Thalidomide appears to undergo primarily non-enzymatic hydrolysis in plasma to multiple metabolites, as the four amide bonds in thalidomide allow for rapid hydrolysis under physiological pH. Evidences for enzymatic metabolism of thalidomide is mixed, as _in vitro_ studies using rat liver microsome have detected 5-hydroxythalidomide (5-OH), a monohydroxylated metabolite of thalidomide catalyzed by the CYP2C19 enzyme, and the addition of [omeprazole], a CYP2C19 inhibitor, inhibits the metabolism of thalidomide. 5-hydroxythalidomide (5-OH) has also been detected in the plasma of 32% of androgen-independent prostate cancer patients undergoing oral thalidomide treatment. However, significant interspecies difference in thalidomide metabolism has been noted, potentially signifying that animals like rats and rabbits rely on enzymatic metabolism of thalidomide more than human.
Studies on thalidomide metabolism in humans have not been done. In animals, nonenzymatic hydrolytic cleavage appears to be the main pathway of degradation, producing seven major and at least five minor hydrolysis products. Thalidomide may be metabolized hepatically by the enzymes of the cytochrome p450 enzyme system. Thalidomide does not appear to induce or inhibit its own metabolism. However, it may interfere with enzyme induction caused by other compounds. The end product of metabolism, phthalic acid, is excreted as a glycine conjugate.
The chiral inversion and hydrolysis of thalidomide and the catalysis by bases and human serum albumin were investigated by /utilizing/ a stereoselective HPLC assay. Chiral inversion was catalyzed by albumin, hydroxyl ions, phosphate and amino acids. Basic amino acids (arginine and lysine) had a superior potency in catalyzing chiral inversion compared to acid and neutral ones. The chiral inversion of thalidomide is thus subject to specific and general base catalysis and it is suggested that the ability of HSA to catalyze the reaction is due to basic groups of the amino acids arginine and lysine and not to a single catalytic site on the macromolecule. The hydrolysis of thalidomide was also base catalyzed. ... Albumin had no effect on hydrolysis and there was no difference between the catalytic potencies of acidic, neutral and base amino acids. ... Chiral inversion is deduced to occur by electrophilic substitution involving specific and general base catalysis, whereas hydrolysis is thought to occur by nucleophilic substitution involving specific and general base as well as nucleophilic catalysis. As nucleophilic attack is sensitive to steric properties of the catalyst, steric hindrance might be the reason albumin is not able to catalyze hydrolysis. (1)H NMR experiments revealed that the three teratogenic metabolites of thalidomide, in sharp contrast to the drug itself had complete chiral stability. This leads to the speculation that, were some enantioselectivity to exist in the teratogenicity of thalidomide, it could result from fast hydrolysis to chirally stable teratogenic metabolites.
Thalidomide has been shown to be an inhibitor of angiogenesis in a rabbit cornea micropocket model; however, it has failed to demonstrate this activity in other models. These results suggest that the anti-angiogenic effects of thalidomide may only be observed following metabolic activation of the compound. This activation process may be species specific, similar to the teratogenic properties associated with thalidomide. Using a rat aorta model and human aortic endothelial cells, we co-incubated thalidomide in the presence of either human, rabbit, or rat liver microsomes. These experiments demonstrated that thalidomide inhibited microvessel formation from rat aortas and slowed human aortic endothelial cell proliferation in the presence of human or rabbit microsomes, but not in the presence of rat microsomes. In the absence of microsomes, thalidomide had no effect on either microvessel formation or cell proliferation, thus demonstrating that a metabolite of thalidomide is responsible for its anti-angiogenic effects and that this metabolite can be formed in both humans and rabbits, but not in rodents. /There are five primary metabolites of thalidomide [4-OH-thalidomide, 3-OH-thalidomide, 39-OH-thalidomide, 49-OH-thalidomide, and 59-OH-thalidomide], and the antiangiogenic property could be the result of either of these compounds, or of an intermediate. Also, thalidomide undergoes rapid spontaneous hydrolysis in aqueous solutions at a pH of 6.0 or greater to form three primary products [4-phthalimidoglutaramic acid, 2-phthalimidoglutaramic acid, and a-(o-carboxybenzamido) glutarimide] and eight minor products. Furthermore, each of the five metabolites of the parent compound undergoes similar hydrolysis./
Three CD-1 mice were dosed orally with 3000 mg/kg thalidomide in 1% carboxymethylcellulose daily for three days and plasma samples were obtained 2, 4 and 6 hours postdose on the third day. Extracts of mouse plasma from thalidomide treated mice contained at least four components that absorbed at 230 nm, not observed in control plasma extracts. The first two components did not match any standards and may represent other metabolites, possibly hydrolysis products of thalidomide. The second pair of components closely matched standards for 4-hydroxythhalidomide and thalidomide respectively.
