In humans, the majority of the deferiprone is metabolized, primarily by UGT1A6. The contribution of extrahepatic (e.g., renal) UGT1A6 is unknown. The major metabolite of deferiprone is the 3-O-glucuronide, which lacks iron binding capability. Peak serum concentration of the glucuronide occurs 2 to 4 hours after administration of deferiprone in fasting subjects.
IDENTIFICATION AND USE: Deferiprone is a heavy metal antagonist that chelates iron. It is indicated for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate. HUMAN EXPOSURE AND TOXICITY: No cases of acute overdose have been reported. However, neurological disorders such as cerebellar symptoms, diplopia, lateral nystagmus, psychomotor slowdown, hand movements and axial hypotonia have been observed in children treated with 2.5 to 3 times the recommended dose for more than one year. The neurological disorders progressively regressed after deferiprone discontinuation. At the prescribed dose, deferiprone can cause agranulocytosis that can lead to serious infections and death. Neutropenia may precede the development of agranulocytosis. Based on evidence of genotoxicity and developmental toxicity in animal studies, deferiprone can cause fetal harm when administered to a pregnant woman. ANIMAL STUDIES: Single oral doses of deferiprone of up to 100 mg/kg to mice and rats produced transient hypersalivation, whereas higher doses (300-600 mg/kg) affected behavior, decreased performance and body temperature, and affected passive avoidance and motility. At doses lower than those used clinically, deferiprone has been shown to penetrate the blood brain barrier in rats, and to interfere with dopamine and serotonin metabolism through inhibitory effects on catechol-O-methyltransferase and tyrosine and tryptophan hydroxylases. In a 12-month rodent toxicology study, following administration of deferiprone at doses of 150 or 200 mg/kg/day in 2 divided doses (75 or 100 mg/kg bid), to non-iron-loaded or iron-loaded rats, respectively, 7 of 50 non-iron-loaded and 3 of 50 iron-loaded animals were either found dead or sacrificed moribund with severe anemia and slight to moderate centrilobular degeneration and necrosis. Animals from which blood samples could be collected prior to their unscheduled termination had elevated levels of total bilirubin, aspartate aminotransferase, and/or alanine aminotransferase of up to ca. 8, 4, and 14 times their respective group mean control value. These findings could be ascribed to hypoxia due to severe anemia (hemoglobin concentration <2.5 g/dL). No findings of severe anemia with or without centrilobular degeneration and necrosis, or isolated findings of centrilobular degeneration and necrosis, were noted in non-iron-loaded or iron-loaded survivors. Relatively mild decreases in RBC and WBC counts in surviving rats partially reversed during a 4-week off-dose period following 12 months' treatment; recovery of bone marrow hypocellularity was complete in iron-loaded, but partial in non-iron-loaded, animals. The mean relative weight of the adrenal and pituitary gland was significantly greater in non-iron-loaded rats given 75 mg/kg deferiprone bid as compared to non-iron-loaded untreated rats. Skeletal and soft tissue malformations occurred in offspring of rats and rabbits that received deferiprone orally during organogenesis at the lowest doses tested (25 mg/kg per day in rats; 10 mg/kg per day in rabbits). These doses were equivalent to 3% to 4% of the maximum recommended human dose (MRHD) based on body surface area. No maternal toxicity was evident at these doses. Embryofetal lethality and maternal toxicity occurred in pregnant rabbits given 100 mg/kg/day deferiprone orally during the period of organogenesis. This dose is equivalent to 32% of the MRHD based on body surface area. A fertility and early embryonic development study of deferiprone was conducted in rats. Sperm counts, motility and morphology were unaffected by treatment with deferiprone. There were no effects observed on male or female fertility or reproductive function at the highest dose which was 25% of the MRHD based on body surface area. Deferiprone was positive in a mouse lymphoma cell assay in vitro. Deferiprone was clastogenic in an in vitro chromosomal aberration test in mice and in a chromosomal aberration test in Chinese Hamster Ovary cells. Deferiprone given orally or intraperitoneally was clastogenic in a bone marrow micronucleus assay in non-iron-loaded mice. A micronucleus test was also positive when mice pre-dosed with iron dextran were treated with deferiprone. Deferiprone was not mutagenic in the Ames bacterial reverse mutation test.
