Hepatic. Cocaine is metabolized to benzoylecgonine and ecgonine methyl ester, which are both excreted in the urine. In the presence of alcohol, a further active metabolite, cocaethylene is formed, and is more toxic then cocaine itself.
The metabolism of cocaine is complex and dependent on both genetic and acquired factors. Three major pathways of cocaine metabolism are well described. Cocaine undergoes N-demethylation in the liver to form norcocaine, a minor metabolite that rarely accounts for more than 5% of drug. However, norcocaine readily crosses the blood-brain barrier and produces clinical effects in animals that are quite similar to cocaine. Nearly half of a dose of cocaine is both nonenzymatically and enzymatically hydrolyzed to form benzoylecgonine (BE). the BE is inject into animals, some reports suggest that it is virtually inactive, while other studies demonstrate cerebral vasoconstriction and seizures. When with injected directly into the cerebral ventricles or applied to the surface of cerebral arteries, BE is a potent vasoconstrictor. Although BE tranverses the blood-brain barrier poorly, the potential effects ar of concern as some BE is probably formed form cocaine that has already entered the central nervous system (CNS). In vitro, BE has little or not effect on cardia sodium or potassium channels. Finally, plasma cholinesterase (PChE) and other esterases metabolize cocaine to ecgonine methyl ester (EME). In normal individuals, between 32% and 49% of cocaine is metabolized to EME. Like BE, EME crosses the blood-brain barrier poorly. Although many authors state that EME has little or no pharmacologic activity, diverse animal models demonstrate contradictory results, concluding that EME is a vasodilator, sedative, anticonvulsant, and protective metabolite against lethal doses of cocaine.
1 to 9% of cocaine is eliminated unchanged in the urine, with a higher proportion in acid urine. The metabolites ecgonine methyl ester, benzoylecgonine, and ecgonine are recovered in variable proportions which depend on the route of administration. At the end of 4 hours, most of the drug is eliminated from plasma, but metabolites may be identified up to 144 hours after administration. Unchanged cocaine is excreted in the stool and in saliva. Cocaine and benzoylecgonine can be detected in maternal milk up to 36 hours after administration, and in the urine of neonates for as much as 5 days.Freebase cocaine crosses the placenta, and norcocaine persists for 4 to 5 days in amniotic fluid, even when it is no longer detectable in maternal blood.
Cocaine metabolism takes place mainly in the liver, within 2 hours of administration. The rate of metabolism varies according to plasma concentration. There are 3 routes of bio-transformation: the major route is hydrolysis of cocaine by hepatic and plasma esterases, with loss of a benzoyl group to give ecgonine methyl ester. Esterase activity varies substantially from one subject to another. The secondary route is spontaneous hydrolysis, probably non-enzymatic, which leads to benzoylecgonine by demethylation. The final degradation of cocaine, which is a sequel to both the principle and secondary routes of metabolism, leads to ecgonine. N-demethylation of cocaine is a minor route leading to norcocaine. The principle metabolites are therefore benzoylecgonine, ecgonine methyl ester, and ecgonine itself, which are inactive; and norcocaine which is active, and may be relevant after acute intoxication. In the presence of alcohol, a further active metabolite, cocaethylene is formed, and is more toxic then cocaine itself. ...
Cocaine is hydrolyzed rapidly by liver and plasma esterases to ecgonine methyl ester, which accounts for 30% to 50% of of the parent product. Nonenzymatic hydrolysis result in the formation of the other major metabolite, benzoylecgonine (approximately 40% of the parent product). Minor metabolites, norcocaine, and ecgonine account for the other degradation products.
