Cardiovascular effects of selected water-miscible solvents for pharmaceutical injections and embolization materials: a comparative hemodynamic study using a sheep model

Article Article scientifique Article Cardiovascular effects of selected water-miscible solvents for pharmaceutical injections and embolization materials: a comparative hemodynamic study using a sheep model eng 2007 author Laurent Alexandre author Mottu Henry 21994 author Chapot René author Zhang Jong Qi author Jordan Olivier 0000-0003-3752-2198 133859 author Rufenacht Patricia 26149 author Doelker Eric 25151 author Merland Jean-Jacques 64-74 17479714 1079-7440 Generally, organic water-miscible solvents are used intravascularly (both intravenously and intra-arterially) for preparing two types of formulations, namely, pharmaceutical injections of poorly soluble drugs and precipitating liquid embolic polymeric materials for the minimally invasive treatment of aneurysms, arteriovenous malformations, or tumors, by arterial route. Although several of such solvents have been used in both drug delivery and interventional radiology, their safety profile is a concern. In particular, there is a lack of comparative investigations of their cardiovascular effects when injected intra-arterially. We selected 13 non-aqueous water-miscible solvents based on their capacity to solubilize drugs or embolic polymeric materials, and on their described use, at least diluted with water, in pharmaceutical formulations. Their in vivo hemodynamic toxicity in male adult sheep after infra-renal aorta catheterization has been estimated with respect to the arterial and venous pressures, as well as the heart rate. Saline solution was used as a control. Three different volumes (0.1, 0.5, and 1.0 mL) were infused rapidly. An increase in arterial pressure and concomitant decrease in venous pressure, which we considered as signs of a cardiovascular toxicity, were observed to a differing extent for all organic solvents. Changes in heart rate were negligible. Based on the intensity of arterial pressure change after a 1-mL infusion, a classification of the toxicity of the solvents following intra-arterial infusion is proposed: Solvents devoid of significant cardiovascular toxicity: dimethyl isosorbide (DMI), Glycofurol 75, polyethylene glycol 200 (PEG 200), diglyme. Solvents with moderate cardiovascular toxicity: tetrahydrofurfuryl alcohol (THFA), ethanol, acetone, Solketal, glycerol formal, dimethyl sulfoxide (DMSO). Solvents with marked cardiovascular toxicity: propylene glycol, ethyl lactate, N-methyl-2-pyrrolidone (NMP). Emphasis is put on the relative character of the proposed ranking and on the lack for certain solvents, at least in the open literature, of data pertaining at other forms of toxic effects (e.g., undesirable pharmacological action, carcinogenicity, teratogenicity, mutagenicity, and irritating and sensitizing properties), all factors that have to be considered when selecting a proper solvent. Animals Blood Pressure/drug effects Chemistry, Pharmaceutical Embolization, Therapeutic/methods Heart Rate/drug effects Infusions, Intra-Arterial Male Models, Animal Pharmaceutical Preparations/administration & dosage/chemistry Polymers/administration & dosage/chemistry Sheep Solubility Solvents/administration & dosage/chemistry/classification/toxicity Time Factors Venous Pressure/drug effects Water/chemistry Dewey 615 31 Section des sciences pharmaceutiques 17 false PDA journal of pharmaceutical science and technology 61 2 16e9c990-7bab-4c3c-b832-79b2fb19293e Article (Accepted version) Restricted article.pdf 112102 application/pdf restrictedAccess Faculté des sciences / Section des sciences pharmaceutiques

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Cardiovascular effects of selected water-miscible solvents for pharmaceutical injections and embolization materials: a comparative hemodynamic study using a sheep model	PDA journal of pharmaceutical science and technology			2007	602	0

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Rufenacht, Patricia