Cytochrome P450db; K+ channel

Quinidine monosulfate causes apoptosis in MES-SA cells and is harmful to them [4].
1. The effect of quinidine on the fast-activating, fast-inactivating potassium current (IK(f] in acutely dissociated melanotrophs of the adult rat pituitary was examined. Macroscopic currents were measured by use of the whole-cell configuration of the patch clamp technique. 2. Bath application of quinidine caused a dose-dependent reduction of the peak amplitude of IK(f). The Kd for blockade of IK(f) at 0 mV was estimated to be 41 +/- 5.6 microM. 3. Quinidine elicited a dose-dependent increase of the rate of the decay of IK(f) and this effect was enhanced by membrane depolarization. The possibility that this phenomenon reflects an open channel blocking reaction is discussed. 4. Quinidine also caused a 5 mV hyperpolarizing shift of the steady-state inactivation curve and increased the half-time for recovery from inactivation. Quinidine did not affect the onset of inactivation measured at -30 mV. 5. Internal quinidine did not appear substantially to affect either the peak amplitude or kinetics of IK(f). 6. A study of some structural analogues showed that hydroquinidine and quinacrine had effects similar to those of quinidine. The effect of quinacrine on the amplitude and kinetics of IK(f) was also pH-dependent. Cinchonine, which bears a close structural resemblance to quinidine, was much less effective as a blocker of IK(f).[1]

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Multidrug resistance (MDR) is one of important issues to cause the chemotherapy failure against cancers including gynecological malignancies. Despite some MDR reversal evidences of natural compounds including quinidine and cinchonine, there are no reports on MDR reversal activity of hydrocinchonine with its analogues quinidine and cinchonine especially in uterine sarcoma cells. Thus, in the current study, we comparatively investigated the potent efficacy of hydrocinchonine and its analogues quinidine and cinchonine as MDR-reversal agents for combined therapy with antitumor agent paclitaxel (TAX). Hydrocinchonine, cinchonine, and quinidine significantly increased the cytotoxicity of TAX in P-glycoprotein (gp)-positive MES-SA/DX5, but not in the P-gp-negative MES-SA cells at nontoxic concentrations by 3-(4,5-dimethylthiazol-2-yl)-2,5--diphenyltetrazolium bromide (MTT) assay. Rhodamine assay also revealed that hydrocinchonine, cinchonine, and quinidine effectively enhanced the accumulation of a P-gp substrate, rhodamine in TAX-treated MES-SA/DX5 cells compared with TAX-treated control. In addition, hydrocinchonine, cinchonine, and quinidine effectively cleaved poly (ADP-ribose) polymerase (PARP), activated caspase-3, and downregulated P-gp expression as well as increased sub-G1 apoptotic portion in TAX-treated MES-SA/DX5 cells. Taken together, hydrocinchonine exerted MDR reversal activity and synergistic apoptotic effect with TAX in MES-SA/DX5 cells almost comparable with quinidine and cinchonine as a potent MDR-reversal and combined therapy agent with TAX.[4]

Quinidine monosulfate affects the epilepsy threshold generated by PTZ [5].
Amphetamine is metabolized by cytochrome P-450 (P450) to p-hydroxyamphetamine and phenylacetone in mammalian species. P450 metabolism is affected by genetic polymorphisms and by xenobiotic interactions in an isozyme-specific fashion. Little is known concerning the isozyme selectivity of amphetamine metabolism. Quinidine selectively inhibits the debrisoquine-specific isozyme (P450db) which displays genetic polymorphism in humans and rats. We now report the effect of quinidine on the metabolism of amphetamine to p-hydroxyamphetamine in vivo. At 0 h male Lewis rats received (po): no treatment (I), 80 mg quinidine/kg in 50% ethanol (II), or 50% ethanol (III), followed at 2 h by 15 mg d-amphetamine sulfate/kg (po). Urine specimens were collected and pooled at 0, 24, and 48 h. Amphetamine and p-hydroxyamphetamine concentrations were determined using a new GC/MS method for simultaneous quantitation. The ethanol vehicle-control (III) had no significant effect on amphetamine metabolism. Quinidine pretreatment (II) resulted in a significant decrease in the excretion of p-hydroxyamphetamine at 24 and 48 h to 7.2 and 24.1% of the vehicle-control levels, respectively, accompanied by a significant increase in amphetamine excretion between 24 and 48 h to 542% of the control. These data show that quinidine inhibits in vivo metabolism of amphetamine in rats and suggest that amphetamine metabolism may, in part, be mediated by an isozyme of P450 which displays genetic polymorphism. The inhibition of amphetamine metabolism results in an increased ratio of parent drug to metabolite concentration (metabolic ratio) in the urine, which mimics the effect of genetic polymorphisms[3].

