	Combined antioxidant (selenium, d-a-tocopherol acetate, ascorbic acid, l-methionine)	Randomized; double blind; placebo-controlled	5	70 patients with CP	33 patients; Antox tablet: 38.5 mg seleniumYeast, 113.4 mg d-a-tocopherol acetate, 126.3 mg ascorbic acid, 480 mg l-methionine; per d; for 6 m	37 patients; placebo	Quality of life1Average daily pain scores1Opiate use1Number of hospital admissions1Outpatient visits1	Serum vitamin C ↑Serum vitamin E ↑Serum beta carotene ↑Serum selenium ↑	Increased frequency of stool, occasional diarrhea, bad taste, and heartburn with nausea
Shah et al[32], 2010	Combined antioxidant (vitamin C, vitamin E, β carotene, selenium, methionine)	Randomized; placebo-controlled	2	137 patients with CP	68 patients; Antox tablet: vitamin C, vitamin E, β carotene, selenium, methionine (Pharma Nord, Morpeth, United Kingdom); at least 6 m	69 patients; placebo	Median visual analogue pain score ↓Cognitive, emotional, social, physical and role function ↑Analgesics and opiate usage ↓	-	-
Bhardwaj et al[33], 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 (Betamore G, Osper Pharmanautics, India); per d; for 6 m	76 patients; placebo	Number of painful days per month ↓Numbers of oral analgesic tablets and parenteral analgesic injections per month ↓Hospitalization ↓Percentage of patients become pain-free ↓Number of man-days lost per month ↓	Lipid peroxidation (TBARS) ↓Serum SOD ↓Total antioxidant capacity (FRAP) ↑Serum vitamin A↑Serum vitamin C ↑Serum vitamin E ↑Erythrocyte superoxide dismutase ↓	Headache & Constipation (all during the first month of treatment)
Kirk et al[34], 2006	Combined antioxidant (selenium, β- carotene, L-methionine, vitamins C and E)	Randomized; double-blind; placebo-controlled; crossover	4	72 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 methionone; 4 times per day; for 10 wk	36 patients; placebo; 4 times per d; for 10 wk	Quality of life ↑Pain ↓Physical and social functioning ↑Health perception ↑Emotional functioning, energy, mental health:1	Plasma selenium ↑Plasma vitamin C ↑Plasma vitamin E ↑Plasma β-carotene ↑	Two patients complained of nausea and one of an unpleasant taste during treatment with Antox
Durgaprasad et al[35], 2005	Curcumin	Randomized; single blind; placebo-controlled	3	20 patients with tropical pancreatitis (CP)	8 patients; capsule: 500 mg curcumin (95%) with 5 mg of piperine; 3 times per day; for 6 wk	7 patients; placebo (lactose)	Median visual analogue pain score1Severity of Pain1	Erythrocyte MDA ↓GSH level1	-
Banks et al[36], 1997	Allopurinol	Randomized, double-blind, two-period crossover clinical trial	4	26 patients with CP	13 patients; 300 mg/d All opurinol; 4 wk	13 patients, placebo	Pain1	Uric acid level ↓	-
Bilton et al[28], 1994	S- adenosyl methionine (SAMe)Selenium and β-carotene + SAMe	Randomized; double-blind; crossover; placebo- controlled	5	20 patients with AP or CP	20 patients; SAMe 2.4 g/d; 10 wk20 patients; SAMe 2.4 g/d, Selenium 600 μg and β-carotene 9000 IU; 10 wk	Placebo	Attack rate and background pain1	Free radical activity ↓Serum selenium ↓Serum β-carotene ↓Serum vitamin E ↓1Serum vitamin C ↓Serum SAMe ↑Free radical activity ↓Serum selenium ↓Serum β-carotene ↑Serum vitamin E ↑1Serum vitamin C ↓Serum SAMe ↑	-
Salim et al[39], 1991	Allopurinol;dimethyl sulfoxide	Randomized; double-blind; placebo- controlled	4	78 patients with CP	25 patients; allopurinol; 50 mg 4 times per day, with analgesic regimen (IM pethidine hydrochloride; 50 mg every 4 hours, and IM metoclopramide hydrochloride; 10 mg every 8 h)	27 patients; placebo with analgesic regimen	Pain free patients ↑Hospitalization ↓Epigastric tenderness ↓	WBC count ↓Serum amylase ↓ Serum LDH ↓	AllergiesGeneral malaiseHeadacheNauseaVomitingDyspepsiaAbdominal pain
Uden et al[37,38], 1990, 1992	Combined antioxidant (selenium , β-carotene, vitamin C, vitamin E, methionine)	Randomized; double-blind; crossover; placebo- controlled	5	28 patients with CP	26 patients; dimethyl sulfoxide; 500 mg 4 times per day; with analgesic regimen23 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	Pain (Mc Gill) ↓	Free radical activity ↓ Serum selenium ↑Serum β-carotene ↑Serum vitamin E ↑Serum SAMe ↓	-

¹No significant difference between groups. ↑: Significant increase as compared with control; ↓: Significant decrease as compared with control; TBARS: Thiobarbitoric 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.

