Near-saturated Solutions Research Articles

POS0478 TOPICAL CALCIUM CHELATORS FOR TARGETING CUTANEOUS CALCIFICATION: PRECLINICAL EVIDENCE OF EFFICACY

BackgroundCutis calcinosis, defined as sub-epidermal deposition of calcium salts, is a painful, disabling, disfiguring, problem in 20-40% of patients with systemic sclerosis. Its pathogenesis remains poorly understood and currently there is no effective disease-modifying pharmacotherapy. One potential strategy is topical application of calcium chelating agents, able to penetrate the epidermal barrier and dissolve subcutaneous calcinotic deposits in situ. To date, the only compound reported for this application has been sodium thiosulfate (STS), with often-contradictory results.ObjectivesTo test the hypothesis, in pre-clinical studies, that polycarboxylic acids can induce calcium dissolution without skin toxicity, with the long-term aim of developing an effective topical treatment for cutis calcinosis.MethodsWe compared the metal ion-chelating agents citric acid (CA) and ethylenediaminetetraacetic acid (EDTA) - polycarboxylic acids with well-characterised chelation profiles – to STS for their ability to chelate calcium, without inducing cytotoxicity or inflammation (pro-inflammatory cytokine expression and release), using in vitro 2D (keratinocyte [HaCaT]; fibroblast ([HCA2]) and recombinant human epidermal (RHE) models. The resultant data was subsequently used to predict therapeutic concentrations for assessment in a validated skin irritation model (SkinEthicTM; Episkin SA) and to assay maximal percutaneous absorption. At relative dermal concentrations, the dissolution performance of each chelator was further assessed using two different models of calcinosis: 1) pharmaceutical dissolution of a hydroxyapatite (HAp) tablet (1) and; 2) dissolution of a calcified extracellular matrix laid down by mineralising SaOS2 in vitro monolayer culture (2).ResultsIncubation with CA, EDTA and STS induced cytotoxicity in both in vitro cell lines studied at concentrations of >10 mM; only EDTA (10 mM) resulted in inflammatory cytokine release (IL8) from cells at these higher concentrations (cf positive control, Lipopolysaccharide 10 mg/mL). When applied topically to RHE models as near-saturated solutions, none of the chelators were categorised as skin irritants. Due to differences in their relative aqueous solubility, higher concentrations of CA (1600 mM) and STS (1200 mM) could be delivered through the RHE model than EDTA (200 mM). Using a simple linear regression model, the rate of compound absorption was: CA, 0.43 ± 0.05; STS, 0.26 ± 0.03 and; EDTA, 0.05 ± 0.01 g/L/hr. At each time-point, the cumulative concentration of compound in the receptor media was CA > STS > EDTA. Incubation with chelators had no effect on the integrity of the RHE by standard histology. Based on the rate of percutaneous absorption, the dissolution performance of each chelator was tested at relative dermal concentrations for phosphate dissolution (nmoles) of HAp (CA, 9.61 ±0.97; EDTA, 5.38 ± 0.28; 3.78 ± 0.58) and in the calcified in vitro model (Figure 1; CA, 3285 ± 105, STS, 947 ± 95, EDTA, 1174 ± 89), showing the superiority of CA in both model systems.Figure 1.Dissolution of a calcified extracellular matrix by citric acidConclusionOverall, this study highlights the promise of polycarboxylic acids, particularly CA, to target subcutaneous calcification, which are neither toxic nor inflammatory to the skin. Specifically, we have identified CA as a potentially more efficacious alternative to STS for the topical treatment of cutis calcinosis.

