Search

Objectives: This report presents an overview of preclinical data available on ferumoxtran-10, an ultrasmall superparamagnetic iron oxide nanoparticular contrast agent proposed for lymph node magnetic resonance imaging., Materials and Methods: Pharmacokinetic, safety pharmacology, single- and repeat-dose toxicity, reproduction toxicity, and genotoxicity studies were performed with ferumoxtran-10 given intravenously (bolus injection) in mice, rats, rabbits, dogs, and monkeys., Results: Ferumoxtran-10 was taken up by macrophages, mostly in liver, spleen, and lymph nodes, within 24 hours after bolus injection and underwent progressive metabolism. Toxicity was observed only at very high exposure levels and mainly was linked to a massive iron load after repeated injections. Ferumoxtran-10 was not mutagenic but was teratogenic in rats and rabbits., Discussion: The preclinical pharmacokinetic and safety profile of ferumoxtran-10 appears to be satisfactory in view of its proposed use as a single-dose diagnostic agent in human for MR imaging of lymph nodes.

Contrary to Tournier's assertion (thesis of 1938), the law of germinal (the seventh month of the eleventh year of the French Republican Calendar) had not been respected by the regular/secular priesthood because it was so ambiguous that they could seize the opportunity to carry on practising the art of medicine or manufacturing and selling drugs. In fact there were three reasons for the lack of steadiness of authorities: the practice of charity, financial concerns and the rise of the science which incited to illegal practice of pharmacy although professionals protested against. On the other hand, the priesthood officials tardily took the decision of forbidding the practice of medicine, surgery and pharmacy until 1936 when it was anew forbidden after a meeting of French cardinals and bishops. In 1941, with the agreement of all concerned persons the problem came to its end.

The land helix, or snail, has been used in medicine since antiquity and prepared according to several formulations. This historical report traces the understanding of their properties from the time of Hippocrates, who proposed the use of snail mucus against protoccle and Pliny who thought that the snail increased the speed of delivery and was "a sovereign remedy to treat pain related to burns, abscesses and other wounds", Galien recommended snails against hydrops foetails. In the 18th century, various snail "preparations" were also recommended for external use with dermatological disorders and internally for symptoms associated with tuberculosis and nephritis. Surprisingly, the 19th century saw a renewed interest in the pharmaceutical and medical use of snails with numerous indications for snail preparations. This interest in snails did not stop at the end of the 19th century. The 1945 edition of Dorvault devotes an entire paragraph to snails, indicating that the therapeutic usage of snails was still alive at that time. Recently the FDA has also shown an interest in snails. Ziconotide (SNXIII), a synthetic peptide coming from snail venom, has been under FDA review since 1999. Pre-clinical and clinical studies of this new drug are promising.

The second part of the XXth century have seen the creation of new systems of administration for drugs, including delayed formulation systems or prolonged-release formulations (PRF). It is first within the industry, and mainly in the USA, that such new formulations were developed, with the purpose to increase the duration of action for pharmaceutical active principles. Several approaches were proposed and developed, jointly with more and more sophisticated evaluation techniques. In France, PRF market increased progressively during the 1980's; it then decreased because of more severe restrictions by health authorities for new drug approvals. In French specialty reference book (Vidal) included 518 PRF in the year 2000, from which 121 were tablets and 118 were hard gelatine capsules.

Alternative medicines continue to grow during these first years of the XXIst century where believes and irrational ideas are popular. Drugs did played and still play a central role for some of them such as homeopathy, radiesthesia, and magnetism, three approaches that are sometime consider as complementary to each others. Pharmacists were related volunterely or not to their history during the XIX and XX centuries, as well as official institutions and political power. The present study shows complexity of these interactions and the role sometime essential the pharmacist had for the recognition of some medical practices.

Synthetic dyes were first discovered at the end of the XVIIIth century (picric acid by Woulfe in 1771) and during the first part of the XIXth century: rosolic acid (Runge, 1834), mauvein (Perkin, 1856), but their development was major at the end of the XIXth century. Their therapeutic use was really starting at the beginning of the XXth century, mainly by local and oral route. It is only in the 1930's that parenteral route of administration was actually developed: methylene blue, methyl violet are some examples that were used for leprosy and filariasis, respectively. After the 2nd world war, one can observe a rapid decrease of the therapeutic use of dyes by intravenous route. Only a few dyes are still used today, such as patent blue V or fluorescein, as drugs for diagnostic use.

