Stability of Diazepam Solution for Injection Following Long-Term Storage in an Ambient Temperature of the Mediterranean Climate.

PURPOSE: Diazepam is utilized as a convulsion antidote following nerve gas attacks. As an emergency medicine, it requires storage at ambient temperatures which often doesn't meet manufacturers' requirements, leading to an early invalidation of the product. Current work investigated this issue. METHODS: Long-term stability of diazepam ampoules for injection stored in an ambient temperature of the Mediterranean climate for ~10 years vs storage at room temperature was studied. RESULTS: Diazepam assay and pH remained within pharmacopeial specifications irrespective of storage conditions. A major degradation product 2-methylamino-5-chlorobenzophenone (MACB) showed a clear trend of accumulation as a function of storage time, exceeding the permitted limit at ~2 years, irrespective of storage conditions. A strong correlation between the discoloration of the solutions and the concentration of MACB was obtained. Intravenous administration of MACB to rats at doses ~2200-fold higher than permissible specification levels caused neither mortality nor any toxicological nor post-mortem findings. CONCLUSIONS: Regarding the parameters tested: diazepam assay, MACB assay, and pH, storing ampoules of diazepam solution for injection in field conditions of high temperatures of the Mediterranean climate did not cause accelerated degradation as compared to room temperature. These findings open an option for the usage of expired ampoules in special scenarios.

Case Files of the University of Massachusetts Toxicology Fellowship: Does This Smoke Inhalation Victim Require Treatment with Cyanide Antidote?

Cyanide toxicity is common after significant smoke inhalation. Two cases are presented that provide framework for the discussion of epidemiology, pathogenesis, presenting signs and symptoms, and treatment options of inhalational cyanide poisoning. An evidence-based algorithm is proposed that utilizes point-of-care testing to help physicians identify patients who benefit most from antidotal therapy.

Nitrite therapy improves survival postexposure to chlorine gas.

Exposure to relatively high levels of chlorine (Cl2) gas can occur in mass-casualty scenarios associated with accidental or intentional release. Recent studies have shown a significant postexposure injury phase to the airways, pulmonary, and systemic vasculatures mediated in part by oxidative stress, inflammation, and dysfunction in endogenous nitric oxide homeostasis pathways. However, there is a need for therapeutics that are amenable to rapid and easy administration in the field and that display efficacy toward toxicity after chlorine exposure. In this study, we tested whether nitric oxide repletion using nitrite, by intramuscular injection after Cl2 exposure, could prevent Cl2 gas toxicity. C57bl/6 male mice were exposed to 600 parts per million Cl2 gas for 45 min, and 24-h survival was determined with or without postexposure intramuscular nitrite injection. A single injection of nitrite (10 mg/kg) administered either 30 or 60 min postexposure significantly improved 24-h survival (from ∼20% to 50%). Survival was associated with decreased neutrophil accumulation in the airways. Rendering mice neutropenic before Cl2 exposure improved survival and resulted in loss of nitrite-dependent survival protection. Interestingly, female mice were more sensitive to Cl2-induced toxicity compared with males and were also less responsive to postexposure nitrite therapy. These data provide evidence for efficacy and define therapeutic parameters for a single intramuscular injection of nitrite as a therapeutic after Cl2 gas exposure that is amenable to administration in mass-casualty scenarios.

Mustard Gas Inhalation Injury: Therapeutic Strategy.

Mustard gas (sulfur mustard [SM], bis-[2-chloroethyl] sulfide) is a vesicating chemical warfare agent and a potential chemical terrorism agent. Exposure of SM causes debilitating skin blisters (vesication) and injury to the eyes and the respiratory tract; of these, the respiratory injury, if severe, may even be fatal. Therefore, developing an effective therapeutic strategy to protect against SM-induced respiratory injury is an urgent priority of not only the US military but also the civilian antiterrorism agencies, for example, the Homeland Security. Toward developing a respiratory medical countermeasure for SM, four different classes of therapeutic compounds have been evaluated in the past: anti-inflammatory compounds, antioxidants, protease inhibitors and antiapoptotic compounds. This review examines all of these different options; however, it suggests that preventing cell death by inhibiting apoptosis seems to be a compelling strategy but possibly dependent on adjunct therapies using the other drugs, that is, anti-inflammatory, antioxidant, and protease inhibitor compounds.

N-acetyl-L-cysteine protects against inhaled sulfur mustard poisoning in the large swine.

