Comparison of plasma and peritoneal concentrations of various categories of MRI blood pool agents in a murine experimental pharmacokinetic model.

The aim of this study was to validate an experimental model designed to distinguish four categories of contrast agents, non specific agents (NDA, Gd-DOTA) characterized by rapid and total extravasation; low diffusion agents (LDA, P760) characterized by delayed extravasation; and rapid (P792) and slow clearance (P717) blood pool agents (BPA) characterized by limited extravasation. Plasma and peritoneal gadolinium concentrations were simultaneously measured after intravenous injection of various contrast agents in mice. Products of each category were compared in this model.The plasma pharmacokinetic profiles were similar for Gd-DOTA and P760 (t1/2=13.3 and 13.8 min, respectively), whereas the half-lives were 22 and 1212 min for P792 and P717, respectively. The plasma clearance was inversely related to the size of the contrast agent. The intraperitoneal diffusion patterns of the various products were related to the molecular volume: C(max) per dose decreased progressively (78.7, 51.2, 44.2, 33.5 1/l) and t(max) increased (7, 15, 40, and 120 min) for Gd-DOTA, P760, P792 and P717, respectively. Nevertheless, the same quantities of Gd-DOTA and P760 (AUC ratio of 78.4 and 76.8, respectively) diffused into the peritoneum, whereas only 44.5% of P792 and 21.5% of P717 extravasated.The data obtained in this peritoneal permeability model with the various categories of contrast agents provide an estimation of the quantities of contrast agents diffusing into a permeable interstitium and may be used to predict the corresponding signal intensity, which can be measured locally.

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.

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.

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.

Nonionic compact dimers: a new generation of isosmolar iodinated contrast media with low viscosity.

RATIONALE AND OBJECTIVES: The authors evaluated compact dimers, a new class of molecule designed to reduce the osmolality of concentrated solutions of x-ray contrast media without increasing their viscosity. MATERIALS AND METHODS: Molecular modeling was used to design a new hexaiodo dimeric structure with low viscosity and good shielding of hydrophobic areas. This design ends in the synthesis of different prototypes, the structure of which was characterized by a single bond between two perpendicular rings and the presence of tertiary amides. The validity of this approach was investigated with measurements of physicochemical properties (viscosity, osmolality, logP) and pharmacologic studies (urinary and biliary excretion, intravenous and intracerebral medial lethal dose). RESULTS: Solutions of the compact dimers at a concentration of 350 mg of iodine per milliliter combine osmolalities that are close to that of blood with viscosities at ambient temperature nearly half those of commercially available dimers. Furthermore, these new compounds have a tolerance level comparable with that of currently used nonionic media (intravenous median lethal dose, > 17.5 g of iodine per kilogram). CONCLUSION: The three-dimensional structure of the compact dimers has made it possible to control both physicotoxicity and chemotoxicity by combining isotonicity and low viscosity with good tolerance.

Physical, chemical and biological evaluations of CMD-A2-Gd-DOTA. A new paramagnetic dextran polymer.

PURPOSE: We investigated the synthesis and physical, chemical and biological characterisation of a carboxymethyl-dextran polymer substituted with the paramagnetic macrocyclic complex Gd-DOTA using an amino spacer. MATERIAL AND METHODS: The product was synthesised in 4 steps. Using rigorous purification conditions in each step, a polymer was obtained, i.e. CMD-A2-Gd-DOTA, whose polydispersity profile was comparable to the initial dextran (I = 1.66-Mw = 50.5 kDa). Approximately 22% of the glucose groups were replaced by Gd-DOTA and 39% were replaced by carboxyl groups. The paramagnetic efficacy of the polymer was 3 times higher than Gd-DOTA alone, which suggests that the injected doses of Gd(III) can be reduced. The vascular residence time of the polymer was measured in rats and rabbits, showing that the pharmacokinetics of the product is similar whatever the dose. Forty-five percent of the product was excreted in urine after 24 h and 1.64% was found in the liver. No acute toxicity was observed at the maximum dose injected (> 5 mmol Gd/kg) and the general biocompatibility of the product tested in vitro was comparable to that of Gd-DOTA. RESULTS AND CONCLUSION: These results show the advantages of using paramagnetic macrocyclic complexes in the synthesis of macromolecules to preserve biological stability, in contrast with linear chelates. Additional studies will be carried out to demonstrate the benefits of this type of product, particularly in functional imaging.

