To study the photostability of carbamazepine polymorphs, the pure materials on the tablet surface were evaluated without physical damage by means of Fourier-transform infrared reflection-absorption infrared spectrometry (FT-IR-RAS) and colorimetric measurement of the carbamazepine polymorphs I, II, and III, after photodegradation at 2 irradiation intensities under a near-UV fluorescent lamp. The surface of sample pellets of all crystalline forms turned gradually from white to yellow-orange upon exposure to light, and the discoloration rate of form II was faster than that of forms I and III, indicating that form II was the most unstable of the three. The semilogarithmic plots of the photodegradation profiles of the various polymorphs were straight lines, including the induction period, indicating that degradation of the drug on the surface followed first-order kinetics. The induction periods of all forms were not significantly different. However, the degradation rate constant of form II was 5.1 and 1.5 times larger than those of forms I and III, respectively.
Carbamazepine is largely metabolized in the liver. CYP3A4 hepatic enzyme is the major enzyme that metabolizes carbamazepine to its active metabolite, carbamazepine-10,11-epoxide, which is further metabolized to its trans-diol form by the enzyme epoxide hydrolase. Other hepatic cytochrome enzymes that contribute to the metabolism of carbamazepine are CYP2C8, CYP3A5, and CYP2B6. Carbamazepine also undergoes hepatic glucuronidation by UGT2B7 enzyme and several other metabolic reactions occur, resulting in the formation of minor hydroxy metabolites and quinone metabolites. Interestingly, carbamazepine induces its own metabolism. This leads to enhanced clearance, reduced half-life, and a reduction in serum levels of carbamazepine.
The pharmacokinetics of a single oral dose of carbamazepine-10,11-epoxide, (100 mg) were compared in 10 patients on chronic monotherapy with lamotrigine, (200-300 mg/day) and in 10 drug-free healthy control subjects. Carbamazepine-10,11-epoxide pharmacokinetic parameters in lamotridge-treated patients were found to be similar to those observed in controls (half-life: 7.2 + or - 1.6 vs 6.1 + or - 0.9 hr; apparent oral clearance: 110.8 + or - 53.1 vs 120.5 + or - 29.9 ml/h/kg; apparent volume of distribution: 1.08 + or 0.37 vs 1.04 + or - 0.25 l/kg respectively; means + or - s.d.). These data indicate that, contrary to previous suggestions, lamotridge has no effect on the metabolic disposition of carbamazepine-10,11-epoxide.
Placental transfer and metabolism of carbamazepine was studied in a dual recirculating placental cotyledon perfusion system and was also evaluated in 16 pairs of maternal venous and cord blood samples. ... Carbamazepine added into the maternal circulation crosses the placenta in the beginning quicker than antipyrine which is in agreement with the different lipid solubilities of these compounds. Because the transfer rates of antipyrine and carbamazepine were about the same, the mechanism of transfer of carbamazepine is probably similar to that of antipyrine (passive diffusion). No metabolites of carbamazepine could be detected in the perfusate by high-performance liquid chromatography or gas chromatography/mass spectrometry. With the improved HPLC methodology for carbamazepine metabolites, six metabolites were detected in clinical samples, including 10-hydroxy-10,11-dihydro-carbamazepine (10-OH-CBZ), which has been described earlier in only 1 uremic patient. Relative levels of metabolites showed significant individual differences. Carbamazepine crosses perfused placenta rapidly, but this does not contribute to carbamazepine metabolites detected in maternal and fetal circulation.
The aim of this work was to study the transport across the blood-brain barrier, blood and liver distribution kinetics, metabolic interaction and local liver metabolism of carbamazepine in the rat, using microdialysis with the internal standard technique as in vivo calibration method. Carbamazepine and its major metabolite, carbamazepine-10,11-epoxide, are homogeneously distributed to hippocampus and cerebellum. The ratios of the areas under the concentration-time curve for both brain regions to blood areas under the concentration-time curve were not different from unity for carbamazepine; they were 0.46 + or - 0.08 (hippocampus) and 0.45 + or - 0.05 (cerebellum) for carbamazepine-10,11-epoxide. In addition, the disposition of carbamazepine and carbamazepine-10,11-epoxide in blood and liver, after a single dose of carbamazepine, was studied in control animals and in rats after pretreatment with clomipramine. A 2-fold increase in the blood areas under concentration curve of carbamazepine and a decrease to 33% of the blood areas under concentration curve of carbamazepine-10,11-epoxide in the pretreated group demonstrate the metabolic inhibition of carbamazepine-10,11-epoxide formation by clomipramine. The ratios of the areas under concentration curve carbamazepine-10,11-epoxide to the areas under the concentration curve carbamazepine, as a measure of carbamazepine-10,11-epoxide formation, were not different for blood and liver within the control and the clomipramine-pretreated groups, but the ratios were significantly lower for liver and blood in the clomipramine group compared with the control animals. In addition, carbamazepine was administered locally in the extracellular fluid of the liver via the microdialysis probe. The liver metabolic ratio, expressed as the ratio of the formed carbamazepine-10,11-epoxide concentration to the carbamazepine concentration administered, ranged from 18.2 + or - 1.2% to 19.6 + or - 1.6%.
Carbamazepine has known human metabolites that include 3-Hydroxycarbamazepine, Carbamazepine 10,11-epoxide, 2-Hydroxycarbamazepine, and 9-Hydroxycarbamazepine.
