MOST URINARY METABOLITES ARE HYDROXYLATED AT ONLY ONE SITE, EITHER ON THE QUINOLINE RING OR ON THE QUINUCLIDINE RING; SMALL AMOUNTS OF DIHYDROXY COMPOUNDS ARE ALSO FOUND. THE FRACTION OF A DOSE OF QUINIDINE THAT IS METABOLIZED & THE METABOLIC PATHWAY APPEAR TO VARY CONSIDERABLY FROM PATIENT TO PATIENT.
Quinidine is metabolized in the liver, principally via hydroxylation to 3-hydroxyquinidine and 2-quinidinone. The metabolites may be pharmacologically active. Approximately 10-50% of a dose is excreted in urine (probably by glomerular filtration) as unchanged drug within 24 hr. /Quinidine/
IDENTIFICATION: Quinidine is a class lA antiarrhythmic drug. Origin of the substance: Quinidine is the d- isomer of quinine. Quinidine is an alkaloid that may be derived from various species of Cinchona. Cinchona barks contain 0.25 to 3.0% quinidine. Quinidine is also prepared from quinine. Quinidine is a powder or white crystals, odorless with a bitter taste. Quinidine bisulfate is colorless crystals which is odorless and has a bitter taste. Quinidine gluconate is a white powder which is odorless and has a bitter taste. Quinidine poly-galacturonate is a powder. Quinidine sulfate is a white powder or odorless crystals with a bitter taste. Indications: Description: Premature ventricular extrasystoles and ventricular tachycardia; supraventricular arrhythmia; maintenance of sinus rhythm after cardioversion of atrial flutter or fibrillation. HUMAN EXPOSURE: Main risks and target organs: Cardio-toxicity is the main risk of quinidine poisoning. Quinidine may induce central nervous system symptoms. Summary of clinical effects: Toxic effects appear within 2 - 4 hours after ingestion but the delay may vary according to the quinidine salt and to the preparation forms. Symptoms may include disturbances of cardiac rhythm (especially in patients with underlying cardiovascular disease), neurotoxicity and respiratory depression. Diagnosis: Cardiac disturbances: circulatory arrest, shock, conduction disturbances, ventricular arrhythmias, ECG changes, Neurological symptoms: tinnitus, drowsiness, syncope, coma, convulsions, delirium. Respiratory depression. Quinidine concentrations may be helpful in diagnosis but are not useful for clinical management. Contraindications: Allergy or idiosyncrasy to cinchona alkaloids; atrioventricular or complete heart block; intraventricular conduction defects; absence of atrial activity; digitalis intoxication; myasthenia gravis and ventricular dysrhythmia of the torsades de pointes type Precautions include the following: Congestive heart failure, hypotension, renal disease, hepatic failure; concurrent use of other antiarhythmic drugs; old age and breast-feeding. Routes of entry: Oral: Oral absorption is the most frequent cause of intoxication. Parenteral: Intoxication after IV administration is rare but has been reported in patients treated with IV quinidine for cardiac dysrhythmia. Absorption by route of exposure: Oral: Quinidine is almost completely absorbed from the gastrointestinal tract. However, because of hepatic first-pass effect, the absolute bioavailability is about 70 to 80% of the ingested dose and may vary between patients and preparations. The time to plasma peak concentration is 1 to 3 hours for quinidine sulfate, 3 to 6 hours for quinidine gluconate and about 6 hours for quinidine polygalacturonate. Sustained-release quinidine is absorbed continuously over 8 to 12 hours. Parenteral: Absorption of quinidine after intramuscular injection may be erratic and unpredictable with incomplete absorption of the administered dose, probably due to precipitation of drug at the site of injection. Other studies indicate no difference between the rate of quinidine absorption when given by intramuscular injection or oral absorption. Distribution by route of exposure: Oral: Protein binding: About 70 to 80% of the drug is bound to plasma protein. Plasma protein binding is decreased in patients with chronic liver disease. Tissue: Quinidine concentrations in liver are 10 to 30 times higher than those in plasma. Skeletal and cardiac muscle, brain and other tissues contain intermediate amounts. The red cell plasma partition ratio is 0.82. Biological half-life by route of exposure: Elimination half-life: