Commercially available eptifibatide injection has an expiration date of 24 months following the date of manufacture when stored as directed. The injection may be transferred to room temperature storage (15-30 °C) for a period not to exceed 2 months. When stored at room temperature, the injection container should be marked to indicate that any unused vials should be discarded after 2 months or by the manufacturer's labeled expiration date (whichever comes first). The manufacturer states that vials of the injection that have been left unrefrigerated only for a brief period (i.e., the vial is still cool to the touch) may be returned to refrigeration without the need to alter the expiration date.
(14)C-eptifibatide was extensively metabolized to deamidated eptifibatide and to several polar metabolites by both rats and monkeys. The drug-derived radioactivity excreted into the bile by rats, and identified as deamidated eptifibatide, was reabsorbed from the intestinal tract and further metabolized to more polar metabolites. The plasma and urine metabolite profiles in rats and monkeys indicate that the metabolic disposition of eptifibatide is similar for the two species.
Eptifibatide is metabolized principally through deamidation to a metabolite that has approximately 41% of the platelet-aggregation inhibitory activity of the parent compound, and through formation of other more polar metabolites. Approximately 27% of a dose of eptifibatide is broken down in plasma into naturally occurring amino acids; no major non-amino acid metabolites have been detected in plasma in humans.
IDENTIFICATION AND USE: Eptifibatide, as the drug Integrilin, is indicated to decrease the rate of a combined endpoint of death, new myocardial infarction (MI), or need for urgent intervention in patients undergoing percutaneous coronary intervention (PCI), including those undergoing intracoronary stenting. HUMAN EXPOSURE AND TOXICITY: Limited information is available on the acute toxicity of eptifibatide. In general, overdosage of eptifibatide in humans may be expected to produce effects that are extensions of the pharmacologic effects of the drug, predominantly bleeding. There have been cases of eptifibatide associated thrombocytopenia, which reinforces the importance of platelet count monitoring after therapy with this agent. Eptifibatide was not genotoxic in the human lymphocyte chromosome aberrations test. ANIMAL STUDIES: Single dose toxicity studies were conducted in rats, rabbits and monkeys; doses up to 500 ug/kg/minute administered by continuous intravenous infusion for 90 minutes did not cause mortality and were well-tolerated by all species. In rabbits, a dose-dependent decrease in platelet counts of the 50 and 500 ug/kg/minute (for 90 minutes)-dosed females was attributed to administration of eptifibatide. Findings in the monkeys were limited to petechial hemorrhages in the femoral and/or abdominal regions, which lasted for one to three days. Three out of five monkeys died or were sacrificed during the study due to contusions, excessive bleeding and/or petechial hemorrhages, which resulted in anemia. Total protein albumin and globulin values were reduced in all monkeys. At necropsy, focal hemorrhages in various organs were observed. In a fertility study in rats, dosing with eptifibatide had no effect on the course of pregnancy. No evidence of fertility or parental toxicity nor effects upon parental reproductive performance were observed at daily doses up to 72.0 mg/kg (24 times the maximum recommended daily human dose). Eptifibatide was not genotoxic in the Ames assay at doses up to 667 ug/mL, in the mouse lymphoma cell forward mutation assay at doses up to 1,000 ug/mL, or in the mouse micronucleus test.
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
Eptifibatide is approximately 25% bound to plasma proteins, principally (9-16%) to albumin.The volume of distribution of eptifibatide in patients with coronary artery disease is about 185-260 mL/kg and is somewhat higher (220-270 mL/kg) in healthy individuals.
