Short-term Curcuminoid Supplementation for Chronic Pulmonary Complications due to Sulfur Mustard Intoxication: Positive Results of a Randomized Double-blind Placebo-controlled Trial

Y. Panahi; M. Ghanei; S. Bashiri; A. Hajihashemi; A. Sahebkar

doi:10.1055/s-0034-1389986

Drug Research, Table of Contents

Drug Res (Stuttg) 2015; 65(11): 567-573
DOI: 10.1055/s-0034-1389986

Original Article

Short-term Curcuminoid Supplementation for Chronic Pulmonary Complications due to Sulfur Mustard Intoxication: Positive Results of a Randomized Double-blind Placebo-controlled Trial

Authors

Y. Panahi

¹Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
M. Ghanei

¹Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
S. Bashiri

¹Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
A. Hajihashemi

¹Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
A. Sahebkar

²Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

³Metabolic Research Centre, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia

Abstract

Pulmonary problems are among the most frequent chronic complications of sulfur mustard (SM) intoxication and are often accompanied by deregulated production of pro-inflammatory cytokines. Curcuminoids, comprising curcumin, demethoxycurcumin and bisdemethoxycurcumin, are phytochemicals with remarkable anti-inflammatory properties that are derived from dried rhizomes of the plant Curcuma longa L. (turmeric). The present pilot study aimed to investigate the clinical effects of supplementation with curcuminoids on markers of pulmonary function and systemic inflammation in SM-intoxicated subjects. In a randomized double-blind placebo-controlled trial, 89 male subjects who were suffering from chronic SM-induced pulmonary complications were recruited and assigned to either curcuminoids (500 mg TID per oral; n=45) or placebo (n=44) for a period of 4 weeks. Efficacy measures were changes in the spirometric parameters (FVC, FEV1, FEV1/FVC) and serum levels of inflammatory mediators including interleukins 6 (IL-6) and 8 (IL-8), tumor necrosis factor-α (TNFα), transforming growth factor-β (TGFβ), high-sensitivity C-reactive protein (hs-CRP), calcitonin gene related peptide (CGRP), substance P and monocyte chemotactic protein-1 (MCP-1). 78 subjects completed the trial. Although FEV1 and FVC remained comparable between the groups, there was a greater effect of curcuminoids vs. placebo in improving FEV1/FVC (p=0.002). Curcuminoids were also significantly more efficacious compared to placebo in modulating all assessed inflammatory mediators: IL-6 (p<0.001), IL-8 (p=0.035), TNFα (p<0.001), TGFβ (p<0.001), substance P (p=0.016), hs-CRP (p<0.001), CGRP (p<0.001) and MCP-1 (p<0.001). Curcuminoids were safe and well-tolerated throughout the trial. Short-term adjunctive therapy with curcuminoids can suppress systemic inflammation in patients suffering from SM-induced chronic pulmonary complications.

Key words

randomized controlled trial - sulfur mustard - curcumin - cytokine - inflammation - respiratory function

