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Basic & Clinical Pharmacology &... Feb 2017Among the most readily existing chemical warfare agents, sulphur mustard (SM), also known as mustard gas, is the most commonly used agent owing to its ease of synthesis... (Review)
Review
Investigating Prevalence and Pattern of Long-term Cardiovascular Disorders in Sulphur Mustard-exposed Victims and Determining Proper Biomarkers for Early Defining, Monitoring and Analysis of Patients' Feedback on Therapy.
Among the most readily existing chemical warfare agents, sulphur mustard (SM), also known as mustard gas, is the most commonly used agent owing to its ease of synthesis and stockpiling. Unprotected exposure mostly results in debilitation rather than lethal injuries, leaving an exposed victim incapacitated for days to even months. Although acute toxicity of sulphur mustard has been fairly established, the long-term post-exposure effects either chronic or short-term but significant are still evolving. A total of 30,000 Iranian victims of the Iran-Iraq imposed war have now - after 30 years - formed the key population demonstrating long-term effects from sulphur mustard exposure. Recent studies have shown that the prevalence of several long-term cardiovascular disorders (CVDs) has significantly increased among SM-exposed victims including coronary artery disorders (CAD), coronary artery ectasia (CAE), congestive heart failure (CHF) and myocardium abnormalities. The more important point is the lack of a determinant biomarker for early screening, recognizing, treating, monitoring and estimating exposed victims' response to applied therapy. Additionally, unidentified risk factors significantly decrease the chance of a successful therapy and result in undesired failure of a comprehensive therapeutic strategy. In this MiniReview, we examined the literature in detail to evaluate relevant reports considering long-term cardiovascular complications of SM, detecting possible risk factors and determining possible preventing events.
Topics: Anti-Infective Agents; Antidotes; Biomarkers; Cardiovascular Diseases; Chemical Warfare Agents; Cytokines; Early Diagnosis; Humans; Inflammation Mediators; Mustard Gas; Oxidative Stress; Predictive Value of Tests; Prevalence; Prognosis; Time Factors
PubMed: 27607565
DOI: 10.1111/bcpt.12666 -
Journal of Ophthalmic & Vision Research 2015To evaluate the effectiveness of topical cyclosporine A 0.05% for treatment of mustard gas-induced ocular surface disorders with special attention to conjunctival goblet...
PURPOSE
To evaluate the effectiveness of topical cyclosporine A 0.05% for treatment of mustard gas-induced ocular surface disorders with special attention to conjunctival goblet cell density in patients with severe dry eye.
METHODS
This prospective clinical study included 20 eyes of 20 patients previously exposed to mustard gas with dry eye syndrome unresponsive to artificial tears. Before and after treatment with topical cyclosporine A 0.05% twice daily for 3 months, subjects were evaluated for improvement in symptoms using the ocular surface disease index (OSDI) and signs by tear breakup time (TBUT), Schirmer test and measurement of superior bulbar conjunctival goblet cell density. Limbal stem cell deficiency (LSCD) and the degree of corneal squamous cell metaplasia were also assessed before and after treatment.
RESULTS
Before treatment, mean OSDI score, Schirmer test I value and mean TBUT were 42.8 ± 6.1, 4.2 ± 1.2 mm and 2.5 ± 1.3 s, respectively. After 3 months of treatment with topical cyclosporine A, these scores reached 36.4 ± 5.2, 5.8 ± 1.6 mm and 4.9 ± 2.1 s, respectively showing a statistically significant improvement (P < 0.001) in all parameters. Mean goblet cell density was 23.3 ± 17.1/high power field (hpf) at baseline which was significantly increased to 47.7 ± 16.1/hpf at the end of the study (P < 0.001). There was no improvement, however, in corneal conjunctivalization, LSCD and the degree of corneal squamous cell metaplasia based on impression cytology reports (P > 0.05).
CONCLUSION
Treatment with topical cyclosporine A 0.05% in patients with severe dry eye due to mustard gas injury increases goblet cell density in the bulbar conjunctiva and improves symptoms of the disease.
PubMed: 26005548
DOI: 10.4103/2008-322X.156089 -
Inhalation Toxicology Jun 2011Sulfur mustard (SM), a potent chemical weapon agent, was used by Iraqi forces against Iranian in the Iraq-Iran war (1981-1989). Chronic obstructive pulmonary disease... (Review)
Review
Sulfur mustard (SM), a potent chemical weapon agent, was used by Iraqi forces against Iranian in the Iraq-Iran war (1981-1989). Chronic obstructive pulmonary disease (COPD) is a late toxic pulmonary consequence after SM exposure. The COPD observed in these patients is unique (described as Mustard Lung) and to some extent different from COPD resulted from other well-known causes. Several mechanisms have been hypothesized to contribute to the pathogenesis of COPD including oxidative stress, disruption of the balance between apoptosis and replenishment, proteinase-antiproteinase imbalance and inflammation. However, it is not obvious which of these pathways are relevant to the pathogenesis of mustard lung. In this paper, we reviewed studies addressing the pathogenicity of mustard lung, and reduced some recent ambiguities in this field. There is ample evidence in favor of crucial role of both oxidative stress and apoptosis as two known mechanisms that are more involved in pathogenesis of mustard lung comparing to COPD. However, according to available evidences there are no such considerable data supporting neither proteolytic activity nor inflammation mechanism as the main underlying pathogenesis in Mustard Lung.