The half-life is about 6 to 7 hours. It is increased in chronic liver disease and in the elderly. It does not appear to be altered in congestive heart failure or renal failure. Metabolism: 50 to 90% of quinidine is metabolized in the liver to hydroxylated products. Metabolites include 3-hydroxyquinidine, 2 oxoquinidinone, 0-desmethylquinidine, quinidine-N-oxide. The principal metabolite is 3 hydroxyquinidine which exerts similar effects to quinidine and may account for part of the observed antiarrhythmic effects. The elimination kinetics of hydroxyquinidine appear to be similar to those of quinidine. Elimination by route of exposure Kidney: The amount excreted unchanged in urine is variable but is about 17% of an administered dose. Up to 50% of a dose of quinidine (unchanged + metabolites) is excreted in urine within 24 hours after administration. Renal excretion is dependent upon the pH of the urine. Excretion varies inversely with urine pH. Excretion is reduced in renal insufficiency and in congestive heart failure. Liver: 50 to 90% of a dose of quinidine is metabolized in the liver. Bile: Approximately 1 to 3% is excreted in the feces via the bile. Breast milk: Quinidine is excreted in breast milk. Mode of action Toxicodynamics: Quinidine reduces the permeability of heart muscle to electrolytes (membrane stabilizer) and is a general cardiac depressant. It has a negative inotropic effect; inhibits the spontaneous diastolic depolarization; slow conduction; lengthens the effective refractory period; and raises the electrical threshold. This results in depression of contractility, impaired conductivity (atrioventricular and intraventricular) and decreased excitability but with possible abnormal stimulus re-entry mechanism. Quinidine has an anticholinergic effect and peripheral vasodilator properties. In experimental studies the following progression changes was observed: ECG: bradycardia, prolongation of the PR interval, lengthening of the QT interval, widening of the QRS with development of an idioventricular rhythm and then in ventricular standstill. Sometimes the terminal event was ventricular fibrillation. Blood pressure decreases progressively. A significant decrease of blood pressure was noted with the appearance of QRS widening and blood pressure was close to zero when slow idioventricular rhythm appeared. Electrolytes abnormalities: decrease in plasma concentrations of potassium, sodium and magnesium with the development of acidosis. Electrolytes: Hypokalaemia may occur and is probably related to an intracellular transport of potassium by a direct effect on cellular membrane permeability. Neurologic symptoms: Syncope and convulsions may represent a direct toxic effect on CNS or may be related to cerebral ischaemia due to circulatory or respiratory failure. Pharmacodynamics: Quinidine slows the rate of firing of the normal and of ectopic rhythmic foci; it raises the threshold for electrically induced arrhythmias; it protects against ventricular arrhythmias; and it prevents or terminates circus movement flutter. Teratogenicity: Quinidine has been implicated as a cause of light cranial nerve damage to the fetus at doses much larger than those needed to treat arrhythmias. Interactions: Several interactions have been reported. Quinidine has a synergistic action with warfarin (decrease of prothrombin level). Quinidine potentiates both non-depolarizing and depolarizing neuromuscular blocking agents. The cardiodepressant effects of other antiarrhythmic agents are increased by concurrent use of quinidine; amiodarone increases quinidine concentrations in the blood. Quinidine concentrations are reduced by: rifampicin, anticonvulsants, nifedipine and acetazolamide. Quinidine concentrations are increased by antacids, cimetidine, verapamil and amiodarone; the risk of quinidine toxicity is increased by terfenadine, astemizole, and thiazide and loop diuretics. Quinidine increases the plasma concentrations of propafenone and digoxin. Main adverse effects: Numerous adverse effects during quinidine therapy have been reported. Cardiovascular: Hypotension after IV administration; Syncope; proarrhythmic effect: "torsades de pointes"; and ECG: widening of QRS interval; prolongation of PR and QT intervals. CNS: