A brief history of toxicology in France during the last two centuries (1789-1989).

The history of toxicology in France over the last two centuries has been marked by numerous authors who have progressively broadened the fields of investigation: initially concerned with criminal or accidental poisonings, they have also taken an interest in the environment, workers' health, doping and illicit products, the dangers of radioactivity or combat gases, the risks associated with drugs, etc. Often pharmacists, these toxicology experts were specialists in analytical chemistry and developed numerous methods to refine the detection and characterization of potentially toxic products, and to better understand the mechanisms of toxicity produced by these substances.

[Physico-chemical and toxicological profile of gadolinium chelates as contrast agents for magnetic resonance imaging]. / Physico-chimie et profil toxicologique d'agents de contraste pour l'imagerie par résonance magnétique, les chélates de gadolinium.

Gadolinium chelates (GC) are contrast agents widely used to facilitate or to enable diagnosis using magnetic resonance imaging (MRI). From a regulatory viewpoint, GC are drugs. GC have largely contributed to the success of MRI, which has become a major component of clinician's diagnostic armamentarium. GC are not metabolised and are excreted by the kidneys. They distribute into the extracellular compartment. Because of its high intrinsic toxicity, gadolinium must be administered as a chelate. GC can be classified according to two key molecular features: (a) nature of the chelating moiety: either macrocyclic molecules in which gadolinium is caged in the pre-organized cavity of the ligand, or linear, open-chain molecules, (b) ionicity: Gd chelates can be ionic (meglumine or sodium salts) or non-ionic. The thermodynamic and kinetic stabilities of the various GCs differ according to these structural characteristics. The kinetic stability of macrocyclic GCs is much higher than that of linear GCs and the thermodynamic stability of ionic GCs is generally higher than that of non-ionic GC, thus leading to a lower risk of gadolinium dissociation. This class of drugs has enjoyed an excellent reputation in terms of safety for a long time, until a causal link with a recently-described serious disease, nephrogenic systemic fibrosis (NSF), was evidenced. It is acknowledged that the vast majority of NSF cases are related to the administration of some linear CG in renally-impaired patients. Health authorities, worldwide, released recommendations which drastically reduced the occurrence of new cases.

Multiple sclerosis and access to healthcare in the Pays de la Loire region: preliminary study based on 130 self-applied double questionnaires.

OBJECTIVE: To check whether the use of an autoquestionnaire is adapted to obtain information about perceptions of multiple sclerosis (MS) patients concerning access to healthcare in the Pays de la Loire region of France. PATIENTS AND METHODS: Patients with MS were asked to complete a questionnaire concerning access to 31 healthcare professionals or social services. The questionnaires were anonymous and consisted of one page for the patient and one page for a member of his or her entourage. The questionnaires were returned in a prepaid stamped addressed envelope. The first 130 exploitable questionnaires were analysed. RESULTS: Over 50% of patients with MS found access to general practitioners, neurologists, nurses and pharmacists useful, as well as access to less MS-specific specialists, for example, dentists, ophthalmologists or gynaecologists. Physical medicine and rehabilitation practitioners were not required until later in the course of the disease. Patients and their entourage rated the importance of access to care differently for bladder and sexual problems, and for support for cognitive and psychological problems. CONCLUSION: This study validates the use of a questionnaire to obtain information about patient perceptions of access to healthcare. The study also suggests a hierarchy of care needs, insufficient patient information, and disparities in access to care related to where the patients live.

[Nanoparticles: the industrial viewpoint. Applications in diagnostic imaging]. / Nanoparticules : le point de vue d'un industriel. Applications en imagerie diagnostique.

Iron oxide particles can be divided into two categories: small superparamagnetic iron oxide (SPIO) and ultrasmall superparamagnetic iron oxide (USPIO). Both describe nanoparticles most often formulated with dextran or dextran derivatives. For magnetic resonance imaging, these agents are of major importance because of their superparamagnetic effect, that is the magnetic field generated locally by their presence. Clinical applications have been well differentiated: 1) SPIO (larger than 50nm) are mainly used via intravenous infusion to detect and characterize small focal lesions in the liver. SPIO can also be given orally to visualize the digestive tract; 2) USPIO (smaller than 50nm) have a longer plasmatic half-life (>36hours) and exhibit slower uptake by liver and spleen after intravenous administration. This allows the product to access macrophages in normal (lymph nodes) or diseased tissue (multiple sclerosis, graft rejection, atheroma plaques, stroke, rhumatoid arthritis). They can also be used as biomarkers to evaluate the efficacy of treatments. In addition to routine clinical applications, these agents are also under investigation to improve diagnoses in oncological, inflammatory and degenerative as well as cardiovascular diseases (risk of atheroma plaques).