Topics: Animals; Apoptosis; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Humans; Inflammation; Inhalation Exposure; Lung Injury; Mustard Gas; Oxidative Stress; Peptide Hydrolases; Pulmonary Disease, Chronic Obstructive
PubMed: 21639706
DOI: 10.3109/08958378.2011.576278 -
Singapore Medical Journal May 2007Chronic skin lesions are common late complications of sulphur mustard exposure in veterans injured in chemical warfare. Pruritus is the most common complaint in the... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Chronic skin lesions are common late complications of sulphur mustard exposure in veterans injured in chemical warfare. Pruritus is the most common complaint in the chronic phase, with significant effects on the patient's quality of life. The current study evaluated the efficacy of a combination of one percent phenol and one percent menthol in the control of pruritus in these affected patients.
METHODS
This randomised, double-blinded clinical trial was performed in chemical warfare-injured veterans with mustard gas-induced pruritus. 80 subjects were selected randomly and divided into two equal groups. One group was treated with a combination of one percent phenol and one percent menthol twice a day, while the other group received a placebo. The therapeutic effects and side effects were evaluated during a six-week treatment course. Pruritus score with a range of 1-48 points was used to calculate the severity of pruritus before and after treatment in both groups.
RESULTS
The final pruritus score in the drug group was significantly different, compared with the placebo group (p-value equals 0.03). There was also a statistically-significant difference between the pre-treatment (19 points) and post-treatment (15.5 points) pruritus scores in the drug group (p-value equals 0.001), but there was no significant difference in the response in the placebo group (p-value equals 0.66). Only a few patients had complaints about the drug, and these were generally minor. The most common complaints were of the greasy nature of the drug and its intolerable odour.
CONCLUSION
A phenol one percent and menthol one percent combination has significant therapeutic effects for mustard gas-induced pruritus in chemical warfare-injured veterans, in comparison with the placebo.
Topics: Administration, Topical; Antipruritics; Chemical Warfare Agents; Double-Blind Method; Drug Combinations; Humans; Male; Menthol; Mustard Gas; Phenol; Pruritus; Skin Diseases
PubMed: 17453095
DOI: No ID Found -
Saudi Journal of Gastroenterology :... 2013Gastro-esophageal reflux has been suggested to be associated with several pulmonary complications such as asthma, and post-transplant bronchiolitis obliterans (BO)....
BACKGROUND/AIM
Gastro-esophageal reflux has been suggested to be associated with several pulmonary complications such as asthma, and post-transplant bronchiolitis obliterans (BO). Pepsin or bile salts in the sputum is shown to be an optimal molecular marker of gastric contents macro/micro aspiration. In this study, we investigated sputum pepsin as a marker of micro-aspiration in sulfur mustard (SM) exposed cases compared to healthy controls.
MATERIALS AND METHODS
In a case controlled study, 26 cases with BO and 12 matched healthy controls were recruited and all cases were symptomatic and their exposure to SM was previously documented during Iran-Iraq conflict. Pepsin levels in sputum and total bile acids were measured using enzymatic assay. The severity of respiratory disorder was categorized based upon the spirometric values.
RESULT
The average concentration of pepsin in sputum was higher in the case group (0.29 ± 0.23) compared with healthy subjects (0.13 ± 0.07; P ± 0.003). Moreover, the average concentration of bile acids in the sputum cases was not significantly different in comparison to the controls ( P = 0.5).
CONCLUSION
Higher pepsin concentrations in sputum of SM exposed patients compared with healthy control subjects indicate the occurrence of significantly more gastric micro-aspiration in SM exposed patients.