Secretion in milk and transplacental transfer of two iodized oils, Lipiodol UF and Oriodol, in rabbits.

Many countries in the world are inhabited by populations suffering from iodine deficiency. These populations are affected by serious diseases directly related to iodine deficiency. Iodized oil (Lipiodol UF or Oriodol) is routinely used orally or intramuscularly to treat these populations, including pregnant women. The experiments of the present study in gravid or lactating rabbits show that there is transplacental transfer of iodine and secretion of iodine in milk after administration of iodized oil and consequently an accumulation of iodine in the thyroid glands of the mother, the fetus and the neonate. The advantages of treating pregnant women with iodized oil in the populations concerned is thus confirmed. The oral route can be substituted by the intramuscular route.

High-performance liquid chromatographic determination of iobitridol in plasma, urine and bile.

Iobitridol is a new non-ionic, low-osmolality contrast medium for urography and angiography. We have developed a method for determining iobitridol in body fluids using high-performance liquid chromatography with ultraviolet detection. The method, which is specific and reproducible, does not require an internal standard. Determinations can be carried out in body fluids against a set of standards in ethanol. The method was validated for the quantification of iobitridol in biological samples obtained during pharmacokinetic studies.

Transplacental passage and milk excretion of iobitridol.

RATIONALE AND OBJECTIVES: Iobitridol, a new nonionic, low-osmolality urographic and angiographic contrast medium, is a marker of extracellular fluid. Excretion of iobitridol in goat's milk and transplacental passage in the gestating rabbit were evaluated compared with iohexol. METHODS: Both products were determined in biologic samples by two analytic methods: ultraviolet spectrometry (milk) and high-pressure liquid chromatography (maternal and fetal blood and amniotic fluid). RESULTS: Excretion in the milk represents 0.7% of the administered dose for iobitridol and 1.6% for iohexol. Transplacental passage is nonexistent. Iobitridol and iohexol behave in a similar manner. CONCLUSIONS: These preclinical results allow more effective prediction of the safety of iobitridol in pregnant or lactating women. However, precautions for use must be respected in the absence of specific studies in this population group.

Interlaboratory study for the assessment of potential irritative properties of hygiene products on the hamster cheek pouch.

An interlaboratory study was carried out to determine the feasibility and reliability of a method using the hamster cheek pouch as a model for assessing the potential irritative properties of substances intended to be applied to the lips or other mucous membranes. The test substances were applied once daily to both pouches for 14 consecutive days. Local and general tolerances were appraised throughout the study. At the end of the study, histologic examination of the pouches and the main organs was performed. Results of the feasibility study, conducted on various types of commercial products, indicated that this model is suitable for preparations of various consistence and composition. Results of the reliability study, carried out on gel-type preparations containing various concentrations of a known irritant, sodium lauryl sulfate, indicated that the method elicits a dose-dependent reaction for this compound. This hamster cheek pouch method was reproducible for the various parameters under consideration: local tolerance, general tolerance, histologic examination. For all products, results were in good agreement among the various laboratories participating in the study. The French regulatory authorities of the Fraud Repression Department have accepted it as an official method for the evaluation of the potential irritative properties of cosmetics and hygiene products intended to be applied to the lips or other mucous membranes.

Whole body quantitative autoradiographic study of the biodistribution of iobitridol in rats.