IDENTIFICATION AND USE: Cocaine is a semi-synthetic drug obtained from ecgonine, a product of the saponification of coca alkaloids. Cocaine freebase and cocaine hydrochloride are white solid crystals. Street cocaine used by addicts can be mixed with amphetamines, anti-histamines, benzocaine, inositol, lactose, lidocaine, mannitol, opioids, phencyclidine, procaine, sugars, tetracaine, and sometimes arsenic, caffeine, quinidine, and even flour or talc. Cocaine hydrochloride has a very limited use for anesthesia. Cocaine is Schedule II Controlled Substance. HUMAN STUDIES: The target organs are central nervous system (CNS) and the cardio-vascular system. Abuse of cocaine leads to strong psychological dependence. In low doses acute intoxication causes euphoria and agitation. Larger doses cause hyperthermia, nausea, vomiting, abdominal pain, chest pain, tachycardia, ventricular arrhythmia, hypertension, extreme anxiety, agitation, hallucination, and mydriasis. These can be followed by CNS depression with irregular respirations, convulsions, coma, cardiac disturbances, collapse and death. Chronic intoxication produces euphoria, agitation psychomotor, suicidal ideation, anorexia, weight loss, hallucinations and mental deterioration. A withdrawal syndrome with severe psychiatric effects can occur (euphoria, depression). Cocaine causes hyperthermia as a result of two mechanisms: the increase in muscular activity and a direct effect on thermal regulatory centers. The visceral effects on liver and kidney are due to dopaminergic action of cocaine, or its metabolites, or to impurities. The abrupt increase intra-alveolar pressure can cause alveolar rupture and pneumomediastinum. Rhabdomyolysis occurs as a result of several different mechanisms: direct effect on muscle and muscle metabolism, tissue ischemia, the effects of drugs taken with cocaine, such as alcohol and heroin. The principle effects of cocaine are the result of its sympathetic action: cocaine prevents the re-uptake of dopamine and noradrenaline, which accumulate and stimulate neuronal receptors. At the same time, the release of serotonin a sedative neurotransmitter, is inhibited. There may also be a direct effect on peripheral organs. Applied locally, cocaine blocks neuronal transmission: this results in a powerful local anesthetic action at the level of sensory nerve terminals. A recent meta-analysis shows an increase in congenital malformation rate in the offspring of cocaine-users, particularly for abnormalities of the limbs, the genito-urinary tract, and the cardiovascular, neurological, and digestive systems. Patients with choline esterase deficiency may develop severe reactions. ANIMAL STUDIES: Rats given a moderate dose of cocaine show increased locomotor activity and stereotypic behavior. These behaviors are thought to be mediated by the mesolimbic and nigrostriatal dopamine pathways, respectively. In rats exposed to continuous cocaine, persistent changes in acetylcholine and GABA receptors in the caudate were observed 30 days after removal of cocaine pellets, suggesting that they were long lasting or permanent. In contrast to continuous cocaine infusion, daily injections of 20 mg of cocaine for 5 days failed to produce neurodegeneration but did result in behavioral sensitization. Studies with animals demonstrate that cocaine is three times as lethal as heroin. Ninety percent of animals with free access to cocaine are dead in three months, while only 30% of those with free access to heroin are dead in the same amount of time. Monkeys with unlimited access to cocaine will choose it over food until they starve. Cocaine-induced hepatotoxicity was encountered while studying sensitization to the stimulant effects of cocaine. The surface of livers from mice that had received four or five daily injections of 20 mg/kg cocaine had an unusual pitted or roughened appearance. It was found that a single injection of 50 mg/kg cocaine could produce severe fatty necrosis of the liver. Cocaine caused a 36% drop in fetal oxygen partial pressure following a 2 mg/kg dose of cocaine to the ewe, simultaneously, it caused a 25% rise in fetal blood pressure. ECOTOXICITY STUDIES: Cyto-genotoxic effects were evidenced in mussels exposed to crack cocaine concentrations ranging from 5 to 500 ug/L. Exposure to cocaine and its metabolites significantly altered the protein profile of zebrafish embryos, modulating the expression of diverse proteins belonging to different functional classes, including cytoskeleton, eye constituents, lipid transport, lipid and energy metabolism, and stress response. Expression of vitellogenins and crystallins was modulated by cocaine and its main metabolites.
