The Cutaneous Lesions of Dioxin Exposure: Lessons from the Poisoning of Victor Yushchenko

Several million people are exposed to dioxin and dioxin-like compounds, primarily through food consumption. Skin lesions historically called "chloracne” are the most specific sign of abnormal dioxin exposure and classically used as a key marker in humans. We followed for 5 years a man who had been exposed to the most toxic dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), at a single oral dose of 5 million-fold more than the accepted daily exposure in the general population. We adopted a molecular medicine approach, aimed at identifying appropriate therapy. Skin lesions, which progressively covered up to 40% of the body surface, were found to be hamartomas, which developed parallel to a complete and sustained involution of sebaceous glands, with concurrent transcriptomic alterations pointing to the inhibition of lipid metabolism and the involvement of bone morphogenetic proteins signaling. Hamartomas created a new compartment that concentrated TCDD up to 10-fold compared with serum and strongly expressed the TCDD-metabolizing enzyme cytochrome P450 1A1, thus representing a potentially significant source of enzymatic activity, which may add to the xenobiotic metabolism potential of the classical organs such as the liver. This historical case provides a unique set of data on the human tissue response to dioxin for the identification of new markers of exposure in human populations. The herein discovered adaptive cutaneous response to TCDD also points to the potential role of the skin in the metabolism of food xenobiotic

Radiopaque polymeric materials for medical applications : current aspects of biomaterial research

The aim of this review is to give an overview and some insight into different radiopaque polymeric materials that are currently used as medical implants or inserts. The advantages and limitations of each radiopaque polymeric material are summarized. The main method used to make medical implants radiologically visible is based on blending polymers with conventional radiopaque agents, blends which usually are a physical mixture of acrylic derivatives and inorganic salts. Other methods reported involve either the formation of single-phase radiopaque polymer salt complexes somehow preventing the release of the radiopacifying element by entrapment of the complex in a crosslinked network, or radiopaque polymerized monomers characterized by a radiopacifying element associated with the monomer unit prior to polymerization. In the near future, research will certainly concentrate on biocompatible radiopaque polymers with covalently bound opaque elements leading to stable polymers with properties equivalent to the nonopaque, parent polymer

Iodine-containing cellulose mixed esters as radiopaque polymers for direct embolization of cerebral aneurysms and arteriovenous malformations

The present study deals with the synthesis and characterization of radiopaque polymers which could, when solubilized in an appropriate water-miscible solvent, be useful embolic materials for the treatment of cerebral aneurysms and arteriovenous malformations. For this purpose cellulose (both microcrystalline and powdered) and partially substituted cellulose acetate (two different viscosity grades) were selected as starting materials to prepare iodine-containing polymers through various synthetic routes. The materials obtained were characterized by IR and NMR spectroscopy, molecular weight, iodine content, radiopacity and solubility in selected injectable organic solvents. The embolic liquids were evaluated for their precipitation behavior in a phosphate buffer solution (pH 7.4) mimicking physiological conditions using an in vitro aneurysm model. A sheep model was also used to assess in vivo the radiopacity and precipitation properties of a highly concentrated solution of a cellulose acetate 2,3,4-triiodobenzoate mixed ester. All materials with 4-iodo- and 2,3,5-triiodobenzoyl groups gave sufficient radiopacity to be regarded as possible embolization materials, whereas iododeoxycellulose and iododeoxycellulose acetate were not radiopaque because of their low iodine content. Esters synthesized using cellulose as starting material were not soluble in the selected organic solvents due to the presence of many residual hydroxyl groups, but could be used for other biomedical applications where insoluble radiopaque materials are used. In contrast, solubility of the materials as well as satisfactory precipitation properties were ensured using cellulose acetate as the starting material. In conclusion, cellulose acetate iodobenzoate mixed esters dissolved in diglyme or dimethyl isosorbide (dimethyl sulfoxide is probably less appropriate because of its toxicity and hemolytic properties) could be useful embolic liquids for the treatment of cerebral aneurysms or arteriovenous malformations

Comparative hemolytic activity of undiluted organic water-miscible solvents for intravenous and intra-arterial injection

In humans, nonaqueous solvents are administered intravascularly in two kinds of situations. They have been used in subcutaneous or intramuscular pharmaceutical formulations to dissolve water-insoluble drugs. The need for these vehicles had increased in recent years, since the drug development process has yielded many poorly watersoluble drugs. The use of water-miscible nonaqueous solvents is therefore one of the approaches for administering these products as reference solutions useful in formulation bioequivalence studies. The intravascular use of organic solvents has also gained importance owing to a new approach for the treatment of cerebral malformations using precipitating polymers dissolved in water-miscible organic solvents. At present, the solvent most commonly used for the liquid embolics to solubilize the polymers is dimethyl sulfoxide, which exhibits some local and hemodynamic toxicities. In order to find new, less toxic vehicles for pharmaceutical formulations for the intravenous and intra-arterial routes and for embolic materials, 13 water-miscible organic solvents currently used (diluted with water) for pharmaceutical applications, were evaluated in this study. Their hemolytic activity and the morphological changes induced when mixed with blood (1:99, 5:95, 10:90 solvent:blood) were estimated in vitro. From these data, the selected organic solvents could be subdivided into four groups depending on their hemolytic activity: very highly hemolytic solvents (ethyl lactate, dimethyl sulfoxide), highly hemolytic solvents (polyethylene glycol 200, acetone), moderately hemolytic solvents (tetrahydrofurfuryl alcohol, N-methyl-2-pyrrolidone, glycerol formal, ethanol, Solketal, glycofurol) and solvents with low hemolytic activity (propylene glycol, dimethyl isosorbide, diglyme).</p

