Nutraceuticals as potential therapeutics for vesicant-induced pulmonary fibrosis.

Exposure to vesicants, including sulfur mustard and nitrogen mustard, causes damage to the epithelia of the respiratory tract and the lung. With time, this progresses to chronic disease, most notably, pulmonary fibrosis. The pathogenic process involves persistent inflammation and the release of cytotoxic oxidants, cytokines, chemokines, and profibrotic growth factors, which leads to the collapse of lung architecture, with fibrotic involution of the lung parenchyma. At present, there are no effective treatments available to combat this pathological process. Recently, much interest has focused on nutraceuticals, substances derived from plants, herbs, and fruits, that exert pleiotropic effects on inflammatory cells and parenchymal cells that may be useful in reducing fibrogenesis. Some promising results have been obtained with nutraceuticals in experimental animal models of inflammation-driven fibrosis. This review summarizes the current knowledge on the putative preventive/therapeutic efficacy of nutraceuticals in progressive pulmonary fibrosis, with a focus on their activity against inflammatory reactions and profibrotic cell differentiation.

Effect of Zataria multiflora on serum cytokine levels and pulmonary function tests in sulfur mustard-induced lung disorders: A randomized double-blind clinical trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Zataria multiflora (Z. multiflora) belongs to the Lamiaceae family and has several traditional uses owing to its antiseptic, aesthetic, antispasmodic, analgesic, and antidiarrheal properties. AIM OF THE STUDY: We aimed to investigate the effect of Z. multiflora on serum cytokine levels and pulmonary function tests (PFT) in patients exposed to sulfur mustard (SM) for a long term (27-30 years). MATERIALS AND METHODS: Thirty-five patients were randomly assigned to the placebo group (P) and two experimental groups treated with Z. multiflora extracts, i.e., 5 and 10 mg/kg/day (Z5 and Z10). Serum levels of cytokines including IL (2, 4, 6, 8, and 10) and IFN-γ as well as PFT indices such as maximum mid-expiratory flow (MMEF) and maximum expiratory flow at 25, 50, and 75% of vital capacity (VC) (MEF25, 50, and 75) were assessed at the beginning (phase 0) and at the end of 4 and 8 weeks (phases I and II, respectively) after starting the treatment. RESULTS: Serum levels of IL-2, IL-6, and IL-8 were significantly decreased, while serum levels of IL-10 and IFN-γ were significantly increased in the Z5 and Z10 treatment groups in phases I and II as compared to those in phase 0 (p < 0.05 to p < 0.001). MMEF and MEF25, 50, and 75 values were significantly increased in the Z5 group in phase II and in the Z10 group in phases I and II compared to those in phase 0 (p < 0.05 to p < 0.001). The percent change in serum cytokine levels and the change in MEF25, 50, and 75 during the two-month treatment period were significantly higher in the treatment groups than in the placebo group. CONCLUSIONS: Two months of treatment with Z. multiflora reduced inflammation, while it enhanced anti-inflammatory cytokines and improved PFT indices in SM-exposed patients.

Advanced biotherapy for the treatment of sulfur mustard poisoning.

CONTEXT: Sulfur mustard (SM), a bifunctional alkylating agent, can react with a variety of biochemical molecules (DNA, RNA, proteins and other cell components) to cause a series of serious health issues or even death. Although a plethora of research has been done, the pathogenesis of SM poisoning has yet to be fully understood due to its high complexity. As a consequence, a specific antidote has not yet been developed and the treatment of SM poisoning remains a medical challenge. In recent years, various biological products and cell transplantation in the treatment of SM poisoning offered a significant clinical treatment progress. By highlighting these and other research studies, we hereby summarize the progress in this field in an effort to provide useful information on the clinical treatment of SM poisoning. OBJECTIVE: This review summarizes the major advances of SM poisoning therapy by means of biological products (peptide and protein drugs, polysaccharides drugs, nucleic acid drugs, etc.), and cell transplantation (e.g., bone marrow, limbal stem cells, mesenchymal stem cells), as well as other relevant biotherapeutic approaches. METHOD: We searched the database PubMed for published domestic and international articles using web based resources for information on histological, immunochemical, ultrastructural, and treatment features of SM-induced manifestations in both animal models and human tissues. To this end, we applied keywords containing mustard gas, chemical warfare, SM, eye, lung and skin. RESULTS AND CONCLUSION: Our review provides a comprehensive understanding of the advances of available biotherapies in SM poisoning, and its potential for the treatment of SM-induced injuries. Potentially, our review will provide new insights for future research studies in this field.