The Germinal an XI law is supposed to close a period of time where several people were allowed to prepare and deliver drugs. Concerning clergy, this law will not be totally applied. Several priests and religious, during the XIXe century, will create and distribute pharmaceutical products. Oudin, Cottance and Chaupitre, all priests, are a few of key examples. L'abbé Perdrigeon was a priest that discover his calling to cure by treating Napoleon III's soldiers during 1870 war. It remains form it the so-called "Contrecoups de l' Abbé Perdrigeon ", product still commercialized. The present publication describes the legal and cultural feature in which illegal exercise of Pharmacy and Medicine took place by clergy, and the reasons why priests and nuns wanted to pursue this usage until the 1941 law.

Land helix, so called snails, have been used in medicine since Antiquity. We find them until today in pharmaceutical specialties and it is the subject of several studies. Why this gastropod has much interested and what products were used, based on this unique active ingredient? Some famous pharmacists like Mure, Figuier and Barin-Barthélémy, made specialties that were well known along the 19th century as proven by the Dorvault reference book in 1877. But the history of snails in medicine continued during the 20th century with hélicidine, commercialized in France in 1957, and with HPA (HElix Pomatia Lectin) that is fixed by metastatic tissues.

When one look at pharmaceutical advertising and trademarks at the beginning of the 20th century, several of them emphasize the interest of pharmaceutical specialties based on animal blood. This fashion goes back to Fuster's work in 1865 on tuberculosis, but also to Deschiens, Catillon, Adrian and mainly Richet. This interest for blood derivatives in therapy will progressively disappear after teh Second World war and with antibiotic discovery. Consequently, it has been a century of glory for these specialties that seem strange today in the context of HIV and ESB issues. But some of these research will be the basis for modern works on erythropoetin (the famous EPO).

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).

Between the law of germinal an XI and the 1941 law, the relationship between the pharmaceutical industry and the French government were driven by the official practice of pharmacy. The State trues pharmacist who has to contrôle financially and deontologically his company. After 1941, the State will more and more regulate and control all the activities of the pharmaceutical products industry due to the major financial impact of these products on Health Care and Social Security budgets. French State will be progressively concerned with medical information and good practices (good manufacturing practices, good laboratory practices...) It will also regulate the pricing of new drugs, the development process and will encourage the marketing of innovative products. These rules, on the basis of the European directive of 1965, will be more or less harmonized for all European countries. Since 1989, this harmonization process is looking for an expansion outside of Europe, at least for the marketing authorization, in order to facilitate the registration of innovative products in all countries. One can then observe on a period of two centuries the evolution from freedom of the pharmaceutical industry more and more to a strict controlled freedom.

During the Second World War, French pharmaceutical industry was facing several crises at the same time: economic, social and political crisis, in its relationship with the German occupying forces and the Vichy regime. However, the industrial pharmacy continued its investments and innovation: several specialties were born. Other specialties are largely increasing their sales as they replace missing food (sugar, oil). Relationship with the occupying forces are first to try to escape constraints that are imposed to the companies. But contracts signed with German companies are obviously related to the defeated position of France. Allied are also a source of breach between French companies and their subsidiaries abroad (UK or USA). In this context, the new French law of September 11, 1941 on French Pharmacy appears for Vichy's regime and German occupying forces as a way among others to control the French pharmaceutical industry.

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.

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.

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 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.

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.

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.

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.

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.

