In vitro and in vivo evaluation of pyridinium oximes: mode of interaction with acetylcholinesterase, effect on tabun- and soman-poisoned mice and their cytotoxicity

The increased concern about terrorist use of nerve agents prompted us to search for new more effective oximes against tabun and soman poisoning. We investigated the interactions of five bispyridinium oximes: K027 [1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium) propane dibromide], K048 [1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide], K033 [1,4-bis(2-hydroxyiminomethylpyridinium) butane dibromide], TMB-4 [1,3-bis(4-hydroxyiminomethylpyridinium) propane dibromide] and HI-6 [(1-(2-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-2-oxapropane dichloride)] with human erythrocyte acetylcholinesterase (AChE; E.C. 3.1.1.7) and their effects on tabun- and soman-poisoned mice. All the oximes reversibly inhibited AChE, and the enzyme-oxime dissociation constants were between 17 and 180 microM. Tabun-inhibited AChE was completely reactivated by TMB-4, K027 and K048, with the overall reactivation rate constants of 306, 376 and 673 min(-1)M(-1), respectively. The reactivation of tabun-inhibited AChE by K033 reached 50% after 24h, while HI-6 failed to reactivate any AChE at all. Soman-inhibited AChE was resistant to reactivation by 1mM oximes. All studied oximes protected AChE from phosphorylation with both soman and tabun. In vivo experiments showed that the studied oximes were relatively toxic to mice; K033 was the most toxic (LD50=33.4 mg/kg), while K027 was the least toxic (LD50=672.8 mg/kg). The best antidotal efficacy was obtained with K048, K027 and TMB-4 for tabun poisoning, and HI-6 for soman poisoning. Moreover, all tested oximes showed no cytotoxic effect on several cell lines in concentrations up to 0.8mM. The potency of the oximes K048 and K027 to protect mice from five-fold LD50 of tabun and their low toxicity make these compounds leading in the therapy of tabun poisoning. The combination of HI-6 and atropine is the therapy of choice for soman poisoning.     

Lessepsian migration and tetrodotoxin poisoning due to Lagocephalus sceleratus in the eastern Mediterranean

Background

The Suez Canal permits migration of fish from the Indo-Pacific Ocean to the Mediterranean Sea. This phenomenon (Lessepsian migration) has enabled poisonous fish species to colonize the Mediterranean Sea.

Objective

To report clinical tetrodotoxin poisoning after consumption of the Lessepsian immigrant fish Lagocephalus sceleratus caught on the Israeli coast of the eastern Mediterranean.

Case series

Thirteen patients aged 26-70 years were admitted after consuming L. sceleratus. Signs of toxicity appeared within 1 h. The main manifestations included vomiting, diarrhea, headache, paraesthesias, slurred speech, muscle weakness, dyspnea, hypertension, tachycardia, respiratory arrest, seizures and coma. Treatment was supportive, including mechanical ventilation (two patients). Patients recovered within 4 days. All fish were identified as L. sceleratus, a species known to contain tetrodotoxin.

Discussion

The diagnosis of tetrodotoxin poisoning was suggested by typical clinical manifestations together with temporal proximity to consumption of tetrodotoxin-containing fish. To the best of our knowledge, this is the first case series of tetrodotoxin poisoning reported from the eastern Mediterranean and due to L. sceleratus. Man made disruption of the ecological balance has resulted in the spread of tetrodotoxin-containing fish from the Indo-Pacific region to the Mediterranean Sea. Increased awareness is required to identify tetrodotoxin poisoning in an atypical fauna.     

Anodic voltammetric assay of lansoprazole and omeprazole on a carbon paste electrode

The electrochemical oxidations of lansoprazole and omeprazole have been studied at a carbon paste electrode by cyclic and differential-pulse voltammetry in Britton-Robinson buffer solutions (0.04 M; pH 6.0-10.0). The drug produced a single oxidation step. By differential-pulse voltammetry, a linear response was obtained in B-R buffer pH 6.0 in a concentration range from 2.0 x 10(-7) to 5.0 x 10(-5) M for lansoprazole or omeprazole. The detection limits were 1.0 x 10(-8) and 2.5 x 10(-8) M for lansoprazole and omeprazole, respectively. The method was successfully applied for the analysis of omeprazole and lansoprazole in capsules. The results were comparable to those obtained by spectrophotometry.     

Dialkylphosphorus metabolites in the urine and activities of esterases in the serum as biochemical indices for human absorption of organophosphorus pesticides

Ninety-seven agricultural workers were monitored for absorption of the organophosphorus pesticides methidathion, vamidothion, and azinphos-methyl, which were sprayed in an orchard during two seasons. Low levels of only one dialkylphosphorus metabolite (dimethyl phosphorothioate) were found in only eight workers in pre-exposure urine samples. More than one dialkylphosphorus metabolite was detected in almost all exposed individuals in after-exposure urine samples. The highest concentrations were measured after exposure to azinphos-methyl; the median concentrations of dimethyl phosphorodithioate and dimethyl phosphorothioate were 0.92 and 0.78 nmol/mg creatinine with a concentration range up to 14.3 and 53.7, respectively. Three diethylphosphorus metabolites were also detected in some samples, but at lower concentrations. Cholinesterase activities were decreased (31–48%) in the serum of 12 workers; four of those workers had no dialkylphosphorus metabolites in the urine. Paraoxonase and arylesterase activities in the serum were unaffected by the absorption of pesticides, and there was no correlation between the activities of these esterases and the metabolite concentrations in the urine. This study confirmed that dialkylphosphorus metabolites in the urine are a more sensitive index of absorption than cholinesterase inhibition in the serum but lack of correlation between cholinesterase inhibition and metabolite concentration indicates that both parameters should be monitored.     

