Advertisement

Clinical Pharmacology and Toxicology of Mustard Compounds

  • Adel Ghorani-Azam
  • Mahdi Balali-MoodEmail author
Chapter

Abstract

Sulfur mustard (SM) and nitrogen mustard (NM) are the two types of mustard compounds (MCs). SM has mainly been used as a chemical warfare agent (CWA), but NM has been administered as an anti-cancer drug. MCs are alkylating agents and initially synthesised for military purposes as a chemical blistering agent. However, they were also used as medications in the treatment of several diseases such as psoriasis and variety of cancers. MCs, especially SM can cause acute and chronic toxicities, particularly acute toxic effects and complications in the eyes, lungs, kidneys, skin and other vital organs in human. Several therapeutic strategies have been proposed so far to treat these complications, but no specific antidote has been introduced for these health problems. Conventional medical treatments with antioxidants e.g. N-acetyl cysteine and sodium thiosulfate and some anti-inflammatory drugs such as corticosteroids have been used, but their effects are not satisfactory. Nowadays, some new therapeutic strategies such as antimicrobial peptides, gene and stem cell therapy, and herbal medicines have been proposed for the treatment of SM complications.

In this chapter, we have reviewed clinical pharmacology of NM and acute, chronic and late clinical complications of SM poisoning in all affected organs. In addition, we have discussed conventional treatment as well as some new therapeutic approaches.

Keywords

Sulfur mustard Nitrogen mustard Acute effects Chronic Poisoning Delayed toxicity Mustard gas Intoxication 

Notes

Glossary

Alkylating agent

A molecule that transfer an alkyl group to target molecule, which acts as anticancer drugs by inhibiting DNA replication and transcription.

Biotransformation

Chemical modification of a compound in the body of living organism.

Bronchiectasis

A pulmonary disease in which some parts of lung airways is enlarged mainly due to inflammation or infection.

Calmodulin

A calcium binding protein in eukaryotic cells that regulates biological activities of calcium dependent proteins in many cellular processes.

Chemical warfare agent (CWA)

A chemically toxic substance that are used as chemical weapons in battlefield.

Corneal conjunctivalization

The presence of goblet cells in the corneal epithelium.

Epigenetic therapy

The use of drugs or epigenome-influencing techniques to treat diseases.

Keratitis

Inflammation of the cornea.

Lipophilicity

Ability of a chemical compound to dissolve in lipids and non-polar solvents.

Nitrogen mustard (NM)\

A cytotoxic chemotherapy agents similar to sulfur mustard.

Organization for Prohibition of Chemical Weapons (OPCW)

An international organization for preventing the use of chemical warfare agents and collaborating with many academics to find suitable therapy for medical conditions caused by these agents.

Pharmacodynamics

Studies effects of a drug to the body.

Pharmacokinetic

Studies effects of the body to a drug.

Steatosis

The process in which lipids are accumulated in the liver cells.

Sulfur mustard (SM)

Also known as mustard gas, is a cytotoxic, alkylating and blistering chemical warfare agents.

Teratogenicity

The property or capability of producing congenital anomalies.

Tracheobronchitis

Inflammation of the bronchi.

