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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. [ABSTRACT FROM AUTHOR]

Evaluates properties of the radiographic contrast media P760 gadolinium chelate. Diffusion through the vascular endothelium; Structure of the drug; Pharmacokinetics.

Abstract: This review describes the pharmacokinetics, efficacy, and safety of gadopiclenol, a new macrocyclic gadolinium-based contrast agent (GBCA) recently approved by the Food and Drug Administration at the dose of 0.05 mmol/kg. Gadopiclenol is a high relaxivity contrast agent that shares similar pharmacokinetic characteristics with other macrocyclic GBCAs, including a predominant renal excretion. In pediatric patients aged 2-17 years, the pharmacokinetic parameters (assessed through a population pharmacokinetics model) were comparable to those observed in adults, indicating no need for age-based dose adjustment. For contrast-enhanced magnetic resonance imaging (MRI) of the central nervous system (CNS) and body indications, gadopiclenol at 0.05 mmol/kg was shown to be noninferior to gadobutrol at 0.1 mmol/kg in terms of 3 lesion visualization parameters (ie, lesion border delineation, internal morphology, and contrast enhancement). Moreover, for contrast-enhanced MRI of the CNS, compared with gadobenate dimeglumine at 0.1 mmol/kg, gadopiclenol exhibited superior contrast-to-noise ratio at 0.1 mmol/kg and comparable contrast-to-noise ratio at 0.05 mmol/kg. A pooled safety analysis of 1047 participants showed a favorable safety profile for gadopiclenol. Comparative studies showed that the incidence and nature of adverse drug reactions with gadopiclenol were comparable to those observed with other GBCAs. Importantly, no significant safety concerns were identified in pediatric and elderly patients, as well as in patients with renal impairment. Overall, these findings support the clinical utility and safety of gadopiclenol for MRI in adult and pediatric patients aged 2 years and older in CNS and body indications., Competing Interests: Conflicts of interest and sources of funding: All authors are employed by Guerbet. The clinical studies performed for the evaluation of the efficacy and safety of gadopiclenol were funded by Guerbet., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Gadopiclenol is a new high-relaxivity macrocyclic gadolinium-based contrast agent for magnetic resonance imaging of the central nervous system and other body regions. The product has been approved by US Food and Drug Administration and is currently being evaluated by European Medicines Agency. For risk assessment of the single diagnostic use in humans, the safety profile of gadopiclenol was evaluated with a series of preclinical studies., Materials and Methods: With exception of dose-ranging studies, all safety pharmacology and toxicology studies were performed in compliance with Good Laboratory Practice principles. Safety pharmacology studies were conducted to assess potential effects on cardiovascular (in vitro and in dogs), respiratory (in rats and guinea pigs), neurological (in rats), and renal endpoints (in rats). Toxicology studies were also performed to investigate acute toxicity (in rats and mice), extended single-dose (in rats and dogs) and repeated-dose toxicity (in rats and dogs), reproductive (in rats), developmental (in rats and rabbits) and juvenile toxicity (in rats), as well as genotoxicity (in vitro and in rats), local tolerance (in rabbits), potential immediate hypersensitivity (in guinea pigs), and potential tissue retention of gadolinium (in rats)., Results: Safety pharmacology studies conducted at high intravenous (IV) doses showed a satisfactory tolerance of gadopiclenol in the main body systems. After either single or repeated IV dosing (14 and 28 days) in rats and dogs, gadopiclenol was well tolerated even at high doses. The no-observed-adverse-effect level values (ie, the highest experimental dose without adverse effects) representing between 8 times in rats and 44 times in dogs (based on the exposure), the exposure achieved in humans at the intended diagnostic dose, provide a high safety margin. No or only minor and reversible effects on body weight, food consumption, clinical signs, clinical pathology parameters, or histology were observed at the highest doses. The main histological finding consists in renal tubular vacuolations (exacerbated after repeated exposure), which supports a well-known finding for this class of compounds that has no physiological consequence on kidney function. Reproductive toxicity studies showed no evidence of effects on reproductive performance, fertility, perinatal and postnatal development in rats, or reproductive development in rats or rabbits. The safety profile of gadopiclenol in juvenile rats was satisfactory like in adults. Gadopiclenol was not genotoxic in vitro in the Ames test, a mouse lymphoma assay, and a rat in vivo micronucleus test. There were no signs of local intolerance at the injection site after IV and intra-arterial administration in rabbits. However, because of minor signs of intolerance after perivenous administration, misadministration must be avoided. Gadopiclenol exhibited no signs of potential to induce immediate hypersensitivity in guinea pigs., Conclusions: High safety margins were observed between the single diagnostic dose of 0.05 mmol/kg in humans and the doses showing effects in animal studies. Gadopiclenol is, therefore, well tolerated in various species (mice, rats, dogs, rabbits, and guinea pigs). All observed preclinical data support the clinical approval., Competing Interests: Conflicts of interest and sources of funding: All authors are Guerbet employees., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Seven gadolinium-based contrast agents (GBCAs), four linear and three macrocyclic, were evaluated for potential effects on development, including behavior of juvenile CD-1 mice., Methods: The GBCAs were administered via intravenous injection once daily on postnatal day (PND) 9, 12, 15, 18, and 21 (PND 1 was the day of delivery) at doses up to twice the human equivalent clinical dose (i.e., 0.63 mmol Gd/kg for gadoxetate disodium and 2.5 mmol Gd/kg for the other GBCAs). Mice were bled for evaluation of exposure (plasma) to gadolinium (Gd) on PND 9, 12, and 70. At scheduled euthanasia, the liver, spleen, brain, skin (dorsal surface), bone (left femur), and kidneys were excised from up to six mice/sex/group on PND 10, 22, or 70 for the determination of Gd levels and histopathological analysis. All mice were monitored for toxicity, growth and survival, sexual maturation, and behavior., Conclusion: Gd was quantifiable in the brain tissues with levels declining over time. There was no long-term effect on the growth and development for mice exposed to any of the GBCAs. There was no impact on neurodevelopment as assessed by brain histology and validated neurobehavioral tests, including a functional observational battery, motor activity, and learning and memory as evaluated in the Morris water maze. For all GBCAs, the highest dose tested represented the no-observable-adverse-effect level in juvenile mice., (© 2023 Charles River Laboratories, Inc., Horsham, PA. Birth Defects Research published by Wiley Periodicals LLC.)

