STABLE IN LIGHT & HEAT BUT IS HYGROSCOPIC WHEN EXPOSED TO HIGH RELATIVE HUMIDITIES
旋光度：
Specific optical rotation: +13.7 deg at 25 °C/D ( c = 2 in water)
解离常数：
pKa2 = 9.49 (est)
计算性质
辛醇/水分配系数(LogP)：
-0.1
重原子数：
14
可旋转键数：
9
环数：
0.0
sp3杂化的碳原子比例：
1.0
拓扑面积：
64.5
氢给体数：
4
氢受体数：
4
ADMET
代谢
乙胺丁醇主要通过醛脱氢酶氧化成醛代谢物，随后转化为2,2'-(乙二亚胺基)二丁酸这种二羧酸。
Ethambutol is mainly oxidized by an aldehyde dehydrogenase to an aldehyde metabolite, followed by conversion to the dicarboxylic acid 2,2'-(ethylinediimino)di-butyric acid.
来源:DrugBank
代谢
... 其中高达15%以两种代谢物形式排出，一种为醛和一种为二羧酸衍生物。
... Up to 15% is excreted in the form of two metabolites, an aldehyde and a dicarboxylic acid derivative.
Ethambutol is partially inactivated in the liver by oxidation to an aldehyde intermediate, 2,2?-(ethylenediimino)-di-butyraldehyde, which is converted to the decarboxylic acid derivative, 2,2?-(ethylenediimino)-di-butyric acid.
IDENTIFICATION: Ethambutol is used to treat tuberculosis. Ethambutol is an odorless crystalline hygroscopic powder. It is soluble in water, alcohol, chloroform, methyl alcohol, and very slightly soluble in ether. HUMAN EXPOSURE: Summary: Main risks and target organs: During chronic treatment ethambutol may produce visual and neurological disturbances, allergic reactions, gastrointestinal symptoms, psychiatric symptoms and transient impairment of liver function. This last event has a very low incidence. Increased serum uric acid levels and acute gouty arthritis have been reported. Summary of clinical effects: Acute overdosage may cause gastrointestinal symptoms, hallucinations and optic neuritis. Acute overdosage symptoms include nausea, abdominal pain, fever, mental confusion, visual hallucinations, and optic neuropathy (retrobulbar neuritis) with doses over 10 g. The effects of overdosage are not well established. During chronic treatment the following have been reported: Visual disturbances: Ethambutol may produce a reduction of visual acuity which appear to be due to optic neuritis. Central scotoma and green-red colour blindness may also occur. Allergic reactions: Rash, anaphylactoid reactions, dermatitis and pruritus. Gastrointestinal symptoms: Abdominal pain, anorexia, nausea, vomiting. Neurological disturbances and psychiatric symptoms: Headache, peripheral neuritis, dizziness, mental confusion, disorientation and hallucinations. Other side effects: Jaundice, transient impairment of liver function, fever, increase of serum uric acid levels, joint pain, acute gouty arthritis, malaise. Ethambutol may diffuse into milk. Ethambutol is a synthetic oral antibiotic derivative of ethylenediamine. Contraindications: Ethambutol hydrochloride is contraindicated in patients who are known to be hypersensitive to this drug. Renal impairment, old age and optic neuritis are relative contraindications. Routes of entry: Oral: Ethambutol is only available for oral use. Absorption by route of exposure: About 80% of an oral dose of ethambutol is absorbed from the gastro-intestinal tract, and the remainder appears in the feces unchanged. Absorption is not significantly impaired by food. Distribution by route of exposure: Ethambutol diffuses readily into red blood cells and into the cerebrospinal fluid when the meninges are inflamed. The concentration in erythrocytes at steady state is approximately twice the plasma concentration. It has been reported to cross the placenta and is excreted in breast milk. Biological half-life by route of exposure: The serum half-life in therapeutic doses is 3 hours, increasing in renal failure, as 80% is excreted renally. Metabolism: The main path of metabolism appears to be an initial oxidation of the alcohol to an aldehydic intermediate, followed by conversion to a dicarboxylic acid. Elimination by route of exposure: During the 24 hour period following oral administration of ethambutol, approximately 50% of the initial dose is excreted unchanged in the urine, while an additional 8% to 15% appears in the form of metabolites. From 20 to 22% of the initial dose is excreted in the feces as unchanged drug. Mode of action: Toxicodynamics: The underlying cause of visual alterations appears to be a disturbance of metabolism due to depletion of copper and zinc which serve as prosthetic groups for many enzymes. The eye normally contains a considerable store of zinc. Much of the zinc is in the pigmented cells of the