Carbamazepine inhibits sustained repetitive firing by blocking use-dependent sodium channels. Pain relief is believed to be associated with blockade of synaptic transmission in the trigeminal nucleus and seizure control with reduction of post-tetanic potentiation of synaptic transmission in the spinal cord. Carbamazepine also possesses anticholinergic, central antidiuretic, antiarrhythmic, muscle relaxant, antidepressant (possibly through blockade of norepinephrine release), sedative, and neuromuscular-blocking properties.
Prospective studies indicate that a sizeable proportion of patients taking carbamazepine have transient serum aminotransferase elevations (ranging from 1% to 22%). These elevations are usually benign, not associated with liver histological abnormalities and usually resolve even with drug continuation. In addition, most patients on carbamazepine develop mild-to-moderate elevations in gamma glutamyltranspeptidase (GGT) levels, probably indicative of hepatic enzyme induction rather than liver injury. Marked aminotransferase elevations (more than 5 fold elevated) occur less frequently.
Clinically apparent hepatotoxicity from carbamazepine is uncommon but well described, there being several hundred cases reported in the literature. Carbamazepine hepatotoxicity most often occurs in the setting of anticonvulsant hypersensitivity syndrome with onset of fever, followed by rash, facial edema, lymphadenopathy, elevations in white count and eosinophilia or atypical lymphocytosis, 1 to 8 weeks after starting therapy (Case 1 and 2). This syndrome is usually referred to as Drug Rash with Eosinophilia and Systemic Symptoms [DRESS]. The most frequent form of systemic involvement in DRESS syndrome is liver injury. The liver involvement ranges from mild and transient elevations in serum enzymes to abrupt onset of an acute hepatitis-like syndrome that can be severe and even fatal. However, the most common pattern of enzyme elevations in carbamazepine related DRESS syndrome is a mixed or cholestatic injury. Liver biopsy shows the cholestatic injury with focal hepatocellular necrosis, prominence of eosinophils and occasionally granulomas. In fatal cases, liver histology also shows bridging, submassive or massive necrosis. Other systemic involvement in carbamazepine induced DRESS syndrome includes myositis, nephritis and pneumonitis. Carbamazepine induced DRESS syndrome has also been linked to several cases of vanishing bile duct syndrome in which a severe cholestatic hepatitis with immunoallergic features is followed by persistence of cholestasis with itching, jaundice and prominent elevations in alkaline phosphatase levels. In most instances, vanishing bile duct syndrome gradually improves with time, but some instances are severe and unremitting, leading eventually to end stage liver disease and death or need for liver transplantation several months or even years fter onset (Case 3).
Carbamazepine hepatotoxicity can also occur without immunoallergic features in which case the latency to onset can be as long as 6 to 12 months after starting. The cases of carbamazepine liver injury without immunoallergic features tend to be hepatocellular rather than cholestatic or mixed and are more likely to be severe (Case 4). Carbamazepine is a commonly listed agent in case series of acute liver failure.
Likelihood score: A (Well established cause of clinically apparent liver injury).
The bioavailability of carbamazepine is in the range of 75-85% of an ingested dose. After one 200 mg oral extended-release dose of carbamazepine in a pharmacokinetic study, the Cmax carbamazepine was measured to be 1.9 ± 0.3 mcg/mL. The Tmax was 19 ± 7 hours. After several doses of 800 mg every 12 hours, the peak concentrations of carbamazepine were measured to be 11.0 ± 2.5 mcg/mL. The Tmax was reduced to 5.9 ± 1.8 hours. Extended-release carbamazepine demonstrated linear pharmacokinetics over a range of 200–800 mg. **Effect of food on absorption** A meal containing high-fat content increased the rate of absorption of one 400 mg dose but not the AUC of carbamazepine. The elimination half-life remained unchanged between fed and fasting state. The pharmacokinetics of an extended-release carbamazepine dose was demonstrated to be similar when administered in the fasted state or with food. Based on these findings, food intake is unlikely to exert significant effects on carbamazepine absorption.
After an oral dose of radiolabeled carbamazepine, 72% of the administered radioactive dose was detected in the urine and the remainder of the ingested dose was found in the feces. Carbamazepine is mainly excreted as hydroxylated and conjugated metabolites, and minimal amounts of unchanged drug.
The volume of distribution of carbamazepine was found to be 1.0 L/kg in one pharmacokinetic study. Another study indicates that the volume of distribution of carbamazepine ranges between 0.7 to 1.4 L/kg.. Carbamazepine crosses the placenta, and higher concentrations of this drug are found in the liver and kidney as opposed to lung and brain tissue. Carbamazepine crosses variably through the blood-brain barrier.
In a pharmacokinetic study, the apparent oral clearance of carbamazepine was 25 ± 5 mL/min after one dose of carbamazepine and 80 ± 30 mL/min after several doses.
来源:DrugBank
吸收、分配和排泄
吸收：缓慢且不定，但几乎完全通过胃肠道吸收。
Absorption: Slow and variable, but almost completely absorbed from gastrointestinal tract.
[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.
Tellurium tetraethoxide reacts with primary thioamides at room temperature, forming nitriles in high yields. On the other hand, the reactions with amides are largely temperature-dependent, giving predominantly esters at 80 °C and nitriles at a higher temperature. Similarly, tellurium tetraethoxide readily induces the C–N bond cleavage of ureas to give carbamates and amines.
[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] 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.
SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS
申请人：BLUM Andreas
公开号：US20140135309A1
公开（公告）日：2014-05-15
This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I
wherein Ar, R
1
and R
2
are as defined herein, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.