IDENTIFICATION AND USE: Thalidomide is a white to off-white crystalline powder. Thalidomide is an immunomodulatory agent with anti-inflammatory, antiangiogenic, and sedative and hypnotic activity. It is used for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). It is also used as maintenance therapy for prevention and suppression of the cutaneous manifestations of erythema nodosum leprosum recurrence. It is used in combination with dexamethasone for the treatment of patients with newly diagnosed multiple myeloma. HUMAN EXPOSURE AND TOXICITY: Overdosage of thalidomide may cause prolonged sleep as a result of the drug's sedative and hypnotic effects, but fatalities are unlikely since the drug does not cause respiratory depression. In 3 reported suicide attempts involving deliberate ingestion of up to 14.4 g of thalidomide, all individuals recovered without reported sequelae. Thalidomide is a known human teratogen. The severe malformation induced by thalidomide may involve defects of the limbs, axial skeleton, head and face, eyes, ears, tongue, teeth, central nervous, respiratory, cardiovascular, and genitourinary systems, and the gastrointestinal tract. The neurological complications may include severe mental retardation secondary to sensory deprivation. Thus, thalidomide is contraindicated during pregnancy. Thalidomide is also known to cause nerve damage that may be permanent. Peripheral neuropathy is a common (> or =10%) and potentially severe adverse reaction of treatment with thalidomide that may be irreversible. Seizures have been reported, including tonic-clonic (grand mal) seizures. Serious dermatologic reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, which may be fatal, have also been reported. The use of thalidomide in multiple myeloma patients causes an increased risk of venous thromboembolism, such as deep venous thrombosis and pulmonary embolism. ANIMAL STUDIES: In an acute toxicity study, guinea pigs administered a 650 mg/kg oral dose became quiet and sedated. Two-year carcinogenicity studies were conducted in male and female mice, male and female rats. No compound-related tumorigenic effects were observed at the highest dose levels in male and female mice (9 to 14-fold human exposure), and male rats (12-fold human exposure). In female rats, a tumorigenic effect was not observed at 300 mg/kg/day (16-fold human exposure). In another carcinogenicity study, 56 adult beagle dogs were orally administered thalidomide for 53 weeks. There were no deaths during the study. There was no gross and histopathologic evidence of any tumors. A large number of reproductive studies have shown that thalidomide is a potent teratogen. Cynomolgus monkeys were orally administered thalidomide at 15 or 20 mg/kg-d on days 26-28 of gestation, and fetuses were examined on day 100-102 of gestation. Limb defects such as micromelia/amelia, paw/foot hyperflexion, polydactyly, syndactyly, and brachydactyly were observed in seven of eight fetuses. The teratogenicity of thalidomide in rats was investigated after a single maternal intravenous injection during the organogenesis period. Thalidomide induced skeletal deformities of thoracic ribs and of the spinal column in fetuses upon maternal administration of the drug. Deformities of the eyeball in fetuses were induced by the maternal administration of the drug on day 10 and 12. A single dose (500 mg/kg) of thalidomide was administered orally to pregnant rabbits in various stages of organogenesis. Head anomalies in fetuses were induced at a high frequency by the maternal administration of thalidomide on day 7. Microphthalmia in fetuses was observed with a single administration from day 7 to 12 of gestation. Contracture of forearms and club foot in fetuses resulted from the maternal administration of thalidomide on day 8 or 9 of gestation, respectively. With a single administration on day 8 or 9 of gestation, kinky tail in fetuses resulted, and brachyury was observed with a high frequency from day 8 to 11 of gestation. Skeletal anomalies such as fusion or displacement of coccygeal vertebral bodies were observed at a high frequency with a single treatment from day 8 to 10 of gestation. Among the internal anomalies observed was abnormal lobation of the lung, and abnormal lobation of the liver, cardiovascular anomalies. Fertility studies were conducted in male and female rabbits; no compound-related effects in mating and fertility indices were observed at any oral thalidomide dose level including the highest of 100 mg/kg/day to female rabbits and 500 mg/kg/day to male rabbits. Thalidomide was neither mutagenic nor genotoxic in the following assays: the Ames bacterial (Salmonella typhimurium and Escherichia coli) reverse mutation assay, a Chinese hamster ovary cell forward mutation assay, and an in vivo mouse micronucleus test.