Introduction: The offspring of CD-1 mice exposed during pregnancy to one of seven gadolinium-based contrast agents (GBCAs) were evaluated for potential effects on postnatal development and behavior. The GBCAs, comprising four linear (gadopentetate dimeglumine, gadodiamide, gadobenate dimeglumine, and gadoxetate disodium) and three macrocyclic (gadoterate meglumine, gadoteridol, and gadobutrol), were administered via intravenous injection once daily from Gestation Day 6 through 17 following confirmed mating (Day 0) at doses of at least twice the human equivalent recommended clinical dose (i.e., 0.63 mmol Gd/kg for gadoxetate disodium and 2.5 mmol Gd/kg for the other GBCAs). All dams were allowed to deliver naturally. F0 generation females were monitored for maternal toxicity and gadolinium (Gd) levels in blood and brain. Offspring were evaluated for Gd levels in blood and brain at birth and on Day 70 postpartum. F1 generation mice were evaluated for survival and growth preweaning. Selected pups/litter were evaluated postweaning for sexual maturation, growth, and behavior. Gd was quantifiable in the brain of the F1 offspring on PND 1, with levels declining over time. There was no long-term effect of any GBCA on the growth and development of any offspring. There was no impact on neurodevelopment, as assessed by brain histology and validated neurobehavioral tests, including a battery of functional observational tests, motor activity, and learning and memory as evaluated in the Morris water maze., Conclusion: At the end of the postweaning period, the highest dose tested was considered the no-observable-adverse-effect level (NOAEL) in the F0 and F1 offspring for all tested GBCAs., (© 2023 Charles River Laboratories, Inc., Horsham, PA. Birth Defects Research published by Wiley Periodicals LLC.)

