Ketamine presents a mainly hepatic metabolism and its major metabolite is norketamine. The biotransformation of ketamine corresponds to N-dealkylation, hydroxylation of the cyclohexone ring, conjugation to glucuronic acid and dehydration of the hydroxylated metabolites for the formation of cyclohexene derivatives.
The biotransformation of ketamine includes N-dealkylation (metabolite I), hydroxylation of the cyclohexone ring (metabolites III and IV), conjugation with glucuronic acid and dehydration of the hydroxylated metabolites to form the cyclohexene derivative (metabolite II). Following intravenous administration, the ketamine concentration has an initial slope (alpha phase) lasting about 45 minutes with a half-life of 10 to 15 minutes. This first phase corresponds clinically to the anesthetic effect of the drug. The anesthetic action is terminated by a combination of redistribution from the CNS to slower equilibrating peripheral tissues and by hepatic biotransformation to metabolite I. This metabolite is about 1/3 as active as ketamine in reducing halothane requirements (MAC) of the rat. The later half-life of ketamine (beta phase) is 2.5 hours.
The pharmacokinetics of ketamine-HCl in the cat was described by a 2-compartment open model. The n-dealkylated amine metabolite of ketamine-HCl was detected in plasma of all cats and peak levels which were 0.27 to 0.38 times ketamine-HCl level were reached between 5 and 20 min after injection.
... The pharmacokinetics and distribution of ketamine and its biotransformation products in dogs after extradural administration of ketamine at L4-5 /were studied/. ... The apparent formation rate constant of norketamine was greater than that of dehydronorketamine. However, the concentrations of the biotransformation products in CSF were smaller than those of the parent drug. These results are similar to the distribution of ketamine and its metabolites in different cerebral structures and tissues. The concentrations decreased in concert with the increase in polarity of the metabolites. A specific distribution for all compounds was observed. Ketamine showed a greater affinity for brainstem, while norketamine and dehydronorketamine were distributed mostly in cerebellum and kidney, respectively.
IDENTIFICATION AND USE: Ketamine is a cyclohexanone derivative used as an anesthetic agent in human and veterinary procedures. Ketamine hydrochloride injection, USP is indicated as the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation. HUMAN STUDIES: Ketamine is a unique anesthetic because it has both hypnotic and analgesic effects and also potential hallucinogenic side effects. Lack of cardiopulmonary depression makes the drug a popular choice for anesthesia in the prehospital setting. In recent years ketamine has been found to have anti-hyperalgesic and opioid saving effects, opening to new ways of managing post-operative and chronic pain states. Ketamine has been used as a drug of abuse. Ketamine produces a variety of symptoms including, but not limited to, anxiety, dysphoria, disorientation, insomnia, flashbacks, hallucinations, and psychotic episodes. Ketamine dependence and tolerance are possible following prolonged administration. A withdrawal syndrome with psychotic features has been described following discontinuation of long-term ketamine use. Frequent recreational users of ketamine have been found to have impaired memory 3 days after their last dose, compared with infrequent users. Flashbacks have also been reported. Frequent use result in tolerance and the need to increase the dose in order to maintain similar effects. Respiratory depression may occur with overdosage or too rapid a rate of administration of ketamine, in which case supportive ventilation should be employed. Mechanical support of respiration is preferred to administration of analeptics. ANIMAL STUDIES: Ketamine hydrochloride administration altered the hemogram of rhesus monkeys when compared to physical restraint for venipuncture. The alterations were decreases in the leukocyte count, total plasma proteins, and hematocrit. The decrease in the leukocyte count was due primarily to a decrease in lymphocytes with a smaller decrease in neutrophils. Ketamine decreased locomotor activity and increased cell death in the prefrontal cortex of monkeys with 6 months of ketamine treatment when compared with the control monkeys. Such decreases were not found in the 1-month ketamine-treated group. Pre- or post-training systemic administration of ketamine (0.3, 1 and 3 mg/kg ip) in a dose-dependent manner disrupted rats performance in spatial and non-spatial recognition memory tests, suggesting that ketamine affected pre- and post-training memory components. Intraperitoneal injections of ketamine 75 mg/kg in rats of both sexes (age 1-16 weeks) revealed a significant relationship between increased age and decreased duration of sleeping time for both sexes during the first 3 weeks of age. This decrease in sleeping time seemed to be associated with the increased production of the cyclohexanone oxidation metabolite of ketamine. After 3 weeks of age there was a greater sleeping time in the female rat than the male and this seemed to be associated with a greater ability of the male to produce the cyclohexanone oxidation metabolite. In rats, ketamine, or its urinary metabolites, disrupted the proliferation of bladder epithelial cells, resulting in defected bladder epithelial barrier. A single 24-hr episode of ketamine anesthesia, occurring during a sensitive period of brain development, resulted in very long-lasting deficits in brain function in rhesus monkeys. The pattern of neurodegeneration induced by ketamine in fetuses was different from that in neonates, and loss of neurons attributable to ketamine exposure was 2.2 times greater in the fetal than neonatal brains. A subanesthetic dose of ketamine increased exploratory locomotion in one strain of mice, but decreased it in another strain of mice. Therefore, hereditary factors may play an important role in ketamine-induced responses. Epidural ketamine injection was associated with caudal anti-nociception, sedation and ataxia in the dromedary camels. Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours.
Ketamine has several clinically useful properties, including analgesia and less cardiorespiratory depressant effects than other anaesthetic agents, it also causes some stimulation of the cardiocascular system. Ketamine has been reported to produce general as well as local anaesthesia. It interacts with N-methyl-D-aspartate (NMDA) receptors, opioid receptors, monoaminergic receptors, muscarinic receptors and voltage sensitive Ca ion channels. Unlike other general anaesthetic agents, ketamine does not interact with GABA receptors.
