IDENTIFICATION AND USE: Gadoteridol is used as injectable contrast medium for Magnetic Resonance Imaging (MRI). 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 ProHance dose and allow a sufficient period of time for elimination of the drug from the body prior to re-administration. The possibility of a reaction, including serious, life threatening, or fatal, anaphylactic or cardiovascular reactions, or other idiosyncratic reactions, should always be considered, especially in those patients with a history of a known clinical hypersensitivity or a history of asthma or other allergic respiratory disorders. The literature describe a case of vasovagal response and anaphylactoid reaction during iv administration of gadoteridol. In an in vitro test, gadoteridol did not demonstrate any potential to hemolyze human erythrocytes when incubated in high concentrations with whole blood, suggesting there is little probability gadoteridol will cause hemolysis in vivo. ANIMAL STUDIES: Gadopentetate dimeglumine (Magnevist), gadoteridol (ProHance), gadodiamide (Omniscan), and gadoversetamide (Optimark) were evaluated at standard concentration and compared with a control (physiologic saline) and the conventional ionic radiographic contrast medium meglumine diatrizoate (Renografin 60) in mice. Of the four MR contrast agents, gadopentetate dimeglumine caused the greatest tissue damage, and gadoteridol and gadodiamide-the two lowest osmolar agents-the least after sc injection in the hindlimb. ProHance administered to rats at 10 mmol/kg/day (33 times the maximum recommended human dose of 0.3 mmol/kg or 6 times the human dose based on a mmol/m comparison) for 12 days during gestation doubled the incidence of postimplantation loss. When rats were administered 6.0 or 10.0 mmol/ kg/day for 12 days, an increase in spontaneous locomotor activity was observed in the offspring. ProHance increased the incidence of spontaneous abortion and early delivery in rabbits administered 6 mmol/kg/day (20 times the maximum recommended human dose or 7 times the human dose based on a mmol/m comparison) for 13 days during gestation. ProHance did not demonstrate genotoxic activity in bacterial reverse mutation assays using Salmonella typhimurium and Escherichia coli, in a mouse lymphoma forward mutation assay, in an in vitro cytogenetic assay measuring chromosomal aberration frequencies in Chinese hamster ovary cells, nor in an in vivo mouse micronucleus assay at intravenous doses up to 5.0 mmol/kg.
参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
... The physicochemical properties of gadoteridol, a macrocyclic nonionic gadolinium complex, were studied together with its pharmacokinetics and biodistribution in rats and dogs. ... Studies in rats were conducted after single iv injections at 0.1 or 0.35 mmol/kg using (153)Gd-labeled gadoteridol or with seven daily doses of 0.1 mmol/kg to examine the levels of residual gadolinium in organs. Nonradioactive biodistribution and excretion studies were performed in dogs following injection at 0.1 mmol/kg. ... After injection, the dose was rapidly cleared from rat blood and excreted such that more than 90% of the dose appeared in the urine within 4 hr of injection. At 7 and 14 days postinjection, only extremely low levels of gadolinium were observed in liver and bone; these levels were two to eight times lower than the levels reported after the injection of gadopentetate dimeglumine. ... Differences observed in the long-term retention of gadolinium between gadoteridol and gadopentetate dimeglumine were consistent with the reported greater in vivo resistance to transmetallation of gadolinium macrocycles compared with the linear gadolinium chelate molecules.
... To assess the safety and pharmacokinetics of gadoteridol injection (0.5 M) ... 18 healthy male volunteers ... were assigned to one of six dosing groups: 0.05, 0.1, 0.15, 0.2, 0.25, and 0.3 mmol/kg gadoteridol (0.5 M), in an ascending dose study. Physical examination, vital signs, electrocardiogram, clinical laboratory tests, and serum and urine samples were obtained at selected time points before and after administration of gadoteridol. ... No significant changes in vital signs, physical examination, clinical laboratory values, or electrocardiogram, that were believed ... to be related to the administration of the contrast agent, were observed. A single adverse event (transient hive) believed to be related to contrast agent administration was observed in one volunteer. Pharmacokinetic data show that the elimination half-life and the distribution half-life were independent of the dose used. The mean distribution half-life was 0.20 +/- 0.04 hours, the mean elimination half-life was 1.57 +/- 0.08 hours, and greater than 94% of the drug was excreted in the urine in 24 hours.
The present invention relates to the novel compound, 1,4,7,10-tetraazabicyclo[8.2.2]tetradecan-2-one of formula (I), its preparation and the use thereof for the preparation of tetraazamacrocycles and the mono and diacetic acid derivatives. ##STR1##
The present invention relates to the novel compound, 1,4,7,10-tetraazabicyclo[8.2.2]tetradecan-2-one of formula (I), its preparation and the use thereof for the preparation of tetraazamacrocycles. ##STR1##
Process for producing tetraazabicyclo monoacetic acid
申请人：Dibra S.p.A.
公开号：US06020485A1
公开（公告）日：2000-02-01
The present invention relates to the novel compound, 1,4,7,10-tetraazabicyclo[8.2.2]tetradecan-2-one of formula (I), its preparation and the use thereof for the preparation of tetraazamacrocycles. ##STR1##