Objectives: The aims of this study were to evaluate the pharmacokinetics (PK) of gadopiclenol, a new macrocyclic gadolinium based-contrast agent, in subjects with impaired renal function, and to assess its dialysability in subjects with end-stage renal disease (ESRD)., Methods and Materials: This 2-center, open-label, phase 1 study included 5 successive cohorts of 8 adult subjects: healthy subjects (cohort 1), subjects with mild (cohort 2), moderate (cohort 3), severe (cohort 4) renal impairment, or ESRD (cohort 5), who received a single intravenous injection of gadopiclenol (0.1 mmol/kg). Blood and urine samples were collected at different time points in cohorts 1 to 4, and blood and dialysate samples were collected at each hemodialysis session (4-hour session on day 1, day 3, and day 5) in cohort 5. Gadopiclenol elimination and safety were assessed for up to 6 months. Pharmacokinetics parameters were calculated using noncompartmental analysis., Results: A total of 40 subjects were included, with a mean age of 51.5 years (range, 18-71 years). No significant difference in the mean maximum concentration values and the distribution volume was observed among cohorts 1 to 4. Urinary excretion of unchanged gadopiclenol was delayed with the degree of renal impairment and ranged between 96% and 84% in subjects with mild to severe renal impairment. Compared with that of healthy subjects, the mean area under the plasma concentration curve was 54%, 148%, and 769% higher in subjects with mild, moderate, or severe renal impairment, respectively. The mean terminal half-life was prolonged with the degree of renal impairment (1.9, 3.3, 3.8, and 11.7 hours for cohorts 1-4). In ESRD subjects, gadopiclenol was effectively removed from the plasma (95% to 98%) after the first hemodialysis session. Gadopiclenol concentration in plasma was below the limit of quantification for all subjects after the second hemodialysis session. Gadopiclenol concentration was below limit of quantification in all plasma and urine samples collected at 1, 3, and 6 months. Five subjects (12.5%) experienced adverse events related to gadopiclenol, none serious and all resolved. Laboratory measurements, vital signs, and electrocardiography did not raise any safety concern., Conclusions: Gadopiclenol elimination half-life was prolonged in subjects with mild to severe renal impairment, yet its renal clearance remains complete or nearly complete. In ESRD subjects, gadopiclenol was effectively removed from the plasma after 1 hemodialysis session, and up to 3 hemodialysis sessions were sufficient to completely clear it. No safety concern was raised. Therefore, no dose adjustment seems necessary in this patient population., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: The primary objective of this study was to investigate the pharmacokinetic profile of gadoterate meglumine in pediatric patients younger than 2 years; the secondary objectives were to document its efficacy and safety., Material and Methods: This was a Phase IV open-label, prospective study conducted in 9 centers (4 countries). Forty-five patients younger than 2 years with normal estimated glomerular filtration rate and scheduled to undergo routine gadolinium-enhanced magnetic resonance imaging (MRI) of any organ were included and received a single intravenous injection of gadoterate meglumine (0.1 mmol/kg). To perform the population pharmacokinetics analysis, 3 blood samples per subject were drawn during 3 time windows at time points allocated by randomization., Results: Gadoterate meglumine concentrations were best fitted using a 2-compartmental model with linear elimination from central compartment. The median total clearance adjusted to body weight was estimated at 0.06 L/h per kg and increased with estimated glomerular filtration rate according to a power model. The median volume of distribution at steady state (Vss) adjusted to body weight was estimated at 0.047 L/kg. Estimated median terminal half-life (t1/2β) was 1.35 h, and the median systemic exposure (area under the curve) was 1591 μmol h/L. Efficacy was assessed by comparing precontrast +postcontrast images to precontrast images in a subset of 28 subjects who underwent an MRI examination of brain, spine, and associated tissues. A total of 28 lesions were identified and analyzed in 15 subjects with precontrast images versus 30 lesions in 16 subjects with precontrast + postcontrast images. Lesion visualization was improved with a mean (SD) increase in scores at subject level of 0.7 (1.0) for lesion border delineation, 0.9 (1.6) for internal morphology, and 3.1 (3.2) for contrast enhancement. Twenty-six adverse events occurred postinjection in 13 subjects (28.9%), including 3 serious reported in 1 subject (2.2%). One subject (2.2%) experienced 1 rash of moderate intensity considered as related to gadoterate meglumine., Conclusions: The pharmacokinetic profile of gadoterate meglumine after a single intravenous injection of 0.1 mmol/kg was appropriately described in newborns and infants younger than 2 years, for whom no dose adjustment is required. The improved efficacy of gadoterate meglumine for contrast-enhanced MRI examination of brain, spine, and associated tissues, as well as its good safety profile, was also demonstrated in this population.

