Novel sulfated polysaccharides disrupt cathelicidins, inhibit RAGE and reduce cutaneous inflammation in a mouse model of rosacea.

BACKGROUND: Rosacea is a common disfiguring skin disease of primarily Caucasians characterized by central erythema of the face, with telangiectatic blood vessels, papules and pustules, and can produce skin thickening, especially on the nose of men, creating rhinophyma. Rosacea can also produce dry, itchy eyes with irritation of the lids, keratitis and corneal scarring. The cause of rosacea has been proposed as over-production of the cationic cathelicidin peptide LL-37. METHODOLOGY/PRINCIPAL FINDINGS: We tested a new class of non-anticoagulant sulfated anionic polysaccharides, semi-synthetic glycosaminoglycan ethers (SAGEs) on key elements of the pathogenic pathway leading to rosacea. SAGEs were anti-inflammatory at ng/ml, including inhibition of polymorphonuclear leukocyte (PMN) proteases, P-selectin, and interaction of the receptor for advanced glycation end-products (RAGE) with four representative ligands. SAGEs bound LL-37 and inhibited interleukin-8 production induced by LL-37 in cultured human keratinocytes. When mixed with LL-37 before injection, SAGEs prevented the erythema and PMN infiltration produced by direct intradermal injection of LL-37 into mouse skin. Topical application of a 1% (w/w) SAGE emollient to overlying injected skin also reduced erythema and PMN infiltration from intradermal LL-37. CONCLUSIONS: Anionic polysaccharides, exemplified by SAGEs, offer potential as novel mechanism-based therapies for rosacea and by extension other LL-37-mediated and RAGE-ligand driven skin diseases.

Physical and chemical stability of iron sucrose in parenteral nutrition.

INTRODUCTION: Current literature supports iron dextran as the only iron preparation compatible with parenteral nutrition (PN). Iron sucrose has been used for iron replacement therapy because of its lower rate of adverse events. The purpose of this study is to determine the physical and chemical stability of iron sucrose in PN. METHODS: Physical and chemical stability of iron sucrose in nonlipid PN solutions (PN 1 for neonates and PN 2 for patients weighing >20 kg) is tested over time in triplicate. Physical stability is determined by visually inspecting each PN solution for particulate matter and by filtering and analyzing each aliquot quantitatively for crystal precipitates. Chemical stability is confirmed if the iron concentrations by mass spectrometry remain within United States Pharmacopeia (USP) standards. RESULTS: Visual clarity is maintained in all PN solutions at hours 0 through 4. PN solution 1 remains clear for hours 8 through 24, whereas PN solution 2 shows an increase in particulate matter by 8 hours. All PN solutions 2 are considered visually incompatible by hour 24. Physical stability of iron sucrose for PN solutions 1 and 2 from hours 0 to 4 is within the USP guidelines for crystalline particulate matter. At hour 24, only solution 1 remains within USP guidelines. Chemical stability data indicate that iron concentrations are maintained throughout the 24-hour time period. CONCLUSION: The physical stability of iron sucrose in PN is time and concentration dependent. Concentrations >0.25 mg/dL showed increasing particulate and should not be added to PN. However, iron sucrose is chemically stable in PN solutions.

The accuracy and precision of measuring Lorazepam from three liquid preparations.

OBJECTIVES: Commercially available lorazepam solution contains both polyethylene glycol (PEG) and propylene glycol. When large doses are administered for deep sedation in the pediatric intensive care unit (PICU), PEG may cause diarrhea, and the accumulation of propylene glycol may result in toxicity. These adverse effects may be avoided by preparing a slurry from crushed lorazepam tablets suspended in water immediately prior to administration. This slurry, which is extemporaneously prepared at bedside by nurses, lacks a suspending agent, and, therefore, the rapid settling of drug particles may produce suspensions that are not homogeneous. Thus, there may be significant inaccuracy and imprecision in dosage measurement. The objective of this study was to compare the accuracy and precision of lorazepam dosage measurement from three liquid preparations: 1) tablet slurry prepared at bedside by a nurse; 2) lorazepam suspension extemporaneously prepared by a pharmacist; and 3) the commercially available lorazepam solution. METHODS: Sixteen PICU nurses measured three doses of lorazepam (0.5 mg, 1.5 mg, 3.5 mg) in triplicate from each of the three liquid preparations using oral syringes. PICU nurses prepared the slurry by mixing crushed lorazepam tablet(s) with water and drawing up the appropriate dose in an oral syringe. Additionally, nurses drew up the appropriate dose from a pharmacist-prepared lorazepam suspension (1 mg/mL) and the commercially available lorazepam solution (2 mg/mL). All samples were analyzed by HPLC and the groups were compared using two-way ANOVA. RESULTS: Dosage accuracy for the slurry (91.2 ± 7.8%) and suspension (109.2 ± 4.9%) were significantly different from the commercially available solution (101.5 ± 3.1%) (P < .05). Imprecision in dosage measurement, as determined by the relative standard deviation, was greatest for the slurry (8.6%) as compared to the suspension (4.5%) and commercially available solution (3.0%). CONCLUSIONS: Dosage measurement from lorazepam slurry and suspension led to significant deviation from the intended dose. Dosage measurement using the slurry was the least precise among the three preparations.

Chemical stability of extemporaneously prepared Lorazepam suspension at two temperatures.

The objective of this study was to determine the chemical stability of extemporaneously prepared lorazepam suspension (1 mg/mL) stored at two temperatures (4°C and 22°C) for 3 months. Lorazepam tablets marketed by two manufacturers (Mylan Pharmaceuticals and Watson Laboratories) were used to extemporaneously formulate two independently prepared suspensions. Each suspension was prepared using sterile water, Ora-Plus(®) and Ora-Sweet(®) to achieve a final concentration of 1 mg/mL. The two brands of tablets required different volumes of vehicles to prepare a pharmaceutically optimal suspension. The suspensions were stored in amber glass bottles at 4°C and 22°C for 91 days. Samples were analyzed by high performance liquid chromatography at baseline and on days 2, 3, 7, 14, 21, 28, 42, 63, and 91. The suspensions were considered stable if the mean lorazepam concentration remained greater than 90% of the initial concentration.The chemical stabilities of these two extemporaneously prepared lorazepam suspensions were comparable throughout the study. Both lorazepam suspensions were stable for 63 days when stored at 4°C or 22°C, and both were stable for 91 days when refrigerated at 4°C. When stored at room temperature, the suspension prepared from the Watson tablet retained 88.9 ± 1.4% of the initial concentration on day 91 and was therefore considered unstable, while the suspension prepared from the Mylan tablet was stable for the entire 91-day study.

Extemporaneously compounded sterile medications: relevance of new United States pharmacopeial standards to pain clinicians.

The United States Pharmacopeia (USP) is the United States' congressionally authorized book of standards for pharmaceutical manufacturing in the United States. The most current edition of the USP includes a new chapter entitled Pharmaceutical Compounding-Sterile Preparations that sets standards for all health care professionals who prepare, store or dispense sterile preparations. Extemporaneously compounded sterile formulations are sometimes needed for symptom control in pain and palliative practice. The implications and relevance of this new USP chapter to pain and palliative care clinicians-and the importance of all clinicians understanding the implications of how their patient's compounded sterile products are prepared-are discussed.