Cinchonism: headache, fever, visual disturbances, mydriasis, tinnitus, nausea, vomiting and rashes. Gastrointestinal: Nausea, vomiting, diarrhoea, colic have been reported. Hepatic: Granulomatous hepatitis or hepatitis with centrilobular necrosis. Skin: Skin rashes with drug fever and photosensitivity may result. Hematologic: Thrombocytopenia (immunologic reaction) has been noted. Clinical effects: Acute poisoning: Ingestion: Severity of quinidine poisoning is related to the cardiotoxic effects. Symptoms appear usually within 2 to 4 hours and may include: cardiovascular symptoms: hypotension, cardiogenic shock, cardiac arrest. ECG may show: decrease of T wave; prolongation of QT and QRS intervals; atrioventricular block; ventricular dysrhythmia (torsade de pointes). Neurological symptoms: tinnitus, drowsiness, syncope, coma, convulsion, blurred vision and diplopia. Respiratory symptoms: hypoventilation and apnea. Cardiotoxicity may be enhanced if other cardiotoxic drugs have been ingested (antiarrhythmic drugs, tricyclic antidepressants). Parenteral exposure: After IV administration symptoms appear more rapidly. Chronic poisoning: Ingestion: The most relevant symptoms of chronic poisoning are: ECG disturbances; syncope due to ventricular dysrhythmia, (torsade de pointes) and cinchonism gastrointestinal disturbances Course, prognosis, cause of death: The usual course of quinidine poisoning is dominated by the cardiovascular disturbances which usually occur within 2 to 4 first hours but may first appear as late as 12 hours after exposure (and perhaps even later after ingestion of a slow- release preparation). Symptoms may last for 24 to 36 hours. Patients who survive 48 hours after acute poisoning are likely to recover. Death may result from cardiac arrest by asystole or electromechanical dissociation and, rarely, by ventricular fibrillation. Systematic description of clinical effects: Cardiovascular: Acute: Cardiovascular symptoms are the major features of quinidine toxicity. Tachycardia due to anticholinergic effects is usually observed initially or in moderate intoxication. In severe intoxication, bradycardia due to atrioventricular block may occur. Hypotension and shock: hypotension due to peripheral vasodilation is common. In severe intoxication, cardiogenic shock with increased central venous pressure is usually observed and is related to decreased cardiac contractility. Cardiac arrest may occur, which may be related to electromechanical dissociation, ventricular dysrhythmia or asystole. Cardiac dysrhythmias are common and may include: atrioventricular block, idioventricular rhythm, ventricular tachycardia and fibrillation, torsades de pointes. ECG changes are always present in symptomatic intoxication: repolarization abnormalities, decreased T wave, increase of U wave, prolongation of QT and PR intervals, widening of QRS complexes (> 0.08 sec), atrioventricular block. Syncope due to torsade de pointes may occur. Chronic: ECG changes with repolarization abnormalities, decreased T wave and increase of QT interval are a common feature during quinidine therapy. Syncope is related to transient torsade de pointes and occurs in 1 to 8% of patients receiving quinidine. The occurrence of torsade de pointes is not correlated with plasma quinidine levels but is favored by an increase in the QT interval. Respiratory: Acute: Respiratory depression or apnea is mostly associated with severe cardiac disturbances such as shock or ventricular dysrhythmia. Pulmonary edema with normal pulmonary capillary wedge pressure following an attempted suicide has been documented. Neurological: CNS: Acute: Drowsiness, delirium, coma and convulsions may appear without cardiac symptoms. However, cardiac failure should always be considered when CNS symptoms appear. Cinchonism may sometimes appear. Chronic: Cinchonism. Delirium has been reported. Peripheral nervous system: Chronic: Quinidine can potentiate the neuromuscular blocking action of some skeletal muscle relaxants and may cause the return of respiratory paralysis if it is given shortly after recovery from neuromuscular blockade. Autonomic nervous system: Acute: Quinidine has an anticholinergic effect. However, this effect is usually limited to the vagal system. Skeletal