A 26-Week Toxicity Assessment of AIR001 (Sodium Nitrite) by Inhalation Exposure in Rats and by Intravenous Administration in Dogs.

Historically, nitrogen oxides (NOx) in food, drinking water, as well as in the atmosphere have been believed to be associated with adverse health consequences. More recently, NOx have been implicated in normal homeostatic regulation, and exogenous administration has been associated with health benefits. One such potential health benefit is the prospect that inhaled nitrite will lower pulmonary blood pressure (BP) in patients with pulmonary arterial hypertension (PAH), a disease with poor prognosis due to the lack of effective treatment. To characterize potential chronic toxicity associated with inhaled AIR001 (sodium nitrite) for use in the treatment of PAH, 26-week exposures to AIR001 were carried out by inhalation administration in rats and by intravenous infusion in dogs. The studies revealed that methemoglobinemia was the primary adverse effect in both species. Methemoglobin levels less than 40% were well tolerated in both species, while levels greater than 50% methemoglobin caused death in some rats. Additionally, a decrease in systemic BP was also observed with inhaled AIR001 exposure in dogs. These acute secondary and exaggerated pharmacological effects occurred daily throughout the 26-week treatment period. Chronic exposure did not alter the magnitude of either methemoglobinemia or hypotension or result in additional toxicity or compensatory responses. Based on the exposure levels that produced these pharmacodynamic responses in animals, relative to those measured in early clinical studies, it appears that an adequate margin of safety exists to support the continued clinical development of inhaled AIR001.

When patients become cyanotic: acquired methemoglobinemia.

BACKGROUND: The authors conducted literature review to create a heightened awareness of the potential for developing toxic methemoglobinemia from local anesthetics. Methemoglobin normally is present in the blood at levels less than 1 percent. Levels may become toxic as hemoglobin is oxidized to methemoglobin after local anesthetics such as benzocaine and prilocaine are administered. TYPES OF STUDIES REVIEWED: The authors searched the medical and pharmaceutical industry literature. They found and reviewed case studies of incidences of methemoglobinemia that resulted from local anesthetic overdoses. RESULTS: Cases of local anesthetic-induced methemoglobinemia in dental practice are under-recognized and rare. Reported cases of prilocaine-induced methemoglobinemia have resulted in recent changes in some prilocaine literature. These changes include maximum recommended doses for patients of various weights. CLINICAL IMPLICATIONS: Dentists should identify patients who are at increased risk of developing methemoglobinemia before administering local anesthetics. They also should follow new recommended dosing guidelines for prilocaine and be aware of symptoms of this adverse reaction.

Oxidative damage in the red cells of vitamin E-deficient rats.

One month-old male Sprague-Dawley rats were maintained on a basal vitamin E-deficient diet supplemented with either 0 or 50 ppm vitamin E for 5 months. Washed red blood cells were resuspended in phosphate buffered-saline, pH 7.4, that contained 0-50 mM glucose and 0-20 mM ethylenediamine tetraacetic acid (EDTA), and were incubated at 37 degrees C for up to 22 h. Contrary to expectations, glucose in the incubation medium accelerated, rather than retarded, the rates of hemolysis, lipid peroxidation and methemoglobin formation in the vitamin E-deficient cells. EDTA, on the other hand, partially inhibited the extent of oxidative damage. Vitamin E-supplemented cells were resistant to oxidative damage in the presence or absence of glucose and/or EDTA. The levels of reduced glutathione (GSH) and activity of catalase were decreased faster in the vitamin E-deficient cells than the supplemented cells, and the rates of their decline were slowed down by either glucose or EDTA. The activities of GSH peroxidase and superoxide dismutase were not significantly altered in the red cells of either group during incubation. The results obtained suggest that reactive oxygen species and reduced metal ions play important roles in initiating oxidative damage to the red cells of vitamin E-deficient rats. However, the agent responsible for initiating the hemolytic event has yet to be established.

[Vitamin A requirement of growing swine. 1. Effect of vitamin A supply on growth of piglets and fattening swine]. / Untersuchungen zum Vitamin-A-Bedarf des wachsenden Schweines. 1. Mitteilung. Der Einfluss der Vitamin-A-Versorgung auf das Wachstum von Ferkeln und Mastschweinen.

For the purpose of ascertaining the vitamin A requirement seven experiments with 303 pigs in the live weight range between 6.5 and 114 kg were made. In three experiments under in practice conditions we checked the standard vitamin A supplement to the mixed feed with 1,732 pigs (live weight range between 8.5 and 110 kg). The supplement to vitamin-A-free rations and to those poor in or free of carotene amounted to between 0 and 8,000 IU/kg feed. Above that, between 0 and 16 mg beta-carotene and 1,000 mg nitrite/kg feed were supplemented. As long as the vitamin A store in the liver during weaning amounted to greater than 50 IU and greater than 100 IU/g at the beginning of fattening, feed intake, live weight growth and feed expenditure were not influenced by the supplement of vitamin and provitamin resp. The supplement of 250 IU resulted in the same weight growth from weaning to the end of fattening as that of 4,000 IU. Nitrite supplement had a negative effect at 250 IU, at 500 IU vitamin A consumption and weight growth tended to be only insignificantly lower. The methaemoglobin content decreasing in the course of the experiment reflects the adaptation of the pigs to the nitrite load. The consumption and growth depression caused by vitamin A deficiency could be observed from the 7th week of the experiment when casein-swelling starch rations were fed, but from the 13th week of the experiment only when cereal-soybean oilmeal rations were fed. The weight of liver, spleen, kidneys, heart and brain was not influenced by vitamin A supply. The same applies to the body composition and retention with the exception of two deficiency piglets, which contained less fat in the empty body than the control animals.

Methaemoglobinaemia following treatment dispensed by witch doctors. Two cases of potassium permanganate poisoning.

Two cases of acute acquired methaemoglobinaemia following the ingestion of witch doctor's preparations, are presented. Chemical analysis of the ingested powder revealed a mixture of soot and potassium permanganate. Both patients were comatose and deeply cyanosed but the response to oxygen, methylene blue and vitamin C was good.