Download PDF
Drug Res (Stuttg) 2015; 65(11): 567-573
DOI: 10.1055/s-0034-1389986
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

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
1   Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
,
M. Ghanei
1   Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
,
S. Bashiri
1   Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
,
A. Hajihashemi
1   Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
,
A. Sahebkar
2   Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
3   Metabolic Research Centre, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia
› Author Affiliations
Further Information

Publication History

received 03 July 2014

accepted 21 August 2014

Publication Date:
30 September 2014 (online)

Also available at
    Permissions and Reprints

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
 

  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 10 Westergren-Thorsson G, Larsen K, Nihlberg K et al. Pathological airway remodelling in inflammation. Clin Respir J 2010; 4 (Suppl. 01) 1-8
    PubMedSearch in Google Scholar
  • 11 MacNee W. Oxidative stress and lung inflammation in airways disease. Eur J Pharmacol 2001; 429: 195-207
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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;
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 20 Anand P, Kunnumakkara AB, Newman RA et al. Bioavailability of curcumin: problems and promises. Mol Pharm 2007; 4: 807-818
    CrossrefPubMedSearch in Google Scholar
  • 21 Strimpakos AS, Sharma RA. Curcumin: preventive and therapeutic properties in laboratory studies and clinical trials. Antioxidants & redox signaling 2008; 10: 511-545
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 23 Shehzad A, Khan S, Sup Lee Y. Curcumin molecular targets in obesity and obesity-related cancers. Future Oncol 2012; 8: 179-190
    CrossrefPubMedSearch in Google Scholar
  • 24 Sahebkar A. Molecular mechanisms for curcumin benefits against ischemic injury. Fertility and sterility 2010; 94: e75-e76 author reply e7
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 27 Shehzad A, Rehman G, Lee YS. Curcumin in inflammatory diseases. BioFactors 2013; 39: 69-77
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 31 Hossain DM, Bhattacharyya S, Das T et al. Curcumin: the multi-targeted therapy for cancer regression. Frontiers in bioscience 2012; 4: 335-355
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 33 Srivastava G, Mehta JL. Currying the heart: curcumin and cardioprotection. Journal of cardiovascular pharmacology and therapeutics 2009; 14: 22-27
    CrossrefPubMedSearch in Google Scholar
  • 34 Srivastava RM, Singh S, Dubey SK et al. Immunomodulatory and therapeutic activity of curcumin. International immunopharmacology 2011; 11: 331-341
    CrossrefPubMedSearch in Google Scholar
  • 35 Monroy A, Lithgow GJ, Alavez S. Curcumin and neurodegenerative diseases. BioFactors 2013; 39: 122-132
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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;
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 41 Panahi Y, Rahimnia AR, Sharafi M et al. Curcuminoid treatment for knee osteoarthritis: a randomized double-blind placebo-controlled trial. Phytother Res 2014;
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 45 Venkatesan N. Pulmonary protective effects of curcumin against paraquat toxicity. Life sciences 2000; 66: PL21-PL28
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 47 Punithavathi D, Venkatesan N, Babu M. Curcumin inhibition of bleomycin-induced pulmonary fibrosis in rats. British journal of pharmacology 2000; 131: 169-172
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 51 Polasa K, Raghuram TC, Krishna TP et al. Effect of turmeric on urinary mutagens in smokers. Mutagenesis 1992; 7: 107-109
    CrossrefPubMedSearch in Google Scholar
  • 52 Sin DD, Man SF. Interleukin-6: a red herring or a real catch in COPD?. Chest 2008; 133: 4-6
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 62 Holroyde MC, Altounyan RE, Cole M et al. Bronchoconstriction produced in man by leukotrienes C and D. Lancet 1981; 2: 17-18
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 68 Lao CD, Ruffin MTt, Normolle D et al. Dose escalation of a curcuminoid formulation. BMC complementary and alternative medicine 2006; 6: 10
    CrossrefPubMedSearch in Google Scholar
  • 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
    Thieme ConnectPubMedSearch in Google Scholar
  • 70 Kim DH, Phillips JF, Lockey RF. Oral curcumin supplementation in patients with atopic asthma. Allergy & rhinology 2011; 2: e51-e53
    PubMedSearch in Google Scholar