Rationale and Objectives: The authors (a) compared the proarrhythmic effects of ioxaglate (152 mmol/L sodium) and iohexol (no sodium) in a rabbit model and (b) assessed the effect of adding 150 mmol/L sodium to isotonic iohexol., Materials and Methods: Either ioxaglate (320 mg of iodine per milliliter) or iohexol (350 mg of iodine per milliliter) was selectively injected into the right coronary artery (1.5 mL over 30 seconds) of 10 rabbits, some of which also received the alpha 1-adrenergic receptor agonist methoxamine. To validate the model, the class III antiarrhythmic agent clofilium was injected intravenously during methoxamine infusion. Frontal electrocardiography was performed continuously to detect polymorphic ventricular tachycardia (PVT). In a second study, the authors assessed the frequency of arrhythmias after injection of isotonic iohexol solution (145 mg of iodine per milliliter), either alone or with 150 mmol/L sodium., Results: Methoxamine significantly lengthened the QT, QTc, and RR intervals (P < .05). The use of clofilium alone induced no PVT, whereas five of eight methoxamine-infused rabbits developed PVT after clofilium injection (P = .03). Both contrast media prolonged the repolarization period. Iohexol alone induced a higher frequency of PVT than did ioxaglate alone (P = .0006). Methoxamine infusion did not potentiate the frequency of PVT in the ioxaglate-injected rabbits. The addition of sodium to isotonic iohexol prevented the occurrence of PVT (P = .0006)., Conclusion: Although ioxaglate prolonged the repolarization period, it did not cause a higher frequency of arrhythmia when injected in association with methoxamine. Iohexol, which contains no sodium, induced a high frequency of arrhythmia. The addition of a physiologic concentration of sodium to isotonic iohexol can prevent ventricular arrhythmias.

Several studies were undertaken to compare four magnetic resonance imaging (MRI) contrast media (CM) as regards acute haemodynamic effects in rats and to investigate the mechanisms involved. (1) Normotensive rats received a rapid bolus intravenous injection of 0.5 mmol kg-1 of each CM. The effects of Gd-DOTA, Gd-HP-DO3A, Gd-DTPA and Gd-DTPA-BMA on blood pressure (BP) were compared. (2) The haemodynamic effects of Gd-DTPA (0.5 mmol kg-1) were compared to those of isovolumic and isoosmolar Zn-DTPA and glucose solutions. (3) The haemodynamic profiles of Gd-DTPA and Gd-DTPA-BMA were recorded with and without addition of ionized calcium. (4) The mechanism of Gd-HP-DO3A-induced transient rise in BP was investigated by evaluating the effects of phentolamine or diltiazem pretreatment. For (1) the greatest drop in BP occurred following Gd-DTPA (a linear chelate) injection (-18 +/- 2% vs baseline, P < 0.01). Gd-DTPA-BMA, another lineate chelate, also induced a slight but significant reduction in BP (-8 +/- 2% at 45 s, P < 0.05). Gd-DOTA, a macrocyclic CM, had virtually no haemodynamic effects. For (2) the Gd-DTPA-induced drop in BP was greater than that of the osmolality-matched glucose control and lower than that of osmolality-matched Zn-DTPA. For (3) a transmetallation phenomenon versus free ionized calcium is possible in the case of both linear CM (Gd-DTPA and Gd-DTPA-BMA) since Ca2+ significantly reduced the CM-induced decrease in BP. For (4) a transient rise in BP was observed following Gd-HP-DO3A, another macrocyclic chelate, associated with a concomitant increase in stroke volume. This effect was antagonized neither by phentolamine nor by diltiazem. The decrease in BP following injection of Gd-DTPA or Gd-DTPA-BMA may not only be osmolality-related since (a) Gd-DOTA solution, whose osmolality is greater than that of Gd-DTPA-BMA, had a lesser effect, and (b) this hypotensive effect was corrected by a addition of ionized calcium. The transient Gd-HP-DO3A-induced rise in BP is probably the consequence of a positive inotropic effect.

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...).

Superparamagnetic agents in magnetic resonance imaging: physico-chemical characteristics and clinical applications. Superparamagnetic agents have been the subject of extensive research over the last decade. They consist of iron oxide nanoparticles which are highly effective in Magnetic Resonance Imaging (MRI). The particle size varies widely and influences their physicochemical and pharmacokinetic properties. Their main present and future applications by the parenteral route are: imaging of gastrointestinal tract, liver and spleen, lymph nodes. Ultrasmall superparamagnetic iron oxide particles (USPIO) are also blood pool agents which could be used for perfusion imaging (i.e. brain or myocardial ischemic diseases) as well as for imaging of vessels in Magnetic Resonance Angiography. These agents open up an important field of research into more specific agents adapted to clinicians' needs in diagnostic imaging.