Full Text

References

References
1 Balali-Mood M, Hefazi M, Mahmoudi M et al. Long-term complications of sulphur mustard poisoning in severely intoxicated Iranian veterans. Fundam Clin Pharmacol 2005; 19: 713-721
2 Khateri S, Ghanei M, Keshavarz S et al. Incidence of lung, eye, and skin lesions as late complications in 34,000 Iranians with wartime exposure to mustard agent. J Occup Environ Med 2003; 45: 1136-1143
3 Emad A, Rezaian GR. The diversity of the effects of sulfur mustard gas inhalation on respiratory system 10 years after a single, heavy exposure: analysis of 197 cases. Chest 1997; 112: 734-738
4 Attaran D, Khajedaloui M, Jafarzadeh R et al. Health-related quality of life in patients with chemical warfare-induced chronic obstructive pulmonary disease. Arch Iran Med 2006; 9: 359-363
5 Balali-Mood M, Hefazi M. Comparison of early and late toxic effects of sulfur mustard in Iranian veterans. Basic Clin Pharmacol Toxicol 2006; 99: 273-282
6 Ghanei M, Fathi H, Mohammad MM et al. Long-term respiratory disorders of claimers with subclinical exposure to chemical warfare agents. Inhal Toxicol 2004; 16: 491-495
7 Vernooy JH, Kucukaycan M, Jacobs JA et al. Local and systemic inflammation in patients with chronic obstructive pulmonary disease: soluble tumor necrosis factor receptors are increased in sputum. Am J Respir Crit Care Med 2002; 166: 1218-1224
8 Polatli M, Cakir A, Cildag O et al. Microalbuminuria, von Willebrand factor and fibrinogen levels as markers of the severity in COPD exacerbation. J Thromb Thrombolysis 2008; 26: 97-102
9 Tonstad S, Cowan JL. C-reactive protein as a predictor of disease in smokers and former smokers: a review. Int J Clin Pract 2009; 63: 1634-1641
10 Westergren-Thorsson G, Larsen K, Nihlberg K et al. Pathological airway remodelling in inflammation. Clin Respir J 2010; 4 (Suppl. 01) 1-8
11 MacNee W. Oxidative stress and lung inflammation in airways disease. Eur J Pharmacol 2001; 429: 195-207
12 Tkacova R, Kluchova Z, Joppa P et al. Systemic inflammation and systemic oxidative stress in patients with acute exacerbations of COPD. Respir Med 2007; 101: 1670-1676
13 Attaran D, Lari SM, Khajehdaluee M et al. Highly sensitive C-reactive protein levels in Iranian patients with pulmonary complication of sulfur mustard poisoning and its correlation with severity of airway diseases. Human & experimental toxicology 2009; 28: 739-745
14 Attaran D, Lari SM, Towhidi M et al. Interleukin-6 and airflow limitation in chemical warfare patients with chronic obstructive pulmonary disease. International journal of chronic obstructive pulmonary disease 2010; 5: 335-340
15 Panahi Y, Davoudi SM, Sahebkar A et al. Efficacy of Aloe vera/olive oil cream versus betamethasone cream for chronic skin lesions following sulfur mustard exposure: a randomized double-blind clinical trial. Cutaneous and ocular toxicology 2012; 31: 95-103
16 Panahi Y, Ghanei M, Vahedi E et al. Effect of recombinant human IFNgamma in the treatment of chronic pulmonary complications due to sulfur mustard intoxication. Journal of immunotoxicology 2013;
17 Panahi Y, Sahebkar A, Davoudi SM et al. Efficacy and safety of immunotherapy with interferon-gamma in the management of chronic sulfur mustard-induced cutaneous complications: comparison with topical betamethasone 1%. TheScientificWorldJournal 2012; 2012: 285274
18 Panahi Y, Sarayani A, Beiraghdar F et al. Management of sulfur mustard-induced chronic pruritus: a review of clinical trials. Cutaneous and ocular toxicology 2012; 31: 220-225
19 Sahebkar A. Baicalin as a potentially promising drug for the management of sulfur mustard induced cutaneous complications: a review of molecular mechanisms. Cutaneous and ocular toxicology 2012; 31: 226-234
20 Anand P, Kunnumakkara AB, Newman RA et al. Bioavailability of curcumin: problems and promises. Mol Pharm 2007; 4: 807-818
21 Strimpakos AS, Sharma RA. Curcumin: preventive and therapeutic properties in laboratory studies and clinical trials. Antioxidants & redox signaling 2008; 10: 511-545
22 Sahebkar A. Why it is necessary to translate curcumin into clinical practice for the prevention and treatment of metabolic syndrome?. BioFactors 2013; 39: 197-208