Table 3 Controlled clinical trials for antioxidant management to prevent post-endoscopic retrograde cholangiopancreatography pancreatitis

Ref.	Drug/supplements	Study design	Jadad score	n	Treatment (intervention)		Outcome (results)		Adverse effects/events	Other comments
					Case	Control	Primary	Other
Abbasinazari et al[40], 2011	Allopurinol	Randomized double blind clinical trial	3	74	29 patients;	45 patients; no medication	Rate of PEP1(11.5% vs 12.5%)	Serum amylase activity1	-	-
Martinez-Torres et al[41], 2009	Allopurinol	Randomized; double-blind; placebo-controlled	5	170	85 patients; 300 mg oral allopurinol 15 h and 3 h before ERCP	85 patients; placebo	Rate of PEP ↓ (2.3% vs 9.4%)	Serum amylase activity ↓	-	21.7% absolute benefit in patients with high-risk procedures favoring allopurinol, no difference in low-risk procedures
Kapetanos et al[42], 2009	Pentoxifylline	Randomized;	2	590	205 patients; 400 mg oral Pentoxifylline, 40 h, 32 h, 24 h, 16 h and 8 h before ERCP (total dose 2 g)	205 patients; no medication	Rate of PEP1(7.3% vs 2.9%)	TNF-α1IL-61	-	-
	Octreotide				180 patients; 0.5 mg subcutaneous octreotide, 64 h, 56 h, 48 h, 40 h, 32 h, 24 h, 16 h and 8 h before ERCP (total dose 4 mg)	205 patients; no medication	Rate of PEP1(5% vs 2.9%)	TNF-α↓IL-61
Romagnuolo et al[43], 2008	Allopurinol	Randomized; double blind; placebo- controlled	4	586	293 patients; 300 mg oral allopurinol 60 min before ERCP	293 patients; placebo	Rate of PEP1(5.5% vs 4.1%)	Disease-related adverse events1Procedure-related complications1Hospitalization1	-	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
Kapetanos et al[44], 2007	Pentoxifylline	Randomized;	2	320	158 patients; 400 mg oral pentoxifylline, 40 h, 32 h, 24 h, 16 h and 8 h before ERCP (total dose 2 g)	162 patients; no medication	Rate of PEP1(5.6% vs 3%)	Hemorrhage1Serum amylase activity1	Nausea and vomiting in 10% of the patients who received the drug	-
Milewski et al[45], 2006	N-acetylcysteine	Randomized; placebo-controlled	2	106	55 patients; 600 mg oral N-acetylcysteine 24 h and 12 h before ERCP and 1200 mg IV for 2 d after the ERCP	51 patients; isotonic IV saline b.d for 2 d after the ERCP	Rate of PEP1(7.3% vs 11.8%)	Urine amylase activity1Serum amylase activity1	-	-
Katsinelos et al[46], 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 PEP ↓(3.2% vs 17.8%)	Hospitalization ↓Severity of Pancreatitis ↓	-	-
Katsinelos et al[47], 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 PEP1Hospitalization1	-	Nausea Skin rash Diarrhea Vomiting	2 patients with suspected SOD
Mosler et al[48], 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 PEP1(13.0% vs 12.1%)	Severity of pancreatitis1	-	4% absolute benefit in high-risk patients; 4% absolute harm in average risk
Lavy et al[49], 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 PEP1(10% vs 9.4%)	Severe pancreatitis ↓	-	-
Budzyńska et al[50], 2001	Allopurinol	Randomized; placebo-controlled	3	300	99 patients; 200 mg oral Allopurinol 15 h and 3 h before ERCP	101 patients; placebo	Rate of PEP1(12.1% vs 7.9%)	Severity of pancreatitis1	-	3-arm study, with third arm (n = 100) given prednisone

¹No significant difference between groups. ↑: Significant increase as compared with control; ↓: Significant decrease as compared with control; PEP: Post-endoscopic pancreatitis.