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.

The present article combines and summarizes the preclinic studies carried out in vitro and in vivo to determine the pharmacologic and biochemical profile of iobitridol, a new nonionic iodinated low-osmolality contrast medium (CM). The effects of this product on the main hemodynamic, bronchopulmonary, neurologic, renal, blood chemistry and electrophysiologic parameters and RBC morphology were studied in detail in comparison with CM in the same chemical category or with reference substances of the same osmolality. The in vivo studies were performed under conditions resembling clinical use. Iobitridol showed an excellent pharmacologic and biochemical profile, which was identical or superior to that of other products in its category.

Contrast agents may be categorised as non-specific or specific agents. Non-specific agents are freely diffusible in the extracellular and extravascular compartment with the exception of the brain where only blood brain barrier lesions enables the contrast agent to pass. In the specific agent group, a new class of products has been developed, that of blood pool contrast agent, which are distributed in the total intravascular volume and are slowly cleared from the blood. Crossing the healthy capillary wall is limited and depends both on the pathological state of the endothelial permeability tissue of the organ under interest and on the characteristics of the contrast agent (size, charge, molecular shape...). The diagnostic efficacy in perfusion imaging including cerebral perfusion is modulated by the pharmacokinetic profile of the blood pool contrast agent. One way to improve the vascular residence time, consists in binding a vector such as synthetic polymer or a biological macromolecule and a lanthanide like Gd3+, Mn2+, Dy3+ or metal ions. A second way is the synthesis of ultrasmall iron oxide nanoparticles which could escape rapid recognition by the monocyte macrophage phagocytic system mainly of liver and spleen. Because of their cristalline structure and the large number of non-paired spins, five electrons for the iron metal, the nanoparticles behave as magnetic domain when an external field is applied. They consequently have a high dipolar magnetic moment, and can produce a T2 effect in vivo, resulting in a drop in the magnetic resonance signal. Possible interests and developments toward perfusion imaging are demonstrated in experimental models studies.

Purpose: The toxicologic profile of iobitridol, a new nonionic low-osomolality contrast medium, was evaluated in compliance with the current regulatory requirements in Europe, the USA and Canada., Material and Methods: The toxicity of iobitridol was tested following acute or repeated i.v. administration in several different species (mouse, rat, dog); single oral administration in the mouse and intracisternal injection in the rat. Furthermore, teratogenicity and mutagenicity were evaluated in the rat and rabbit. Local perivenous toxicity was assessed in the rabbit., Results: The acute toxicity of iobitridol in the mouse is equivalent to that of iohexol, a reference product tested under the same conditions. Chronic administration (daily injections i.v. injection over 4 weeks) in the rat and dog did not demonstrate any particular toxicity for iobitridol. It should be noted that, unlike iohexol, iobitridol did not provoke any vacuolization of the renal tubular cells in the rat following repeated injections. Furthermore, this contrast agent did not show any teratogenic or mutagenic potential. The typical local inflammatory signs observed following perivenous injection in the rabbit were low in intensity and reversible., Conclusion: The toxicologic profile of iobitridol appears to be favorable and does not show any particular risk for clinical use under the usual indications of water soluble iodinated contrast agents.

Electro-corticographic tracings (two longitudinal leads, bipolar assembly) were recorded from curarized rabbits (5/group) receiving selective internal carotid artery injections of either iobitridol, a new non-ionic contrast medium, or iohexol, the high osmolar diatrizoate or hypertonic mannitol (isotonic to the non-ionic agents). A further group was submitted to the surgical preparation but was not injected. The solutions were injected at a dose of 2.5 ml during 30 seconds. The animals were anaesthetized (halothane) during the surgical period. The permeability of the blood-brain barrier was assessed by means of the extravasation of Evans'blue. Tracings were visually assessed and a semi-quantitative method for blind evaluation of fast/slow rhythms was used. This method was pharmacologically validated by the use of pentobarbital and pentylenetetrazole. Diatrizoate and iohexol induced respectively 3 and 2 paroxystic tracings during or immediately after the injection period. Iobitridol and hypertonic mannitol did not cause such effect. Paroxystic tracings in the iohexol group were not associated with extravasation of Evans'blue in the cerebral parenchyma. Blood brain barrier was disrupted in all rabbits receiving the high osmolar agent diatrizoate. Tracings of the control group were characterized by a progressive increase of fast rhythms, as those of the iobitridol and mannitol groups. On the contrary, iohexol and especially diatrizoate induced an increase in the proportion of slow waves. Taken together, these data suggest that iobitridol shows an excellent tolerability potential for clinical use.

