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Biomedical subjects

B Bonnemain

Publications and source records attributed to B Bonnemain.

At least 19 recordsLinked to original sources
PubMed2003

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).

Administration, Oral↗
PubMed2002

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.

Analysis of Variance↗
PubMed2001

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.

Abdomen↗
PubMed2001

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.

Animals↗
PubMed2001

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.

Acute Kidney Injury↗
PubMed2001

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.

Animals↗
PubMed2001

[The Swiss Commission of Goiter of January 21, 1922].

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.

Goiter↗
PubMed2000

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.

Animals↗
PubMed2000

[Lipiodol therapeutic indications from 1901 to 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.

Drug Therapy↗
PubMed2000

[Iodine usage about 1880 by Antoine de Finance's formulary].

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.

Drug Therapy↗
PubMed1999

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.

Journal Article↗
PubMed1999

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.

Animals↗
PubMed1999

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.

Animals↗
PubMed1998

Role of sodium in contrast medium-induced polymorphic ventricular tachycardia: results in a rabbit model of lengthened QT interval.

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.

Adrenergic alpha-Agonists↗
PubMed1998

Haemodynamic effects of macrocyclic and linear gadolinium chelates in rats: role of calcium and transmetallation.

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.

Animals↗
PubMed1998

Superparamagnetic agents in magnetic resonance imaging: physicochemical characteristics and clinical applications. A review.

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.

Contrast Media↗