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.