23 Shehzad A, Khan S, Sup Lee Y. Curcumin molecular targets in obesity and obesity-related cancers. Future Oncol 2012; 8: 179-190
24 Sahebkar A. Molecular mechanisms for curcumin benefits against ischemic injury. Fertility and sterility 2010; 94: e75-e76 author reply e7
25 Jurenka JS. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Altern Med Rev 2009; 14: 141-153
26 Shehzad A, Ha T, Subhan F et al. New mechanisms and the anti-inflammatory role of curcumin in obesity and obesity-related metabolic diseases. Eur J Nutr 2011; 50: 151-161
27 Shehzad A, Rehman G, Lee YS. Curcumin in inflammatory diseases. BioFactors 2013; 39: 69-77
28 Sahebkar A. Are Curcuminoids Effective C-Reactive Protein-Lowering Agents in Clinical Practice? Evidence from a Meta-Analysis. Phytotherapy research 2014; 28: 633-642
29 Meng B, Li J, Cao H. Antioxidant and antiinflammatory activities of curcumin on diabetes mellitus and its complications. Current pharmaceutical design 2013; 19: 2101-2113
30 Sahebkar A, Mohammadi A, Atabati A et al. Curcuminoids Modulate Pro-Oxidant-Antioxidant Balance but not the Immune Response to Heat Shock Protein 27 and Oxidized LDL in Obese Individuals. Phytotherapy research 2013; 27: 1883-1888
31 Hossain DM, Bhattacharyya S, Das T et al. Curcumin: the multi-targeted therapy for cancer regression. Frontiers in bioscience 2012; 4: 335-355
32 Shehzad A, Wahid F, Lee YS. Curcumin in cancer chemoprevention: molecular targets, pharmacokinetics, bioavailability, and clinical trials. Archiv der Pharmazie 2010; 343: 489-499
33 Srivastava G, Mehta JL. Currying the heart: curcumin and cardioprotection. Journal of cardiovascular pharmacology and therapeutics 2009; 14: 22-27
34 Srivastava RM, Singh S, Dubey SK et al. Immunomodulatory and therapeutic activity of curcumin. International immunopharmacology 2011; 11: 331-341
35 Monroy A, Lithgow GJ, Alavez S. Curcumin and neurodegenerative diseases. BioFactors 2013; 39: 122-132
36 Panahi Y, Badeli R, Karami N et al. Investigation of the Efficacy of Adjunctive Therapy with Bioavailability-Boosted Curcuminoids in Major Depressive Disorder. Phytother Res 2014; 4
37 Coban D, Milenkovic D, Chanet A et al. Dietary curcumin inhibits atherosclerosis by affecting the expression of genes involved in leukocyte adhesion and transendothelial migration. Molecular nutrition & food research 2012; 56: 1270-1281
38 Mohammadi A, Sahebkar A, Iranshahi M et al. Effects of supplementation with curcuminoids on dyslipidemia in obese patients: a randomized crossover trial. Phytotherapy research: PTR 2013; 27: 374-379
39 Panahi Y, Khalili N, Hosseini MS et al. Lipid-modifying effects of adjunctive therapy with curcuminoids – piperine combination in patients with metabolic syndrome: Results of a randomized controlled trial. Complement Ther Med 2014;
40 Kunnumakkara AB, Anand P, Aggarwal BB. Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. Cancer letters 2008; 269: 199-225
41 Panahi Y, Rahimnia AR, Sharafi M et al. Curcuminoid treatment for knee osteoarthritis: a randomized double-blind placebo-controlled trial. Phytother Res 2014;
42 Ghanei M, Ghayumi M, Ahakzani N et al. Noninvasive diagnosis of bronchiolitis obliterans due to sulfur mustard exposure: could high-resolution computed tomography give us a clue?. La Radiologia medica 2010; 115: 413-420
43 Panahi Y, Ghanei M, Aslani J et al. The therapeutic effect of gamma interferon in chronic bronchiolitis due to mustard gas. Iranian journal of allergy, asthma, and immunology 2005; 4: 83-90
44 Suzuki M, Betsuyaku T, Ito Y et al. Curcumin attenuates elastase- and cigarette smoke-induced pulmonary emphysema in mice. American journal of physiology Lung cellular and molecular physiology 2009; 296: L614-L623
45 Venkatesan N. Pulmonary protective effects of curcumin against paraquat toxicity. Life sciences 2000; 66: PL21-PL28
46 Kalpana C, Menon VP. Curcumin ameliorates oxidative stress during nicotine-induced lung toxicity in Wistar rats. The Italian journal of biochemistry 2004; 53: 82-86
47 Punithavathi D, Venkatesan N, Babu M. Curcumin inhibition of bleomycin-induced pulmonary fibrosis in rats. British journal of pharmacology 2000; 131: 169-172