Respiratory morbidity in a population of French dental technicians

Aims: To compare wage earner dental technicians with non-exposed salaried subjects for the prevalence of respiratory symptoms and function, and chest x ray abnormalities.

Methods: A total of 134 dental technicians and 131 non-exposed subjects participated. A medical and an occupational questionnaire were filled in to evaluate the prevalence of respiratory symptoms and occupational exposures. Subjects underwent respiratory tests and chest x ray examination.

Results: Mean age of the dental technicians was 36.6 years with a mean duration of dental work of 16.5 years. There was a significant risk of cough (day and night) and usual phlegm in dental technicians. Respiratory function parameters were lower in dental technicians with a significant difference between exposed and non-exposed groups for % FVC (forced vital capacity), % FEF₂₅ (forced mid expiratory flow), and % FEF₅₀. The prevalence of small opacities increased with age. Small opacities were significantly related to an exposure to asbestos in the past.

Conclusions: Our young population of dental technicians is at risk of respiratory morbidity. They should benefit from adequate technical prevention measures.

     

Job stress and other working conditions: Relationships with smoking behaviors in a representative sample of working Australians

OBJECTIVES: To assess the relationships between current smoking status and psychosocial working conditions. METHODS: A cross-sectional population-based telephone survey was conducted (66% response rate, N = 1,101). Job stress was measured using the demand/control, effort/reward imbalance (ERI), and job pressure models. Multiple regression modelling was conducted for smoking status (current versus non-smokers, and a more restricted analysis of current versus former-smokers) and daily smoking intensity outcomes in relation to job stress measures, working hours, shift work, and other independent variables. RESULTS: After adjustment for age, education, martial status, and hostility, high job strain was positively associated with current smoking in men only. Employment in active jobs was associated with decreased odds of smoking among women only. High strain jobs were associated with decreased odds of current smoking compared to former smoking in women. In men, extreme and moderate job pressure were related to current smoking compared to current non-smoking, and moderate job pressure was associated with current smoking compared with former smokers. Other working conditions associated with smoking were excessive working hours in men and physical demand in women. Daily smoking intensity in current smokers was associated with high psychological demand and with ERI in women. CONCLUSIONS: These results suggest that job stress is related to smoking status at the population level, with different patterns in men and women.     

Alpha interferon in children with Philadelphia chromosome-positive chronic myeloid-leukaemia

The present work focuses on the therapeutic efficacy and the toxicity of alpha interferon in patients younger than age 18 years. 5 patients younger than 18 years were treated and followed up between 1990 and 1999 at the department of haematology (Aziza Othmana Hospital) Hydroxyurea was given as initial treatment to all patients. After a median period of 8 months, these patients received alpha interferon (5 millions units/m2 once). Six months after the beginning of the alpha interferon a complete hematologic response was obtained in all patients. The median overall survival was of 66 months: 3 patients are still alive (2 patients in an advanced stage and one patient in chronic phase) and 2 patients died after transformation. The most common reported side effects of alpha interferon were asthenia, weight loss, fever, myalgia, chills and headaches--these toxic manifestations were mild and were noticed in all our patients. Myelosuppression was noted in two patients. Interferon is well tolerated in patients younger than age years 18 old, with CML. It may offer an alternative to bone marrow transplantation in children in the chronic phase of CML without histocompatible donor. The role of new agents such as STI 571 needs to be evaluated as well.     

Stomach-specific anti-H. pylori therapy. I: Preparation and characterization of tetracyline-loaded chitosan microspheres

The main objective of the study was to develop a stomach-specific drug delivery system to increase the efficacy of tetracycline against Helicobacter pylori. Chitosan microspheres were prepared by ionic cross-linking and precipitation with sodium sulfate. Two different methods were used for drug loading. In method I, tetracycline was mixed with chitosan solution before the simultaneous cross-linking and precipitation. In method II, the drug was incubated with pre-formed microspheres for 48 h. The cumulative amount of tetracycline that was released from chitosan microspheres and the stability of the drug was examined in different pH medium at 37 degrees C. Microspheres with a spherical shape and an average diameter of 2.0-3.0 microm were formed. When the drug was added to the polymer solution before cross-linking and precipitation only 8% (w/w) was optimally incorporated in the final microsphere formulation. When the drug was incubated with the pre-formed microspheres, on the other hand, a maximum of 69% (w/w) could be loaded. Thirty percent of tetracycline either in solution or when released from microspheres was found to degrade at pH 1.2 in 12 h. The preliminary results from this study suggest that chitosan microspheres can be used to incorporate antibiotic drugs and may be effective when administered locally in the stomach against H. pylori.