Bioavailability of oral vs intramuscular iodinated oil (Lipiodol UF) in healthy subjects.

BACKGROUND: In order to fight against iodine deficiency, the essential cause of endemic goiter and cretinism, several health organizations promoted campaigns of iodinated oil (Lipiodol UF) administration using iodinated oil administered intramuscularly. However, it seems preferable to administer iodinated oil orally, as this is more appropriate and since the efficacy of this route has been demonstrated as well as for intramuscular route by controlled clinical trials. OBJECTIVE: To assess the bioavailability of iodinated oil (Lipiodol UF) administered via two different administration routes and the safety profile of this agent. DESIGN: A randomized bioavailability study was performed comparing a single oral dose of 3 capsules (570 mg of iodine) vs a single intramuscular injection of 1 ml of Lipiodol UF (480 mg of iodine) in 36 healthy subjects followed for 9 months. RESULTS: The results show that, at these dosages, the 24 h urinary iodine values are above baseline for both oral and intramuscular administrations (im: >12 months/oral: 6 months) for prolonged period of time. In terms of safety, Lipiodol, administered by im injection or orally, did not induce any undesirable effects or any alteration of thyroid function tests in this study. CONCLUSIONS: In conclusion, this study shows that im or oral administration of a single dose of Lipiodol provides a significant and prolonged iodine supplement. The results obtained confirm the possibility of protection of exposed populations after annual administration of an appropriate single oral dose, without inducing any clinical or laboratory adverse effects. The product, by either route of administration, has a prolonged efficacy in iodine-deficient subjects (im: 2-3 years/oral: 1 year).

Safety and pharmacokinetics of p792, a new blood-pool agent: results of clinical testing in nonpatient volunteers.

RATIONALE AND OBJECTIVES: To evaluate the safety and pharmacokinetics of P792, a new macromolecular blood-pool agent for magnetic resonance imaging (MRI), in nonpatient volunteers. METHODS: This was a single blind, placebo-controlled, ascending-dose study in 32 healthy male volunteers, randomized to receive a single intravenous dose of P792 (0.0065, 0.013, 0.026, and 0.039 mmol/kg). The safety controls consisted of complete pre- and postdose physical examinations, measurement of vital signs, clinical laboratory investigations, and monitoring of adverse events (up to 22 days after injection). For pharmacokinetic analysis, the determination of P792 was performed using the ICP-MS technique for blood and urine samples up to 22 days. RESULTS: No serious adverse events occurred during the study. There were no clinically significant changes in vital signs, or clinical laboratory findings. P792 blood half-life, distribution volume, and renal clearance are consistent with the definition of a rapid clearance blood-pool agent (RCBPA) as defined previously. CONCLUSION: P792 appeared to be a safe and well-tolerated RCBPA in nonpatient subjects. Phase II studies will be conducted to evaluate the efficacy of the blood-pool agent for vascular, perfusion, and permeability imaging in MRI.

Hepatocyte-mediated transport to the bile of AMI-HS, a particulate contrast agent.

RATIONALE AND OBJECTIVES: The elimination of hepatocyte-directed particulate contrast agents has not been studied in the same detail as particles eliminated mainly by the mononuclear phagocyte system. The aim of the present study was to elucidate the fate of these particles by a multidisciplinary approach. METHODS: After intravenous injection of AMI-HS particles directed to the hepatocytes, rats were killed and cytological studies, by both electron microscopy and histochemistry, and spectroscopic studies of the bile were performed. The data were compared with a dynamic magnetic resonance study of the heart and liver. RESULTS: The particles were rapidly cleared from the blood by Kupffer cells and hepatocytes and then found first in the vascular and later in the biliary pole of the hepatocytes. After 24 hours, a relaxometric characterization of the bile showed the presence of unchanged particles in the bile. CONCLUSIONS: These results show the capacity of the liver to excrete unchanged AMI-HS particles directly into the bile.

Physicochemical and biological evaluation of P792, a rapid-clearance blood-pool agent for magnetic resonance imaging.

