Lamotrigine is mainly glucuronidated, forming 2-N-glucuronide conjugate, a pharmacologically inactive metabolite. The total radioactivity detected after a 240mg radiolabeled dose of lamotrigine during clinical trials were as follows: lamotrigine as unchanged drug(10%), a 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), as well as various other minor metabolites (4%).
The metabolites of [(14)C]lamotrigine (78 micromol/kg, iv) in adult male Wistar rats were characterized with particular reference to thioether derivatives of an epoxide intermediate. Biliary recovery of radioactivity from anesthetized and cannulated animals was 7.3 +/- 3.0% (mean +/- SD, n = 4) of the dose over 4 hr; 5.5 +/- 0.5% was recovered in bladder urine after 4 hr. Bile contained [(14)C]lamotrigine (1.4 +/- 0.3%), a glutathione adduct of [(14)C]dihydrohydroxylamotrigine (1.8 +/- 0.3%), i.e., an adduct of an arene oxide, and the glutathione (1.5 +/- 0.7%), cysteinylglycine (1.9 +/- 0.5%), and N-acetylcysteine (0.4 +/- 0.2%) adducts of [(14)C]lamotrigine. Formation of the thioether metabolites was partially blocked by the cytochrome P450 inhibitor, ketoconazole. Urine contained [(14)C]lamotrigine (4.5 +/- 0.5%) and [(14)C]lamotrigine N-oxide (0.9 +/- 0.2%). The radiolabeled material in skin (15.6 +/- 1.4%) was almost entirely [(14)C]lamotrigine. ...
Lamotrigine is metabolized predominantly by glucuronic acid conjugation. The major metabolite is an inactive 2-N-glucuronide conjugate. Exretion occur in the urine and the feces with unchanged lamotrigine (10%), the 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%). (A308)
Half Life: 25 +/- 10 hours (healthy individuals); 42.9 hours (chronic renal failure)
IDENTIFICATION AND USE: Lamotrigine is a white to pale cream-colored powder. Lamotrigine is an anticonvulsant medication that also has utility in the treatment of bipolar disorder. HUMAN EXPOSURE AND TOXICITY: Lamotrigine has been associated with many side effects, including rashes that can progress to Stevens-Johnson syndrome or toxic epidermal necrolysis. It has also been associated with the development of motor tics, most commonly in the head, neck, and shoulders. Cases of life-threatening rashes associated with lamotrigine almost always have occurred within 2-8 weeks of treatment initiation; however, severe rashes rarely have presented following prolonged treatment (e.g., 6 months). Lamotrigine-associated rashes do not appear to have distinguishing features. Because it is not possible to distinguish benign rashes from those that may become severe and/or life-threatening, lamotrigine generally should be discontinued at the first sign of rash (unless the rash is known not to be drug related). However, a rash may become life-threatening or permanently disabling or disfiguring despite discontinuance of the drug. Discontinuance of lamotrigine because of rash was required in 3% of adults receiving the drug as adjunctive therapy and 4.5% of adults receiving the drug as monotherapy in controlled clinical trials; 4.4% of pediatric patients receiving lamotrigine in controlled clinical trials discontinued the drug because of the development of rash. Multiorgan failure and various degrees of hepatic failure, in some cases fatal, have been reported rarely with lamotrigine as adjunctive therapy. The possibility of such potentially fatal adverse effects should be considered in patients who exhibit signs and symptoms associated with multiorgan and/or hepatic impairment following initiation of lamotrigine as adjunctive therapy. During the premarketing development of lamotrigine, 20 sudden and unexplained deaths were reported among a cohort of 4700 patients with epilepsy receiving adjunctive therapy with the drug (5747 patient-years of exposure). Although the rate of these deaths exceeds that expected to occur in a healthy (nonepileptic) population matched for age and gender, this rate was similar to that occurring in a similar population of epileptic patients receiving a chemically unrelated anticonvulsant agent. Among 414 first-trimester exposures to lamotrigine monotherapy, 12 outcomes with major birth defects were reported. Among the 88 first-trimester exposures to lamotrigine polytherapy including valproate, 11 outcomes with major birth defects were reported. Among 182 first-trimester exposures to lamotrigine polytherapy excluding valproate, 5 outcomes with major birth defects were reported. No distinctive pattern of major birth defects was apparent among the offspring exposed to lamotrigine monotherapy or polytherapy. The risk of all major birth defects after first-trimester exposure to lamotrigine monotherapy (2.9%) was similar to