Although there are no detectable plasma concentrations of 9-cis-retinoic acid metabolites after topical application of Panretin gel, in vitro studies indicate that the drug is metabolized to 4-hydroxy-9-cis-retinoic acid and 4-oxo-9-cis-retinoic acid by CYP 2C9, 3A4, 1A1, and 1A2 enzymes. In vivo, 4-oxo-9-cis-retinoic acid is the major circulating metabolite following oral administration of 9-cis-retinoic acid.
IDENTIFICATION AND USE: Alitretinoin is an antineoplastic agent, used for topical treatment of cutaneous lesions in patients with AIDS-related Kaposi's sarcoma. HUMAN STUDIES: The most common adverse events were typical class effects of oral retinoids including headache, flushing, and skin disorders. There was a case of sensitization to alitretinoin reported in the literature. It was not found to be clastogenic in vitro in chromosome aberration test in human lymphocytes. ANIMAL STUDIES: Administration of alitretinoin to pregnant mice at 3 mg/kg on day 7.5 induced a 12% resorption rate and 0% exencephaly in 58 implants. In the 51 live fetuses that were given alitretinoin, there were 9 cases of microphthalmia and 6 cases of anophthalmia. Both the resorption and exencephaly rates indicate that alitretinoin is less potent than trans retinoic acid for these endpoints. An increased incidence of fused sternebrae and limb and craniofacial defects occurred in rabbits given oral doses of 0.5 mg/kg/day during the period of organogenesis. Limb and craniofacial defects also occurred in mice given a single oral dose of 50 mg/kg on day 11 of gestation. Oral alitretinoin was embryocidal, as indicated by early resorptions and post-implantation loss when it was given during the period of organogenesis to rabbits at doses of 1.5 mg/kg/day and to rats at doses of 5 mg/kg/day. Alitretinoin was not found to be mutagenic in in vitro tests including the Chinese hamster ovary cell HGPRT mutation assay. It was not found to be clastogenic in vivo (mouse micronucleus test). ECOTOXICITY STUDIES: In the Japanese flounder Paralichthys olivaceus, at 6-9 days post-hatching, all retinoic acid isomers (including alitretinoin) exerted toxic effects on the skeletal systems, mainly through the RAR pathway.
BACKGROUND: Based on in vitro data with isolated cytochrome P450 (CYP) isoenzymes, alitretinoin interacts only with CYP3A4, and the potential for drug-drug interactions is considered negligible. AIM: To confirm in humans the lack of potential interactions between CYP3A4 and alitretinoin in vivo. METHODS: This was a multiple-dose, open-label, parallel-group, single-centre study, which enrolled 54 healthy male volunteers aged 18-45 years. Subjects were divided into three groups, with 18 in each group: group 1 received either alitretinoin 30 mg and ketoconazole 200 mg, group 2 alitretinoin 30 mg and simvastatin 40 mg, and group 3 alitretinoin 30 mg and cyclosporin A 300-mg. RESULTS: At the highest therapeutic dose of 30 mg, alitretinoin had no significant effect on the pharmacokinetics (PK) of ketoconazole and cyclosporin A. There was a significant but not clinically relevant effect of simvastatin on the area under the curve (AUC) of plasma concentration vs. time and on maximum plasma concentration (C(max)) after repeated administration of alitretinoin. Exposure to simvastatin concomitantly with alitretinoin was decreased by 16% for AUC and 23% for C(max). The CYP3A4 +/- PgP substrates of simvastatin and cyclosporin A did not affect the single or repeated dose PK of alitretinoin. The strong CYP3A4/PgP inhibitor ketoconazole led to significant increases in both AUC and C(max) values for alitretinoin. CONCLUSIONS: Single and repeated doses of alitretinoin do not alter the PK of cyclosporin A and ketoconazole. Simvastatin levels were slightly but significantly reduced by co-administration of alitretinoin. Substrates of CYP3A4 did not affect the PK of alitretinoin. However, ketoconazole significantly increased the plasma levels of alitretinoin, therefore, co-administration with CYP3A4 inhibitors such as ketoconazole may require a dose reduction of alitretinoin.
Patients who are applying Panretin gel should not concurrently use products that contain DEET (N,N-diethyl-m-toluamide), a common component of insect repellent products. Animal toxicology studies showed increased DEET toxicity when DEET was included as part of the formulation.
