There was no detectable biotransformation of gadobenate ion. Dissociation of gadobenate ion in vivo has been shown to be minimal, with less than 1% of the free chelating agent being recovered alone in feces.
IDENTIFICATION AND USE: Gadobenate dimeglumine (MultiHance) is a contract agent for MRI studies, supplied as a colorless to slightly yellow, aqueous solution intended for intravenous use only. HUMAN EXPOSURE AND TOXICITY: Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle and internal organs. The risk for NSF appears highest among patients with: chronic, severe kidney disease, or acute kidney injury. Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (older than 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing. For patients at highest risk for NSF, do not exceed the recommended MultiHance dose and allow a sufficient period of time for elimination of the drug from the body prior to re-administration. Anaphylactic and anaphylactoid reactions have been reported, involving cardiovascular, respiratory, and/or cutaneous manifestations. Some patients experienced circulatory collapse and died. Cardiac arrhythmias have been observed in patients receiving MultiHance in clinical trials. The mutagenic potential of gadobenate dimeglumine was studied by the chromosome aberration test in cultured human lymphocytes. The agent induced no increase in the incidence of aberrant cells or polyploid cells in any treatments both in the presence and absence of metabolic activation. Thus, it is concluded that gadobenate dimeglumine has shown no evidence of clastogenic or polyploidy-inducing activity under these experimental conditions. ANIMAL STUDIES: To support the clinical use of gadobenate dimeglumine for injection as an intravascular magnetic resonance imaging contrast medium through an extensive battery of toxicological safety studies. Single and multiple dose toxicity, reproduction and mutagenicity assessments were carried out in rodents and non-rodents. Initial adverse clinical signs in monkeys were associated with a systemic exposure 34 times higher than that found in humans after 0.1 mmol/kg gadobenate dimeglumine. Good systemic tolerance was observed in repeated dose toxicity studies. In experimental conditions of focal brain ischemia associated with blood-brain barrier lesions, gadobenate dimeglumine was well tolerated up to doses even 10 times higher than the maximum clinical dose (0.3 mmol/kg) intended for brain imaging procedures. Reproductive performance and physical and behavioral development of offspring were unaffected in rats. However, MultiHance has been shown to be teratogenic in rabbits when given intravenously administered at 2 mmol/kg/day (6 times the human dose based on body surface area) during organogenesis (day 6 to 18) inducing microphthalmia/small eye and/or focal retinal fold in 3 fetuses from 3 separate litters. In addition, MultiHance intravenously administered at 3 mmol/kg/day (10 times the human dose based on body surface area) has been shown to increase intrauterine deaths in rabbits. Mutagenicity tests excluded any genotoxic potential of gadobenate dimeglumine. The results were negative in the following genetic toxicity studies: 1) in vitro bacteria reverse mutation assays, 2) an in vitro gene mutation assay in mammalian cells, 3) an in vitro chromosomal aberration assay, 4) an in vitro unscheduled DNA synthesis assay, and 5) an in vivo micronucleus assay in rats.
MultiHance and other drugs may compete for the canalicular multispecific organic anion transporter (MOAT also referred to as MRP2 or ABCC2). Therefore MultiHance may prolong the systemic exposure of drugs such as cisplatin, antracyclines (e.g. doxorubicin, daunorubicin), vinca alkaloids (e.g. vincristine), methotrexate, etoposide, tamoxifen, and paclitaxel. In particular, consider the potential for prolonged drug exposure in patients with decreased MOAT activity (e.g. Dubin Johnson syndrome).
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
来源:Hazardous Substances Data Bank (HSDB)
毒理性
解毒与急救
/SRP:/ 高级治疗：对于昏迷、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W TKO /SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸钠林格氏液（LR）。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。/毒物A和B/
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Gadobenate ion has a rapid distribution half-life (reported as mean + or - SD) of 0.084 + or - 0.012 to 0.605 + or - 0.072 hours. Volume of distribution of the central compartment ranged from 0.074:: 0.017 to 0.158 :: 0.038 L/kg, and estimates of volume of distribution by area ranged from 0.170+ or - 0.016 to 0.282+ or - 0.079 L/kg. These latter estimates are approximately equivalent to the average volume of extracellular body water in man. In vitro studies showed no appreciable binding of gadobenate ion to human serum proteins. /Gadobenate ion/
... The pharmacokinetics were evaluated in rats, rabbits, dogs and monkeys after iv injections of non-labelled gadobenate dimeglumine and, for biodistribution studies, (153)-Gd-labelled gadobenate dimeglumine. Assays were performed by high performance liquid chromatography, X-ray fluorescence and gamma spectrometry. The binding of gadobenate ion to animal and human serum albumin was studied by equilibrium dialysis. ... After iv injection gadobenate dimeglumine distributes into plasma and extracellular fluid as well as into the intrahepatocytic space. Gadobenate ion is cleared from plasma by renal and biliary excretion. It does not accumulate in specific tissues, except temporarily in tissues related to its elimination. Gadobenate ion is not metabolized. Its binding to plasma proteins is too weak to be detected by equilibrium dialysis. ...