References

  1. Aasted A, Darre E, Wulf HC (1987) Mustard gas: clinical, toxicological, and mutagenic aspects based on modern experience. Ann Plast Surg 19:330–333PubMedCrossRefGoogle Scholar
  2. Aghaei S, Moradi A (2010) Eruptive cherry angiomas secondary to exposure to sulfur mustard gas. Int J Dermatol 8: http://ispub.com/IJD/8/2/9937
  3. Alvarez-Gonzalez R, Eichenberger R, Althaus FR (1986) Poly(ADP-ribose) biosynthesis and suicidal NAD+ depletion following carcinogen exposure of mammalian cells. Biochem Biophys Res Commun 138:1051–1057PubMedCrossRefGoogle Scholar
  4. Amirzargar MA, Yavangi M, Rahnavardi M, Jafari M, Mohseni M (2009) Chronic mustard toxicity on the testis: a historical cohort study two decades after exposure. Int J Androl 32:411–416PubMedCrossRefGoogle Scholar
  5. Amrein L, Loignon M, Goulet AC, Dunn M, Jean-Claude B, Aloyz R, Panasci L (2007) Chlorambucil cytotoxicity in malignant B lymphocytes is synergistically increased by 2-(morpholin-4-yl)-benzo[h]chomen-4-one (NU7026)-mediated inhibition of DNA double-strand break repair via inhibition of DNA-dependent protein kinase. J Pharmacol Exp Ther 321:848–855PubMedCrossRefGoogle Scholar
  6. Anastasia A, Carlo-Stella C, Corradini P, Salvi F, Rusconi C, Pulsoni A, Hohaus S, Pregno P, Viviani S, Brusamolino E, Luminari S, Giordano L, Santoro A (2014) Bendamustine for Hodgkin lymphoma patients failing autologous or autologous and allogeneic stem cell transplantation: a retrospective study of the Fondazione Italiana Linfomi. Br J Haematol 166:140–142PubMedCrossRefGoogle Scholar
  7. Asoodeh A, Ghorani-Azam A, Chamani J (2012) Identification and characterization of novel antibacterial peptides from skin secretions of Euphlyctis cyanophlyctis. Int J Pep Res Ther 18:107–115CrossRefGoogle Scholar
  8. Asoodeh A, Sepahi S, Ghorani-Azam A (2014) Purification and modeling amphipathic alpha helical antimicrobial peptides from skin secretions of Euphlyctis cyanophlyctis. Chem Biol Drug Des 83:411–417PubMedCrossRefGoogle Scholar
  9. Baeuerle PA, Henkel T (1994) Function and activation of NF-kappa B in the immune system. Annu Rev Immunol 12:141–179PubMedCrossRefGoogle Scholar
  10. Balali-Mood M (1992) Evaluation of late toxic effects of sulfur mustard poisoning in 1428 Iranian veterans. In: The seminar on late complications of chemical warfare agents in Iranian Veterans. Veteran Foundation, Tehran, pp 15–37Google Scholar
  11. Balali-Mood M, Anari MR (1989) Protective effects of N-acetyl cysteine and sodium thiosulphate on sulphur mustard poisoning. In: Proceedings of the third international symposium on protection against chemical warfare agents, Sweden, pp 11–16Google Scholar
  12. Balali-Mood M, Hefazi M (2005a) The clinical toxicology of sulfur mustard. Arch Iran Med 8:162–179Google Scholar
  13. Balali-Mood M, Hefazi M (2005b) The pharmacology, toxicology, and medical treatment of sulphur mustard poisoning. Fundam Clin Pharmacol 19:297–315PubMedCrossRefGoogle Scholar
  14. Balali-Mood M, Hefazi M (2006) Comparison of early and late toxic effects of sulfur mustard in Iranian veterans. Basic Clin Pharmacol Toxicol 99:273–282PubMedCrossRefGoogle Scholar
  15. Balali-Mood M, Navaeian A (1986) Clinical and paraclinical findings in 233 patients with sulfur mustard poisoning. In: Proceedings of the second world congress on new compounds in biological and chemical warfare. Rijksuniversiteit, Ghent, pp 464–473Google Scholar
  16. Balali-Mood M, Hefazi M, Mahmoudi M, Jalali E, Attaran D, Maleki M, Razavi ME, Zare G, Tabatabaee A, Jaafari MR (2005a) Long-term complications of sulphur mustard poisoning in severely intoxicated Iranian veterans. Fundam Clin Pharmacol 19:713–721PubMedCrossRefGoogle Scholar
  17. Balali-Mood M, Hefazi M, Mahmoudi M, Jalali I, Attaran D, Maleki M, Razavi M-RE, Zare G, Jaafari M-R, Tabatabaee A (2005b) Evaluation of delayed toxic effects of sulfur mustard poisoning in severely intoxicated Iranian veterans: a cross-sectional study. J Med CBR Def 3:0301Google Scholar
  18. Balali-Mood M, Mousavi S, Balali-Mood B (2008) Chronic health effects of sulphur mustard exposure with special reference to Iranian veterans. Emerg Health Threats J 1:e7PubMedPubMedCentralGoogle Scholar
  19. Balali-Mood M, Afshari R, Zojaji R, Kahrom H, Kamrani M, Attaran D, Mousavi SR, Zare GA (2011) Delayed toxic effects of sulfur mustard on respiratory tract of Iranian veterans. Hum Exp Toxicol 30:1141–1149PubMedCrossRefGoogle Scholar
  20. Baraldi PG, Romagnoli R, Guadix AE, Pinedadelasinfantas MJ, Gallo MA, Espinosa A, Martinez A, Bingham JP, Hartley JA (2002) Design, synthesis, and biological activity of hybrid compounds between uramustine and DNA minor groove binder distamycin A. J Med Chem 45:3630–3638PubMedCrossRefGoogle Scholar
  21. Behravan E, Moallem SA, Khateri S, Maraghi E, Jowsey P, Blain PG, Balali-Mood M (2013) DNA damage in Iranian veterans 25 years after wartime exposure to sulphur mustard. J Res Med Sci 18(3):239–244PubMedPubMedCentralGoogle Scholar
  22. Ben-Ari ET (2004) Dual purpose: some cancer therapies used to treat autoimmune diseases. J Natl Cancer Inst 96:577–579PubMedCrossRefGoogle Scholar
  23. Benson JM, Tibbetts BM, Weber WM, Grotendorst GR (2011) Uptake, tissue distribution, and excretion of 14C-sulfur mustard vapor following inhalation in F344 rats and cutaneous exposure in hairless guinea pigs. J Toxicol Environ Health A 74:875–885PubMedCrossRefGoogle Scholar
