About 13% of a digoxin dose is found to be metabolized in healthy subjects. Several urinary metabolites of digoxin exist, including _dihydrodigoxin_ and _digoxigenin bisdigitoxoside_. Their glucuronidated and sulfated conjugates are thought to be produced through the process of hydrolysis, oxidation, and additionally, conjugation. The cytochrome P-450 system does not play a major role in digoxin metabolism, nor does this drug induce or inhibit the enzymes in this system.
In most patients, only small amounts of digoxin are metabolized, but the extent of metabolism is variable and may be substantial in some patients. Some metabolism presumably occurs in the liver, but digoxin is also apparently metabolized by bacteria within the lumen of the large intestine following oral administration and possibly after biliary elimination following parenteral administration. The extent of metabolism by bacteria in the large intestine following oral administration appears to vary inversely with the bioavailability of the preparation. Digoxin undergoes stepwise cleavage of the sugar moieties to form digoxigenin-bisdigitoxoside, digoxigenin-monodigitoxoside, and digoxigenin; these metabolites have progressively decreasing cardioactivity. Digoxigenin is subsequently epimerized and/or conjugated to form cardioinactive compounds. Digoxin also undergoes reduction of the lactone ring to form dihydrodigoxin, which also undergoes stepwise cleavage of the sugar moieties to form dihydrodigoxigenin-bisdigitoxoside, dihydrodigoxigenin-monodigitoxoside, and dihydrodigoxigenin; the reduced metabolites are essentially cardioinactive. Some patients may form substantial amounts of the reduced metabolites; data suggest that, in about 10% of patients receiving digoxin, about 40% or more of the drug excreted in urine will consist of reduced metabolites. Because of the rapid and enhanced absorption, use of liquid-filled capsules may minimize the formation of reduced metabolites in such patients. In patients who form substantial amounts of reduced metabolites, alteration of enteric bacterial flora by some anti-infective agents (e.g., erythromycin) may result in a substantial change in digitalization.
Hepatic (but not dependent upon the cytochrome P-450 system). The end metabolites, which include 3 b-digoxigenin, 3-keto-digoxigenin, and their glucuronide and sulfate conjugates, are polar in nature and are postulated to be formed via hydrolysis, oxidation, and conjugation.
Route of Elimination: Following intravenous administration to healthy volunteers, 50% to 70% of a digoxin dose is excreted unchanged in the urine.
Half Life: 3.5 to 5 days
IDENTIFICATION AND USE: Digoxin is colorless bitter solid. It is a cardiac glycoside that occurs widely in nature and/or can be prepared synthetically. The chief therapeutic use for digoxin is in the treatment of low output congestive heart failure. HUMAN STUDIES: Signs of digoxin toxicity include anorexia, nausea, vomiting, visual changes and cardiac arrhythmias, or third-degree heart block, atrial tachycardia with block, AV dissociation, accelerated junctional rhythm, unifocal or multiform ventricular premature contractions, ventricular tachycardia, and ventricular fibrillation. The earliest and most frequent manifestation of digoxin toxicity in infants and children is the appearance of cardiac arrhythmias, including sinus bradycardia. Increased age is most likely associated with enhanced susceptibility to digoxin toxicity, possibly due to unknown pharmacodynamic changes. ANIMAL STUDIES: Digoxin exposure to rat fetuses at the 15th, 17th and 19th day of pregnancy by treating the mother (with 9 ug digoxin total) caused alterations in the sexual behavior of adult rats. The number of active males was significantly higher in the treated group and ejaculation as well as multiple ejaculation occurred only here. Females also were more receptable after fetal digoxin treatment. Digoxin showed no genotoxic potential in in vitro studies (Ames test and mouse lymphoma). In dogs the acute toxic dose after IV administration has been reported to be 0.177 mg/kg. Cardiac glycosides inhibit the activity of sodium-potassium-activated adenosine triphosphatase (Na+-K+-ATPase), an enzyme required for active transport of sodium across myocardial cell membranes. Inhibition of this enzyme in cardiac cells results in an increase in the contractile state of the heart.
Digoxin binds to a site on the extracellular aspect of the alpha-subunit of the Na+/K+ ATPase pump in the membranes of heart cells (myocytes) and decreases its function. This causes an increase in the level of sodium ions in the myocytes. This effect causes an increase in the length the cardiac action potential, which when combined with the effects of digoxin on the parasympathetic nervous system, lead to a decrease in heart rate. Increased amounts of calcium are then stored in the sarcoplasmic reticulum and released by each action potential, which is unchanged by digoxin. This leads to increased contractility of the heart. Digoxin also increases vagal activity via its action on the central nervous system, thus decreasing the conduction of electrical impulses through the AV node. (L1247)
Digoxin is approximately 70-80% absorbed in the first part of the small bowel. The bioavailability of an oral dose varies from 50-90%, however, oral gelatinized capsules of digoxin are reported to have a bioavailability of 100%. Tmax, or the time to reach the maximum concentration of digoxin was measured to be 1.0 h in one clinical study of healthy patients taking 0.25 mg of digoxin with a placebo. Cmax, or maximum concentration, was 1.32 ± 0.18 ng/ml−1 in the same study, and AUC (area under the curve) was 12.5 ± 2.38 ng/ml−1. If digoxin is ingested after a meal, absorption is slowed but this does not change the total amount of absorbed drug. If digoxin is taken with meals that are in fiber, absorption may be decreased. **A note on gut bacteria** An oral dose of digoxin may be transformed into pharmacologically inactive products by bacteria in the colon. Studies have indicated that 10% of patients receiving digoxin tablets will experience the degradation of at least 40% of an ingested dose of digoxin by gut bacteria. Several antibiotics may increase the absorption of digoxin in these patients, due to the elimination of gut bacteria, which normally cause digoxin degradation. **A note on malabsorption** Patients with malabsorption due to a variety of causes may have a decreased ability to absorb digoxin. P-glycoprotein, located on cells in the intestine, may interfere with digoxin pharmacokinetics, as it is a substrate of this efflux transporter. P-glycoprotein can be induced by other drugs, therefore reducing the effects of digoxin by increasing its efflux in the intestine.