outer zone of the retina, where it serves as a metal prosthetic group for retinol (alcohol) dehydrogenase. Pharmacodynamics: Ethambutol is an oral chemotherapeutic agent which is specifically effective against actively growing microorganisms of the genus Mycobacterium, including M. tuberculosis. Ethambutol is bacteriostatic and appears to inhibit the synthesis of one or more metabolites, thus causing impairment of cell metabolism, arrest of multiplication, and cell death. No cross resistance with other available antimycobacterial agents has been demonstrated. Ethambutol has been shown to be effective against strains of mycobacterium tuberculosis but does not seem to be active against fungi, viruses, or other bacteria. Ethambutol is also active against some atypical mycobacteria including M. kansasii. Primary resistance to ethambutol is uncommon in developed countries but resistant strains of M. tuberculosis are readily produced if the drug is used alone. Human data: Adults: Subclinical impairment of colour discrimination was reported to be relatively common in patients receiving ethambutol daily as part of antituberculous chemotherapy when compared with 50 patients receiving other antituberculous agents. Peripheral neuropathy has been reported in tubercular patients who had received ethambutol among other drugs. Interactions: Results of a crossover study involving 13 tuberculous patients suggest that concomitant administration of aluminium hydroxide may delay and reduce absorption of ethambutol in some patients. Untoward effects may be enhanced when ethambutol is combined with isoniazid or rifampicin. Main adverse effects: Ethambutol may produce decreased visual acuity which appear to be due to optic neuritis and to be related to dose and duration of treatment. The effects are generally reversible when administration of the drug is discontinued promptly. Ethambutol may produce constriction of visual field, central and peripheral scotoma, and green-red color blindness which may be associated with retrobulbar neuritis. Renal clearance of urate may be reduced in about 50% of patients receiving ethambutol and acute gout has been precipitated in patients with gout or impaired renal function. Cholestatic jaundice has been reported. ANIMAL/PLANT STUDIES: Relevant animal data: Toxicological studies in dogs on high prolonged doses, produced evidence of myocardial damage and failure, and depigmentation of the tapetum lucidum of the eyes, the significance of which is not known. Degenerative changes in the central nervous system, apparently not dose-related, have also been noted in dogs receiving ethambutol hydrochloride over a prolonged period. In the rhesus monkey, neurological signs appeared after treatment with high doses given daily over a period of several months. These correlated with specific serum levels of ethambutol hydrochloride and with definite neuro-anatomical changes in the central nervous system. Focal interstitial carditis was also noted in monkeys which received ethambutol hydrochloride in high doses for a prolonged period.
Because ethambutol is almost always used in combination with isoniazid, rifampin or other antituberculosis agents, the frequency of serum aminotransferase elevations attributable to ethambutol alone cannot be estimated with any confidence. The addition of ethambutol to isoniazid, rifampin or pyrazinamide does not appear to increase the rate of transient ALT elevations during therapy. In addition, ethambutol is a rare cause of acute, symptomatic liver injury. Despite 50 years of use, ethambutol has been linked to clinically apparent liver injury in only a few case reports. In the best described instance (Case 1), the onset of symptoms was 2 months after starting combination antituberculosis therapy and, in contrast to liver injury due to isoniazid or pyrazinamide, the pattern of serum enzymes was distinctly cholestatic. The recurrence of liver injury upon rechallenge with ethambutol but not isoniazid made the attribution convincing. Other case reports have described liver injury occurring in the context of DRESS syndrome, arising within 2 to 6 weeks of starting antituberculosis therapy with fever, rash, eosinophilia and other organ involvement such as liver, kidney and lung. Several published instances have described recurrence of injury after rechallenge with ethambutol.