Eptifibatide, a synthetic peptide inhibitor of the platelet glycoprotein IIb/IIIa receptor, has been studied as an antithrombotic agent in a variety of acute ischemic coronary syndromes. The purpose of the present study was to characterize the disposition of (14)C-eptifibatide in man after a single intravenous (i.v.) bolus dose. (14)C-Eptifibatide (approximately 50 uCi) was administered to eight healthy men as a single 135-ug/kg IV bolus. Blood, breath carbon dioxide, urine, and fecal samples were collected for up to 72 hours postdose and analyzed for radioactivity by liquid scintillation spectrometry. Plasma and urine samples were also assayed by liquid chromatography with mass spectrometry for eptifibatide and deamidated eptifibatide (DE). Mean (+/- SD) peak plasma eptifibatide concentrations of 879 +/- 251 ng/mL were achieved at the first sampling time (5 minutes), and concentrations then generally declined biexponentially, with a mean distribution half-life of 5 +/- 2.5 minutes and a mean terminal elimination half-life of 1.13 +/- 0.17 hours. Plasma eptifibatide concentrations and radioactivity declined in parallel, with most of the radioactivity (82.4%) attributed to eptifibatide. A total of approximately 73% of administered radioactivity was recovered in the 72-hour period following (14)C-eptifibatide dosing. The primary route of elimination was urinary (98% of the total recovered radioactivity), whereas fecal (1.5%) and breath (0.8%) excretion was small. Eptifibatide is cleared by both renal and nonrenal mechanisms, with renal clearance accounting for approximately 40% of total body clearance. Within the first 24 hours, the drug is primarily excreted in the urine as unmodified eptifibatide (34%), DE (19%), and more polar metabolites (13%).
Plasma clearance of eptifibatide is proportional to body weight and estimated creatinine clearance and inversely proportional to age. Following a single IV dose of (14)C-radiolabeled eptifibatide (135 ug/kg) in healthy men, renal clearance averaged approximately 40-50% of total body clearance. Clearance is reduced by 50% in patients with moderate to severe renal impairment (estimated Clcr less than 50 mL/minute). Total body clearance in geriatric patients with coronary artery disease is lower than that in younger adults.
Novel diphenylmethyl-Derived Amide Protecting Group for Efficient Liquid-Phase Peptide Synthesis: AJIPHASE
摘要：
An efficient method for the synthesis of peptides bearing an amide at the C-terminal is described. This method involves the attachment of a C-terminal protecting group bearing long aliphatic chains, followed by the repetition of simple reaction and precipitation steps with the combined advantages of liquid-phase peptide synthesis (LPPS) and solid-phase peptide synthesis (SPPS). Using this method, a hydrophobic peptide was successfully synthesized in good yield and high purity, which cannot be obtained satisfactorily by SPPS.
[EN] COMPOUNDS AND THEIR USE AS BACE INHIBITORS<br/>[FR] COMPOSÉS ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE BACE
申请人：ASTRAZENECA AB
公开号：WO2016055858A1
公开（公告）日：2016-04-14
The present application relates to compounds of formula (I), (la), or (lb) and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing Αβ-related pathologies such as Down's syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease.
SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS
申请人：BLUM Andreas
公开号：US20140135309A1
公开（公告）日：2014-05-15
This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I
wherein Ar, R
1
and R
2
are as defined herein, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.
[EN] SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] QUINAZOLINES SUBSTITUÉES PAR SULFOXIMINE POUR COMPOSITIONS PHARMACEUTIQUES
申请人：BOEHRINGER INGELHEIM INT
公开号：WO2014072244A1
公开（公告）日：2014-05-15
This invention relates to novel sulfoximine substituted quinazoline derivatives of formula (I), wherein Ar, R1 and R2 are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.
[EN] MACROCYCLIC FACTOR VIIA INHIBITORS<br/>[FR] INHIBITEURS MACROCYCLIQUES DU FACTEUR VIIA
申请人：BRISTOL MYERS SQUIBB CO
公开号：WO2013184734A1
公开（公告）日：2013-12-12
The present invention provides compounds of Formula (I): as defined in the specification and compositions comprising any of such novel compounds. These compounds are Factor VIIa inhibitors which may be used as medicaments.
PYRIMIDINYL AND 1,3,5-TRIAZINYL BENZIMIDAZOLES AND THEIR USE IN CANCER THERAPY
申请人：Rewcastle Gordon William
公开号：US20110009405A1
公开（公告）日：2011-01-13
Provided herein are pyrimidinyl and 1,3,5-triazinyl benzimidazoles of Formula I, and their pharmaceutical compositions, preparation, and use as agents or drugs for cancer therapy, either alone or in combination with radiation and/or other anticancer drugs.