Topics: Adult; Bile Acids and Salts; Biomarkers; Bronchiolitis Obliterans; Case-Control Studies; Chemical Warfare; Chemical Warfare Agents; Gastroesophageal Reflux; Humans; Iran; Male; Middle Aged; Mustard Gas; Pepsin A; Sputum
PubMed: 23680709
DOI: 10.4103/1319-3767.111954 -
Toxicological Sciences : An Official... Mar 2010Sulfur mustard (SM), a chemical weapon first employed during World War I, targets the skin, eyes, and lung. It remains a significant military and civilian threat. The... (Review)
Review
Sulfur mustard (SM), a chemical weapon first employed during World War I, targets the skin, eyes, and lung. It remains a significant military and civilian threat. The characteristic response of human skin to SM involves erythema of delayed onset, followed by edema with inflammatory cell infiltration, the appearance of large blisters in the affected area, and a prolonged healing period. Several in vivo and in vitro models have been established to understand the pathology and investigate the mechanism of action of this vesicating agent in the skin. SM is a bifunctional alkylating agent which reacts with many targets including lipids, proteins, and DNA, forming both intra- and intermolecular cross-links. Despite the relatively nonselective chemical reactivity of this agent, basal keratinocytes are more sensitive, and blistering involves detachment of these cells from their basement membrane adherence zones. The sequence and manner in which these cells die and detach is still unresolved. Much has been discovered over the past two decades with respect to the mechanisms of SM-induced cytotoxicity and the intracellular and extracellular targets of this vesicant. In this review, the effects of SM exposure on the skin are described, as well as potential mechanisms mediating its actions. Successful therapy for SM poisoning will depend on following new mechanistic leads to develop drugs that target one or more of its sites of action.
Topics: Administration, Cutaneous; Animals; Chemical Warfare Agents; Inflammation; Inflammation Mediators; Irritants; Models, Animal; Mustard Gas; Protein Array Analysis; Skin; Skin Irritancy Tests
PubMed: 19833738
DOI: 10.1093/toxsci/kfp253 -
PloS One 2021Sulfur mustard (SM) is a cytotoxic, vesicating, chemical warfare agent, first used in 1917; corneas are particularly vulnerable to SM exposure. They may develop...
Sulfur mustard (SM) is a cytotoxic, vesicating, chemical warfare agent, first used in 1917; corneas are particularly vulnerable to SM exposure. They may develop inflammation, ulceration, neovascularization (NV), impaired vision, and partial/complete blindness depending upon the concentration of SM, exposure duration, and bio-physiological conditions of the eyes. Comprehensive in vivo studies have established ocular structural alterations, opacity, NV, and inflammation upon short durations (<4 min) of SM exposure. In this study, detailed analyses of histopathological alterations in corneal structure, keratocytes, inflammatory cells, blood vessels, and expressions of cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-9, vascular endothelial growth factor (VEGF), and cytokines were performed in New Zealand white rabbits, in a time-dependent manner till 28 days, post longer durations (5 and 7 min) of ocular SM exposure to establish quantifiable endpoints of injury and healing. Results indicated that SM exposure led to duration-dependent increases in corneal thickness, opacity, ulceration, epithelial-stromal separation, and epithelial degradation. Significant increases in NV, keratocyte death, blood vessels, and inflammatory markers (COX-2, MMP-9, VEGF, and interleukin-8) were also observed for both exposure durations compared to the controls. Collectively, these findings would benefit in temporal delineation of mechanisms underlying SM-induced corneal toxicity and provide models for testing therapeutic interventions.
Topics: Animals; Biomarkers; Blood Vessels; Cell Survival; Chemical Warfare Agents; Cornea; Corneal Injuries; Corneal Keratocytes; Cyclooxygenase 2; Interleukin-8; Matrix Metalloproteinase 9; Mustard Gas; Rabbits
PubMed: 34637469
DOI: 10.1371/journal.pone.0258503 -
BMC Cell Biology Jun 2008Sulphur mustard gas, 2, 2'-dichlorodiethyl sulphide (HD), is a chemical warfare agent. Both mustard gas and its monofunctional analogue, 2-chloroethyl ethyl sulphide...
BACKGROUND
Sulphur mustard gas, 2, 2'-dichlorodiethyl sulphide (HD), is a chemical warfare agent. Both mustard gas and its monofunctional analogue, 2-chloroethyl ethyl sulphide (CEES), are alkylating agents that react with and diminish cellular thiols and are highly toxic. Previously, we reported that lipopolysaccharide (LPS) significantly enhances the cytotoxicity of CEES in murine RAW 264.7 macrophages and that CEES transiently inhibits nitric oxide (NO) production via suppression of inducible NO synthase (iNOS) protein expression. NO generation is an important factor in wound healing. In this paper, we explored the hypotheses that LPS increases CEES toxicity by increasing oxidative stress and that treatment with N-acetyl-L-cysteine (NAC) would block LPS induced oxidative stress and protect against loss of NO production. NAC stimulates glutathione (GSH) synthesis and also acts directly as a free radical scavenger. The potential therapeutic use of the antibiotic, polymyxin B, was also evaluated since it binds to LPS and could thereby block the enhancement of CEES toxicity by LPS and also inhibit the secondary infections characteristic of HD/CEES wounds.