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.

The history of Lipiodol, an iodized oil perfected in 1901 by Marcel Guerbet and Laurent Lafay, offers the example of a product with multiple indications which, initially destined for therapeutic usage, was later successfully turned to radiologic applications; then, sixty years later, returned to its initial purposes. This shows that (1) very often new products find usages which their developers never suspected; (2) research can extend beyond the original synthesis and commercialization of the product; (3) at some point research on a medication becomes multidisciplinary.

Ténébryl was perfected in 1931 by Marcel and André Guerbet. For the company which bore their name and after the discovery of Lipiodol, this was the opportunity to explore a new area in radiology: intravenous urography. The discovery of this product is exemplary in a greater sense, since it contributed to opening the way to a new class of contrast products of which the majority today are iodized products. All the ingredients of industrial research are present here, from risk-taking to successful commercialization.

Two new cases of central nervous system (CNS) large cell lymphoma without evidence of systemic lymphoma in patients with chronic lymphocytic leukaemia (CLL) are reported. This unusual presentation of Richter's syndrome emphasizes the necessity to evoke this diagnosis in the case of neurologic symptoms in CLL.

Contrast agents MRI (Magnetic Resonance Imaging) have been developed to improve the diagnostic information obtained by this technic. They mainly interact on T1 and T2 parameters and increase consequently normal to abnormal tissues contrast. The paramagnetic agents which mainly act on longitudinal relaxation rate (T1) are gadolinium complexes for which stability is the main parameter to avoid any release of free gadolinium. The superparamagnetic agents that decrease signal intensity by an effect on transversal relaxation rate (T2) are developed for liver, digestive and lymph node imaging. Many area of research are now opened for optimal use of present and future contrast agents in MRI.

Rationale and Objectives: A possible involvement of endothelium derived relaxing nitric oxide (NO) in the pathogenesis of iodinated contrast media (CM)-induced nephrotoxicity was investigated in the rat., Methods: Male rats (6 to 12 per group) were uninephrectomized. Six days later, the aorta was clamped above the renal artery and a low-osmolar contrast medium (CM), ioxaglate, was injected (1 mL/min; 3 minutes) via an aortic puncture in the single remaining kidney. Contrast medium was injected with or without the NO-synthase inhibitor L-NAME (100 mg/kg intravenously [i.v.] 5 minutes before CM). One group received L-Arginine, the physiological precursor of NO (100 mg/kg i.v.), 5 minutes before L-NAME. Phenylephrine (300 micrograms/kg; 30 min) was used as a vasoconstrictive NO-independent control. The effects of iohexol, another low-osmolar CM, on creatinine clearance (CrCl) were also studied with and without pretreatment with L-NAME. A control group was subjected to a 3-minute renal ischemia only. Creatinine clearance and urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion were determined before, and 24 and 48 hours after CM administration. Blinded histologic analysis was carried out after completion of the study., Results: When administered alone, neither L-NAME nor L-arginine modified CrCl. Ioxaglate mildly but significantly decreased CrCl at 24 hours (-26.5% of preinjection value). This was similar to the effect observed in the control group subjected to ischemia only. When associated with L-NAME, ioxaglate markedly decreased CrCl (-58 + 11% at 24 hours, P < .05 vs. ioxaglate alone). A similar interaction was noted in the case of iohexol. L-NAME also markedly increased ioxaglate-induced urinary NAG excretion. Phenylephrine had a similar impact on renal function. L-arginine pretreatment reduced the increase in serum creatinine induced by L-NAME+ioxaglate (68 + 17 mumol/L vs. 175 + 59 mumol/L for L-NAME+ioxaglate; P < .05) and urinary NAG excretion. Ioxaglate alone induced only tubular epithelial vacuolization. When associated with L-NAME, this CM induced tubular and vascular lesions, as well as necrosis in the outer medulla. Such histologic effects were clearly inhibited by L-arginine., Conclusion: These data indicate that L-NAME, a specific inhibitor of NO-synthase, and phenylephrine, accentuate the nephrotoxicity of CM in the rat. This is consistent with results from the literature showing that CM-toxicity is enhanced by renal ischemia.