In patients with erythema nodosum leprosum (ENL) the mechanism of action is not fully understood. Available data from in vitro studies and preliminary clinical trials suggest that the immunologic effects of this compound can vary substantially under different conditions, but may be related to suppression of excessive tumor necrosis factor-alpha (TNF-a) production and down-modulation of selected cell surface adhesion molecules involved in leukocyte migration. For example, administration of thalidomide has been reported to decrease circulating levels of TNF-a in patients with ENL, however, it has also been shown to increase plasma TNF-a levels in HIV-seropositive patients. As a cancer treatment, the drug may act as a VEGF inhibitor.
Serum enzyme elevations occur in 8% to 15% of patients taking thalidomide and are more frequent with higher doses. The enzyme abnormalities are usually mild and self-limited, and only rarely require drug discontinuation. In addition, both thalidomide and its derivatives, lenalidomide and pomalidomide, have been implicated in rare instances of clinically apparent, acute liver injury which can be severe and has led to deaths from acute liver failure. The onset of injury is typically within 1 to 8 weeks of starting therapy. The pattern of serum enzyme elevation at the time of presentation can be either hepatocellular or cholestatic; however, the injury tends to be cholestatic and can be prolonged. Immunoallergic and autoimmune features are not common. Several instances of acute liver injury associated with thalidomide therapy have occurred in patients with other apparent causes of liver disease or with preexisting chronic hepatitis B or C. If performed during the acute injury, liver biopsy shows hepatocellular necrosis and inflammatory cell infiltration, consistent with acute drug induced injury. In some instances there is bile duct injury and loss resulting in progressive cholestatic liver injury suggestive of vanishing bile duct syndrome. Thalidomide and its derivatives have also been implicated in causing an increased risk of graft-vs-host disease after autologous or allogeneic hematopoietic stem cell transplantation (HSCT). There appears to be cross reactivity to this complication among thalidomide and its two derivatives. Therapy usually requires discontinuation of the antineoplastic agent as well as treatment with high doses of corticosteroids and tacrolimus or sirolimus.
Reactivation of hepatitis B has been reported in patients receiving thalidomide, lenalidomide and pomalidomide, but generally only after HSCT. In studies of large numbers of patients treated for multiple myeloma with these agents, the major risk factor for reactivation was HSCT rather than the specific antineoplastic drugs being used. Indeed, lenalidomide therapy was associated with a reduced risk of reactivation in patients with HSCT (although dexamethasone, thalidomide and bortezomib were not), perhaps because of the typical immune enhancement caused by lenalidomide.
Likelihood score: B (well known but rare cause of clinically apparent liver injury).
