NITRATE-CIN Study: Protocol of a Randomized (1:1) Single-Center, UK, Double-Blind Placebo-Controlled Trial Testing the Effect of Inorganic Nitrate on Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography for Acute Coronary Syndromes.

BACKGROUND: Contrast-induced nephropathy (CIN), an acute kidney injury resulting from the administration of intravascular iodinated contrast media, is a significant cause of morbidity/mortality following coronary angiographic procedures in high-risk patients. Despite preventative measures intended to mitigate the risk of CIN, there remains a need for novel effective treatments. Evidence suggests that delivery of nitric oxide (NO) through chemical reduction of inorganic nitrate to NO may offer a novel therapeutic strategy to reduce CIN and thus preserve long term renal function. DESIGN: The NITRATE-CIN trial is a single-center, randomized, double-blind placebo-controlled trial, which plans to recruit 640 patients presenting with acute coronary syndromes (ACS) who are at risk of CIN. Patients will be randomized to either inorganic nitrate therapy (capsules containing 12 mmol KNO3) or placebo capsules containing potassium chloride (KCl) daily for 5 days. The primary endpoint is development of CIN using the Kidney Disease Improving Global Outcomes (KDIGO) criteria. A key secondary endpoint is renal function over a 3-month follow-up period. Additional secondary endpoints include serum renal biomarkers (e.g. neutrophil gelatinase-associated lipocalin) at 6 h, 48 h and 3 months following administration of contrast. Cost-effectiveness of inorganic nitrate therapy will also be evaluated. SUMMARY: This study is designed to investigate the hypothesis that inorganic nitrate treatment decreases the rate of CIN as part of semi-emergent coronary angiography for ACS. Inorganic nitrate is a simple and easy to administer intervention that may prove useful in prevention of CIN in at-risk patients undergoing coronary angiographic procedures.

Enhancing safety with potassium phosphates injection.

The inadvertent administration of concentrated potassium chloride resulting in patient death is well-documented in Canada and other countries. Vials of potassium phosphates contain more than twice the concentration of potassium compared to vials of potassium chloride concentrate. If inadequately diluted or administered too rapidly, intravenous potassium phosphate can also lead to serious patient harm. This article contains information reprinted with permission from an ISMP Canada Safety Bulletin (ISMP Canada, 2006, April 25) for the purpose of enhancing safety with potassium phosphates injection.

Final report on the safety assessment of potassium silicate, sodium metasilicate, and sodium silicate.

Potassium Silicate, Sodium Metasilicate, and Sodium Silicate combine metal cations with silica to form inorganic salts used as corrosion inhibitors in cosmetics. Sodium Metasilicate also functions as a chelating agent and Sodium Silicate as a buffering and pH adjuster. Sodium Metasilicate is currently used in 168 formulations at concentrations ranging from 13% to 18%. Sodium Silicate is currently used in 24 formulations at concentrations ranging from 0.3% to 55%. Potassium Silicate and Sodium Silicate have been reported as being used in industrial cleaners and detergents. Sodium Metasilicate is a GRAS (generally regarded as safe) food ingredient. Aqueous solutions of Sodium Silicate species are a part of a chemical continuum of silicates based on an equilibrium of alkali, water, and silica. pH determines the solubility of silica and, together with concentration, determines the degree of polymerization. Sodium Silicate administered orally is readily absorbed from the alimentary canal and excreted in the urine. The toxicity of these silicates has been related to the molar ratio of SiO2/Na2O and the concentration being used. The Sodium Metasilicate acute oral LD50 ranged from 847 mg/kg in male rats to 1349.3 mg/kg in female rats and from 770 mg/kg in female mice to 820 mg/kg in male mice. Gross lesions of variable severity were found in the oral cavity, pharynx, esophagus, stomach, larynx, lungs, and kidneys of dogs receiving 0.25 g/kg or more of a commercial detergent containing Sodium Metasilicate; similar lesions were also seen in pigs administered the same detergent and dose. Male rats orally administered 464 mg/kg of a 20% solution containing either 2.0 or 2.4 to 1.0 ratio of sodium oxide showed no signs of toxicity, whereas doses of 1000 and 2150 mg/kg produced gasping, dypsnea, and acute depression. Dogs fed 2.4 g/kg/day of Sodium Silicate for 4 weeks had gross renal lesions but no impairment of renal function. Dermal irritation of Potassium Silicate, Sodium Metasilicate, and Sodium Silicate ranged from negligible to severe, depending on the species tested and the molar ratio and concentration tested. Sodium Metasilicate was negative in the local lymph node assay (LLNA), but a delayed-type hypersensitivity response was observed in mice. Potassium Silicate was nonirritating in two acute eye irritation studies in rabbits. Sodium Metasilicate (42.4% H2O) was corrosive to the rabbit eye. Sodium Silicate was a severe eye irritant in some eye irritation studies, but was irritating or nonirritating in others. A skin freshener containing Sodium Silicate was nonirritating. Sodium Metasilicate was nonmutagenic in bacterial cells. Rats given Sodium Silicate (600 and 1200 ppm of added silica) in the drinking water in reproductive studies produced a reduced number of offspring: to 67% of controls at 600 ppm and to 80% of controls at 1200 ppm. Three adult rats injected intratesticularly and subcutaneously with 0.8 mM/kg of Sodium Silicate showed no morphological changes in the testes and no effect on the residual spermatozoa in the ductus deferens. Sodium Metasilicate (37% in a detergent) mixed with water was a severe skin irritant when tested on intact and abraded human skin, but 6%, 7%, and 13% Sodium Silicate were negligible skin irritants to intact and abraded human skin. Sodium Silicate (10% of a 40% aqueous solution) was negative in a repeat-insult predictive patch test in humans. The same aqueous solution of Sodium Silicate was considered a mild irritant under normal use conditions in a study of cumulative irritant properties. The Cosmetic Ingredient Review (CIR) Expert Panel recognized the irritation potential of these ingredients, especially in leave-on products. However, because these ingredients have limited dermal absorption and Sodium Metasilicate is a GRAS direct food substance, the Panel deemed the ingredients safe for use in cosmetic products in the practices of use and concentration described in this safety assessment, when formulated to avoid irritation.