CONTEXT: Sulfur mustard is a blister agent that can cause death by pulmonary damage. There is currently no effective treatment. N-acetyl-L-cysteine (NAC) has mucolytic and antioxidant actions and is an important pre-cursor of cellular glutathione synthesis. These actions may have potential to reduce mustard-induced lung injury. OBJECTIVE: Evaluate the effect of nebulised NAC as a post-exposure treatment for inhaled sulfur mustard in a large animal model. MATERIALS AND METHODS: Fourteen anesthetized, surgically prepared pigs were exposed to sulfur mustard vapor (100 µg.kg⁻¹), 10 min) and monitored, spontaneously breathing, to 12 h. Control animals had no further intervention (n = 6). Animals in the treatment group were administered multiple inhaled doses of NAC (1 ml of 200 mg.ml⁻¹ Mucomyst™ at + 30 min, 2, 4, 6, 8, and 10 h post-exposure, n = 8). Cardiovascular and respiratory parameters were recorded. Arterial blood was collected for blood gas analysis while blood and bronchoalveolar lavage fluid were collected for hematology and inflammatory cell analysis. Urine was collected to detect a sulfur mustard breakdown product. Lung tissue samples were taken for histopathological and post-experimental analyses. RESULTS: Five of six sulfur mustard-exposed animals survived to 12 h. Arterial blood oxygenation (PaO2) and saturation levels were significantly decreased at 12 h. Arterial blood carbon dioxide (PaCO2) significantly increased, and arterial blood pH and bicarbonate (HCO3⁻) significantly decreased at 12 h. Shunt fraction was significantly increased at 12 h. In the NAC-treated group all animals survived to 12 h (n = 8). There was significantly improved arterial blood oxygen saturation, HCO3⁻ levels, and shunt fraction compared to those of the sulfur mustard controls. There were significantly fewer neutrophils and lower concentrations of protein in lavage compared to sulfur mustard controls. DISCUSSION: NAC's mucolytic and antioxidant properties may be responsible for the beneficial effects seen, improving clinically relevant physiological indices affected by sulfur mustard exposure. CONCLUSION: Beneficial effects of nebulized NAC were apparent following inhaled sulfur mustard exposure. Further therapeutic benefit may result from a combination therapy approach.

[Pharmacological correction of nonspecific resistance and production of proinflammatory cytokines during chronic intoxication with organophosphorus compound VX].

It is established in experiments on noninbred rats that the use of imunofan (20 mg/kg daily) and polyoxidonium (150 mg/kg daily) for 7 days on the background of chronic intoxication with organophosphorus agent VX (0.01 LD50, single daily treatment for 30 days) resulted in almost complete recovery of phagocytic-metabolic activity of neutrophils, the content of lysozyme, cationic protein of platelet, and levels of proinflammatory cytokines TNFa, IL-1b and IL-6 in the blood. The administration of T-activin (20 mg/kg daily for 7 days) restores these parameters insignificantly. The maximum overall stimulatory effect was produced by polyoxidonium, while the minimum effect was observed for T-activin.

Mass casualties from acute inhalation of chlorine gas.

OBJECTIVES: Chlorine gas is a potent pulmonary irritant that affects the mucous membranes and induces severe disturbances of pulmonary gas exchange within minutes of inhalation. The present study evaluated an extraordinary type of mass inhalational exposure. MATERIAL AND METHODS: Clinical reports of 25 soldiers who were admitted to the emergency department of Maresal Cakmak Military Hospital, Erzurum were retrospectively evaluated. All patients were exposed to chlorine gas as a result of mixing sodium hypochlorite with hydrochloric acid during cleaning activities. RESULTS: All patients were male and the mean age of patients was 22.04+/-2.98 years. The main symptoms were coughing and dyspnea in 18 patients (72%). Forced expiratory volume in 1 second (FEV1) and FEV1/forced volume capacity (FVC) ratio were found to be normal in all patients but FVC and peak expiratory flow (PEF) were below the normal range (80%) in 9 patients (36%). All patients received warmed humidified oxygen combined with nebulized salbutamol. Inhaled budesonide and nebulized sodium bicarbonate were ordered additionally for 19 patients (76%). Thirteen patients (52%) were discharged from the emergency department and 12 patients (48%) were hospitalized. No mortality was observed. CONCLUSION: Chlorine gas is a potent pulmonary irritant that causes acute damage in both the upper and lower respiratory tract. We suggest that inhaled steroids combined with nebulized sodium bicarbonate could be a safe and effective alternative for the treatment of symptomatic patients. Education of the public about the dangers of mixing of hypochlorite bleach with acidic cleaning agents is also very important.

Therapy against organophosphate poisoning: the importance of anticholinergic drugs with antiglutamatergic properties.

Potent cholinesterase inhibitors (e.g., soman, sarin), induce a wide range of deleterious effects including convulsions, behavioral impairments and ultimately, death. Due to the likelihood of various scenarios of military or terrorist attacks by these and other chemical weapons, research has to be aimed at finding optimal therapies. Early accumulation of acetylcholine in synaptic clefts was suggested to trigger an array of toxic events including an excessive release of glutamate, culminating in the activation of its receptors. Stimulation of the N-Methyl-D-Aspartate (NMDA) subtype of these receptors was associated with the neuronal injury that initiates organophosphate-induced brain damage. The notion of a stepwise mechanism yielded treatments based on a combination of an immediate administration of enzyme reactivators and anticholinergic drugs. This strategy dramatically increased survival rates but did not abolish convulsions and failed to prevent the ensuing cognitive dysfunction. Efforts to improve this paradigm by adding anticonvulsants or antiglutamatergic drugs with anti-epileptic characteristics produced dubious results. Under these conditions, benactyzine and caramiphen, agents with anticholinergic and antiglutamatergic properties, provided improved protection when introduced as adjunct agents to oximes, reversible cholinesterase inhibitors and/or specific antimuscarinic drugs such as atropine. In contrast, the specific antimuscarinic drug scopolamine failed to block soman-induced changes in glutamatergic and behavioral parameters even when given prophylactically. These findings along with a large number of additional reports led towards the conclusion that the therapeutic advantage of drugs such as benactyzine and caramiphen could derive from their ability to modulate central cholinergic and glutamate neurotransmission.