that in the general population and in other registries enrolling women exposed to antiepileptic monotherapy (3.3% to 4.5%). Lamotrigine also did not increase the incidence of structural or numerical chromosomal abnormalities in the in vitro human lymphocyte assay. ANIMAL STUDIES: In animal studies, no evidence of carcinogenicity was seen following oral administration of lamotrigine for up to 2 years at maximum tolerated doses (30 mg/kg of body weight per day in mice and 10 to 15 mg/kg per day in rats). Lamotrigine administered i.p. at high doses can induce intrauterine growth retardation and at low multiple doses causes a dose-dependent increase in embryonic resorption, craniofacial and caudal malformations as well as maternal toxicity in the mouse. A study of the teratogenic activity of lamotrigine was carried out in the brain of fetuses of rats who had received the drug. Results showed that fetuses of the experimental group had reduced body weight at birth, increased volume and diameter of the cerebral structure, increased density of the subcortical layer, and ventricle dilatation. A behavioral teratology study was conducted in rats dosed during the period of organogenesis. At day 21 postpartum, offspring of dams receiving 5 mg/kg per day or higher displayed a significantly longer latent period for open field exploration and a lower frequency of rearing. In a swimming maze test performed on days 39 to 44 postpartum, time to completion was increased in offspring of dams receiving 25 mg/kg per day. No evidence of mutagenicity was demonstrated by lamotrigine in vitro in the Ames Salmonella microbial mutagen test or the mammalian mouse lymphoma assay. Lamotrigine also did not increase the incidence of structural or numerical chromosomal abnormalities in the in vivo rat bone marrow assay.
One proposed mechanism of action of Lamotrigine, the relevance of which remains to be established in humans, involves an effect on sodium channels. <i>in vitro</i> pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels and/or calcium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate). Studies on lamotrigine show binding to sodium channels similar to local anesthetics.
Prospective studies suggest that less than 1% of subjects develop elevations in serum aminotransferase levels during long term lamotrigine therapy. However, clinically apparent hepatotoxicity from lamotrigine is well known and is estimated to occur in one in 2,000 to 10,000 treated patients. The liver injury is usually part of a systemic immuno-allergic reaction (anticonvulsant hypersensitivity syndrome [AHS] or drug rash with eosinophilia and systemic symptoms [DRESS] syndrome). The latency is typically short, ranging from one to several weeks. Presenting symptoms are a diffuse maculopapular rash, followed in a few days by high fever, nausea and vomiting. The rash can develop into a systemic hypersensitivity reaction and multiorgan failure or be associated with jaundice and hepatitis. Eosinophilia is common, and facial edema, lymphadenopathy and atypical lymphocytosis can occur. The pattern of liver enzyme elevations is usually hepatocellular and severity ranges from mild-to-moderate ALT elevations accompanying the generalized hypersensitivity reaction, to an icteric hepatitis, to a severe hepatitis and acute liver failure. Liver biopsy shows portal inflammation, hepatocellular necrosis and bile duct proliferation. In some instances of severe hypersensitivity syndrome with acute multiorgan failure, the hepatic involvement may represent ischemic injury.
Lamotrigine has also been linked to rare instances of hemophagocytic lymphohistiocytosis, a rare and severe immune related reaction characterized by unremitting activation of CD8+ T cells and macrophages that causes multiorgan damage including liver injury, hepatitis and liver failure. Cases of HLH linked to lamotrigine arose within 1 to 4 weeks of starting the drug, usually in infants or children, marked clinically by fever, rash, cytopenias, hepatitis, high triglycerides and ferritin levels and bone marrow or liver histology demonstrating hemophagocytosis
Likelihood score: A (well known cause of clinically apparent liver injury).
Lamotrigine is rapidly and entirely absorbed with minimal first-pass metabolism effects, with a bioavailability estimated at 98%. Cmax is reached in the range of 1.4 to 4.8 hours post-dose, but this depends on the dose administered, concomitant medications, and epileptic status. The rate and extent of lamictal absorption is considered equivalent between the compressed tablet form taken with water to that of the chewable dispersible tablets, taken with or without water.