Following its inception in 1994, the certification of European Registered Toxicologists (ERT) by EUROTOX has been recognized as ensuring professional competence as well as scientific integrity and credibility. Criteria and procedures for registration are contained in the ERT "Guidelines for Registration 2012". The register of ERT currently has over 1900 members. In order to continue the harmonisation of requirements and processes between national registering bodies as a prerequisite for official recognition of the ERT title as a standard, and to take account of recent developments in toxicology, an update of the ERT Guidelines has been prepared in a series of workshops by the EUROTOX subcommittees for education and registration, in consultation with representatives of national toxicology societies and registers. The update includes details of topics and learning outcomes for theoretical training, and how these can be assessed. The importance of continuing professional development as the cornerstone of re-registration is emphasised. To help with the process of harmonisation, it is necessary to collate and share best practices of registration conditions and procedures across Europe. Importantly, this information can also be used to audit compliance with the EUROTOX standards. As recognition of professionals in toxicology, including specialist qualifications, is becoming more important than ever, we believe that this can best be achieved based on the steps for harmonisation outlined here together with the proposed new Guidelines., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The purpose of this study was to assess the safety of gadoterate meglumine, a gadolinium-based contrast agent used in magnetic resonance imaging, in neonatal and juvenile rats. Rats received a single intravenous administration on postnatal day (PND) 10 or 6 administrations (from PND 10 to 30), at doses of 0, 0.6, 1.25, and 2.5 mmol/kg/administration, i.e. equivalent to approximately 1, 2 and 4-times the usual human dose. The animals were sacrificed at the end of the treatment period or after a 60-day treatment-free period. No mortality and no significant treatment-related effect on clinical signs, macroscopic and histopathological findings, development, behavior, sexual maturation and hematology parameters were observed. Minor non-adverse changes were observed in clinical biochemistry and urinary parameters. Based on AUC0-t, gadoterate meglumine was more rapidly eliminated at PND 30 vs. PND 10, reflecting maturation of kidney function. At the end of the treatment period, Gd was measurable in all organs sampled after single or repeated dosing and levels were dose-dependent as expected, the highest ones being found in kidneys. The total Gd concentrations were similar in all the organs following a single or repeated dosing. At the end of the treatment-free period, only traces of gadolinium were quantifiable, almost exclusively in kidneys, reflecting the excretory function of this organ. In conclusion, single or repeated administration of gadoterate meglumine to juvenile rats was well tolerated., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A royal decree in 1788 created a Health Board for military hospitals. The board members included Bayen, assisted by Pagmentier. A collection of "Medicinal formulae" was then published with a view to standardizing and simplifying the remedies prepared in pharmacies. It comprised 159 formulae for internal and external medicines together with a nomenclature for 249 simple and compound drugs used in military hospitals.

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.

Dynamic contrast-enhanced MRI (DCEMRI) data were acquired from metastatic and nonmetastatic tumors in rodents to follow the uptake and washout of a low-molecular-weight contrast agent (Gd-DTPA) and a contrast agent with higher molecular weight (P792). The concentration vs. time curves calculated for the tumor rims and centers were analyzed using the two-compartment model (TCM) and a newly developed empirical mathematical model (EMM). The EMM provided improved fits to the experimental data compared to the TCM. Parameters derived from the empirical model showed that the contrast agent washout rate was significantly slower in metastatic tumors than in nonmetastatic tumors for both Gd-DTPA (P < 0.03) and P792 (P < 0.04). The effects of the tumor on blood flow in "normal" tissue immediately adjacent to the tumors were evident: Gd-DTPA uptake and washout rates were much lower in muscle near the tumor (P < 0.05) than normal muscle farther from the tumor. The results suggest that accurate fits of DCEMRI data provide kinetic parameters that distinguish between metastatic and relatively benign cancers. In addition, a comparison of the dynamics of Gd-DTPA and P792 provides information regarding the microenvironment of tumors., (Copyright 2004 Wiley-Liss, Inc.)

The use by the apotharies of the symbol of three reigns of nature: the snake, the palm-tree and the rocks, together with the motto "In his tribus versantur" was fort them away to illustrate their scope of competence. This symbol cannot be seen on many delft-wan, but it illustrates many China-vases, made of "porcelaine de Paris" during the XIXth century. Palm-tree, snake and rocks constitute the main kind of adornment on the pots made by the various manufacturers.

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.

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.

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.

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.