Remifentanil is a potent opioid metabolized by serum and tissue esterases; it is routinely administered to patients with liver failure as anaesthetic and analgo-sedative without variation in doses, even if prolonged clinical effects and respiratory depression have been observed in these patients. The aim of this study was to determine remifentanil enzymatic degradation kinetics bearing in mind the effect of liver esterases in order to trace a more accurate pharmacokinetic profile of the drug. Solution samples were taken over time and analyzed to measure remifentanil concentration by HPLC. We reproduced the physiological settings, varying temperature and pH in vitro and evaluated the kinetics of degradation of remifentanil in the presence of Rhizopus Oryzae esterases, equine liver esterases and porcine liver esterases. Remifentanil kinetics of degradation was accelerated by porcine liver esterases. Remifentanil in vitro half-life decreases with increasing temperatures in the presence of porcine liver esterases. A drug model simulation considering the effect of temperature in the presence of liver esterases was developed. Remifentanil in vitro half-life decreases with increasing temperatures when porcine liver esterases are present. In this paper we propose a model for describing remifentanil degradation kinetics at various temperatures.
Remifentanil is an esterase-metabolized opioid. A labile ester linkage renders this compound susceptible to hydrolysis by nonspecific esterases in blood and tissues. This hydrolysis results in the production of the carboxylic acid metabolite (3-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid), and represents the principal metabolic pathway for remifentanil (> 95%). The carboxylic acid metabolite is essentially inactive (1/4600 as potent as remifentanil in dogs). Remifentanil is not metabolized by plasma cholinesterase (pseudocholinesterase) and is not appreciably metabolized by the liver or lung.
IDENTIFICATION AND USE: Remifentanil is an oil. It is a Schedule II Controlled Substance. It is approved in the US for intravenous administration as an analgesic agent for use during the induction and maintenance of general anesthesia. Remifentanil is also used as an anesthetic agent in animals. HUMAN STUDIES: Remifentanil is a selective mu-receptor agonist with similar potency to fentanyl; the drug shares the actions of the opiate agonists. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of the drug, the risk is greatest during the initiation of therapy or following a dosage increase. Acute overdose can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations. Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use with serotonergic drugs. Remifentanil, like other opioids, has a high potential for abuse. ANIMAL STUDIES: The fertility of female rats was not affected at IV doses as high as 1 mg/kg, when administered for at least 15 days before mating. In another study, reduced birth weights were noted in the high-dose groups in the presence of maternal toxicity. Pregnant rabbits were treated from Gestation Day 6 to 18 with intravenous remifentanil doses of 0.1, 0.5, or 0.8 mg/kg/day. No malformations were reported in surviving fetuses despite clear maternal toxicity. However, remifentanil has been shown to reduce fertility in male rats when tested after 70+ days of daily IV administration of 0.5 mg/kg. Remifentanil was not genotoxic in an Ames test, an in vitro chromosome aberration assay in Chinese hamster ovary cells, an in vivo micronucleus assay in rat erythrocytes, or an in vivo/in vitro unscheduled DNA synthesis assay in rat hepatocytes. In the in vitro mouse lymphoma assay, remifentanil produced a genotoxic response at dose levels >/= 308 ug/mL only in the presence of metabolic activation.
Remifentanil is an esterase-metabolized opioid. The carboxylic acid metabolite is essentially inactive (1/4600 as potent as remifentanil in dogs) and is excreted by the kidneys with an elimination half-life of approximately 90 minutes.
The aims of this paper were to elucidate the difference in concentration among remifentanil blood, cerebrospinal fluid and cerebral extracellular fluid levels, and to verify the presumable existence of a correlation between arterial and cerebral remifentanil. We used brain microdialysis to shed light on this aspect of the pharmacokinetic and to correlate these findings with Minto's model. The study population was formed by 9 patients scheduled for elective intracranial surgery for cerebral supratentorial neoplasia. All patients received general anaesthetic; 100 uL of dialysate were collected. Furthermore, arterial blood samples of 3 mL each were collected, respectively one at the beginning and one at the end of the sampling period. We determined the concentration of remifentanil and its main metabolite, remifentanil acid, in the blood and in the brain. The predictive performance of the Minto pharmacokinetic parameter set was evaluated by examining the performance error. The mean Performance Error was -45.13% (min -21.80, max -88.75) for the first series of arterial samples, -38.29% (min -6.57, max -79.17) for the second one and 67.73% (min 7, max -93.12) for the extra cellular fluid sample. The concentration of remifentanil set pumps was correlated with blood concentration for both series of samples. Neither the set concentration, nor the arterial samples were correlated with extracellular fluid values. There was a wide interindividual variability with regard both to blood and cerebral remifentanil concentration. Moreover, the ratio between arterial blood and cerebral remifentanil was not consistent among our patients in spite of a stable infusion rate of remifentanil; at the end we found a trend of over prediction in the ratio between the various compartments examined.
/MILK/ It is not known whether remifentanil is excreted in human milk. After receiving radioactive-labeled remifentanil, the radioactivity was present in the milk of lactating rats.
A pharmaceutically active inventive compound comprises two independently active analgesic moieties covalently conjoined through a physiologically labile linker. A preferred embodiment comprises an opioid, such as morphine, covalently linked to at least one analgesic compound selected from the group consisting of an opioid or a non-opioid compound through a physiologically labile linker. Suitable covalent linkers are covalently bonded to the two independently active analgesic compounds through one or more lactone, lactam, or sulfonamido linkages. Suitable linkers include endogenous carboxylate, amido, and sulfonamido moieties, and exogenous moieties that form the aforementioned lactone, lactam or sulfonamido linkages.
[EN] LYMPHATIC SYSTEM-DIRECTING LIPID PRODRUGS<br/>[FR] PROMÉDICAMENTS LIPIDIQUES ORIENTANT VERS LE SYSTÈME LYMPHATIQUE
申请人：ARIYA THERAPEUTICS INC
公开号：WO2019046491A1
公开（公告）日：2019-03-07
The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, as well as methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present invention also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a provided lipid prodrug or a pharmaceutical composition thereof.
[EN] COMBINATION THERAPY FOR PREVENTING ADDICTION<br/>[FR] POLYTHÉRAPIE POUR LA PRÉVENTION D'UNE ADDICTION
申请人：AMYGDALA NEUROSCIENCES INC
公开号：WO2019079209A1
公开（公告）日：2019-04-25
Disclosed is a novel combination therapy to reduce or prevent the acquisition of a conditioned response in a mammal comprising administering to the mammal a therapeutically effective amount of an aldehyde dehydrogenase (ALDH-2) inhibitor compound, such as a compound of Formula (I), in combination with a substance that produces the conditioned response, such as a medication containing a dopamine-producing agent such as an opioid, whereby the combination acts to reduce or prevent the acquisition of a conditioned response, and the deleterious side-effect of misuse, dependence, abuse, and/or addiction.
CYCLODEXTRIN-BASED POLYMERS FOR THERAPEUTIC DELIVERY
申请人：Cerulean Pharma Inc.
公开号：US20130196906A1
公开（公告）日：2013-08-01
Provided are methods relating to the use of CDP-therapeutic agent conjugates for the treatment of a disease or disorder, e.g., autoimmune disease, inflammatory disease, central nervous system disorder, cardiovascular disease, or metabolic disorder. Also provided are CDP-therapeutic agent conjugates, particles comprising CDP-therapeutic agent conjugates, and compositions comprising CDP-therapeutic agent conjugates.