Mindfulness-based Stress Reduction (MBSR) and Its Effects on Psychoimmunological Factors of Chemically Pulmonary Injured Veterans.

Mindfulness-based Stress Reduction (MBSR) is a treatment program for relieving stress and coping with chronic illnesses. In recent three decades, studies have shown that MBSR has a positive effect on physical and psychological dimensions of chronic illnesses. Chemically pulmonary injured veterans have chronic pulmonary and psychological problems due to mustard gas exposure and complications of Iran-Iraq war. These stresses have negative effects on their general health and immune system. To the best of our knowledge, this is the first study conducted on psychoneuroimmunology and MBSR in these patients. Forty male pulmonary injured veterans were randomly divided in two groups with 20 participants (MBSR and wait-list control). Then MBSR group received 8 weekly sessions of intervention. We tested mental health based on general health questionnaire (GHQ)-28 questionnaire, health-related quality of life (based on St. George respiratory questionnaire (SGRQ) ) and immunity in MBSR groups; before and after intervention "mixed factorial analyses of variance" test was used for analyzing data fpr each dependent variable and appropriate t-tests were done in The necessary condition. Results showed that mental health and health- related quality of life, in MBSR group compared to wait-list control improved [F (1,38)=26.46, p<0.001; F (1,38)=49.52, p<0.001 respectively] significantly.  Moreover, a significant increase was reported in the lymphocyte proliferation with phytohemagglutinin (PHA) [F (1,38)=16.24, p<0.001], and peripheral blood IL-17 [F (1,38)=56.71, p<0.001] However, lymphocyte (CD4+, CD8+, and NK-cell) percentages were not affected significantly [F (1,38)=2.21, p=0.14] ,[F (1,38)=0.90, p=0.78] and [F (1,38)=1.79, p=0.18], respectively. This study suggests that MBSR may be a new treatment approach for improving immunity and overall health in chemically pulmonary injured veterans.

Effectiveness of donepezil, rivastigmine, and (+/-)huperzine A in counteracting the acute toxicity of organophosphorus nerve agents: comparison with galantamine.

Galantamine, a centrally acting cholinesterase (ChE) inhibitor and a nicotinic allosteric potentiating ligand used to treat Alzheimer's disease, is an effective and safe antidote against poisoning with nerve agents, including soman. Here, the effectiveness of galantamine was compared with that of the centrally active ChE inhibitors donepezil, rivastigmine, and (+/-)huperzine A as a pre- and/or post-treatment to counteract the acute toxicity of soman. In the first set of experiments, male prepubertal guinea pigs were treated intramuscularly with one of the test drugs and 30 min later challenged with 1.5 x LD(50) soman (42 microg/kg s.c.). All animals that were pretreated with galantamine (6-8 mg/kg), 3 mg/kg donepezil, 6 mg/kg rivastigmine, or 0.3 mg/kg (+/-)huperzine A survived the soman challenge, provided that they were also post-treated with atropine (10 mg/kg i.m.). However, only galantamine was well tolerated. In subsequent experiments, the effectiveness of specific treatment regimens using 8 mg/kg galantamine, 3 mg/kg donepezil, 6 mg/kg rivastigmine, or 0.3 mg/kg (+/-)huperzine A was compared in guinea pigs challenged with soman. In the absence of atropine, only galantamine worked as an effective and safe pretreatment in animals challenged with 1.0 x LD(50) soman. Galantamine was also the only drug to afford significant protection when given to guinea pigs after 1.0 x LD(50) soman. Finally, all test drugs except galantamine reduced the survival of the animals when administered 1 or 3 h after the challenge with 0.6 or 0.7 x LD(50) soman. Thus, galantamine emerges as a superior antidotal therapy against the toxicity of soman.