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
背景：先前的研究表明，食物的同时服用可能增强口服维甲酸的生物利用度。目的：评估食物对单次口服剂量后阿利维甲酸药代动力学（PK）的影响。方法：这是一项单次剂量、开放标签、随机交叉研究，纳入了30名18-44岁的健康男性。受试者依次接受阿利维甲酸40 mg的剂量，分别在禁食后（治疗方案A）或标准早餐完成后5分钟（治疗方案B），用药顺序随机分配（A/B或B/A）。两次剂量之间的洗脱期为1周。绘制血浆浓度随时间的变化曲线，并确定标准的PK变量[血浆浓度与时间曲线下面积（AUC）、最大血浆浓度（Cmax）、达到最大血浆浓度的时间（tmax）和消除半衰期（t1/2）]。结果：与禁食相比，阿利维甲酸与食物同服时药物暴露显著增加，平均Cmax（分别为82.8 vs. 25.4 ng/mL）和AUC（分别为220.2 vs. 55.7 ng/mL/hr）显著增加。食物对tmax的延迟效应不太明显（中位数为3.0 vs. 2.0小时）。与食物同服也增加了药物代谢物的暴露。如果阿利维甲酸与食物同服，暴露的变异性显著降低（AUC的变异系数为40% vs. 74%，Cmax的变异系数为49% vs. 85%）。阿利维甲酸总体上耐受性良好，典型的维甲酸不良反应主要是头痛。结论：与食物同服阿利维甲酸可显著提高其生物利用度，但暴露的变异性降低。因此，口服阿利维甲酸应按照产品特性摘要中的说明与食物同服。
BACKGROUND: Previous studies have shown that concomitant administration of food may enhance the bioavailability of oral retinoids. AIM: To assess the influence of food on the pharmacokinetics (PK) of alitretinoin after a single oral dose. METHODS: This was a single-dose, open-label, randomized, crossover study, which enrolled 30 healthy men, aged 18-44 years. Subjects received sequential doses of alitretinoin 40 mg either after fasting (treatment A) or 5 min after completion of a standard breakfast (treatment B), with the dosing sequence randomized (A/B or B/A). The washout period between the two doses was 1 week. Plasma concentrations over time were plotted and standard PK variables [area under the curve (AUC) of plasma concentration vs. time, maximum plasma concentration (C(max)), time to maximum plasma concentration (t(max)) and elimination half-life (t(1/2)] were determined. RESULTS: Drug exposure was markedly increased when alitretinoin was taken with food compared with fasting, and there were significant increases in mean C(max) (82.8 vs.25.4 ng/mL, respectively) and AUC (220.2 vs. 55.7 ng/mL/hr). The delaying effect of food on t(max) was less marked (median of 3.0 vs. 2.0 h). Administration with food also increased exposure to drug metabolites. Variability in exposure was markedly reduced if alitretinoin was taken with vs. without food (percentage coefficient of variation 40% vs. 74% for AUC; 49% vs. 85% for C(max)). Alitretinoin was generally well tolerated, with typical retinoid adverse reactions, mostly comprising headache. CONCLUSIONS: Intake of alitretinoin with food substantially increased the bioavailability of alitretinoin, but variability in exposure was reduced. Consequently, oral alitretinoin should be taken with food as outlined in the manufacturer's summary of product characteristics.
BACKGROUND: Alitretinoin, like all retinoids, is teratogenic, and can only be given to women of childbearing potential if pregnancy is excluded and a strict contraceptive programme is followed. AIM: This study was designed to determine whether alitretinoin in the semen of men treated with alitretinoin poses a teratogenic risk to their female partners. METHODS: In total, 24 healthy men aged 18-45 years received alitretinoin 20 mg (n = 12) or 40 mg (n = 12), once daily for 14 days. Subjects in the 40 mg dose group provided ejaculate at baseline, on day 1, before and approximately 4 hr after dosing on day 2, and at follow-up on study day 21 (+/- 2). RESULTS: Alitretinoin and 4-oxo-alitretinoin were detected in 11 of the 12 semen samples. The highest level of alitretinoin in semen was 7.92 ng/mL. Assuming an ejaculate volume of 10 mL, the amount of drug transferred in semen would be about 80 ng, 1/375,000 of a single 30 mg capsule. Complete absorption of 80 ng of alitretinoin from semen, presuming a volume of distribution confined to 5 L of circulating blood in the partner, would lead to an increase in plasma alitretinoin concentration of 0.016 ng/mL, which appears to be negligible compared with measured endogenous plasma levels. Increases in plasma levels of related retinoids are also negligible. CONCLUSIONS: Alitretinoin in the semen of men receiving up to 40 mg of oral alitretinoin per day is unlikely to be associated with teratogenic risk in their female partners. Barrier contraception is therefore not required for men taking alitretinoin.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
/MILK/ 目前尚不清楚阿利特雷特诺或者其代谢物是否会被分泌入人乳中。
/MILK/ It is not known whether alitretinoin or its metabolites are excreted in human milk.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
有限的资料显示，局部应用阿利特罗汀后，该药物不会被系统性地大量吸收。
Limited data indicate that alitretinoin is not substantially absorbed systemically following topical application of the drug.
[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.
DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
申请人：BAYER PHARMA AKTIENGESELLSCHAFT
公开号：US20160221965A1
公开（公告）日：2016-08-04
The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.
Eflornithine Prodrugs, Conjugates and Salts, and Methods of Use Thereof
申请人：Xu Feng
公开号：US20100120727A1
公开（公告）日：2010-05-13
In one aspect, the present invention provides a composition of a covalent conjugate of an eflornithine analog with an anti-inflammatory drug. In another aspect, the present invention provides a composition of an eflornithine prodrug. In another aspect, the present invention provides a composition of an eflornithine or its derivatives aspirin salt. In another aspect, the present invention provides methods for treating or preventing cancer using the conjugates or salts of eflornithine analogs or eflornithine prodrugs.
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.
[EN] SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] QUINAZOLINES SUBSTITUÉES PAR SULFOXIMINE POUR COMPOSITIONS PHARMACEUTIQUES
申请人：BOEHRINGER INGELHEIM INT
公开号：WO2014072244A1
公开（公告）日：2014-05-15
This invention relates to novel sulfoximine substituted quinazoline derivatives of formula (I), wherein Ar, R1 and R2 are as defined in the description and claims, 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.