and smooth muscle: Chronic: An increase in serum concentrations of skeletal muscle enzymes has been reported in a man treated with quinidine. Gastrointestinal: Acute: Nausea and vomiting may occur. Chronic: Gastrointestinal toxicity (nausea, vomiting, diarrhea and colic) is the most frequent side effect of quinidine. Hepatic: Chronic: Hepatotoxicity has been reported, with an increase in serum concentrations of transaminases, LDH, alkaline phosphatase, and cholestasis. Renal: Acute: No direct nephrotoxic effect has been reported. Acute renal failure related to cardiogenic shock may occur. Dermatological: Chronic: Skin lesions have been attributed to the use of quinidine and include skin rash, photosensitivity and lichen planus. Eye, ear, nose, throat: local effects: Acute: Cinchonism is rarely observed in acute poisonings. Toxic amblyopia, scotoma and impaired color perception may occur at toxic doses. Chronic: Chronic cumulative overdose may cause cinchonism: headache, tinnitus, vertigo, mydriasis, blurred vision, diplopia, photophobia, deafness, and corneal deposits have been reported in a patient who took quinidine for two years. Hematological: Chronic: Thrombocytopenia and hemolytic anemia of immunologic origins have been reported. Immunological: Chronic: Quinidine may cause several immunologic mediated reactions: thrombocytopenia, hemolytic anemia, angioneurotic edema, skin rash, fever. Metabolic: Acid-base disturbances: Acute: Metabolic acidosis may occur in severe intoxication with shock. Fluid and electrolyte disturbances: Acute: Hypokalemia is frequently observed. Special risks: Pregnancy: Chronic: Quinidine has been implicated as a cause of cranial nerve damage to the fetus at doses much larger than those needed to treat arrhythmia. In a neonate born to a woman taking quinidine throughout pregnancy, serum levels were equal to that of the mother. The child's ECG was normal and there was no evidence of teratogenicity. Breast-feeding: Chronic: Quinidine is present in breast milk at levels slightly lower than serum levels. The dose of quinidine received by an infant taking 1l of milk would be below therapeutic doses. However, breast-feeding is not recommended because of potential quinidine accumulation in the immature newborn liver. /Quinidine/
THE ADMIN OF QUINIDINE RESULTS IN AN INCREASE IN THE PLASMA CONCN OF THE GLYCOSIDE IN OVER 90% OF DIGITALIZED PATIENTS. THE DEGREE OF CHANGE IS PROPORTIONAL TO THE DOSE OF QUINIDINE; THE AVERAGE CHANGE IS ABOUT TWO-FOLD. ... THE INITIAL EFFECT OF QUINIDINE MAY BE DUE TO THE DISPLACEMENT OF DIGOXIN FROM BINDING SITES IN TISSUES. /QUINIDINE/
DRUGS ... SUCH AS PHENOBARBITAL OR PHENYTOIN ... MAY SIGNIFICANTLY SHORTEN DURATION OF ACTION OF QUINIDINE BY INCR RATE OF ELIMINATION. ... NITROGLYCERIN CAN CAUSE SEVERE POSTURAL HYPOTENSION IN PATIENTS WHO ARE TAKING QUINIDINE. /QUINIDINE/
QUINIDINE IS WEAK BASE EXCRETED ... BY KIDNEY & ITS BIOLOGICAL HALF-LIFE MAY BE PROLONGED ... IF PH OF URINE IS INCREASED. ... CARBONIC ANHYDRASE INHIBITORS, SODIUM BICARBONATE, & THIAZIDE DIURETICS, ALL OF WHICH INCR URINARY PH MAY SERVE TO INCR LIPID SOLUBILITY & TUBULAR REABSORPTION OF QUINIDINE & THUS PROLONG ITS THERAPEUTIC EFFECT. /QUINIDINE/
QUINIDINE (300 MG), SLOWLY ADMIN IV, CAUSED RETURN OF PARALYSIS INDUCED BY SUCCINYLCHOLINE (40 MG IV). QUINIDINE MAY ENHANCE OR CAUSE A RECURRENCE OF NEUROMUSCULAR EFFECTS OF TUBOCURARINE. /QUINIDINE/
ABOUT 90% OF QUINIDINE IN PLASMA IS BOUND TO PLASMA PROTEINS (ALPHA/ACID GLYCOPROTEIN AND ALBUMIN) THE DRUG ENTERS ERYTHROCYTES & ... BINDS TO HEMOGLOBIN; AT STEADY STATE, CONCN OF QUINIDINE IN PLASMA & ERYTHROCYTES ARE APPROXIMATELY EQUAL. QUINIDINE ACCUMULATES RAPIDLY IN MOST TISSUES EXCEPT BRAIN, & ... VOL OF DISTRIBUTION IS 2-3 L/KG. /QUINIDINE/
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
代谢物和部分母药（20%）通过尿液排出；消除半衰期约为6小时。/奎尼丁/
METABOLITES AND SOME OF THE PARENT DRUG (20%) ARE EXCRETED IN URINE; ELIMINATION HALF-TIME IS ABOUT 6 HR. /QUINIDINE/
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
肝脏代谢和肾脏排泄是消除的主要途径。肠肝循环不会显著改变吸收动力学，这一点从血液浓度可以反映出来。
LIVER METABOLISM & RENAL EXCRETION ARE THE MAIN ROUTES OF ELIMINATION. ENTEROHEPATIC CIRCULATION WOULD NOT SIGNIFICANTLY ALTER ABSORPTION KINETICS AS REFLECTED BY BLOOD CONCENTRATION.