Extrapolating from animal studies to the efficacy in humans of a pretreatment combination against organophosphate poisoning.

The extrapolation from animal data to therapeutic effects in humans, a basic pharmacological issue, is especially critical in studies aimed to estimate the protective efficacy of drugs against nerve agent poisoning. Such efficacy can only be predicted by extrapolation of data from animal studies to humans. In pretreatment therapy against nerve agents, careful dose determination is even more crucial than in antidotal therapy, since excessive doses may lead to adverse effects or performance decrements. The common method of comparing dose per body weight, still used in some studies, may lead to erroneous extrapolation. A different approach is based on the comparison of plasma concentrations at steady state required to obtain a given pharmacodynamic endpoint. In the present study, this approach was applied to predict the prophylactic efficacy of the anticholinergic drug caramiphen in combination with pyridostigmine in man based on animal data. In two species of large animals, dogs and monkeys, similar plasma concentrations of caramiphen (in the range of 60-100 ng/ml) conferred adequate protection against exposure to a lethal-dose of sarin (1.6-1.8 LD(50)). Pharmacokinetic studies at steady state were required to achieve the correlation between caramiphen plasma concentrations and therapeutic effects. Evaluation of total plasma clearance values was instrumental in establishing desirable plasma concentrations and minimizing the number of animals used in the study. Previous data in the literature for plasma levels of caramiphen that do not lead to overt side effects in humans (70-100 ng/ml) enabled extrapolation to expected human protection. The method can be applied to other drugs and other clinical situations, in which human studies are impossible due to ethical considerations. When similar dose response curves are obtained in at least two animal models, the extrapolation to expected therapeutic effects in humans might be considered more reliable.

Evaluation of reactivation test in anaesthetized dogs with experimental intoxication with nerve agents.

Following repeated antidotal treatment of anaesthetized dogs (1 min with atropine, 10 min with atropine and obidoxime, 60 min with atropine and obidoxime) after the intoxication with soman, sarin and VX (1 x LD50, i.m.), the blood cholinesterases (erythrocyte, whole blood, plasma) were monitored and their reactivatability (whole blood) was determined. During this treatment, the activities of erythrocyte acetylcholinesterase (AChE), plasma butyrylcholinesterase (BuChE) and whole blood cholinesterases were monitored. Atropine and obidoxime did not affect cholinesterase activities in control animals, whereas administration of obidoxime to dogs intoxicated with nerve agent caused an increase in the cholinesterase activities. The sensitivity of cholinesterases decreased in the order erythrocyte AChE > whole blood cholinesterases > plasma BuChE, respectively. Following sarin intoxication, blood cholinesterases were increased after the obidoxime administration. Intoxication with VX showed a similar picture but reactivation after the obidoxime administration was greater. In soman intoxication, the picture of cholinesterase changes was similar during the first 30 min of treatment. Then the increase in AChE activity following obidoxime administration was not as high as in the case of sarin and VX intoxication. Thus, the reactivation efficacy of obidoxime during nerve agent intoxication indicates that its repeated administration could be easily monitored using the reactivation test.

Review of the value of huperzine as pretreatment of organophosphate poisoning.