Final report on the safety assessment of Ammonium, Potassium, and Sodium Persulfate.

Ammonium, Potassium, and Sodium Persulfate are inorganic salts used as oxidizing agents in hair bleaches and hair-coloring preparations. Persulfates are contained in hair lighteners at concentrations up to 60%, in bleaches and lighteners at up to 22% and 16%, respectively, and in off-the-scalp products used to highlight hair strands at up to 25%. They are used in professional product bleaches and lighteners at similar concentrations. Much of the available safety test data are for Ammonium Persulfate, but these data are considered applicable to the other salts as well. Acute dermal, oral, and inhalation toxicity studies are available, but only the latter are remarkable, with gross lesions observed in the lungs, liver, stomach, and spleen. In short-term and subchronic feeding studies the results were mixed; some studies found no evidence of toxicity and others found local damage to the mucous membrane in the gastrointestinal tract, but no other systemic effects. Short-term inhalation toxicity was observed when rats were exposed to aerosolized Ammonium Persulfate at concentrations of 4 mg/m3 and greater. Ammonium Persulfate (as a moistened powder) was not an irritant to intact rabbit skin, but was sensitizing (in a saline solution) to the guinea pig. It was slightly irritating to rabbit eyes. Ammonium Persulfate was negative in the Ames test and the chromosomal aberration test. No significant evidence of tumor promotion or carcinogenicity was observed in studies of rats receiving topical applications of Ammonium Persulfate. The persulfates were reported to cause both delayed-type and immediate skin reactions, including irritant dermatitis, allergic eczematous dermatitis, localized contact urticaria, generalized urticaria, rhinitis, asthma, and syncope. The most common causes of allergic dermatitis in hairdressers are the active ingredients in hair dyes, and Ammonium Persulfate has been identified as a frequent allergen. A sensitization study that also examined the incidence of urticarial reactions was performed with 17.5% Ammonium, Potassium, and Sodium Persulfate under occlusive patches. At this concentration and exposure conditions, a mixture of these Persulfates was not sensitizing, and application of Ammonium, Potassium, and Sodium Persulfate did not result in an urticarial reaction. In normal use (i.e., not occluded and rinsed off), it was expected that a concentration greater than 17.5% would also be safe. Given the clinical reports of urticarial reactions, however, manufacturers and formulators should be aware of the potential for urticarial reactions at concentrations of Persulfates greater than 17.5%. Based on the available data, the Cosmetic Ingredient Review (CIR) Expert Panel concluded that Ammonium, Potassium, and Sodium Persulfate are safe as used as oxidizing agents in hair colorants and lighteners designed for brief discontinuous use followed by thorough rinsing from the hair and skin.