... When stored under recommended conditions, commercially available trastuzumab powder for injection should be stable up to the date of expiration marked on the vial. Following reconstitution of the sterile powder with bacteriostatic water for injection containing benzyl alcohol (as supplied by the manufacturer), trastuzumab solutions are stable for 28 days when refrigerated at 2-8 °C. ... Reconstituted solutions of trastuzumab diluted in 0.9% sodium chloride injection are stable for no more than 24 hours when prepared and stored in polyvinyl chloride or polyethylene bags at 2-8 °C. The manufacturer states that 5% dextrose injection should not be used as a diluent for trastuzumab solutions; diluents other than those recommended by the manufacturer may not maintain the stability or sterility of the antibody solution.
计算性质
辛醇/水分配系数(LogP)：
-2.2
重原子数：
21
可旋转键数：
2
环数：
3.0
sp3杂化的碳原子比例：
0.5
拓扑面积：
181
氢给体数：
6
氢受体数：
8
ADMET
代谢
曲妥珠单抗的代谢过程尚未完全了解，但看来该药物的消除涉及通过网状内皮系统清除IgG。
The metabolism of trastuzumab is not fully understood, but it appears that elimination of the drug would involve clearance of IgG through the reticuloendothelial system.
In large registration trials of trastuzumab for breast and other cancers, rates of serum enzyme elevations were low and there were no instances of clinically apparent liver injury. Since its approval and wide scale use, there have been several isolated reports of serum ALT elevations occurring after 1 to 8 cycles of trastuzumab therapy. The abnormalities have been elevations of ALT and AST with no or minimal increase in alkaline phosphatase levels and no symptoms or bilirubin elevations. The abnormalities were invariably self-limited and, in at least one instance, did not recur with use of lower doses of trastuzumab. There have been a few published reports of clinically apparent, acute liver injury with jaundice attributed to trastuzumab but typically when given in combination with other potentially hepatotoxic agents.
Likelihood score: D (possible rare cause of clinically apparent liver injury).
In contrast, in large registration trials, ado-trastuzumab emtansine was linked to serum enzyme elevation or bilirubin elevations in up to 20% to 80% of patients and levels rose to above 5 times the upper limit of normal (ULN) in at least 5%. Furthermore, instances of acute liver injury including deaths from hepatic failure were reported, although details of the timing and pattern of injury were not always provided. Some of these cases may represent acute sinusoidal obstruction syndrome and in other cases acute, direct hepatotoxic injury.
More recently, cases of noncirrhotic portal hypertension have been described in patients on long term trastuzumab emtansine. The typical presentation is with signs and symptoms of portal hypertension after years of therapy and usually with only modest increases in serum aminotransferase elevations and bilirubin. Strikingly, in patients who undergo liver biopsy, cirrhosis is not present, although mild-to-moderate fibrosis is present in some. This phenotype of injury is classified as noncirrhotic portal hypertension, but the underlying liver condition is usually nodular regenerative hyperplasia with elements of sinusoidal obstruction. Hepatic imaging shows a nodular and somewhat shrunken liver and prominent splenomegaly and varices. Typically, patients improve clinically once trastuzumab emtansine is discontinued, although without chemotherapy the malignancy may return and progress. Another syndrome with somewhat similar clinical features associated with long term trastuzumab emtansine therapy is a disordered, nodular liver cause by shrinkage of necrotic hepatic metastases, sometimes referred to as “pseudocirrhosis.” These patients are generally asymptomatic and the diagnosis is made by hepatic imaging often done as a part of routine follow up of the metastatic liver disease.
Likelihood score: B (likely cause of clinically apparent liver injury).
In clinical studies, a 1.5-fold increase in mean trough serum concentrations of trastuzumab was reported when the drug was administered concomitantly with paclitaxel versus an anthracycline and cyclophosphamide. In primate studies, administration of trastuzumab in combination with paclitaxel resulted in a twofold decrease in trastuzumab clearance. The clinical importance of the interaction between trastuzumab and paclitaxel is not known.
The risk of trastuzumab-induced cardiotoxic effects is increased in patients receiving an anthracycline concomitantly. Such combined therapy currently is not recommended by most experts for use in the treatment of metastatic breast cancer.