Today, organophosphate (OP) nerve agents are still considered as potential threats in both military or terrorism situations. OP agents are potent irreversible inhibitors of central and peripheral acetylcholinesterases. Pretreatment of OP poisoning relies on the subchronic administration of the reversible acetylcholinesterase (AChE) inhibitor pyridostigmine (PYR). Since PYR does not penetrate into the brain, it does not afford protection against seizures and subsequent neuropathology induced by an OP agent such as soman. Comparatively, huperzine (HUP) is a reversible AChE inhibitor that crosses the blood-brain barrier. HUP is presently approved for human use or is in course of clinical trials for the treatment of Alzheimer's disease or myasthenia gravis. HUP is also used as supplementary drug in the USA for correction of memory impairment. Besides, HUP has also been successfully tested for pretreatment of OP poisoning. This review summarizes the therapeutical value of HUP in this field. Moreover, the modes of action of HUP underlying its efficacy against OP agents are described. Efficacy appears mainly related to both the selectivity of HUP for red cell AChE which preserves scavenger capacity of plasma butyrylcholinesterases for OP agents and to the protection conferred by HUP on cerebral AChE. Finally, recent data, showing that HUP seems to be devoid of deleterious effects in healthy subjects, are also presented. Globally, this review reinforces the therapeutical value of HUP for the optimal pretreatment of OP poisoning.

Protective efficacy of calcium channel blockers in sulphur mustard poisoning.

The present study was designed to ascertain the in vivo protective efficacy of Ca(2+)-channel blockers against dermally applied sulphur mustard (SM). Male albino mice were exposed to 1.5 LD50 of SM (232 mg/kg) percutaneously and the control group received an equal volume of vehicle (polyethylene glycol 300). Prior to SM application, the animals were administered nifedipine and dextrose saline containing antibiotic by intraperitoneal route. The protection assessed by the mean survival time (MST) was determined by Dunnett's method. The MST was significantly increased in nifedipine treated group. The characteristic biochemical indices of SM intoxication, i.e. lipid peroxidation and reduced glutathione (GSH) were determined in liver from animals sacrificed at 24, 48 and 72 h after exposure. SM application (1 LD50) caused a reduction in GSH level which was restored in nifedipine treated group. SM-induced lipid peroxidation was also prevented by nifedipine administration. The protective effect of nifedipine may be related to its capacity of attenuating SM-induced lipid peroxidation and glutathione depletion.

[Decontamination with clay or alcoholate of pigs percutaneously poisoned with VX and soman]. / Dekontaminacija svinja, perkutano trovanih VX-om i somanom, pomocu gline ili alkoholata.

The efficacy of clay or alcoholate as decontaminants in pigs percutaneously poisoned with 6 LD50 of O-ethyl S-2-diisopropylaminoethyl methylphosphonothioate (VX) and 3 LD50 of 1,2,2-trimethylpropyl methylphosphonofluoridate (soman) nerve gases was tested. It was assessed by the time of onset of the first signs of poisoning and death, as well as by the activity of blood cholinesterase (ChE). No toxic signs or fatalities were observed in decontaminated pigs, regardless of the decontaminant used. In VX poisoning up to 240 min. both decontaminants kept ChE values at normal level. Twenty four hours later, ChE activity in pigs decontaminated with clay was 71%, significantly higher than in pigs decontaminated with alcoholate (49%). In soman poisoning the activity in control group was maintained at almost normal level up to 60 min, followed by rapid fall to 58%. Further readings were impossible due to the death of all animals. No significant difference between decontaminants could be noticed throughout the observation of 24 hr. The values were kept between 80 and 100%, with the trend of rising after 120 min.

What to do in case of an unthinkable chemical warfare attack or accident.

Successful management of casualties in a toxic chemical attack or accident depends on planning, preparation, and training. In many communities, physicians join other emergency rescue personnel to take part in periodic exercises and drills. In case of a large-scale attack or accident, all medical care providers will be needed to care for casualties. Chemical warfare agents are generally considered to be highly toxic, exotic materials, but most are not. Nerve agents are similar to, although more potent than, commonly used insecticides; cyanide and phosgene are widely available; the incapacitating agent BZ has effects identical to those of scopolamine; and most physicians with knowledge of chemotherapy are familiar with the effects of mustard. Although a chemical attack might be perceived as an uncontrollable disaster, the guidelines for successful management are the same as for any toxic chemical accident. Medical care of casualties depends on knowledge of the agent and timely intervention, and those responsible for such care must be ready.