Cocaine produces anesthesia by inhibiting excitation of nerve endings or by blocking conduction in peripheral nerves. This is achieved by reversibly binding to and inactivating sodium channels. Sodium influx through these channels is necessary for the depolarization of nerve cell membranes and subsequent propagation of impulses along the course of the nerve. Cocaine is the only local anesthetic with vasoconstrictive properties. This is a result of its blockade of norepinephrine reuptake in the autonomic nervous system. Cocaine binds differentially to the dopamine, serotonin, and norepinephrine transport proteins and directly prevents the re-uptake of dopamine, serotonin, and norepinephrine into pre-synaptic neurons. Its effect on dopamine levels is most responsible for the addictive property of cocaine.
Cocaine has many serious medical consequences including cardiac arrhythmias, coronary artery spasm and myocardial infarction, cerebrovascular accidents, subarachnoid hemorrhage, seizures, hallucinations, intestinal ischemia, renal infarction, rhabdomyolysis and acute liver injury. Cocaine is a not infrequent cause of sudden “unexplained” death in young adults. Hepatotoxicity usually arises hours to a few days after an acute overdose, generally following or accompanying other major organ involvement. The clinical phenotype of cocaine hepatototoxicity is usually acute hepatic necrosis. Initially, serum aminotransferase and LDH levels are markedly elevated with minimal increase in alkaline phosphatase. The prothrombin time becomes abnormal rapidly and may also reflect disseminated intravascular coagulation (DIC). The serum bilirubin begins to rise after 2 to 3 days. Immunoallergic features and autoantibodies are usually absent. Liver histology usually shows centrolobular (zone 3) necrosis and fatty change, features that resemble ischemic hepatitis or liver injury due to hyperthermia, factors that may partially mediate the hepatotoxic effects of cocaine. In self-limited cases, recovery is rapid and serum aminotransferase levels usually return to normal within 1 to 2 weeks.
来源:LiverTox
毒理性
致癌物分类
对人类不具有致癌性（未被国际癌症研究机构IARC列名）。
No indication of carcinogenicity to humans (not listed by IARC).
来源:Toxin and Toxin Target Database (T3DB)
毒理性
健康影响
继续使用会导致失眠、过度活跃、焦虑、激动和营养不良。过量可能会导致死亡。
Continued use produces insomnia, hyperactivity, anxiousness, agitation and malnutrition. Overdoses can be lethal.
Cocaine is absorbed from all sites of application, including mucous membranes and gastrointestinal mucosa. By oral or intra-nasal route, 60 to 80% of cocaine is absorbed.
Cocaine hydrochloride is absorbed from all sites of application, including mucous membranes and GI mucosa, and absorption may be enhanced in the presence of inflammation. In recreational cocaine users, the relative bioavailability of the drug, as determined by area under the plasma concentration-time curve (AUC), for a 2-mg/kg intranasal or oral dose of a 10% cocaine solution is the same; however, peak plasma concentrations are reportedly higher and occur sooner following oral administration than after intranasal administration. Following topical application of a 10% solution to the nasal mucosa, peak plasma cocaine concentrations occur within 15-120 minutes. Following topical application of cocaine hydrochloride solutions to mucous membranes, the onset of local anesthesia occurs within about 1 minute, is maximal within about 5 minutes, and may persist for 30 minutes or longer, depending on the dose and concentration used. /Cocaine hydrochloride/
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
可卡因能迅速且充分地从鼻腔粘膜、胃肠粘膜、肺泡以及直接静脉注射中被吸收……。
Cocaine is rapidly and well absorbed from the nasal mucosa, gastrointestinal mucosa, pulmonary alveoli and by direct intravenous injection ... .