In large clinical trials, elevations in serum aminotransferase levels occurred in 7.5% of patients treated with deferiprone and led to drug discontinuation in ~1%. In many situations, it was unclear whether the ALT elevations were due to deferiprone therapy as opposed to spontaneous worsening of an underlying chronic hepatitis B or C, which is common in patients with transfusion related iron overload. Furthermore, there have been very few reports of clinically apparent liver injury attributed to deferiprone therapy and the clinical features of hepatic injury from deferiprone (latency to onset, pattern of serum enzyme elevations, clinical symptoms and laboratory findings, subsequent course) have not been defined.
Iron overload itself can cause liver injury and result in significant fibrosis and even cirrhosis. By decreasing hepatic iron stores, deferiprone and other iron chelators should improve liver disease and prevent progression of fibrosis. In a controversial open label study of deferiprone therapy for up to 4 years in 19 patients with thalassemia and iron overload, progression of fibrosis was found in 5 of 12 subjects who underwent repeat liver biopsy after an average of 4 years, compared to none of 12 subjects who were separately followed while being treated with deferoxamine. Several subsequent studies, however, failed to show fibrosis progression in subjects with thalassemia and iron overload treated with deferiprone, particularly among those without concurrent hepatitis C.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).
◉ Summary of Use during Lactation:Deferiprone is likely actively transported into milk through binding with lactoferrin. Because no information is available on the use of deferiprone during breastfeeding and it is orally absorbed, an alternate drug is preferred, especially while nursing a newborn or preterm infant. Australian guidelines recommend against breastfeeding during deferiprone treatment. The US manufacturer recommends withholding breastfeeding for 2 weeks after the last dose.
◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.
Deferiprone may bind to aluminum. The manufacturer states that an interval of at least 4 hours should be allowed between the administration of deferiprone and aluminum-containing antacids.
Concurrent use of Ferriprox with foods, mineral supplements, and antacids that contain polyvalent cations has not been studied. However, since deferiprone has the potential to bind polyvalent cations (e.g., iron, aluminum, and zinc), allow at least a 4-hour interval between Ferriprox and other medications (e.g., antacids), or supplements containing these polyvalent cations.
Deferiprone is absorbed in the upper gastrointestinal tract. Absorption is rapid with maximum plasma concentrations occurring after 1 hour in the fasted state and after 2 hours in the fed state.
Within 5-6 hours of administration, more than 90% of deferiprone is eliminated from the plasma. 75 to 90% of deferiprone is excreted in the urine as the metabolite.
来源:DrugBank
吸收、分配和排泄
分布容积
在健康患者中，分布体积为1L/kg，而在地中海贫血患者中，分布体积为1.6L/kg。
In healthy patients, the volume of distribution is 1L/kg, and in thalassemia patients, the volume of distribution is 1.6L/kg.
In healthy subjects, the mean maximum concentration (Cmax) of deferiprone in serum was 20 ug/mL, and the mean total area under the concentration-time curve (AUC) was 53 ug*hr/mL following oral administration of a 1,500 mg dose of Ferriprox tablets in the fasting state. Dose proportionality over the labeled dosage range of 25 to 33 mg/kg three times per day (75 to 99 mg/kg per day) has not been studied. The elimination half life of deferiprone was 1.9 hours. The accumulation of deferiprone and its glucuronide metabolite at the highest approved dosage level of 33 mg/kg three times per day has not been studied. The volume of distribution of deferiprone is 1.6 L/kg in thalassemia patients, and approximately 1 L/kg in healthy subjects. The plasma protein binding of deferiprone in humans is less than 10%.
Deferiprone is rapidly absorbed from the upper part of the gastrointestinal tract, appearing in the blood within 5 to 10 minutes of oral administration. Peak serum concentrations occur approximately 1 hour after a single dose in fasted healthy subjects and patients, and up to 2 hours after a single dose in the fed state. Administration with food decreased the Cmax of deferiprone by 38% and the AUC by 10%. While a food effect cannot be ruled out, the magnitude of the exposure change does not warrant dose adjustment.