PEAK PLASMA CONCN OF 0.29 UG/ML OF QUINIDINE WERE MEASURED @ 4 HR AFTER ADMIN OF SUSTAINED RELEASE CAPSULE (250 MG QUINIDINE BISULFATE) AND DECLINED STEADILY DURING THE NEXT 8 HR, WHILE AFTER ADMIN OF SUSTAINED RELEASE TABLET (300 MG QUINIDINE SULFATE) THEY WERE FAIRLY EVEN DURING 2-10 HR AFTER DOSING. PLASMA CONCENTRATIONS WERE HIGHER AT LATER TIMES FOR THE CAPSULE THAN FOR THE TABLET. THE BIOAVAILABILITY OF QUINIDINE FROM THE CAPSULES DURING 12 HR WAS 184% COMPARED TO THE TABLET. MEAN QUINIDINE PLASMA CONCN WERE SIGNIFICANTLY GREATER @ 3, 4, 6, 8, & 10 HR AFTER ADMIN OF THE CAPSULE THAN AFTER THE TABLET.
Disclosed is a process of carrying out a Michael reaction with recovery of the catalyst, where a compound of formula (1):
is reacted with a compound of formula (2):
in the presence of a catalyst of formula (4):
where the compounds of formulae (1) and (2) undergo a Michael reaction.
Mild and selective nickel-catalyzed trifluoromethylation and perfluoroalkylation reactions of alkenes were developed to provide fluorinated olefins, including natural products, pharmaceuticals, and variety of synthetic building blocks in good to excellent yields (38 examples). Control experiments, kinetic measurements and in situ EPR studies reveal the importance of radical species and the formation
CRYSTAL OF PYRROLE DERIVATIVE AND METHOD FOR PRODUCING THE SAME
申请人：Daiichi Sankyo Company, Limited
公开号：US20160096803A1
公开（公告）日：2016-04-07
The present invention provides a production intermediate of an atropisomer of a pyrrole derivative having excellent mineralocorticoid receptor antagonistic activity, a method for producing the same, and a crystal thereof. A method for producing an atropisomer of a pyrrole derivative including a step of resolving a compound represented by the following general formula (I) [wherein R
1
represents a methyl group or a trifluoromethyl group, R
2
represents a hydrogen atom or a C1-C3 alkoxy group, and n represents an integer selected from 1 to 3] into its atropisomers, characterized by using an optically active amine having a cinchonine skeletal formula, and a crystal of (S)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide.
A new series of Schiff bases derived from Cinchona alkaloids were developed as chiral ligands for the copper(II)-catalyzed asymmetricHenry reaction. The optimized catalyst can promote the Henry reaction of both aromatic and aliphatic aldehydes with nitromethane or nitroethane. Those reactions can afford the chiral β-nitro alcohol adducts with high enantioselectivities.
Process for the reduction of quinidinone to quinidine
申请人：——
公开号：US04174449A1
公开（公告）日：1979-11-13
Quinidinone is reduced to quinidine through reaction with a reducing agent, selected from aklyl-substituted aluminum hydrides or alkali metal alkyl-substituted aluminum hydrides, in the presence of a stereospecific orienting agent, such as pyridine.