Organic solvents for pharmaceutical parenterals and embolic liquids: <i>a review of toxicity data</i>

Non-aqueous solvents have long been used in subcutaneous or intramuscular pharmaceutical formulations to dissolve water-insoluble drugs. In recent years, the need for these vehicles was increased since the drug discovery process has yielded many poorly water-soluble drugs. Besides, preparations containing embolic materials dissolved in undiluted non-aqueous water-miscible solvents have been proposed for the intravascular treatment of aneurysms, arteriovenous malformations, or tumors. These organic solvents, regarded as chemically and biologicallyinert, may show pharmacological and toxicological effects. Therefore, knowledge of tolerance and activity of nonaqueous solvents is essential before they can be administered, especially when given undiluted. This paper focuses on thirteen organic solvents reported as possible vehicles for injectable products and details toxicological data when they have been administered intravascularly. These solvents can be subdivided into three groups according to their description in the literature either for intravenous pharmaceutical parenterals or for intravascular embolic liquids: well-documented organic solvents (propylene glycol, polyethylene glycols, ethanol), solvents described in specific applications (dimethyl sulfoxide, N-methyl-2-pyrrolidone, glycofurol, Solketal™, glycerol formal, acetone), and solvents not reported in intravascular applications but potentially useful (tetrahydrofurfuryl alcohol, diglyme, dimethyl isosorbide, ethyl lactate). This review of the literature shows that toxicity data on intravascular organic solvents are insufficient because they concern solvents diluted with water and because of the lack of comparative evaluation using the same methodologies

In vitro assessment of new embolic liquids prepared from preformed polymers and water-miscible solvents for aneurysm treatment

Treatment of cerebral aneurysms by embolic liquids has been proposed as an alternative strategy to coil or balloon techniques. In order to assess the feasibility of this approach, a general screening of preformed polymers dissolved in biocompatible, water-miscible solvents has been carried out. The solubilizing capacity of the solvents has been evaluated by the solubility parameters approach. The viscosity of the solutions has been determined and the precipitation characteristics of the embolic liquids have been investigated in phosphate buffer solution pH 7.4 at 37 degrees C to mimic physiological conditions. The radiopaque agent bismuth (III) oxide was added to solutions having appropriate precipitation characteristics and the angiographic assessment, in an in vitro aneurysm model, were consistent with the precipitation properties and confirmed that only hard and coherent masses allowed satisfactory embolization. However, the solubilizing prediction using the calculation of the solubility parameters was only partially successful owing to the highly hydrophilic functional groups of the chosen solvents. This failing justifies the experimental screening that was carried out. This study pointed out that the frequently used solvent dimethyl sulfoxide could be replaced by more biocompatible solvents offering the possibility of using other preformed polymers. In conclusion, nine solutions of the selected polymer-solvent combinations could be used as embolic liquids for the treatment of cerebral aneurysms with respect to their satisfactory precipitation properties and viscosity

The cutaneous lesions of dioxin exposure: lessons from the poisoning of Victor Yushchenko

Several million people are exposed to dioxin and dioxin-like compounds, primarily through food consumption. Skin lesions historically called "chloracne" are the most specific sign of abnormal dioxin exposure and classically used as a key marker in humans. We followed for 5 years a man who had been exposed to the most toxic dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), at a single oral dose of 5 million-fold more than the accepted daily exposure in the general population. We adopted a molecular medicine approach, aimed at identifying appropriate therapy. Skin lesions, which progressively covered up to 40% of the body surface, were found to be hamartomas, which developed parallel to a complete and sustained involution of sebaceous glands, with concurrent transcriptomic alterations pointing to the inhibition of lipid metabolism and the involvement of bone morphogenetic proteins signaling. Hamartomas created a new compartment that concentrated TCDD up to 10-fold compared with serum and strongly expressed the TCDD-metabolizing enzyme cytochrome P450 1A1, thus representing a potentially significant source of enzymatic activity, which may add to the xenobiotic metabolism potential of the classical organs such as the liver. This historical case provides a unique set of data on the human tissue response to dioxin for the identification of new markers of exposure in human populations. The herein discovered adaptive cutaneous response to TCDD also points to the potential role of the skin in the metabolism of food xenobiotics