Chimiotoxicity of iodinated contrast media is essentially due to non specific hydrophobic interactions with biologic proteins and membranes. These hydrophobic interactions depend both on the whole molecular lipophilicity and on the spatial accessibility of lipophilic molecular areas. Measurements of lipophilicity by partition coefficient, partially take into account the spatial localisation of hydrophilic groups around the lipophilic area due to the 1,3,5-triiodo-benzene. These measurements have to be completed by an accurate knowledge of the three-dimensional localisation of hydrophilic groups to improve the biocompatibility of polyiodinated contrast media. The concept of evenly distributed facial hydrophilicity aims to minimize the accessibility to lipophilic area by a localisation of hydrophilic group on each plan of the benzene ring. The molecular structure of ioversol allows to put this concept in concrete form thanks to a tertiary anilide group which imposes on one hydroxy group to be located on each face of the 1,3,5-triiodo-benzene ring, providing facial hydrophilic protection.

The intravenous clinical trial program of ioversol (Optiray), a low osmolar, nonionic, monomeric contrast agent characterized by high hydrophilicity, is evaluated on the basis of results from the first clinical trials conducted in Europe as part of the development of the 300 and 350 mgI/ml formulations: 7 double-blind, comparative trials and 5 single trials were performed in a total of 743 patients, of whom 472 received ioversol and 271 a monomeric nonionic reference product. The diagnostic efficacy of ioversol was equivalent or superior to that of the reference products and tolerance was comparable to that of nonionic agents in terms of pain and heat sensations. No significant difference in adverse reactions was found and all the contrast agents studied were well tolerated by the patients.

The pharmacokinetics of Gd-DOTA meglumine in humans were evaluated in six healthy male volunteers. The agent was injected intravenously at 0.1 mmol/kg over approximately 2 minutes. Its behavior was found to be similar to that of urographic and angiographic iodinated contrast media with a plasma elimination half-life of 91 +/- 14 minutes (mean +/- standard deviation [SD]), a small distribution volume of 171.0 +/- 19.7 mL/kg and rapid urinary excretion. The results suggest rapid passive extravascular diffusion of gadolinium (Gd)-DOTA in the interstitial space without intracellular penetration, followed by a rapid urinary excretion via glomerular filtration. Furthermore, the results are consistent with animal data that showed that the compound does not cross the normal blood brain barrier. Its plasma pharmacokinetics appeared to be similar to those reported for Gd-DTPA. No relevant biological effects were seen with Gd-DOTA, especially in regard to serum iron and bilirubin levels.

The interfacial polymerization process used in the present study produced individual cross-linked albumin microcapsules, the particle size of which depended on the emulsification stirring rate. The variation in cross-linking agent concentration altered the microcapsule wall properties. As shown by SEM observations, microcapsules prepared with low acyl chloride concentrations presented rippled surfaces, while the surfaces of the microcapsules prepared with high acyl chloride concentrations were smooth. It was then suggested that the membranes of the weakly cross-linked microcapsules consisted of cross-linked and denatured albumin. Embolization experiments in the dog kidney showed that the weakly cross-linked microcapsules were biodegradable within 7 days, whereas the highly cross-linked microcapsules were degraded over more than 14 days and led to prolonged ischaemia. The results of the histological experiments carried out on a further eight dogs supported the previous findings yielded by the angiographical experiments. Moreover, they indicated that no foreign body reaction occurred. The lack of this inflammatory granuloma should be attributed to the rapid biodegradation of the microcapsules which produced reversible ischaemic lesions.