  24. Black RM, Brewster K, Clarke RJ, Hambrook JL, Harrison JM, Howells DJ (1992) Biological fate of sulphur mustard, 1,1′-thiobis(2-chloroethane): isolation and identification of urinary metabolites following intraperitoneal administration to rat. Xenobiotica 22:405–418PubMedCrossRefGoogle Scholar
  25. Boursnell JC, Cohen JA et al (1946) Studies on mustard gas (beta beta’-dichlorodiethyl sulphide) and some related compounds; the fate of injected mustard gas (containing radioactive sulphur) in the animal body. Biochem J 40:756–764PubMedCentralCrossRefGoogle Scholar
  26. Brodsky B, Erlanger-Rosengarten A, PROSCURA E, Shapira E, Wormser U (2008) From topical antidote against skin irritants to a novel counter-irritating and anti-inflammatory peptide. Toxicol Appl Pharmacol 229:342–350PubMedCrossRefGoogle Scholar
  27. Brugger W, Ghielmini M (2013) Bendamustine in indolent non-Hodgkin’s lymphoma: a practice guide for patient management. Oncologist 18:954–964PubMedPubMedCentralCrossRefGoogle Scholar
  28. Cai Y, Ma Q, Zhang L, Zhao J, Zhu M, Hu W, Jiang P, Yuan W (2004) Therapeutic effects of rhEPO, rhG-CSF on sulfur mustard induced toxicity in dogs. Wei Sheng Yan Jiu 33:649–651PubMedGoogle Scholar
  29. Cerny T, Kupfer A, Zeugin T, Brunner KW (1990) Bioavailability of subcutaneous ifosfamide and feasibility of continuous outpatient application in cancer patients. Ann Oncol 1:365–368PubMedCrossRefGoogle Scholar
  30. Cerny T, Graf A, Rohner P, Zeugin T, Brunner KW, Kupfer A (1991) Subcutaneous continuous infusion of ifosfamide and cyclophosphamide in ambulatory cancer patients: bioavailability and feasibility. J Cancer Res Clin Oncol 117(Suppl 4):S129–S134PubMedCrossRefGoogle Scholar
  31. Cheson BD, Rummel MJ (2009) Bendamustine: rebirth of an old drug. J Clin Oncol 27:1492–1501PubMedCrossRefGoogle Scholar
  32. Chien YH, Bau DT, Jan KY (2004) Nitric oxide inhibits DNA-adduct excision in nucleotide excision repair. Free Radic Biol Med 36:1011–1017PubMedCrossRefGoogle Scholar
  33. Chou CJ, Farkas ME, Tsai SM, Alvarez D, Dervan PB, Gottesfeld JM (2008) Small molecules targeting histone H4 as potential therapeutics for chronic myelogenous leukemia. Mol Cancer Ther 7:769–778PubMedPubMedCentralCrossRefGoogle Scholar
  34. Clifford P, Bhardwaj BV, Whittaker LR (1965) Intensive nitrogen mustard therapy with abdominal aortic occlusion in nasopharyngeal carcinoma. Br J Cancer 19:51–71PubMedPubMedCentralCrossRefGoogle Scholar
  35. Dabney JM, Buehn MJ, Dobbins DE (1991) Perfused prenodal lymphatics are constricted by prostaglandins. Am J Physiol 260:H1–H5PubMedGoogle Scholar
  36. Dachir S, Fishbeine E, Meshulam Y, Sahar R, Chapman S, Amir A, Kadar T (2004) Amelioration of sulfur mustard skin injury following a topical treatment with a mixture of a steroid and a NSAID. J Appl Toxicol 24:107–113PubMedCrossRefGoogle Scholar
  37. Dacre JC, Goldman M (1996) Toxicology and pharmacology of the chemical warfare agent sulfur mustard. Pharmacol Rev 48:289–326PubMedGoogle Scholar
  38. Davison C, Rozman RS, Smith PK (1961) Metabolism of bis-beta-chloroethyl sulfide (sulfur mustard gas). Biochem Pharmacol 7:65–74PubMedCrossRefGoogle Scholar
  39. Detke S, Stein JL, Stein GS (1980) Influence of chlorambucil, a bifunctional alkylating agent, on DNA replication and histone gene expression in HeLa S3 cells. Cancer Res 40:967–974PubMedGoogle Scholar
  40. Dillman JF 3rd, Mcgary KL, Schlager JJ (2004) An inhibitor of p38 MAP kinase downregulates cytokine release induced by sulfur mustard exposure in human epidermal keratinocytes. Toxicol In Vitro 18:593–599PubMedCrossRefGoogle Scholar
  41. Drivsholm A, Videbaek A (1966) Alkeran (Melphalan) in the treatment of myelomatosis. Acta Med Scand Suppl 445:187–193PubMedGoogle Scholar
  42. Duff JK, Dennis J, Clift RA, Clifford P, Oettgen HF (1961) High-dose nitrogen mustard therapy with intermittent aortic occlusion. Br Med J 2:1523–1528PubMedPubMedCentralCrossRefGoogle Scholar
  43. Easton DF, Peto J, Doll R (1988) Cancers of the respiratory tract in mustard gas workers. Br J Ind Med 45:652–659PubMedPubMedCentralGoogle Scholar
  44. Eldad A, Weinberg A, Breiterman S, Chaouat M, Palanker D, Ben-Bassat H (1998) Early nonsurgical removal of chemically injured tissue enhances wound healing in partial thickness burns. Burns 24:166–172PubMedCrossRefGoogle Scholar
  45. Etezad-Razavi M, Mahmoudi M, Hefazi M, Balali-Mood M (2006) Delayed ocular complications of mustard gas poisoning and the relationship with respiratory and cutaneous complications. Clin Experiment Ophthalmol 34:342–346PubMedCrossRefGoogle Scholar
  46. Fine BP, Munoz R, Uy CS, Ty A (1976) Nitrogen mustard therapy in children with nephrotic syndrome unresponsive to corticosteroid therapy. J Pediatr 89:1014–1016PubMedCrossRefGoogle Scholar
  47. Fonseca SB, Kelley SO (2011) Peptide-chlorambucil conjugates combat pgp-dependent drug efflux. ACS Med Chem Lett 2:419–423PubMedPubMedCentralCrossRefGoogle Scholar
  48. Fox M, Scott D (1980) The genetic toxicology of nitrogen and sulphur mustard. Mutat Res 75:131–168PubMedCrossRefGoogle Scholar
  49. Freitag L, Firusian N, Stamatis G, Greschuchna D (1991) The role of bronchoscopy in pulmonary complications due to mustard gas inhalation. Chest 100:1436–1441PubMedCrossRefGoogle Scholar