Short term use of ketamine for anesthesia has been associated with rare instances of serum enzyme elevations, but not with clinically apparent liver injury. With chronic or intermittent use, however, unusual biliary and hepatic complications have been described. In a manner similar to its effects on the urinary tract, ketamine can also cause abnormalities in the biliary system with dilation and irregularity of the intra- and extra-hepatic bile ducts. Patients typically developed right upper quadrant pain and tenderness associated with elevations in serum alkaline phosphatase and aminotransferase levels, with minimal or no increase in bilirubin (Case 1). Biliary imaging may reveal dilation and irregularity of the intra- and extra-hepatic bile ducts with fusiform dilation of the common bile duct suggestive of choledochal cysts. Liver biopsy demonstrates changes suggestive of chronic liver obstruction or sclerosing cholangitis. Discontinuation of ketamine is usually followed by slow improvement and the abnormalities found on biliary imaging may no longer be demonstrable several months later.
Ketamine absorption is very rapid and the bioavailability is around 93%. After the first pass metabolism, only 17% of the administered dose is absorbed. It distributes very rapidly and presents a distribution half-life of 1.95 min. The Cmax levels at peak reach 0.75 mcg/ml in plasma and 0.2 mcg/ml in cerebrospinal fluid.
Pharmacokinetic studies have resulted in the recovery of 85-95% of the administered dose in urine mainly in the form of metabolites. Some other routes of elimination of ketamine are bile and feces. When administered intravenously the resultant recovery is distributed by 91% of the administered dose in urine and 3% in feces.
来源:DrugBank
吸收、分配和排泄
分布容积
中心室在非稳态和稳态下的表观分布容积分别为371.3毫升/千克和4060.3毫升/千克。
The apparent volume of distribution of the central compartment and at steady-state are 371.3 ml/kg and 4060.3 ml/kg, respectively.
来源:DrugBank
吸收、分配和排泄
清除
盐酸氯胺酮的清除率很高，大约为95 L/h/70kg。
The clearance rate of ketamine is high and of around 95 L/h/70kg.
Ketamine has a large volume of distribution and rapid clearance that make it suitable for continuous infusion without the lengthening in duration of action seen with thiopental. Protein binding is much lower with ketamine than with the other parenteral anesthetics.
DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
申请人：BAYER PHARMA AKTIENGESELLSCHAFT
公开号：US20160221965A1
公开（公告）日：2016-08-04
The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.
A series of phenylalkylaminoalkyl derivatives of Formula I
wherein Ar is naphtyl or phenyl;
R¹ is hydrogen, fluoro or R⁴CONH-;
R² is hydrogen or C₁-₆ alkyl;
R₃ is C₁-₆ alkyl;
R⁴ is C₁-₆ alkyl or phenyl- C₁-₆ alkyl;
x is zero or the integers 1 and 2;
m is selected from the integers 1 to 6; and
n is selected from the integers 2 and 3,
has been found to provide effective antiischemic protection for CNS tissue, particularly neurons. A method of treatment to protect against CNS ischemia, such as that resulting from trauma or stroke or other ischemic conditions, comprises administration of these novel compounds to an individual in need of such treatment.
Eflornithine Prodrugs, Conjugates and Salts, and Methods of Use Thereof
申请人：Xu Feng
公开号：US20100120727A1
公开（公告）日：2010-05-13
In one aspect, the present invention provides a composition of a covalent conjugate of an eflornithine analog with an anti-inflammatory drug. In another aspect, the present invention provides a composition of an eflornithine prodrug. In another aspect, the present invention provides a composition of an eflornithine or its derivatives aspirin salt. In another aspect, the present invention provides methods for treating or preventing cancer using the conjugates or salts of eflornithine analogs or eflornithine prodrugs.
[EN] NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS<br/>[FR] NOUVEAUX COMPOSÉS ET COMPOSITIONS PHARMACEUTIQUES LES COMPRENANT POUR LE TRAITEMENT DE TROUBLES INFLAMMATOIRES
申请人：GALAPAGOS NV
公开号：WO2017012647A1
公开（公告）日：2017-01-26
The present invention discloses compounds according to Formula (I), wherein R1, R3, R4, R5, L1, and Cy are as defined herein. The present invention also provides compounds, methods for the production of said compounds of the invention, pharmaceutical compositions comprising the same and their use in allergic or inflammatory conditions, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 and/or interferons. The present invention also methods for the prevention and/or treatment of the aforementioned diseases by administering a compound of the invention.
[EN] ALPHA-KETOAMIDE DERIVATIVE, AND PRODUCTION METHOD AND USE THEREOF<br/>[FR] DERIVE D'ALPHA-CETOAMIDE, SON PROCEDE DE PRODUCTION ET D'UTILISATION
申请人：SENJU PHARMA CO
公开号：WO2005056519A1
公开（公告）日：2005-06-23
The present invention provides a compound represented by the formula (I): (INSERT CHEMICAL FORMULA) (wherein R1 is a lower alkyl substituted by a lower alkoxy or a heterocyclic group, or a heterocyclic group; R2 is a lower alkyl optionally substituted by a phenyl; and R3 is a lower alkyl optionally substituted by a halogen, a lower alkoxy or a phenyl, or a fused polycyclic hydrocarbon group), which is well absorbed orally, exhibits durability of good blood level and has potent calpain inhibitory activity.