RATIONALE AND OBJECTIVES: To summarize the physicochemical characterization, pharmacokinetic behavior, and biological evaluation of P792, a new monogadolinated MRI blood-pool agent. METHODS: The molecular modeling of P792 was described. The r1 relaxivity properties of P792 were measured in water and 4% human serum albumin at different magnetic fields (20, 40, 60 MHz). The stability of the gadolinium complex was assessed. The pharmacokinetic and biodistribution profiles were studied in rabbits. Renal tolerance in dehydrated rats undergoing selective intrarenal injection was evaluated. Hemodynamic safety in rats and in vitro histamine and leukotriene B4 release were also tested. RESULTS: The mean diameter of P792 is 50.5 A and the r1 relaxivity of this monogadolinium contrast agent is 29 L x mmol(-1) x s(-1) at 60 MHz. The stability of the gadolinium complex in transmetallation is excellent. The pharmacokinetic and biodistribution profiles are consistent with that of a rapid-clearance blood-pool agent: P792 is mainly excreted by glomerular filtration, and its diffusion across normal endothelium is limited. Renal and hemodynamic safety is comparable to that of the nonspecific agent gadolinium-tetraazacyclododecane tetraacetic acid. No histamine or leukotriene B4 release was found in RBL-2H3 isolated mastocytes. CONCLUSIONS: The relaxivity of P792 at clinical field is very high for a monogadolinium complex without protein binding. The pharmacokinetic and biodistribution profiles are consistent with those of a rapid-clearance blood-pool agent. Its initial safety profile is satisfactory. Experimental and clinical studies are underway to confirm the potential of P792 in MRI.

Carboxymethyldextran-A2-Gd-DOTA enhancement patterns in the abdomen and pelvis in an animal model.

The aim of this study was to assess MR signal enhancement patterns of carboxymethyldextran (CMD)-A2-Gd-DOTA, a new macromolecular contrast agent, in the abdomen and pelvis of New Zealand white rabbits. Nine New Zealand white rabbits underwent MRI before and following injection of 0.05 mmol/kg body weight (bw) CMD-A2-Gd-DOTA (52.1 kDa), using turbo FLASH-, dynamic FLASH 60 degrees-, T1- and T2-weighted spin-echo and turbo spin-echo sequences up to 10 days p.i. Changes in blood and tissue signal intensities (deltaSI) and relaxation rates (deltaR1) were calculated. Differences between pre- and post-contrast MRI data were compared using the Scheffé test. CMD-A2-Gd-DOTA demonstrated significant blood-pool enhancement and significant tissue enhancement on T1-weighted images, whereas no significant signal changes were observed on T2-weighted images (P < 0.05). Kidney parenchyma, pelvis and bladder demonstrated a subsequent enhancement, resembling renal elimination of the majority of the contrast agent. Liver parenchyma demonstrated a slow, delayed decay of the contrast enhancement due to storage and biodegradation of larger subfractions of the contrast agent. All tissue signal intensities were back to baseline 10 days p.i. CMD-A2-Gd-DOTA is a new macromolecular contrast agent with blood-pool effect, significant signal enhancement of abdominal organs and pelvic bone marrow, partial storage in the liver and baseline tissue signal intensities by 10 days p.i.

Preclinical profile of the monodisperse iodinated macromolecular blood pool agent P743.

RATIONALE AND OBJECTIVES: To summarize the chemical synthesis, physicochemical characterization, pharmacokinetic behavior, and biological evaluation of P743, a new macromolecular iodinated contrast medium. METHODS: The synthesis and molecular modeling of the iodinated macromolecule P743 are described. The pharmacokinetic profile was established in rabbits and rats. Acute toxicity in mice, renal tolerance in normal rabbits, and renal tolerance in uninephrectomized, dehydrated rats undergoing selective intrarenal injection was evaluated. In vitro permeability effects on isolated mastocytes and on the coagulation pathways were carried out. Computed tomography vascular imaging was performed after intravenous injection of P743 (300 mg I/kg) in rabbits and compared with the nonspecific nonionic agent iobitridol. RESULTS: P743 is a monodisperse, macromolecular iodinated contrast medium. In both rabbits and rats, P743 showed a pharmacokinetic profile consistent with that of a rapid-clearance blood-pool agent. Its diffusion through the endothelium was found to be low in vitro, thus confirming early confinement of this macromolecule, unlike nonspecific contrast media. In both species, P743 was excreted by glomerular filtration. Acute toxicity disclosed no mortality at the highest volume that could be injected into mice, leading to a median lethal dose greater than 8.9 g I/kg. Renal tolerance was found to be good in both euvolemic rabbits and uninephrectomized, dehydrated rats. No histamine or leukotriene B4 release was found on RBL-2H3 isolated mastocytes. P743 did not interfere with the coagulation pathways. Imaging experiments confirmed that P743 remains in the vascular compartment for a longer time than does iobitridol, thus allowing vascular enhancement that is twice as high as that of iobitridol in the recirculation phase. CONCLUSIONS: The pharmacokinetic and imaging profiles of P743, a new, monodisperse, macromolecular blood-pool iodinated contrast medium, were consistent with those of a rapid-clearance blood-pool agent. Its initial safety profile is satisfactory. Further experimental imaging studies are required to define the clinical interest in such molecules.