The elimination of digoxin is proportional to the total dose, following first order kinetics. After intravenous (IV) administration to healthy subjects, 50-70% of the dose is measured excreted as unchanged digoxin in the urine. Approximately 25 to 28% of digoxin is eliminated outside of the kidney. Biliary excretion appears to be of much less importance than renal excretion. Digoxin is not effectively removed from the body by dialysis, exchange transfusion, or during cardiopulmonary bypass because most of the drug is bound to extravascular tissues.
This drug is widely distributed in the body, and is known to cross the blood-brain barrier and the placenta. The apparent volume of distribution of digoxin is 475-500 L. A large portion of digoxin is distributed in the skeletal muscle followed by the heart and kidneys. It is important to note that the elderly population, generally having a decreased muscle mass, may show a lower volume of digoxin distribution.
The clearance of digoxin closely correlates to creatinine clearance, and does not depend on urinary flow. Individuals with renal impairment or failure may exhibit extensively prolonged half-lives. It is therefore important to titrate the dose accordingly and regularly monitor serum digoxin levels. One pharmacokinetic study measured the mean body clearance of intravenous digoxin to be 88 ± 44ml/min/l.73 m². Another study provided mean clearance values of 53 ml/min/1.73 m² in men aged 73-81 and 83 ml/min/1.73 m² in men aged 20-33 years old after an intravenous digoxin dose.
/MILK/ Maximum milk concentrations of 0.96 and 0.61 ng/mL observed at 4-6 hrs after administering single dose of 0.25 mg to 2 women. Maternal plasma concentration slightly higher than concentration in milk.
[EN] FLUORINATED 2,4-DIAMINOPYRIMIDINE COMPOUNDS AS MER TYROSINE KINASE (MERTK) INHIBITORS AND USES THEREOF<br/>[FR] COMPOSÉS DE 2,4-DIAMINOPYRIMIDINE FLUORÉS UTILISÉS EN TANT QU'INHIBITEURS DE LA TYROSINE KINASE MER (MERTK) ET LEURS UTILISATIONS
申请人：TRILLIUM THERAPEUTICS INC
公开号：WO2019006548A1
公开（公告）日：2019-01-10
A class of fluorinated 2,4-diaminopyrimidine compounds of Formula (I) have been prepared for use in the treatment of cancers and other MERTK related disorders. (Formula (I))
[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] TARGETING COMPOUNDS<br/>[FR] COMPOSÉS DE CIBLAGE
申请人：ZAFGEN INC
公开号：WO2019118612A1
公开（公告）日：2019-06-20
The disclosure provides, at least in part, liver, intestine and/or kidney-targeting compounds and their use in treating liver, intestine and/or kidney disorders, such as non-alcoholic steatohepatitis, alcoholic steatohepatitis, hepatocellular carcinoma, liver cirrhosis, and hepatitis B; and/or chronic kidney disease, glomerular disease such as IGA nephropathy, lupus nephritis, or polycystic kidney disease. The compounds are contemplated to have activity against methionyl aminopeptidase 2.
METHOD FOR THE PREPARATION OF (4S)-4-(4-CYANO-2-METHOXYPHENYL)-5-ETHOXY-2,8-DIMETHYL-1,4-DIHYDRO-1-6-NAPHTHYRIDINE-3-CARBOXAMIDE AND THE PURIFICATION THEREOF FOR USE AS AN ACTIVE PHARMACEUTICAL INGREDIENT
申请人：BAYER PHARMA AKTIENGESELLSCHAFT
公开号：US20180244670A1
公开（公告）日：2018-08-30
The present invention relates to a novel and improved process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (I)
Amino-substituted heterocycles, compositions thereof, and methods of treatment therewith
申请人：D'Sidocky Neil R.
公开号：US20080242694A1
公开（公告）日：2008-10-02
Provided herein are Heterocyclic Compounds having the following structure:
wherein R
1
, R
2
, X, Y and Z are as defined herein, compositions comprising an effective amount of a Heterocyclic Compound and methods for treating or preventing cancer, inflammatory conditions, immunological conditions, metabolic conditions and conditions treatable or preventable by inhibition of a kinase pathway comprising administering an effective amount of a Heterocyclic Compound to a patient in need thereof.