3-Hydroxy-4-pyrones as Precursors of 4-Methoxy-3-oxidopyridinium Ylides. An Expeditious Entry to Highly Substituted 8-Azabicyclo[3.2.1]octanes
摘要：
3-Hydroxy-4-pyridones, which are easily prepared from commercially available 3-hydroxy-4-pyrones, can be readily transformed into 4-methoxy-3-oxidopyridinium ylides by treatment with methyl trifluoromethanesulfonate and subsequent deprotonation with a non-nucleophilic base. These ylides are capable of undergoing cycloaddition to several electron-deficient alkenes, thus allowing the synthesis of highly functionalized azabicyclo[3.2,1]octane moieties. The rich substitution patterns of these frameworks might allow their divergent conversion to a variety of natural and non-natural tropane alkaloids.
[EN] NOVEL HEPCIDIN MIMETICS AND USES THEREOF<br/>[FR] NOUVEAUX MIMÉTIQUES D'HEPCIDINE ET LEURS UTILISATIONS
申请人：BAYER HEALTHCARE LLC
公开号：WO2018128828A1
公开（公告）日：2018-07-12
The present invention relates to novel peptides acting as hepcidin mimetics, as well as analogues and derivatives thereof. The invention further relates to compositions comprising the peptides of the present invention, and to the use of the peptides in the prophylaxis and treatment of hepcidin-associated disorders, including prophylaxis and treatment of iron overload diseases such as hemochromatosis, iron-loading anemias such as thalassemia, and diseases being associated with ineffective or augmented erythropoiesis, as well as further related conditions and disorders described herein.
The present disclosure provides ionophore compounds, which are useful for facilitating delivery of a metal ion to a cell, tissue or organ of interest. The present disclosure provides compositions comprising the subject ionophore compounds. The present disclosure provides methods of delivering a metal ion intracellularly to a target cell. The present disclosure also provides methods of treating a condition associated with a metal deficiency in an individual.
[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.
SUBSTITUTED 2,4 DIAMINO-QUINOLINE AS NEW MEDICAMENT FOR FIBROSIS, AUTOPHAGY AND CATHEPSINS B (CTSB), L (CTSL) AND D (CTSD) RELATED DISEASES
申请人：Genoscience Pharma SAS
公开号：EP3620164A1
公开（公告）日：2020-03-11
The present invention relates to novel 2-primary amino-4-secondary amino-quinoline derivatives, their manufacture, pharmaceutical compositions comprising them and their use as medicaments. The active compounds of the present invention can be useful as a medicament in the treatment and/or the decreasing and/or the prevention of fibrosis and/or fibrosis related diseases, or for use as a medicament in the treatment and/or the decreasing and/or the prevention of the autophagy and/or autophagy related diseases and for the inhibition of the autophagy flux, or for use in the inhibition of cathepsins B (CTSB), L (CTSL) and/or D (CTSD) and/or cathepsins B (CTSB), L (CTSL) and/or D (CTSD) related diseases; with the proviso that said compounds are not to be used for the treatment of any forms of cancers.
[EN] COMBINATION OF HEPATITIS B VIRUS (HBV) VACCINES AND PYRIDOPYRIMIDINE DERIVATIVES<br/>[FR] ASSOCIATION DE VACCINS CONTRE LE VIRUS DE L'HÉPATITE B (VHB) ET DE DÉRIVÉS DE PYRIDOPYRIMIDINE
申请人：JANSSEN SCIENCES IRELAND UNLIMITED CO
公开号：WO2020255038A1
公开（公告）日：2020-12-24
Therapeutic combinations of hepatitis B virus (HBV) vaccines and a pyridopyrimidine derivative are described. Methods of inducing an immune response against HBV or treating an HBV-induced disease, particularly in individuals having chronic HBV infection, using the disclosed therapeutic combinations are also described. The invention provides therapeutic combinations or compositions and methods for inducing an immune response against hepatitis B viruses (HBV) infection.