[The Swiss Commission of Goiter of January 21, 1922]. / La Commission suisse du goitre du 21 janvier 1922, une séance historique quant á l'usage du sel iodé en Suisse et dans les pays occidentaux.

The Swiss Commission of Goiter met for the first time the 21st of January, 1922 and has been the first step of an historical event in terms of Public Health: the first requirement for salt iodination for the prevention of goiter. The minutes of this commission as well as the following scientific publications until 1930 indicate that the debate was still very vigorous about this recommendation but mainly about the origin of goiter and the iodine dose to be used. This dose went progressively from less than 10 mg of iodine per kilo of salt to the present WHO recommendation of 20 to 40 mg of iodine per kilo of salt. Another key point was the strategy of implementation of iodine. Two complementary approaches were proposed and implemented: iodine supplement to children at school and iodized salt available for the whole population. One point seemed clear for everyone at that time: iodine was not the source of goiter. Later scientific studies have shown that iodine deficiency was indeed the origin of goiter and associated pathologies.

Niosomes as carriers of radiopaque contrast agents for X-ray imaging.

Non-ionic surfactant vesicles (niosomes) are considered as carriers of iobitridol, a diagnostic agent used for X-ray imaging. The niosomes, with a diameter between 150 and 175 nm, are prepared using the film-hydration method followed by sonication. These vesicles were obtained with appropriate mixtures of D-alpha tocopheryl polyethylene glycol 1000 succinate, polyoxyethylene glycol 4000 stearate, sorbitan monostearate, cholesterol and dicetylphosphate. Methods allowing the increase of the rate of encapsulation and the stability of the vesicles were carried out. In addition to the study of the formulation of the vesicles, the physico-chemical and morphological properties of the vesicles have been studied.

Physical, chemical, and biological evaluations of P760: a new gadolinium complex characterized by a low rate of interstitial diffusion.

An original gadolinium chelate, termed P760, which diffuses through the vascular endothelium but at a much lower rate than nonspecific agents (NSA), is described. P760 is a gadolinium macrocyclic compound based on a DOTA structure that is substituted by hydrophilic bulky groups branched on the amino-carboxylic residues. The molecular weight is 5293, and the molecular volume, measured by light scattering, is 30 times higher (11.5 nm3) than that of gadolinium (Gd)-DOTA (0.38 nm3). The increase in molecular volume and weight has two consequences: a) higher relaxivity (r1; 24.7 mM-1.s-1 compared with 3.4 mM-1.s-1 for Gd-DOTA at 20 Mhz, 37 degrees C); and b) a lengthening of its transport rate through the endothelium. P760 presents a peculiar pharmacokinetic profile: at early times post injection, the blood concentrations are higher than those of Gd-DOTA, but after 20 minutes, the blood concentrations are equal for the two compounds. The body clearances of the products are identical (i.e., glomerular filtration rate). P760 molecules are large enough to have a restricted diffusion through the endothelium but, conversely, small enough to pass freely through the glomerular membrane. This limited extravasation has been observed in rabbits by magnetic resonance angiography or in investigations of tumor permeability. Further experimental imaging studies are needed to define the clinical interest of such properties.

[Lipiodol therapeutic indications from 1901 to 1930]. / Les usages therapeutiques du lipiodol, seule "huile iodee vraie", entre 1901 et 1930.

Iodine and iodide used to be very successful drugs, sometimes at massive doses. Highly iodinated oil such as lipiodol from Lafay discovered in 1901 were part of expanding the therapeutic use of iodine for various pathologies such as syphilis, cardiovascular and respiratory diseases, leprosy, goiter... The present publication reviews unpublished documents and publications from 1901 to 1930 on lipiodol to give an overview of therapeutic indications for this agent and the rationale behind it. In some areas such as asthma, iodide was still in use until the eighties. Prevention and treatment of endemic goiter is the only remaining domain for the therapeutic usage of lipiodol. It is the only reason why this product is on the WHO essential drugs list.

[Iodine usage about 1880 by Antoine de Finance's formulary]. / L'usage therapeutique de l'iode vers 1880 a travers le formulaire magistral personnel d'Antoine de Finance, medecin de famille.