◉ Summary of Use during Lactation:Limited information indicates that maternal doses of ethambutol up to 15 mg/kg daily produce low levels in milk and would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. The amount of ethambutol in milk is insufficient to treat tuberculosis in the breastfed infant. The Centers for Disease Control and Prevention and other professional organizations state that breastfeeding should not be discouraged in women taking ethambutol.
◉ Effects in Breastfed Infants:In one uncontrolled study, 6-beta-hydroxycortisol levels were measured in 10 male infants whose mothers had tuberculosis and took ethambutol 1 gram daily plus isoniazid 300 mg daily and the infants of mothers (apparently without tuberculosis) who took no chronic drug therapy. The infants of mothers taking the antituberculars had consistently lower 6-beta-hydroxycortisol levels on 8 occasions at 15-day intervals from 90 to 195 days of age, but these differences were statistically significant on days 120 and 195 only. The authors attributed the lower levels to inhibition of hepatic metabolism of cortisol to 6-beta-hydroxycortisol by the antitubercular drugs in milk. However, ethambutol is not known to inhibit drug metabolism, so if the effect occurs it is more likely caused by isoniazid.
Ethambutol was used as part of a seven-drug regimen to treat a pregnant woman with multidrug-resistant tuberculosis during the second and third trimesters of pregnancy and postpartum. The infant was breastfed (extent and duration not stated). At age 4.6 years, the child was developing normally except for a mild speech delay.
Two mothers in Turkey were diagnosed with tuberculosis at the 30th and 34th weeks of pregnancy. They immediately started isoniazid 300 mg, rifampin 600 mg, pyridoxine 50 mg daily for 6 months, plus pyrazinamide 25 mg/kg and ethambutol 25 mg/kg daily for 2 months. Both mothers breastfed their infants (extent not stated). Their infants were given isoniazid 5 mg/kg daily for 3 months prophylactically. Tuberculin skin tests were negative after 3 months and neither infant had tuberculosis at 1 year of age. No adverse effects of the drugs were mentioned.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.
Patient administered digitoxin (0.1 mg/day orally) while taking ethambutol (20-25 mg/kg/day) had markedly decreased serum levels of digitoxin compared to controls (16.6 versus 35 ng/mL). Binding of digitoxin by blood proteins was same in both groups. Its metabolism was probably increased.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
相互作用
同时使用乙胺丁醇和其他具有神经毒性的药物可能会增加神经毒性的风险，如视神经炎和周围神经炎。
Concurrent administration of ethambutol with other neurotoxic medications may increase the potential for neurotoxicity, such as optic and peripheral neuritis.
Oral ethambutol is approximately 75-80% orally bioavailable. A 25 mg/kg oral dose of ethambutol reaches a Cmax of 2-5 µg/mL, with a Tmax of 2-4 hours. In a separate study, the AUC0-8 varied from 6.3 ± 5.5 h\*mg/L to 10.8 ± 7.6 h\*mg/L depending on CYP1A2 genetic polymorphisms.
Ethambutol is 50% eliminated in the urine as the unmetabolized parent compound and 8-15% as inactive metabolites. 20-22% of a dose is eliminated unchanged in the feces.
来源:DrugBank
吸收、分配和排泄
分布容积
结核病和HIV共感染的患者，乙胺丁醇的估算分布容积为76.2升。
Patients coinfected with tuberculosis and HIV have an estimated ethambutol volume of distribution of 76.2 L.
来源:DrugBank
吸收、分配和排泄
清除
结核病和HIV共感染的患者，乙胺丁醇的预计口服清除率为77.4升/小时。
Patients coinfected with tuberculosis and HIV have an estimated ethambutol oral clearance of 77.4 L/h.
Approximately 75-80% of an oral dose of ethambutol hydrochloride is rapidly absorbed from the GI tract. Absorption is not substantially affected when the drug is administered with food. Following a single oral ethambutol hydrochloride dose of 25 mg/kg, peak serum ethambutol concentrations of 2-5 mcg/mL are attained within 2-4 hours; serum concentrations of the drug are undetectable 24 hours after the dose.