  50. Friedman HS, Archer GE, Mclendon RE, Schuster JM, Colvin OM, Guaspari A, Blum R, Savina PA, Fuchs HE, Bigner DD (1994) Intrathecal melphalan therapy of human neoplastic meningitis in athymic nude rats. Cancer Res 54:4710–4714PubMedGoogle Scholar
  51. Ganesan K, Raza SK, Vijayaraghavan R (2010) Chemical warfare agents. J Pharm Bioallied Sci 2:166–178PubMedPubMedCentralCrossRefGoogle Scholar
  52. Gao X, Ray R, Xiao Y, Barker PE, Ray P (2007) Inhibition of sulfur mustard-induced cytotoxicity and inflammation by the macrolide antibiotic roxithromycin in human respiratory epithelial cells. BMC Cell Biol 8:17PubMedPubMedCentralCrossRefGoogle Scholar
  53. Garreis F, Gottschalt M, Paulsen FP (2010) Antimicrobial peptides as a major part of the innate immune defense at the ocular surface. Dev Ophthalmol 45:16–22PubMedCrossRefGoogle Scholar
  54. Ghabili K, Agutter PS, Ghanei M, Ansarin K, Panahi Y, Shoja MM (2011) Sulfur mustard toxicity: history, chemistry, pharmacokinetics, and pharmacodynamics. Crit Rev Toxicol 41:384–403PubMedCrossRefGoogle Scholar
  55. Ghanei M, Shohrati M, Harandi AA, Eshraghi M, Aslani J, Alaeddini F, Manzoori H (2007) Inhaled corticosteroids and long-acting beta 2-agonists in treatment of patients with chronic bronchiolitis following exposure to sulfur mustard. Inhal Toxicol 19:889–894PubMedCrossRefGoogle Scholar
  56. Ghanei M, Poursaleh Z, Harandi AA, Emadi SE, Emadi SN (2010) Acute and chronic effects of sulfur mustard on the skin: a comprehensive review. Cutan Ocul Toxicol 29:269–277PubMedCrossRefGoogle Scholar
  57. Ghasemi-Boroumand M, Karamy GR, Pourfarzam SH, Emadi SN, Ghasemi H (2007) Late concurrent ophthalmic, respiratory, coetaneous and psychiatric complications of chemical weapons exposure in 479 war patients. Daneshvar Med 14:81–92Google Scholar
  58. Ghassemi-Broumand M, Agin K, Kangari H (2004) The delayed ocular and pulmonary complications of mustard gas. Cutan Ocul Toxicol 23:293–302CrossRefGoogle Scholar
  59. Ghotbi L, Hassan Z (2002) The immunostatus of natural killer cells in people exposed to sulfur mustard. Int Immunopharmacol 2:981–985PubMedCrossRefGoogle Scholar
  60. Gold MB, Scharf BA (1995) Hematological profile of the euthymic hairless guinea pig following sulfur mustard vesicant exposure. J Appl Toxicol 15:433–438PubMedCrossRefGoogle Scholar
  61. Goodman LS, Wintrobe MM, Dameshek W, Goodman MJ, Gilman A, McLennan MT (1946) Nitrogen mustard therapy: use of methyl-bis(beta-chloroethyl)amine hydrochloride and tris(beta-chloroethyl)amine hydrochloride for Hodgkin’s disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. JAMA 132:126–132CrossRefGoogle Scholar
  62. Graef I, Karnofsky DA et al (1948) The clinical and pathologic effects of the nitrogen and sulfur mustards in laboratory animals. Am J Pathol 24:1–47PubMedPubMedCentralGoogle Scholar
  63. Graham JS, Chilcott RP, Rice P, Milner SM, Hurst CG, Maliner BI (2005) Wound healing of cutaneous sulfur mustard injuries: strategies for the development of improved therapies. J Burns Wounds 4:e1PubMedPubMedCentralGoogle Scholar
  64. Graham JS, Stevenson RS, Mitcheltree LW, Hamilton TA, Deckert RR, Lee RB, Schiavetta AM (2009) Medical management of cutaneous sulfur mustard injuries. Toxicology 263:47–58PubMedCrossRefGoogle Scholar
  65. Grube K, Burkle A (1992) Poly(ADP-ribose) polymerase activity in mononuclear leukocytes of 13 mammalian species correlates with species-specific life span. Proc Natl Acad Sci U S A 89:11759–11763PubMedPubMedCentralCrossRefGoogle Scholar
  66. Gu TY (2014) Mechanism and treatment of sulfur mustard-induced cutaneous injury. Chin J Traumatol 17:345–350PubMedGoogle Scholar
  67. Haddad H, Mohammad F, Dai Q (2014) Bendamustine-induced immune hemolytic anemia in a chronic lymphocytic leukemia patient: a case report and review of the literature. Hematol Oncol Stem Cell Ther 7:162–164PubMedCrossRefGoogle Scholar
  68. Hartley JA, Lown JW, Mattes WB, Kohn KW (1988) DNA sequence specificity of antitumor agents. Oncogenes as possible targets for cancer therapy. Acta Oncol 27:503–510PubMedCrossRefGoogle Scholar
  69. Hefazi M, Attaran D, Mahmoudi M, Balali-Mood M (2005) Late respiratory complications of mustard gas poisoning in Iranian veterans. Inhal Toxicol 17:587–592PubMedCrossRefGoogle Scholar
  70. Hefazi M, Maleki M, Mahmoudi M, Tabatabaee A, Balali-Mood M (2006) Delayed complications of sulfur mustard poisoning in the skin and the immune system of Iranian veterans 16–20 years after exposure. Int J Dermatol 45:1025–1031PubMedCrossRefGoogle Scholar
  71. Henemyre-Harris CL, Adkins AL, Chuang AH, Graham JS (2008) Addition of epidermal growth factor improves the rate of sulfur mustard wound healing in an in vitro model. Eplasty 8:e16PubMedPubMedCentralGoogle Scholar
  72. Hirsch J (2006) An anniversary for cancer chemotherapy. JAMA 296:1518–1520PubMedCrossRefGoogle Scholar
  73. Hossein BM, Nasim V, Sediqa A (2008) The protective effect of Nigella sativa on lung injury of sulfur mustard-exposed Guinea pigs. Exp Lung Res 34:183–194PubMedCrossRefGoogle Scholar
  74. Hua A, Daniel R, Jasseron MP, Thiriot C (1993) Early cytotoxic effects induced by bis-chloroethyl sulphide (sulphur mustard): [Ca2+]i rise and time-dependent inhibition of B77 fibroblast serum response. J Appl Toxicol 13:161–168PubMedCrossRefGoogle Scholar