The absolute bioavailability has not yet been characterized in human subjects due to its poor aqueous solubility. The mean time to peak plasma concentrations (Tmax) ranged from 2.9 to 5.7 hours following a single dose from 50 to 400 mg. Patients with Hansen’s disease may have an increased bioavailability of thalidomide, although the clinical significance of this is unknown. Due to its low aqueous solubility and thus low dissolution is the gastrointestinal tract, thalidomide's absorption is slow, with a tlag of 20-40 min. Therefore, thalidomide exhibits absorption rate-limited pharmacokinetics or "flip-flop" phenomenon. Following a single dose of 200 mg in healthy male subjects, cmax and AUC∞ were calculated to be 2.00 ± 0.55 mg/L and 19.80 ± 3.61 mg*h/mL respectively.
Thalidomide is primarily excreted in urine as hydrolytic metabolites since less than 1% of the parent form is detected in the urine. Fecal excretion of thalidomide is minimal.
The volume of distribution of thalidomide is difficult to determine due to spontaneous hydrolysis and chiral inversion, but it is estimated to be 70-120 L.
来源:DrugBank
吸收、分配和排泄
清除
thalidomide 的口服清除率为 10.50 ± 2.10 L/h。
The oral clearance of thalidomide is 10.50 ± 2.10 L/h.
A two-step synthesis of thalidomide is presented. The sequence requires no purifications. Treatment of L-glutamine with N-carbethoxyphthalimide produces N-phthaloyl-L-glutamine. Cyclization of N-phthaloyl-L-glutamine to afford thalidomide is accomplished by treatment with CDI in the presence of a catalytic amount of DMAP.
[EN] TARGETED DELIVERY AND PRODRUG DESIGNS FOR PLATINUM-ACRIDINE ANTI-CANCER COMPOUNDS AND METHODS THEREOF<br/>[FR] ADMINISTRATION CIBLÉE ET CONCEPTIONS DE PROMÉDICAMENTS POUR COMPOSÉS ANTICANCÉREUX À BASE DE PLATINE ET D'ACRIDINE ET MÉTHODES ASSOCIÉES
申请人：WAKE FOREST SCHOOL OF MEDICINE
公开号：WO2013033430A1
公开（公告）日：2013-03-07
Acridine containing cispiaiin compounds have been disclosed that show greater efficacy against cancer than other cisplatin compounds. Methods of delivery of those more effective eisp!aiin compounds to the nucleus in cancer ceils is disclosed using one or more amino acids, one or more sugars, one or more polymeric ethers, C i^aikylene-phenyl-NH-C(0)-R.15, folic acid, av03 iniegriii RGD binding peptide, tamoxifen, endoxifen, epidermal growth factor receptor, antibody conjugates, kinase inhibitors, diazoles, triazol.es, oxazoies, erlotinib, and/or mixtures thereof; wherein R]§ is a peptide.
[EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
申请人：GILEAD APOLLO LLC
公开号：WO2017075056A1
公开（公告）日：2017-05-04
The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.
Compositions for Treatment of Cystic Fibrosis and Other Chronic Diseases
申请人：Vertex Pharmaceuticals Incorporated
公开号：US20150231142A1
公开（公告）日：2015-08-20
The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.
SULFONAMIDE, SULFAMATE, AND SULFAMOTHIOATE DERIVATIVES
申请人：Wang Zhong
公开号：US20120077814A1
公开（公告）日：2012-03-29
The disclosure provides biologically active compounds of formula (I):
and pharmaceutically acceptable salts thereof, compositions containing these compounds, and methods of using these compounds in a variety applications, such as treatment of diseases or disorders associated with E1 type activating enzymes, and with Nedd8 activating enzyme (NAE) in particular.
[EN] COMPOUNDS AND METHODS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES<br/>[FR] COMPOSÉS ET PROCÉDÉS POUR LE TRAITEMENT DE MALADIES NEURODÉGÉNÉRATIVES
申请人：TAVARES FRANCIS XAVIER
公开号：WO2016168118A1
公开（公告）日：2016-10-20
Novel compounds of formula (II) are disclosed. Compounds of formula (II) comprise ornithine derivatives or compounds that may metabolize to ornithine. Also disclosed are methods for the treatment of neurodegenerative diseases such as Alzheimer's Disease using compounds of formula (II).