48 Punithavathi D, Venkatesan N, Babu M. Protective effects of curcumin against amiodarone-induced pulmonary fibrosis in rats. British journal of pharmacology 2003; 139: 1342-1350
49 Vanisree AJ, Sudha N. Curcumin combats against cigarette smoke and ethanol-induced lipid alterations in rat lung and liver. Molecular and cellular biochemistry 2006; 288: 115-123
50 Xu M, Deng B, Chow YL et al. Effects of curcumin in treatment of experimental pulmonary fibrosis: a comparison with hydrocortisone. Journal of ethnopharmacology 2007; 112: 292-299
51 Polasa K, Raghuram TC, Krishna TP et al. Effect of turmeric on urinary mutagens in smokers. Mutagenesis 1992; 7: 107-109
52 Sin DD, Man SF. Interleukin-6: a red herring or a real catch in COPD?. Chest 2008; 133: 4-6
53 Yanbaeva DG, Dentener MA, Spruit MA et al. IL6 and CRP haplotypes are associated with COPD risk and systemic inflammation: a case-control study. BMC medical genetics 2009; 10: 23
54 Emad A, Emad Y. Levels of cytokine in bronchoalveolar lavage (BAL) fluid in patients with pulmonary fibrosis due to sulfur mustard gas inhalation. Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research 2007; 27: 38-43
55 Oh SW, Cha JY, Jung JE et al. Curcumin attenuates allergic airway inflammation and hyper-responsiveness in mice through NF-kappaB inhibition. Journal of ethnopharmacology 2011; 136: 414-421
56 Shakibaei M, John T, Schulze-Tanzil G et al. Suppression of NF-kappaB activation by curcumin leads to inhibition of expression of cyclo-oxygenase-2 and matrix metalloproteinase-9 in human articular chondrocytes: Implications for the treatment of osteoarthritis. Biochemical pharmacology 2007; 73: 1434-1445
57 Jobin C, Bradham CA, Russo MP et al. Curcumin blocks cytokine-mediated NF-kappa B activation and proinflammatory gene expression by inhibiting inhibitory factor I-kappa B kinase activity. Journal of immunology 1999; 163: 3474-3483
58 Shishodia S, Amin HM, Lai R et al. Curcumin (diferuloylmethane) inhibits constitutive NF-kappaB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma. Biochemical pharmacology 2005; 70: 700-713
59 Surh YJ, Chun KS, Cha HH et al. Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutation research 2001; 480-481: 243-268
60 Abe Y, Hashimoto S, Horie T. Curcumin inhibition of inflammatory cytokine production by human peripheral blood monocytes and alveolar macrophages. Pharmacological research: the official journal of the Italian Pharmacological Society 1999; 39: 41-47
61 Biswas SK, McClure D, Jimenez LA et al. Curcumin induces glutathione biosynthesis and inhibits NF-kappaB activation and interleukin-8 release in alveolar epithelial cells: mechanism of free radical scavenging activity. Antioxidants & redox signaling 2005; 7: 32-41
62 Holroyde MC, Altounyan RE, Cole M et al. Bronchoconstriction produced in man by leukotrienes C and D. Lancet 1981; 2: 17-18
63 Lam S, Chan H, LeRiche JC et al. Release of leukotrienes in patients with bronchial asthma. The Journal of allergy and clinical immunology 1988; 81: 711-717
64 Marom Z, Shelhamer JH, Sun F et al. Human airway monohydroxyeicosatetraenoic acid generation and mucus release. The Journal of clinical investigation 1983; 72: 122-127
65 Panahi Y, Sahebkar A, Amiri M et al. Improvement of sulphur mustard-induced chronic pruritus, quality of life and antioxidant status by curcumin: results of a randomised, double-blind, placebo-controlled trial. The British journal of nutrition 2012; 108: 1272-1279
66 Panahi Y, Sahebkar A, Parvin S et al. A randomized controlled trial on the anti-inflammatory effects of curcumin in patients with chronic sulphur mustard-induced cutaneous complications. Annals of clinical biochemistry 2012; 49: 580-588
67 Cheng AL, Hsu CH, Lin JK et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer research 2001; 21: 2895-2900
68 Lao CD, Ruffin MTt, Normolle D et al. Dose escalation of a curcuminoid formulation. BMC complementary and alternative medicine 2006; 6: 10
69 Shoba G, Joy D, Joseph T et al. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta medica 1998; 64: 353-356
70 Kim DH, Phillips JF, Lockey RF. Oral curcumin supplementation in patients with atopic asthma. Allergy & rhinology 2011; 2: e51-e53