RESULTS
We found that 10 mM NAC, when administered simultaneously or prior to treatment with 500 muM CEES, increased the viability of LPS stimulated macrophages. Surprisingly, NAC failed to protect LPS stimulated macrophages from CEES induced loss of NO production. Macrophages treated with both LPS and CEES show increased oxidative stress parameters (cellular thiol depletion and increased protein carbonyl levels). NAC effectively protected RAW 264.7 cells simultaneously treated with CEES and LPS from GSH loss and oxidative stress. Polymyxin B was found to partially block nitric oxide production and diminish CEES toxicity in LPS-treated macrophages.
CONCLUSION
The present study shows that oxidative stress is an important mechanism contributing to CEES toxicity in LPS stimulated macrophages and supports the notion that antioxidants could play a therapeutic role in preventing mustard gas toxicity. Although NAC reduced oxidative stress in LPS stimulated macrophages treated with CEES, it did not reverse CEES-induced loss of NO production. NAC and polymyxin B were found to help prevent CEES toxicity in LPS-treated macrophages.
Topics: Acetylcysteine; Animals; Cell Survival; Free Radical Scavengers; Glutathione; Lipopolysaccharides; Macrophages; Mice; Microscopy, Fluorescence; Mustard Gas; Nitric Oxide; Oxidative Stress; Polymyxin B
PubMed: 18570648
DOI: 10.1186/1471-2121-9-33 -
Inhalation Toxicology 2022Over 40% of veterans from the Persian Gulf War (GW) (1990-1991) suffer from Gulf War Illness (GWI). Thirty years since the GW, the exposure and mechanism contributing to... (Review)
Review
Over 40% of veterans from the Persian Gulf War (GW) (1990-1991) suffer from Gulf War Illness (GWI). Thirty years since the GW, the exposure and mechanism contributing to GWI remain unclear. One possible exposure that has been attributed to GWI are chemical warfare agents (CWAs). While there are treatments for isolated symptoms of GWI, the number of respiratory and cognitive/neurological issues continues to rise with minimum treatment options. This issue does not only affect veterans of the GW, importantly these chronic multisymptom illnesses (CMIs) are also growing amongst veterans who have served in the Afghanistan-Iraq war. What both wars have in common are their regions and inhaled exposures. In this review, we will describe the CWA exposures, such as sarin, cyclosarin, and mustard gas in both wars and discuss the various respiratory and neurocognitive issues experienced by veterans. We will bridge the respiratory and neurological symptoms experienced to the various potential mechanisms described for each CWA provided with the most up-to-date models and hypotheses.
Topics: Humans; Chemical Warfare Agents; Persian Gulf Syndrome; Gulf War; Veterans; Sarin
PubMed: 36394251
DOI: 10.1080/08958378.2022.2147257 -
Toxicology and Applied Pharmacology Dec 2010Sulfur mustard is a potent vesicant that induces inflammation, edema and blistering following dermal exposure. To assess molecular mechanisms mediating these responses,...
Expression of proliferative and inflammatory markers in a full-thickness human skin equivalent following exposure to the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide.
Sulfur mustard is a potent vesicant that induces inflammation, edema and blistering following dermal exposure. To assess molecular mechanisms mediating these responses, we analyzed the effects of the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide, on EpiDerm-FT™, a commercially available full-thickness human skin equivalent. CEES (100-1000 μM) caused a concentration-dependent increase in pyknotic nuclei and vacuolization in basal keratinocytes; at high concentrations (300-1000 μM), CEES also disrupted keratin filament architecture in the stratum corneum. This was associated with time-dependent increases in expression of proliferating cell nuclear antigen, a marker of cell proliferation, and poly(ADP-ribose) polymerase (PARP) and phosphorylated histone H2AX, markers of DNA damage. Concentration- and time-dependent increases in mRNA and protein expression of eicosanoid biosynthetic enzymes including COX-2, 5-lipoxygenase, microsomal PGE₂ synthases, leukotriene (LT) A₄ hydrolase and LTC₄ synthase were observed in CEES-treated skin equivalents, as well as in antioxidant enzymes, glutathione S-transferases A1-2 (GSTA1-2), GSTA3 and GSTA4. These data demonstrate that CEES induces rapid cellular damage, cytotoxicity and inflammation in full-thickness skin equivalents. These effects are similar to human responses to vesicants in vivo and suggest that the full thickness skin equivalent is a useful in vitro model to characterize the biological effects of mustards and to develop potential therapeutics.
Topics: Biomarkers; Blotting, Western; Cell Proliferation; Dose-Response Relationship, Drug; Eicosanoids; Histones; Humans; Irritants; Keratinocytes; Mustard Gas; Poly Adenosine Diphosphate Ribose; Proliferating Cell Nuclear Antigen; RNA, Messenger; Reverse Transcriptase Polymerase Chain Reaction; Skin; Time Factors
PubMed: 20840853
DOI: 10.1016/j.taap.2010.09.005