Emergency and supportive measures: Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, and arrhythmias if they occur. Treat nausea and vomiting with metoclopramide and fluid loss caused by gastroenteritis with intravenous crystalloid fluids. ... Immediately stop the infusion and withdraw as much fluid as possible by negative pressure on the syringe. Surgical intervention may be necessary. ... Specific drugs and antidotes: Very few specific treatments or antidotes are available. Decontamination: Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. Enhanced elimination: Because of the rapid intracellular incorporation of most of these agents, dialysis and other extracorporeal removal procedures are generally not effective. /Antineoplastic agents/
/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/
In patients with metastatic breast cancer receiving a loading dose of 4 mg/kg IV followed by a weekly maintenance dose of 2 mg/kg IV, peak and trough plasma concentrations of trastuzumab at steady state (between weeks 16 and 32) averaged approximately 123 and 79 ug/mL, respectively.1 In patients with metastatic breast cancer receiving trastuzumab 500 mg once weekly by short-duration IV infusion, peak plasma concentrations of the drug averaged 377 ug/mL.
Following administration of trastuzumab by short-duration IV infusion, the mean apparent volume of distribution is about 44 mL/kg (approximately equal to serum volume). It is not known whether trastuzumab crosses the blood-brain barrier or distributes into the CSF. It also is not known whether trastuzumab crosses the placenta or distributes into milk in humans; however, placental transfer of trastuzumab and distribution of the drug into milk have been observed in monkeys.
Single or combination chemotherapy with paclitaxel, docetaxel, carboplatin, and trastuzumab was administered to 9 baboons at a mean (SD) gestational age of 117 (26) days (paclitaxel, 100 mg/sq m (n = 2); docetaxel, 100 mg/sq m (n = 2); paclitaxel, 175 mg/sq m with carboplatin, area under the curve of 6 at standard dosage (n = 2) and 50% dosage (n = 1); docetaxel, 75 mg/sq m with carboplatin, area under the curve 6 (n = 1); and docetaxel, 75 mg/sq m with trastuzumab, 8 mg/kg (n = 1). Serial fetal and maternal blood samples, amniotic fluid, maternal urine, and fetal and maternal tissue samples were collected for the first 76 hours after drug infusion. Levels of carboplatin were determined by atomic absorption spectrometry, docetaxel and paclitaxel by high-performance liquid chromatography, and trastuzumab by enzyme-linked immunosorbent assay.... The transplacental passages of trastuzumab were 85.0% and 3.0%, 2 and 26 hours after trastuzumab infusion, respectively. After 26 hours, amniotic fluid contained 36.4% of the fetal plasma concentration. Fetal tissue concentrations varied between 5.0% and 14.0% of the maternal concentration.
Chemistry of the 8-Nitroguanine DNA Lesion: Reactivity, Labelling and Repair
作者：Katie J. Alexander、Matthew McConville、Kathryn R. Williams、Konstantin V. Luzyanin、Ian A. O'Neil、Richard Cosstick
DOI：10.1002/chem.201705541
日期：2018.2.26
nucleotides, despite the fact that their biological effects are closely linked to their chemical properties. To this end, a selection of chemical reactions have been performed on 8‐nitroguanine nucleosides and oligodeoxynucleotides. Reactions with alkylating reagents reveal how the 8‐nitro substituent affects the reactivity of the purine ring, by significantly decreasing the reactivity of the N2 position
Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
申请人：——
公开号：US20020147160A1
公开（公告）日：2002-10-10
The present invention provides nucleoside compounds and certain derivatives thereof which are inhibitors of RNA-dependent RNA viral polymerase. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such nucleoside compounds alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the nucleoside compounds of the present invention.
The present invention provides an immunomodulatory compound comprising a carbohydrate polymer comprising mannose, wherein the carbohydrate polymer is conjugated to at least one immune modulator. The present invention also provides for the use of this compound in immunomodulatory compositions for vaccination and gene therapy methods, together with processes for its preparation.
Nucleosides. 5. Synthesis of guanine and formycin B derivatives as potential inhibitors of purine nucleoside phosphorylase
作者：Ji Wang Chern、Horng Yuh Lee、Chien Shu Chen、Donna S. Shewach、Peter E. Daddona、Leroy B. Townsend
DOI：10.1021/jm00060a010
日期：1993.4
In an effort to develop potent human purinenucleosidephosphorylase (PNP) inhibitors as immunosuppressive and chemotherapeutic agents, several 8-aminoguanine derivatives were synthesized and evaluated as potential PNP inhibitors. These studies were designed to investigate the hydrophobic effect of a substituent on the N-9 of the purine heterocycle and/or the C-5' positions. Compounds such as 8-aminoguanosine
NUCLEOSIDE DERIVATIVES AS INHIBITORS OF RNA-DEPENDENT RNA VIRAL POLYERMASE
申请人：MERCK SHARP & DOHME CORP.
公开号：US20170183373A1
公开（公告）日：2017-06-29
The present invention provides nucleoside compounds and certain derivatives thereof which are inhibitors of RNA-dependent RNA viral polymerase. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such nucleoside compounds alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the nucleoside compounds of the present invention.