Cocaine is absorbed by all routes of administration, but the proportion absorbed depends on the route. After oral administration, cocaine appears in blood after about 30 minutes, reaching a maximum concentration in 50 to 90 minutes. In acid medium, cocaine is ionized, and fails to cross into cells. In alkaline medium, there is less ionization and the absorption rapidly increases. By the nasal route, clinical effects are evident 3 minutes after administration, and last for 30 to 60 minutes, the peak plasma concentration being around 15 minutes. By oral or intra-nasal route, 60 to 80% of cocaine is absorbed. By inhalation, the absorption can vary from 20 to 60%, the variability being related to secondary vasoconstriction. Freebase does not undergo first-pass hepatic metabolism, and plasma concentrations rise immediately to 1 to 2 mg/L. The effects on the brain occur very rapidly, after about 8 to 12 seconds, are very violent ("flash"), and last only 5 to 10 minutes. By the intravenous route blood concentrations rise to a peak within a few minutes.
When smoked, absorption of the free base from the lung is rapid and efficient, producing concn in plasma of more than 900 ng/mL; peak values of 150 to 200 ng/mL are reached 30 to 40 minutes after the inhalation of 96 mg of crystalline cocaine hydrochloride.
Method for preparing organoboron derivative containing oxygen and aromatic ring as labeled precursor of dopamine positron emission tomography imaging agent
[EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
申请人：MERCK SHARP & DOHME
公开号：WO2016089721A1
公开（公告）日：2016-06-09
The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.
4' SUBSTITUTED COMPOUNDS HAVING 5-HT6 RECEPTOR AFFINITY
申请人：Dunn Robert
公开号：US20080318941A1
公开（公告）日：2008-12-25
The present disclosure provides compounds having affinity for the 5-HT
6
receptor which are of the formula (I):
wherein R
1
, R
2
, R
5
, R
6
, B, D, E, G, Q, x and n are as defined herein. The disclosure also relates to methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
Heterobicyclic compounds of Formula (I):
or a pharmaceutically-acceptable salt, tautomer, or stereoisomer thereof, as defined in the specification, and compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, Huntington's Disease, and the like.
Formula (I)的杂环化合物：
或其药用可接受的盐、互变异构体或立体异构体，如规范中所定义，并含有它们的组合物，以及制备这种化合物的方法。本文还提供了通过抑制PDE10来治疗由此可治疗的疾病或疾病的方法，如肥胖症、非胰岛素依赖型糖尿病、精神分裂症、躁郁症、强迫症、亨廷顿病等。
[EN] 3-(6-ALKOXY-5-CHLOROBENZO[D]ISOXAZOL-3-YL)PROPANOIC ACID USEFUL AS KYNURENINE MONOOXYGENASE INHIBITORS<br/>[FR] ACIDE 3-(6-ALKOXY-5-CHLOROBENZO[D]ISOXAZOL-3-YL)PROPANOÏQUE UTILE EN TANT QU'INHIBITEUR DE LA KYNURÉNINE MONOOXYGÉNASE
申请人：GLAXOSMITHKLINE IP DEV LTD
公开号：WO2016097144A1
公开（公告）日：2016-06-23
Compound of formula (I) wherein R1 is heteroaryl either unsubstituted or substituted by methyl, ethyl, halo or =O; and R2 is H, methyl or ethyl; and salts thereof are KMO inhibitors and may be useful in the treatment of various disorders, for example acute pancreatitis, chronic kidney disease, acute kidney disewase, acute kidney injury, other conditions associated with systemic inflammatory response syndrome (SIRS), Huntington's disease, Alzheimer's disease, spinocerebellar ataxias, Parkinson's disease, AIDS-dementia complex, HIV infection, amylotrophic lateral sclerosis (ALS), depression, schizophrenia, sepsis, cardiovascular shock, severe trauma, acute lung injury, acute respiratory distress syndrome, acute cholecystitis, severe burns, pneumonia, extensive surgical procedures, ischemic bowel, severe acute hepatic disease, severe acute hepatic encephalopathy or acute renal failure.
The present invention relates to a compound of formula I
1
wherein R, X and n are defined hereinabove, and to a pharmaceutically acceptable salt thereof. The compound may be used for the treatment of diseases related to the A2A receptor.