Lamotrigine is excreted in both the urine and feces. Following oral administration of 240 mg radiolabelled lamotrigine, about 94% of total drug and its metabolites administered is recovered in the urine and 2% is recovered in the feces. One pharmacokinetic study recovered 43 to 87% of a lamotrigine dose in the urine mainly as glucuronidated metabolites. 2-N-glucuronide is mainly excreted in the urine.
The mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranges from 0.9 to 1.3 L/kg and is independent of dose administered. Lamotrigine accumulated in the kidney of the male rat, and likely behaves in a similar fashion in humans. Lamotrigine also binds to tissues containing melanin, such as the eyes and pigmented skin.
The mean apparent plasma clearance (Cl/F) ranges from 0.18 to 1.21 mL/min/kg. The values vary depending on dosing regimen, concomitant antiepileptic medications, and disease state of the individual. In one study, healthy volunteers on lamictal monotherapy showed a clearance of about 0.44 mL/min/kg after a single dose.
/MILK/ Lamotrigine is distributed into milk. Because of the potential for serious adverse reactions to lamotrigine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.
[EN] SUBSTITUTED N-HETEROCYCLIC CARBOXAMIDES AS ACID CERAMIDASE INHIBITORS AND THEIR USE AS MEDICAMENTS<br/>[FR] CARBOXAMIDES N-HÉTÉROCYCLIQUES SUBSTITUÉS UTILISÉS EN TANT QU'INHIBITEURS DE LA CÉRAMIDASE ACIDE ET LEUR UTILISATION EN TANT QUE MÉDICAMENTS
申请人：BIAL BIOTECH INVEST INC
公开号：WO2021055627A1
公开（公告）日：2021-03-25
The invention provides substituted N-heterocyclic carboxamides and related compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat a medical disorder, e.g., cancer, lysosomal storage disorder, neurodegenerative disorder, inflammatory disorder, in a patient.
[EN] COMPOUNDS AND THEIR USE AS BACE INHIBITORS<br/>[FR] COMPOSÉS ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE BACE
申请人：ASTRAZENECA AB
公开号：WO2016055858A1
公开（公告）日：2016-04-14
The present application relates to compounds of formula (I), (la), or (lb) and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing Αβ-related pathologies such as Down's syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease.
[EN] COMPOUNDS THAT MODULATE EGFR ACTIVITY AND METHODS FOR TREATING OR PREVENTING CONDITIONS THEREWITH<br/>[FR] COMPOSÉS MODULANT L'ACTIVITÉ DES RÉCEPTEURS EGFR ET MÉTHODES POUR TRAITER OU PRÉVENIR DES TROUBLES À L'AIDE DE CEUX-CI
申请人：GATEKEEPER PHARMACEUTICALS INC
公开号：WO2011140338A1
公开（公告）日：2011-11-10
Provided are compounds and methods for treating or preventing kinase-mediated disorders therewith.
提供了用于治疗或预防激酶介导的疾病的化合物和方法。
[EN] IMIDAZOLIUM REAGENT FOR MASS SPECTROMETRY<br/>[FR] RÉACTIF D'IMIDAZOLIUM POUR SPECTROMÉTRIE DE MASSE
申请人：HOFFMANN LA ROCHE
公开号：WO2021234004A1
公开（公告）日：2021-11-25
The present invention relates to compounds which are suitable to be used in mass spectrometry as well as methods of mass spectrometric determination of analyte molecules using said compounds.
本发明涉及适用于质谱的化合物，以及利用该化合物进行分析物分子的质谱测定方法。
[EN] KINASE INHIBITORS FOR THE TREATMENT OF DISEASE<br/>[FR] INHIBITEURS DE KINASE POUR LE TRAITEMENT D'UNE MALADIE
申请人：DANA FARBER CANCER INST INC
公开号：WO2015006492A1
公开（公告）日：2015-01-15
The invention relates to compounds and their use in the treatment of disease. Novel irreversible inhibitors of wild-type and mutant forms of EGFR, FGFR, ALK, ROS, JAK, BTK, BLK, ITK, TEC, and/or TXK and their use for the treatment of cell proliferation disorders are described.