COORDINATION OF (4S, 9S)-4,9-DIETHYL-2,11-DIOXA-5, 8-DIAZA-1 δ5- PHOSPHATRICYCLO[6.3.0.01.5]UNDECANE WITH RETENTION OF HYDROPHOSPHORANE STRUCTURE: OBTAINING AND CHARACTERISTIC FEATURES OF ADDUCTS WITH BF3AND ZnCl2
摘要：
Reactions of tricyclic hydrophosphorane, (4S, 9S)-4, 9-diethyl-2, 11-dioxa-5, 8-diaza-1 lambda(5)-phospha-tricyclo[6.3.0.0(1.5)]undecane (1), with BF(3)xEt(2)O and with ZnCl2 under mild conditions have been investigated. The phosphorane ligand in the complexes obtained (2 and 3, respectively) was found to maintain its tricyclic structure, while the BF3 and ZnCl2 groups coordinate to the apical nitrogen and oxygen atoms of the trigonal bipyramid of phosphorane. The structure of the complexes has been evaluated by the following set of methods: IR and NMR B-11, C-13, F-19, P-31 spectroscopy mass-spectrometry, X-ray photoelectron spectroscopy, ultracentrifugation and elemental analysis. Spectral peculiarities and dynamic behavior in different solvents of compound 2 have been examined in detail.
[EN] METALLOENZYME INHIBITOR COMPOUNDS<br/>[FR] COMPOSÉS INHIBITEURS DE MÉTALLOENZYMES
申请人：VPS 3 INC
公开号：WO2018165520A1
公开（公告）日：2018-09-13
Provided are compounds having HDAC6 modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by HDAC6.
提供具有HDAC6调节活性的化合物，以及通过HDAC6介导的治疗疾病、疾病或症状的方法。
[EN] OXAZOLIDINONE COMPOUNDS AND METHODS OF USE THEREOF AS ANTIBACTERIAL AGENTS<br/>[FR] COMPOSÉS OXAZOLIDINONE ET PROCÉDÉS D'UTILISATION DE CES DERNIERS EN TANT QU'AGENTS ANTIBACTÉRIENS
申请人：MERCK SHARP & DOHME
公开号：WO2017066964A1
公开（公告）日：2017-04-27
The present invention relates to oxazolidinone compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, E, and R1 are as defined herein. The present invention also relates to compositions which comprise at least one oxazolidinone compound of the invention. The invention also provides methods for inhibiting growth of mycobacterial cells as well as a method of treating mycobacterial infections by Mycobacterium tuberculosiscomprising administering a therapeutically effective amount of an oxazolidinone of the invention and/or apharmaceutically acceptable salt thereof, or a composition comprising such compound and/or salt.
[EN] DERIVATIVES OF AMANITA TOXINS AND THEIR CONJUGATION TO A CELL BINDING MOLECULE<br/>[FR] DÉRIVÉS DE TOXINES D'AMANITES ET LEUR CONJUGAISON À UNE MOLÉCULE DE LIAISON CELLULAIRE
申请人：HANGZHOU DAC BIOTECH CO LTD
公开号：WO2017046658A1
公开（公告）日：2017-03-23
Derivatives of Amernita toxins of Formula (I), wherein, formula (a) R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X, L, m, n and Q are defined herein. The preparation of the derivatives. The therapeutic use of the derivatives in the targeted treatment of cancers, autoimmune disorders, and infectious diseases.
[EN] A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS<br/>[FR] CONJUGUÉ D'UN AGENT CYTOTOXIQUE À UNE MOLÉCULE DE LIAISON CELLULAIRE AVEC DES LIEURS RAMIFIÉS
申请人：HANGZHOU DAC BIOTECH CO LTD
公开号：WO2020257998A1
公开（公告）日：2020-12-30
Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.
[EN] CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES<br/>[FR] DÉRIVÉ DE DIMÈRE DE PYRROLOBENZODIAZÉPINE RÉTICULÉ (PBD) ET SES CONJUGUÉS
申请人：HANGZHOU DAC BIOTECH CO LTD
公开号：WO2020006722A1
公开（公告）日：2020-01-09
A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.