  75. Husain K, Dube SN, Sugendran K, Singh R, Das Gupta S, Somani SM (1996) Effect of topically applied sulphur mustard on antioxidant enzymes in blood cells and body tissues of rats. J Appl Toxicol 16:245–248PubMedCrossRefGoogle Scholar
  76. (IARC), I. A. F. R. O. C (1999) IARC monographs on the evaluation of the carcinogenic risk of chemicals to man. World Health Organization, Lyon, FranceGoogle Scholar
  77. Illig L, Paul E, Eyer P, Weger H, Born W (1979) The treatment of psoriasis vulgaris with S-mustard-Vaseline externally, taking especially into consideration the possible carcinogenic risk. Z Hautkr 54:941–951PubMedGoogle Scholar
  78. (IMC), I. O. M. U. C. O. T. S. O. T. H. E. O. M. G. A. L (1993) Dermatological effects of brsmustard agents and lewisite. In: Pechura CM, Rall DP (eds) Veterans at risk: the health effects of mustard gas and lewisite. National Academies Press (US), Washington, DCGoogle Scholar
  79. Ivarsson U, Nilsson H, Santesson J (1992) A FOA briefing book on chemical weapons. In: Threat, effects and protection. Försvarets forskningsanstalt (FOA), Sundbyberg, p 77Google Scholar
  80. Javadi MA, Yazdani S, Sajjadi H, Jadidi K, Karimian F, Einollahi B, Ja’farinasab MR, Zare M (2005) Chronic and delayed-onset mustard gas keratitis: report of 48 patients and review of literature. Ophthalmology 112:617–625PubMedCrossRefGoogle Scholar
  81. Joseph LB, Gerecke DR, Heck DE, Black AT, Sinko PJ, Cervelli JA, Casillas RP, Babin MC, Laskin DL, Laskin JD (2011) Structural changes in the skin of hairless mice following exposure to sulfur mustard correlate with inflammation and DNA damage. Exp Mol Pathol 91:515–527PubMedPubMedCentralCrossRefGoogle Scholar
  82. Joseph LB, Heck DE, Cervelli JA, Composto GM, Babin MC, Casillas RP, Sinko PJ, Gerecke DR, Laskin DL, Laskin JD (2014) Structural changes in hair follicles and sebaceous glands of hairless mice following exposure to sulfur mustard. Exp Mol Pathol 96:316–327PubMedPubMedCentralCrossRefGoogle Scholar
  83. Jowsey PA, Blain PG (2014) Whole genome expression analysis in primary bronchial epithelial cells after exposure to sulphur mustard. Toxicol Lett 230:393–401PubMedCrossRefGoogle Scholar
  84. Kalaycio M (2009) Bendamustine: a new look at an old drug. Cancer 115:473–479PubMedCrossRefGoogle Scholar
  85. Kalita S, Verma AK, Prasad SB (2014) Chlorambucil and ascorbic acid-mediated anticancer activity and hematological toxicity in Dalton’s ascites lymphoma-bearing mice. Indian J Exp Biol 52:112–124PubMedGoogle Scholar
  86. Kazemzadeh N, Kadkhodaei A, Soltani B, Soltani S, Rismantab Sani S (2014) Pathologic lesions of liver, kidney and lung in the autopsy of 100 mustard gas-exposed Iranian War Veterans. Iran J Pathol 9:181–186Google Scholar
  87. Keramati MR, Balali-Mood M, Mousavi SR, Sadeghi M, Riahi-Zanjani B (2013) Biochemical and hematological findings of Khorasan veterans 23 years after sulfur mustard exposure. J Res Med Sci 18:855–859PubMedPubMedCentralGoogle Scholar
  88. Keyes DC (2005) Medical response to terrorism: preparedness and clinical practice. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  89. Keyser BM, Andres DK, Nealley E, Holmes WW, Benton B, Paradiso D, Appell A, Carpin C, Anderson DR, Smith WJ, Ray R (2013) Postexposure application of Fas receptor small-interfering RNA to suppress sulfur mustard-induced apoptosis in human airway epithelial cells: implication for a therapeutic approach. J Pharmacol Exp Ther 344:308–316PubMedCrossRefGoogle Scholar
  90. Keyser BM, Andres DK, Holmes WW, Paradiso D, Appell A, Letukas VA, Benton B, Clark OE, Gao X, Ray P, Anderson DR, Ray R (2014) Mustard gas inhalation injury: therapeutic strategy. Int J Toxicol 33:271–281PubMedCrossRefGoogle Scholar
  91. Kuhne A, Sezer O, Heider U, Meineke I, Muhlke S, Niere W, Overbeck T, Hohloch K, Trumper L, Brockmoller J, Kaiser R (2008) Population pharmacokinetics of melphalan and glutathione S-transferase polymorphisms in relation to side effects. Clin Pharmacol Ther 83:749–757PubMedCrossRefGoogle Scholar
  92. Kumar O, Vijayaraghavan R (1998) Effect of sulphur mustard inhalation exposure on some urinary variables in mice. J Appl Toxicol 18:257–259PubMedCrossRefGoogle Scholar
  93. Kumar P, Sharma U, Vijayaraghavan R (2013) Study of the efficacy of CC-2 and Fuller’s earth combination as a decontaminant against sulphur mustard (mustard gas) dermal intoxication in mice. Def Sci J 41:363–366CrossRefGoogle Scholar
  94. Kunak ZI, Toygar M, Poyrazoğlu Y (2012) Novel molecular strategies against sulfur mustard toxicity. TAF Prev Med Bull 11:231–236CrossRefGoogle Scholar
  95. Lewisite, I. O. M. U. C. O. T. S. O. T. H. E. O. M. G. A (1993) Dermatological effects of mustard agents and lewisite. In: Pechura C, Rall D (eds) Veterans at risk: the health effects of mustard gas and lewisite. National Academies Press (US), Washington, DCGoogle Scholar
  96. Logan TP, Millard CB, Shutz M, Schulz SM, Lee RB, Bongiovanni R (1999) Cutaneous uptake of 14C-HD vapor by the hairless guinea pig. Drug Chem Toxicol 22:375–387PubMedCrossRefGoogle Scholar
  97. Mahmoudi M, Hefazi M, Rastin M, Balali-Mood M (2005) Long-term hematological and immunological complications of sulfur mustard poisoning in Iranian veterans. Int Immunopharmacol 5:1479–1485PubMedCrossRefGoogle Scholar