[Nerve gas--guidelines for care of victims of terrorism]. / Nervegass--retningslinjer ved terror.

The threat from chemical warfare agents such as nerve agents against civilians has traditionally been considered irrelevant. Following the recent terrorist attacks in the US on 11 September 2001 and in Madrid, Spain on 11 March 2004, the threat from such weapons is taken seriously. Hospitals must therefore be prepared to take care of civilian victims. Emergency preparedness implies education and training of healthcare professionals, stocking of antidotes, and training of personnel. This involves decontamination of patients, establishment of routines to avoid contamination of hospitals, and the ability to determine if patients and first responders are contaminated with chemicals and to avoid such contamination. Treatment against nerve agents includes atropine, acetylcholinesterase reactivators (obidoxime or pralidoxime) and benzodiazepines (diazepam). Because these drugs are not sufficiently effective in protecting the brain, new and more effective countermeasures must be developed.

[The group intoxication by tear-gas]. / Zbiorowe zatrucie gazem drainiaco-lzawiacym.

The case of group intoxication of 52 pupils by tear CS gas (2-chlorobenzelidenemaloninitrile) at school is presented. The most often clinical signs observed at hospital admitted children, at 13-16 year old were detail described. The special attend was given for 4 cases, heavy clinical intoxication observed for young girls. The clinical symptoms, action of xenobiotics and clinical treatment compare with literature data, were discussed.

Mass casualties from acute inhalation of chloramine gas.

Mass exposure to chloramine gas has not been reported. We report two groups of 36 patients (72 total) suffering from acute inhalation of chloramine gas. Chloramine gas is produced from mixing common household cleaning agents containing sodium hypochlorite (bleach) and ammonia. The first mass casualty event occurred when 36 male soldiers were exposed during a "cleaning party" in their barracks. Ten days later, 36 female soldiers were exposed in a similar manner and presented to our emergency department. In each event, commonly available cleaning agents--liquid bleach and ammonia--were mixed together, liberating toxic chloramine gas. Nebulized sodium bicarbonate solution has been suggested for treatment of chlorine gas inhalation, but no report of nebulized sodium bicarbonate for treatment of chloramine gas inhalation injury exists. In our series, 22 patients exposed to chloramine gas were treated with a nebulized solution of 3.75% sodium bicarbonate. This treatment made no significant statistical or clinical difference in outcome. We present the largest case series of patients presenting to an emergency department for treatment of acute inhalation of chloramine gas.

Therapeutic efficacy of obidoxime or HI-6 with atropine against intoxication with some nerve agents in mice.

1 The toxicity of pinacolyl methylphosphonofluoridate (soman, GD), cyclohexyl methylphosphonofluoridate (cyclohe xylsarin, GF) and 2-dimethylaminoethyl-(dimethylamido)-phosphonofluoridate (GV) and the therapeutic efficacy of two oximes (obidoxime and HI-6) in combination with atropine against mentioned nerve agents were evaluated in mice. 2 The 24-h i.m. LD50 of GD was 101 micrograms/kg (99.5-104.0), LD50 of GF was 170 micrograms/kg (151.0-190.0 and LD50 of GV was 25.2 micrograms/kg (23.0-27.7). 3 The efficacy of two oximes, obidoxime (15 and 30 mg/kg) or HI-6 (15 and 30 mg/kg) in combination with atropine (21 mg/kg) was tested. HI-6 was significantly more effective in reducing mortality than obidoxime following poisoning with all three nerve agents. 4 Higher doses of both oximes showed significantly more effective therapeutic efficacy against all nerve agents studied.

Treatment of acute chlorine gas inhalation with nebulized sodium bicarbonate.

Three male patients, 19 to 20 years old, were exposed to chlorine gas secondary to a leak in the chlorination system of an indoor pool. All of the patients were symptomatic with cough, chest pain, and shortness of breath. Physical examinations, arterial blood gases, and chest radiographs were normal. All patients were given a nebulized solution of 3.75% sodium bicarbonate which resulted in prompt relief of their symptoms. None of the patients suffered from prolonged symptomatology. This therapy appears to be useful in treating chlorine gas inhalation; however, it cannot be routinely recommended without prospective clinical studies evaluating its efficacy and safety.