Gadobenate ion is eliminated predominately via the kidneys, with 78% to 96% of an administered dose recovered in the urine. Total plasma clearance and renal clearance estimates of gadobenate ion were similar, ranging from 0.093 + or - 0.010 to 0.133 + o r- 0.270 L/hr/kg and 0.082+ or - 0.007 to 0.104 + or - 0.039 L/hr/kg, respectively. The clearance is similar to that of substances that are subject to glomerular filtration. The mean elimination half-life ranged from 1.17+ or - 0.26 to 2.02 + or - 0.60 hours. A small percentage ofthe administered dose (0.6% to 4%) is eliminated via the biliary route and recovered in feces.
It is not known to what extent gadobenate dimeglumine is excreted in human milk. It is known from rat experiments that less than 0.5% of the administered dose is transferred via milk from mother to neonates.
[EN] TWO-WAY MAGNETIC RESONANCE TUNING NANOPROBE ENHANCED SUBTRACTION IMAGING<br/>[FR] IMAGERIE À SOUSTRACTION AMÉLIORÉE PAR NANOSONDE À ACCORD DE RÉSONANCE MAGNÉTIQUE BIDIRECTIONNELLE
申请人：UNIV CALIFORNIA
公开号：WO2021126989A1
公开（公告）日：2021-06-24
The present invention provides a nanocarrier having an interior and an exterior, the nanocarrier comprising: a plurality of amphiphilic compounds that self-assemble to form the nanocarrier; and a first magnetic resonance imaging (MRI) contrast agent and a second MRI contrast agent in the interior; wherein one MRI contrast agent is paramagnetic, and the other MRI contrast agent is superparamagnetic, and the first MRI contrast agent and the second MRI contrast agent are configured within the interior to substantially cancel the magnetic signal of each contrast agent. The present invention also provides a method of using the nanocarriers for imaging and detecting a disease, as well as novel telodendrimer compounds.
Kinetics of the Exchange Reactions between Gd(DTPA)<sup>2−</sup>, Gd(BOPTA)<sup>2−</sup>, and Gd(DTPA-BMA) Complexes, Used As MRI Contrast Agents, and the Triethylenetetraamine-Hexaacetate Ligand
and Gd(DTPA-BMA) differs very considerably; the rates of the ligand exchangereactions of Gd(DTPA-BMA), thus the rates of its dissociation, are 2 to 3 orders of magnitude higher than those of Gd(DTPA) and Gd(BOPTA). The rates of the ligand exchangereactions increase with increasing concentration of the endogenous citrate, phosphate, or carbonateions at a pH of 7.4, but the effect of citrate and phosphate
在6.5-11.0的pH范围内研究了在MRI中用作造影剂的Gd（DTPA），Gd（BOPTA）和Gd（DTPA-BMA）配合物之间发生的配体交换反应的动力学。通过在0.15 M NaCl中在25°C下测量水质子弛豫率来实现。该反应的速率成正比TTHA的浓度，这表明反应发生用的直接攻击为H我TTHA （6-我） - （我= 0，1，2和3）上的Gd物种3+配合物，通过三元中间体的形成。pH值从6.5增至9时，中性Gd（DTPA-BMA）的交换反应速率增加，因为质子化程度较低的H iTTHA （6- i）-物种可以更有效地攻击Gd 3+复合物。[Gd（DTPA）] 2-和[Gd（BOPTA）] 2-的交换反应速率也从pH 8.5升高到11，但是从6.5升高到8.5，反应速率出乎意料地降低。通过假设一般酸催化的有效性来解释这种减少。当Gd 3+解离时，来自H i TTHA （6- i）-物种（i
Process for the preparation of chelated compounds
申请人：Bracco Imaging S.p.A
公开号：EP2338874A1
公开（公告）日：2011-06-29
The present invention generally relies on a process for the preparation of chelated compounds, comprising the selective interaction between a solid matrix and a chelating agent. In more details, the present invention enables the preparation of chelated compounds useful as diagnostic or therapeutic agents either by a batch or a column procedure, in high yields and in a reliable way.
SURFACE-MODIFIED POLYMERIC SUBSTRATES GRAFTED WITH A PROPERTIES-IMPARTING COMPOUND USING CLIP CHEMISTRY
申请人：Centre National de la Recherche Scientifique (CNRS)
公开号：US20190247551A1
公开（公告）日：2019-08-15
The present invention relates to an efficient method for grafting a properties-imparting compound onto a polymeric substrate containing carbon-hydrogen (C—H) bonds using clip chemistry. The method of the invention includes coating the substrate with the properties-imparting compound and irradiating it with a reactive light source, and repeating this sequence at least once. The present invention further relates to surface-modified polymeric substrates grafted with a properties-imparting compound, in particular obtained with the method of the invention, medical devices comprising same, and non-medical of said surface-modified polymeric substrates.
[EN] PROCESS FOR THE PREPARATION OF CHELATED COMPOUNDS<br/>[FR] PROCÉDÉ DE SYNTHÈSE DE COMPOSÉS CHÉLATÉS
申请人：BRACCO IMAGING SPA
公开号：WO2011073236A1
公开（公告）日：2011-06-23
The present invention generally relies on a process for the preparation of chelated compounds, comprising the selective interaction between a solid matrix and a chelating agent. In more details, the present invention enables the preparation of chelated compounds useful as diagnostic agents, in high yields and in a reliable way.