  98. Maisonneuve A, Callebat I, Debordes L, Coppet L (1994) Distribution of [14C]sulfur mustard in rats after intravenous exposure. Toxicol Appl Pharmacol 125:281–287PubMedCrossRefGoogle Scholar
  99. Maki RG (2012) Ifosfamide in the neoadjuvant treatment of osteogenic sarcoma. J Clin Oncol 30:2033–2035PubMedCrossRefGoogle Scholar
  100. Malhotra R, Ganesan K, Sugendran K, Swamy R (1999) Chemistry and toxicology of sulphur mustard-a review. Def Sci J 49:97–116CrossRefGoogle Scholar
  101. Manning KP, Skegg DC, Stell PM, Doll R (1981) Cancer of the larynx and other occupational hazards of mustard gas workers. Clin Otolaryngol Allied Sci 6:165–170PubMedCrossRefGoogle Scholar
  102. Mattes WB, Hartley JA, Kohn KW (1986) DNA sequence selectivity of guanine-N7 alkylation by nitrogen mustards. Nucleic Acids Res 14:2971–2987PubMedPubMedCentralCrossRefGoogle Scholar
  103. Mcnutt P, Tuznik K, Nelson M, Adkins A, Lyman M, Glotfelty E, Hughes J, Hamilton T (2013) Structural, morphological, and functional correlates of corneal endothelial toxicity following corneal exposure to sulfur mustard vapor. Invest Ophthalmol Vis Sci 54:6735–6744PubMedCrossRefGoogle Scholar
  104. Meier HL, Millard CB (1998) Alterations in human lymphocyte DNA caused by sulfur mustard can be mitigated by selective inhibitors of poly(ADP-ribose) polymerase. Biochim Biophys Acta 1404:367–376PubMedCrossRefGoogle Scholar
  105. Merat S, Perez JP, Ruttimann M, Bordier E, Lienhard A, Lenoir B, Pats B (2003) Acute poisoning by chemical warfare agent: sulfur mustard. Ann Fr Anesth Reanim 22:108–118PubMedCrossRefGoogle Scholar
  106. Minsavage GD, Dillman JF 3rd (2007) Bifunctional alkylating agent-induced p53 and nonclassical nuclear factor kappaB responses and cell death are altered by caffeic acid phenethyl ester: a potential role for antioxidant/electrophilic response-element signaling. J Pharmacol Exp Ther 321:202–212PubMedCrossRefGoogle Scholar
  107. Miremadi A, Oestergaard MZ, Pharoah PD, Caldas C (2007) Cancer genetics of epigenetic genes. Hum Mol Genet 16(Spec No 1):R28–R49PubMedCrossRefGoogle Scholar
  108. Mol MA, Smith WJ (1996) Ca2+ homeostasis and Ca2+ signalling in sulphur mustard-exposed normal human epidermal keratinocytes. Chem Biol Interact 100:85–93PubMedCrossRefGoogle Scholar
  109. Mol ME, de Vries R, Kluivers AW (1991) Effects of nicotinamide on biochemical changes and microblistering induced by sulfur mustard in human skin organ cultures. Toxicol Appl Pharmacol 107:439–449PubMedCrossRefGoogle Scholar
  110. Momeni AZ, Enshaeih S, Meghdadi M, Amindjavaheri M (1992) Skin manifestations of mustard gas. A clinical study of 535 patients exposed to mustard gas. Arch Dermatol 128:775–780PubMedCrossRefGoogle Scholar
  111. Montillo M, Ricci F, Tedeschi A, Vismara E, Morra E (2010) Bendamustine: new perspective for an old drug in lymphoproliferative disorders. Expert Rev Hematol 3:131–148PubMedCrossRefGoogle Scholar
  112. Naderi M, Ghanei M, Jadidi K, Gholami-Fesharaki M, Poursaleh Z (2014) Long term ocular effects of mustard gas poisoning: a cross-sectional study in Iraqi Kurdish civilians. J Allergy Ther 5:2Google Scholar
  113. Noorbakhsh K, Balali-Mood M (1994) Evaluation of gastrointestinal complications of sulfur mustard poisoning in Iranian combatants. Med J Islam Repub Iran 7:217–219Google Scholar
  114. Panahi Y, Sahebkar A, Amiri M, Davoudi SM, Beiraghdar F, Hoseininejad SL, Kolivand M (2012a) Improvement of sulphur mustard-induced chronic pruritus, quality of life and antioxidant status by curcumin: results of a randomised, double-blind, placebo-controlled trial. Br J Nutr 108:1272–1279PubMedCrossRefGoogle Scholar
  115. Panahi Y, Sahebkar A, Parvin S, Saadat A (2012b) A randomized controlled trial on the anti-inflammatory effects of curcumin in patients with chronic sulphur mustard-induced cutaneous complications. Ann Clin Biochem 49:580–588PubMedCrossRefGoogle Scholar
  116. Panahi Y, Ghanei M, Ghabili K, Ansarin K, Aslanabadi S, Poursaleh Z, Golzari SE, Etemadi J, Khalili M, Shoja MM (2013) Acute and chronic pathological effects of sulfur mustard on genitourinary system and male fertility. Urol J 10:837–846PubMedGoogle Scholar
  117. Papirmeister B, Westling AW, Schroer J (1969) Mustard: the relevance of DNA damage to the development of the skin lesion. DTIC Document. Army Medical Research Laboratory (US), Edgewood Arsenal, MDGoogle Scholar
  118. Pechura CM, Rall DP (1993) History and analysis of mustard agent and lewisite research programs in the United States. In: Veterans at risk: the health effects of mustard gas and lewisite. National Academies Press (US), Washington, DCGoogle Scholar
  119. Perry MR, Benson EM, Kohne JW, Plahovinsak JL, Babin MC, Platoff GE, Platoff GE Jr, Yeung DT (2015) A novel sulfur mustard (HD) vapor inhalation exposure system for accurate inhaled dose delivery. J Pharmacol Toxicol Methods 71:120–128PubMedCrossRefGoogle Scholar
  120. Polavarapu A, Stillabower JA, Stubblefield SG, Taylor WM, BAIK MH (2012) The mechanism of guanine alkylation by nitrogen mustards: a computational study. J Org Chem 77:5914–5921PubMedCrossRefGoogle Scholar