RATIONALE AND OBJECTIVES: Iobitridol is a new nonionic low-osmolality contrast medium. During preclinical development of this agent, it was of interest to verify that it behaves like other urographic and angiographic contrast agents (i.e., as a tracer of extracellular fluid). METHODS: Male and female rats were imaged using a quantitative autoradiographic method after intravenous administration of iodine-125-labeled product at a dose of 300 mg iodine/kg. RESULTS: The radioactivity was rapidly distributed with substantial uptake in the thyroid, kidneys, and skin after 10 minutes. The central nervous system showed no uptake. The radioactivity was rapidly eliminated (i.e., after 24 and 48 hours, only traces were found) except in the thyroid (because of free radiolabeled iodides present in small quantities in the administered solution). The considerable renal uptake after administration can be attributed to urinary excretion of the radioactivity (86% of the administered dose after 24 hours). Total elimination was achieved after 48 hours. No sex-related effects were observed. CONCLUSION: The absence of a target organ, the abundant and rapid urinary elimination, and the absence of transfer across the blood-brain barrier suggest that iobitridol is a tracer of extracellular fluid.

Preparation and characterization of novel poly(methylidene malonate 2.1.2.)-made nanoparticles.

Poly(methylidene malonate 2.1.2.) (PMM 2.1.2.) nanoparticles were prepared in phosphate buffer through emulsion polymerization of monomeric units; the kinetics of the reaction was monitored by spectrophotometry at 400 nm. Average nanoparticle sizes, molecular weights, and biodegradability of this potential drug carrier were determined under various conditions. As previously demonstrated for other similar monomers, i.e. IHCA or IBCA, pH influenced the physico-chemical characteristics of the nanoparticles obtained. Ethanol release from the ester-bearing side chains indicated that the polymers were susceptible to hydrolysis when incubated in basic pH or in rat plasma. A secondary degradation pathway, yielding formaldehyde through a reverse Knoevenagel's reaction, was minimal. Cytotoxicity studies of this new vector, in vitro, against L929 fibroblast cells demonstrated that PMM 2.1.2. nanoparticles were better tolerated than other poly(alkylcyanoacrylate) (PACA) carriers. Pharmacokinetic studies were also carried out to observe the fate of 14C-labelled PMM 2.1.2. nanoparticles after intravenous administration to rats. Forty eight hour post-injection, more than 80% of the radioactivity was recovered in urine and faeces. The body distribution of the polymer was estimated by measuring the radioactivity associated with liver, spleen, lung and kidneys. Five minutes after injection, a maximum of 24 +/- 2% of the total radioactivity was detected in the liver and less than 0.4% in the spleen. The liver-associated radioactivity decreased according to a biphasic profile and less than 8% of the total radioactivity remained after 6 days.

The effect of alcohol ingestion on the susceptibility of mice to viral infections.

The influence of acute alcoholization on the evolution of different viral diseases was studied in orally alcoholized mice. Ethanol increased mice susceptibility to encephalomyocarditis and influenza only when it was administered after virus infection. There was no dose-effect correlation. Vaccinia and Herpes virus infections were not modified by alcoholization. Hypotheses concerning the mechanisms of alcohol action were put forward.

Cutaneous hypersensitivity tests in guinea-pig of lanolin and derivatives used in cosmetology.

Summary Among the warnings which are now necessary in Europe for the protection of the consumer and which must appear on the packagings of cosmetic and corporal hygiene products, there is one concerning lanolin. The regulation requires the mention 'Important, this product contains lanolin'. Cutaneous allergic reactions have been reported in the last few years after application of products containing lanolin or lanolin derivatives although lanolin has been used for a long time. The paper describes tests of cutaneous hypersensitivity on the guinea-pig with lanolin, lanolin alcohol and a semi-liquid lanolin. No reaction was observed with a purified lanolin, even if it was old. A weak allergenic effect was shown with the semi-liquid derivative. Sensitization reactions were observed with a sample of lanolin fatty alcohols. These results were analysed and compared to those published in literature.