After the discovery of iodine by Courtois in 1812, this metal was very much in vogue for all the XIXth century for the treatment of numerous diseases. Antoine de Finance (1846-1898), family physician, described iodine and iodine derivatives usage in his own formulary, following the usual contemporary references (Bouchardat, Dorvault). As for those references, iodine was useful for diseases as different as lung diseases, tumors and syphilis but he added angor. As opposed to Bouchardat that used more than 129 formulations for iodine and iodine derivatives, Antoine de Finance is limited to 6 of them. This trend of using iodine for medicine will continue after the XIXth century and will remain essential at the beginning of the XXth century with the discovery of stable iodinated oils such as Lipiodol created in 1901 and first used for syphilis. This therapeutic usage of iodine will remain until today for preventive and curative treatment of iodine deficiency disorders.

P760 and P775: MRI contrast agents characterized by new pharmacokinetic properties.

RATIONALE AND OBJECTIVES: In this paper we discuss novel MR imaging blood pool agents characterized by new pharmacokinetic properties. METHODS: The pharmacokinetics of the products were studied in a rabbit model. The potential of these new products was demonstrated in experimental MR imaging. RESULTS AND CONCLUSION: Three main classes of blood pool agents have been defined and characterized according to their pharmacokinetic properties: low diffusion agents, rapid clearance blood pool agents, slow clearance blood pool agents. Each kind of blood pool agent is expected to have different diagnostic applications.

Electron microscopy study of intrahepatic ultrasmall superparamagnetic iron oxide kinetics in the rat. Relation with magnetic resonance imaging.

Ultrasmall superparamagnetic iron oxide (USPIO) contrast agents for use in magnetic resonance imaging (MRI) are currently undergoing clinical evaluation. However, the images observed and the kinetic profiles obtained differ from one agent to another. In this study, BD IX rats received an intravenous penis injection of the USPIO contrast agents AMI-HS and AMI-227. A cytologic study of the liver was performed, and the data obtained were compared with those of MRI. Images acquired in light microscopy, transmission electron microscopy, microanalysis and electron diffraction provided data on the cell categories involved in the processing of these contrast agents, the importance and modalities of each category relative to this processing, and the modalities of agent elimination. AMI-HS was rapidly removed from the bloodstream by Kupffer's cells and hepatocytes and then eliminated through bile ducts. AMI-227 remained much longer in the blood compartment since it was processed very slowly by endothelial and Kuppfer's cells in the near absence of hepatocytic participation and thus of elimination by the bile ducts. These results allowed us to base our interpretation of MRI sequences on cytologic observations.

Subcutaneous and intravenous delivery of diagnostic agents to the lymphatic system: applications in lymphoscintigraphy and indirect lymphography.

Lymph node status is important in the staging of many malignancies. Although tissue characterization by histologic analysis of biopsy samples may improve staging, noninvasive staging is more acceptable to both patients and clinicians. Several imaging techniques may serve this goal. Modern noninvasive techniques such as computed tomography and magnetic resonance detect lymph node abnormality by nodal enlargement, but that does not always imply malignant involvement. On the other hand, many nodes are infiltrated or replaced by tumour without change in size. This becomes a serious diagnostic defect by these modalities. Consequently, attention has been focused to develop contrast agents and radiolabelled complexes for better cancer detection as well as characterization of individual tumours in lymph nodes. For delivery of such materials to regional lymph nodes one can take advantage from the distinct physiological function of the lymphatic capillaries. The thin-walled and fenestrated lymphatic microvessel is easily penetrated by particulate and macromolecular agents after injection into the extracellular space. Once inside the vessel, materials that are transported with the lymph either specifically target certain nodal elements (e.g. neoplastic cells) or become cleared by macrophages located in the lymph nodes. Indeed, interstitial delivery of diagnostic agents have been of benefit in determining regional spread of cancer and assessing lymphatic function either by lymphoscintigraphy or indirect lymphography. On the other hand, development of contrast materials that can reach lymph nodes after a single intravenous injection is highly desirable because of the large number of lymph nodes in the body and access being difficult to most of them. Today, a number of contrast agents exist that can reach a vast array of lymph nodes in the body, particularly those that are not readily accessible for histologic evaluation, after a single intravascular injection to help distinguish between normal and tumour-bearing nodes or reactive and metastatic nodes with magnetic resonance. In this article we critically examine advantages and limitations of both subcutaneous and intravenous routes of injection for the delivery of diagnostic agents to the lymphatic system.

[Vascular contrast agents. Definition and potential applications]. / Les produits à rémanence vasculaire. Définition et applications potentielles.

Blood pool agents are characterized by a biodistribution limited to the vascular space after intravenous injection. This is different from uroangiographic agents in CT Scanner or Gd chelates in MRI which are markers for the intra and extravascular space. This unique property is potentially useful for diagnostic applications such as ischemic diseases (myocardial or cerebral perfusion defects), vascular diseases and diagnostic or follow-up of endothelial permeability disorders (diabetic patients, tumors...).