  121. Poursaleh Z, Harandi AA, Vahedi E, Ghanei M (2012) Treatment for sulfur mustard lung injuries; new therapeutic approaches from acute to chronic phase. Daru 20:27PubMedPubMedCentralCrossRefGoogle Scholar
  122. Pulichino AM, Rowland S, Wu T, Clark P, Xu D, Mathieu MC, Riendeau D, Audoly LP (2006) Prostacyclin antagonism reduces pain and inflammation in rodent models of hyperalgesia and chronic arthritis. J Pharmacol Exp Ther 319:1043–1050PubMedCrossRefGoogle Scholar
  123. Qabar A, Nelson M, Guzman J, Corun C, Hwang BJ, Steinberg M (2005) Modulation of sulfur mustard induced cell death in human epidermal keratinocytes using IL-10 and TNF-alpha. J Biochem Mol Toxicol 19:213–225PubMedCrossRefGoogle Scholar
  124. Rancourt RC, Ahmad A, Veress LA, Rioux JS, Garlick RB, White CW (2014) Antifibrinolytic mechanisms in acute airway injury after sulfur mustard analog inhalation. Am J Respir Cell Mol Biol 51:559–567PubMedPubMedCentralCrossRefGoogle Scholar
  125. Razavi S, Salamati P, Saghafinia M, Abdollahi M (2012) A review on delayed toxic effects of sulfur mustard in Iranian veterans. Daru 20:51CrossRefGoogle Scholar
  126. Renshaw B (1947) Observations on the role of water in the susceptibility of human skin to injury by vesicant vapors. J Invest Dermatol 9:75–85PubMedCrossRefGoogle Scholar
  127. Riahi-Zanjani B, Balali-Mood M, Mousavi SR, Karimi G, Sadeghi M, Shirmast E, Mahmoudi M (2014) Serum cytokine profiles of Khorasan veterans 23 years after sulfur mustard exposure. Cytokine 70:161–164PubMedCrossRefGoogle Scholar
  128. Rice P (2003) Sulphur mustard injuries of the skin. Pathophysiology and management. Toxicol Rev 22:111–118PubMedCrossRefGoogle Scholar
  129. Roberts JJ, Warwick GP (1963) Studies of the mode of action of alkylating agents. Vi. the metabolism of bis-2-chloroethylsulphide (mustard gas) and related compounds. Biochem Pharmacol 12:1329–1334PubMedCrossRefGoogle Scholar
  130. Rodriguez V, Cabanillas F, Bodey GP, Freireich EJ (1982) Studies with ifosfamide in patients with malignant lymphoma. Semin Oncol 9:87–92PubMedGoogle Scholar
  131. Rohani A, Akbari V, Moghadam FT (2010) A case control study of cardiovascular health in chemical war disabled Iranian victims. Indian J Crit Care Med 14:109–112PubMedPubMedCentralCrossRefGoogle Scholar
  132. Rosenthal DS, Simbulan-Rosenthal CM, Iyer S, Spoonde A, Smith W, Ray R, Smulson ME (1998) Sulfur mustard induces markers of terminal differentiation and apoptosis in keratinocytes via a Ca2+−calmodulin and caspase-dependent pathway. J Invest Dermatol 111:64–71PubMedCrossRefGoogle Scholar
  133. Rosenthal DS, Simbulan-Rosenthal CM, Iyer S, Smith WJ, Ray R, Smulson ME (2000) Calmodulin, poly(ADP-ribose)polymerase and p53 are targets for modulating the effects of sulfur mustard. J Appl Toxicol 20(Suppl 1):S43–S49PubMedGoogle Scholar
  134. Ruff AL, Dillman JF (2007) Signaling molecules in sulfur mustard-induced cutaneous injury. Eplasty 8:e2PubMedPubMedCentralGoogle Scholar
  135. Safarinejad MR (2001) Testicular effect of mustard gas. Urology 58:90–94PubMedCrossRefGoogle Scholar
  136. Sanchorawala V, Wright DG, Seldin DC, Falk RH, Berk JL, Dember LM, Finn KT, Skinner M (2002) Low-dose continuous oral melphalan for the treatment of primary systemic (AL) amyloidosis. Br J Haematol 117:886–889PubMedCrossRefGoogle Scholar
  137. Sanjarmoosavi N, Shahsavan M, Hassanzadeh-Nazarabadi M (2012) Teratogenic effects of sulfur mustard on mice fetuses. Iran J Basic Med Sci 15:853–859PubMedPubMedCentralGoogle Scholar
  138. Schmidt A, Scherer M, Thiermann H, Steinritz D (2013) Mesenchymal stem cells are highly resistant to sulfur mustard. Chem Biol Interact 206:505–511PubMedCrossRefGoogle Scholar
  139. Shakarjian MP, Heck DE, Gray JP, Sinko PJ, Gordon MK, Casillas RP, Heindel ND, Gerecke DR, Laskin DL, Laskin JD (2010) Mechanisms mediating the vesicant actions of sulfur mustard after cutaneous exposure. Toxicol Sci 114:5–19PubMedCrossRefGoogle Scholar
  140. Shakil FA, Kuramoto A, Yamakido M, Nishimoto Y, Kamada N (1993) Cytogenetic abnormalities of hematopoietic tissue in retired workers of the Ohkunojima poison gas factory. Hiroshima J Med Sci 42:159–165PubMedGoogle Scholar
  141. Shohrati M, Ghanei M, Harandi AA, Foroghi S, Harandi AA (2012) Effect of nebulized morphine on dyspnea of mustard gas-exposed patients: a double-blind randomized clinical trial study. Pulm Med 2012:610921PubMedPubMedCentralCrossRefGoogle Scholar
  142. Sidell FR, Takafuji ET, Franz DR (1997) Medical aspects of chemical and biological warfare. Borden Institute, Washington, DC. DTIC DocumentGoogle Scholar
  143. Simbulan-Rosenthal CM, Ray R, Benton B, Soeda E, Daher A, Anderson D, Smith WJ, Rosenthal DS (2006) Calmodulin mediates sulfur mustard toxicity in human keratinocytes. Toxicology 227:21–35PubMedCrossRefGoogle Scholar
  144. Smith KJ, Graham JS, Moeller RB, Okerberg CV, Skelton H, Hurst CG (1995) Histopathologic features seen in sulfur mustard induced cutaneous lesions in hairless guinea pigs. J Cutan Pathol 22:260–268PubMedCrossRefGoogle Scholar
  145. Somani SM, Babu SR (1989) Toxicodynamics of sulfur mustard. Int J Clin Pharmacol Ther Toxicol 27:419–435PubMedGoogle Scholar
  146. Sorensen OE, Cowland JB, Theilgaard-Monch K, Liu L, Ganz T, BORREGAARD N (2003) Wound healing and expression of antimicrobial peptides/polypeptides in human keratinocytes, a consequence of common growth factors. J Immunol 170:5583–5589PubMedCrossRefGoogle Scholar