Assessment of the electro-Fenton pathway for the removal of naphthalene from contaminated waters in remote regions

This work investigates the effectiveness of the electro-Fenton reaction for the treatment of wastewaters contaminated with petroleum hydrocarbons. More specific attention was given to field deployment applications in remote regions, such as the sub-Antarctic, where there is a need for low-cost technologies that can aid in remediation efforts. Naphthalene, a high priority pollutant for removal within these regions, was chosen as a model contaminant and treated with inexpensive graphite electrodes to promote the electro-Fenton pathway. Results show that naphthalene can be fully removed from a near-saturated solution, 20 mg/L, in less than 3 h of treatment. The underlying removal mechanisms were identified, and a kinetic model is presented that can accurately predict treatment outcomes at varying operating conditions of applied electric currents, 0–5 mA, and iron(II) concentrations, 0–2.0 mM. Optimal operating conditions for the electro-Fenton pathway were found to be at an applied current of 5 mA and an iron(II) concentration of 0.06 mM; this resulted in a specific energy consumption of 5.6 kWhr/kg of naphthalene removed, low enough to be operated in remote regions via sustainable energy sources.

Investigations into the Pharmacodynamic Effects of Dermally Administered Microemulsions Containing β-Blockers

Water uptake from the skin changes dermally applied near-saturated solutions of beta-blockers in microemulsion-bases into supersaturated microemulsions. Due to an enhanced thermodynamic activity, high absorption rates are expected from these preparations. The pharmacodynamic effect after dermal administration of such preparations has been evaluated using rabbits as a suitable in-vivo model. The dose dependency, influence of lipophilicity and of the thermodynamic activity of the drug is described. Assessment of dermal doses which were therapeutically equivalent to i.v. doses as, for example, shown with carazolol is possible. Although not all observed pharmacodynamic effects were due to these influences but rather due to the numerous other skin-vehicle-drug interactions which could not be explained with this model, the presented in-vivo model is helpful in evaluation of beta-blockers which were suitable candidates for transdermal administration.

Sonochemically induced decomposition of energetic materials in aqueous media

This study demonstrates that ultrasound rapidly degrades the energetic compounds RDX (cyclo-1,3,5-trinitramine-2,4,6-trimethylene) and ADN (ammonium dinitramide) in aqueous microheterogeneous media. The conditions for effective degradation of these nitramines, as monitored by UV absorption spectroscopy, were determined by varying sonication time, the heterogeneous phase and its suspension density, and the concentration of NaOH. In the presence of 5 mg/ml of aluminum powder and at pH∼12 (10 mM NaOH), 74% of the RDX and 86% of the ammonium dinitramide (ADN) in near-saturated solutions decompose within the first 20 min of sonication (20 kHz; 50 W; ⩽5 °C). Sonication without Al powder and base yields minimal degradation of either RDX and ADN (∼5–10%) or the nitrite/nitrate ions that are expected byproducts during RDX and ADN degradation. Sonication at high pH in the presence of dispersed aluminosilicate zeolite, alumina, or titanium dioxide also yields minimal degradation. Preliminary electrochemical studies and product analyses indicate that in situ ultrasonic generation of metallic aluminum and/or aluminum hydride drives reductive denitration of the nitramines. Sonochemical treatment in the presence of a reductant offers an effective and rapid waste remediation option for energetic waste compounds.

Raman Spectral Investigation of the Complex Species of Ferric Chloride in Concentrated Aqueous Solution

Raman spectra of concentrated aqueous solutions of ferric chloride were recorded in the spectral range 50 to 500 cm−1. In near-saturated solutions, spectra show a four-line pattern typical of the tetrahedral FeCl4– complex: 390 cm−1 (w); 335 cm−1 (vs, p); 135 cm−1 (w); 110 cm−1 (s). At lower concentrations a new species dominates the spectrum, showing characteristic Raman lines at 318 cm−1 (s, p) and 165 cm−1 (vw). Conventional investigations of spectral changes with concentration of Fe(III) and chloride, coupled with group theoretical arguments, indicate that the stoichiometry of the complex must be FeCl3 or lower. Of the several symmetries that a FeCl3 complex might assume (C2v, C3v, D2h (dimer), and D3h), the D3h trigonal bipyramid structure FeCl3·2H2O with three equatorial chloride ligands and two axial waters is most compatible with the spectral evidence.