  147. Soroush MR, Ghanei M, Assari S, Khoddami Vishteh HR (2009) Urogenital history in veterans exposed to high-dose sulfur mustard: a preliminary study of self-reported data. Urol J 6:114–119; discussion 119PubMedGoogle Scholar
  148. Stolzenbach G, Garbrecht M (1979) Cyclic induction chemotherapy with cyclophosphamide, vincristine, prednisone, and bleomycin of high-grade malignant non-Hodgkin's lymphomas according to the Kiel classification. J Cancer Res Clin Oncol 93:93–98CrossRefGoogle Scholar
  149. Storme T, Deroussent A, Mercier L, Prost E, Re M, Munier F, Martens T, Bourget P, Vassal G, Royer J, Paci A (2009) New ifosfamide analogs designed for lower associated neurotoxicity and nephrotoxicity with modified alkylating kinetics leading to enhanced in vitro anticancer activity. J Pharmacol Exp Ther 328:598–609PubMedCrossRefGoogle Scholar
  150. Sugendran K, Jeevaratnam K, Vijayaraghavan R, Gupta SD (2013) Therapeutic efficacy of saline and glucose saline against dermally applied sulphur mustard intoxication in mice. Def Sci J 44:21–23CrossRefGoogle Scholar
  151. Tewari-Singh N, Jain AK, Orlicky DJ, White CW, Agarwal R (2014) Cutaneous injury-related structural changes and their progression following topical Nitrogen mustard exposure in hairless and haired mice. PLoS One 9:e85402PubMedPubMedCentralCrossRefGoogle Scholar
  152. Veress LA, Anderson DR, Hendry-Hofer TB, Houin PR, Rioux JS, Garlick RB, Loader JE, Paradiso DC, Smith RW, Rancourt RC, Holmes WW, White CW (2015) Airway tissue plasminogen activator prevents acute mortality due to lethal sulfur mustard inhalation. Toxicol Sci 143:178–184PubMedCrossRefGoogle Scholar
  153. Vijayaraghavan R, Kulkarni A, Pant S, Kumar P, Lakshmana R, Gupta P, Gautam A, Ganesan K (2005) Differential toxicity of sulfur mustard administered through percutaneous, subcutaneous, and oral routes. Toxicol Appl Pharmacol 202:180–188PubMedCrossRefGoogle Scholar
  154. Vojvodic V, Milosavljevic Z, Boskovic B, Bojanic N (1985) The protective effect of different drugs in rats poisoned by sulfur and nitrogen mustards. Fundam Appl Toxicol 5:S160–S168PubMedCrossRefGoogle Scholar
  155. Watson AP, Jones TD, Griffin GD (1989) Sulfur mustard as a carcinogen: application of relative potency analysis to the chemical warfare agents H, HD, and HT. Regul Toxicol Pharm 10:1–25CrossRefGoogle Scholar
  156. Weber WM, Kracko DA, Lehman MR, Irvin CM, Blair LF, White RK, Benson JM, Grotendorst GR, Cheng YS, Mcdonald JD (2010) Inhalation exposure systems for the development of rodent models of sulfur mustard-induced pulmonary injury. Toxicol Mech Methods 20:14–24PubMedPubMedCentralCrossRefGoogle Scholar
  157. Weinberger B, Laskin JD, Sunil VR, Sinko PJ, Heck DE, Laskin DL (2011) Sulfur mustard-induced pulmonary injury: therapeutic approaches to mitigating toxicity. Pulm Pharmacol Ther 24:92–99PubMedCrossRefGoogle Scholar
  158. Wheeler GP (1962) Studies related to the mechanisms of action of cytotoxic alkylating agents: a review. Cancer Res 22:651–688PubMedGoogle Scholar
  159. Wheeler GP, Alexander JA (1969) Effects of nitrogen mustard and cyclophosphamide upon the synthesis of DNA in vivo and in cell-free preparations. Cancer Res 29:98–109PubMedGoogle Scholar
  160. Willems J (1989) Clinical management of mustard gas casualties. Ann Med Mil Belg 3:1–61Google Scholar
  161. Wormser U (1991) Toxicology of mustard gas. Trends Pharmacol Sci 12:164–167PubMedCrossRefGoogle Scholar
  162. Wormser U, Brodsky B, Green BS, Arad-Yellin R, Nyska A (1997) Protective effect of povidone-iodine ointment against skin lesions induced by sulphur and nitrogen mustards and by non-mustard vesicants. Arch Toxicol 71:165–170PubMedCrossRefGoogle Scholar
  163. Xu J, Baldwin D, Kindrachuk C, Hegedus D (2006) Serine proteases and metalloproteases associated with pathogenesis but not host specificity in the Entomophthoralean fungus Zoophthora radicans. Can J Microbiol 52:550–559PubMedCrossRefGoogle Scholar
  164. Xu H, Nie Z, Zhang Y, Li C, Yue L, Yang W, Chen J, Dong Y, Liu Q, Lin Y, Wu B, Feng J, Li H, Guo L, Xie J (2014) Four sulfur mustard exposure cases: overall analysis of four types of biomarkers in clinical samples provides positive implication for early diagnosis and treatment monitoring. Toxicol Rep 1:533–543CrossRefGoogle Scholar
  165. Yanagida J, Hozawa S, Ishioka S, Maeda H, Takahashi K, Oyama T, Takaishi M, Hakoda M, Akiyama M, Yamakido M (1988) Somatic mutation in peripheral lymphocytes of former workers at the Okunojima poison gas factory. Jpn J Cancer Res 79:1276–1283PubMedCrossRefGoogle Scholar
  166. Yokoyama WM (1993) Recognition structures on natural killer cells. Curr Opin Immunol 5:67–73PubMedCrossRefGoogle Scholar
  167. Yule SM, Price L, Mcmahon AD, Pearson AD, Boddy AV (2004) Cyclophosphamide metabolism in children with non-Hodgkin’s lymphoma. Clin Cancer Res 10:455–460PubMedCrossRefGoogle Scholar
  168. Zandieh T, Marzban S, Tarabadi F, Ansari H (1990) Defects of cell-mediated-immunity in mustard gas injury after years. Scand J Immunol. Blackwell Science Ltd, Oxford, pp 423–423Google Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Medical Toxicology Research Center, Faculty of MedicineMashhad University of Medical SciencesMashhadIran

Personalised recommendations