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This study aimed to investigate the effects of dextromethorphan (DM) or dextromethorphan/quinidine (DM/Q) against pentylenetetrazole (PTZ)- induced seizure threshold in mice and the probable involvement of N-methyl d-aspartate (NMDA), sigma-1 and serotonin 1A (5-HT1A) receptors.
Results: DM (25 and 50 mg/kg) significantly increased PTZ- induced seizure threshold. DM/Q at doses of 10/20 and 25/20 mg/kg had anticonvulsant effect, while at a dose of 50/20 mg/kg attenuated anticonvulsant effect of DM 50 mg/kg. Ketamine (5 mg/kg) or WAY-100635 (1 mg/kg) potentiated, while BD-1047 (2.5 and 5 mg/kg) attenuated the anticonvulsant effect of DM/Q 10/20 mg/kg.
Conclusion: The results of present study demonstrate that combination with quinidine potentiates the anticonvulsant effect of DM at lower doses, while attenuates it at higher dose. Meanwhile, the effects of DM/Q on seizure activity likely involve an interaction with NMDA, the sigma-1 or the 5-HT1A receptor which may be secondary to the elevation of DM levels.[5]

Cytotoxicity assay [4]
Cell Types: MES-SA and MESSA/DX5 cells
Tested Concentrations: 10 μM
Incubation Duration: 24 hrs (hours)
Experimental Results: Concentration-dependent cytotoxicity to MES-SA cells.

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Apoptosis analysis [4]
Cell Types: MES-SA and MESSA/DX5 Cell
Tested Concentrations: 10 μM
Incubation Duration: 24 hrs (hours)
Experimental Results: The content of sub-G1 DNA in the apoptotic part induced by paclitaxel increased, while paclitaxel did not affect sub-G1 DNA Influence the contents to undergo apoptosis.

Animal/Disease Models: NMRI strain male mice (age 5-6 weeks, weight 25-30 grams) [5]
Doses: 10, 20 and 30 mg/kg
Route of Administration: intraperitoneal (ip) injection; intraperitoneal (ip) injection. 10, 20 and 30 mg/kg;
Experimental Results: The 30 mg/kg dose increased the threshold dose for tonic hindlimb extension attacks compared with saline-treated controls (p<0.05).

Absorption, Distribution and Excretion
Approximately 90% of Quinidine in plasma is bound to plasma proteins (alpha/acid glycoproteins and albumin). The drug enters red blood cells and binds to hemoglobin; at steady state, the concentrations of Quinidine in plasma and red blood cells are roughly equal. Quinidine accumulates rapidly in most tissues except brain tissue, with a volume of distribution of 2–3 liters/kg. Metabolites and a portion of the original drug (20%) are excreted in the urine; the elimination half-life is approximately 6 hours. Quinidine is primarily eliminated through hepatic metabolism and renal excretion. Enterohepatic circulation does not significantly alter absorption kinetics, which is reflected in plasma drug concentrations. Four hours after administration of a sustained-release capsule (250 mg Quinidine sulfate), the peak plasma Quinidine concentration was 0.29 μg/mL, which steadily decreased over the next 8 hours; while after administration of a sustained-release tablet (300 mg Quinidine sulfate), plasma Quinidine concentrations remained essentially stable for 2–10 hours post-administration. Capsule dosage forms showed higher plasma concentrations in the later stages compared to tablets. Within 12 hours, the bioavailability of Quinidine in capsules was 184% that of tablets. Mean plasma Quinidine concentrations were significantly higher at 3, 4, 6, 8, and 10 hours after capsule administration compared to tablet administration. For more complete data on absorption, distribution, and excretion of Quinidine sulfate (24 items), please visit the HSDB record page. Metabolism/Metabolites Quinidine is metabolized in humans to 2'-hydroxyQuinidine. Quinidine; excerpt from table/ Most urinary metabolites undergo hydroxylation at only one site, either the quinoline ring or the Quinidine ring; small amounts of dihydroxy compounds are also present. The metabolic proportions and pathways of Quinidine vary significantly among patients. Quinidine is primarily metabolized in the liver, via hydroxylation to 3-hydroxyQuinidine and 2-Quinidineone. These metabolites may possess pharmacological activity. Approximately 10-50% of the dose is excreted unchanged in the urine within 24 hours (possibly through glomerular filtration). Quinidine

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Biological Half-Life
The elimination half-life of Quinidine in healthy individuals is 4 to 10 hours, with a typical average of 6 to 7 hours. The half-life is significantly prolonged in older adults, even if they appear healthy. Quinidine is primarily excreted in the urine; the elimination half-life is approximately 6 hours. The plasma half-life of Quinidine in healthy individuals is typically 6 to 8 hours, but it can be 3 to 16 hours or longer. In a study of patients with Plasmodium falciparum malaria, the mean elimination half-life of the drug was 12.8 hours (range: 6.6–24.8 hours). /Quinidine/

Toxicity Summary
Identification: Quinidine is a Class IA antiarrhythmic drug. Source: Quinidine is the d-isomer of quinine. Quinidine is an alkaloid that may be derived from various cinchona trees. Cinchona bark contains 0.25% to 3.0% Quinidine. Quinidine can also be prepared from quinine. Quinidine is a white powder or crystal, odorless, and bitter. Quinidine sulfate is a colorless crystal, odorless, and bitter. Quinidine gluconate is a white powder, odorless, and bitter. Quinidine polygalacturonic acid is a powder. Quinidine sulfate is a white powder or odorless crystal, bitter. Indications: Description: Ventricular premature beats and ventricular tachycardia; supraventricular arrhythmias; maintenance of sinus rhythm after cardioversion of atrial fibrillation or atrial flutter. Human Exposure: Major Risks and Target Organs: Cardiotoxicity is the major risk of Quinidine poisoning. Quinidine may induce central nervous system symptoms. Clinical Overview: Symptoms of poisoning usually appear within 2–4 hours after ingestion, but the delay may vary depending on the Quinidine salt and formulation. Symptoms may include cardiac arrhythmias (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, somnolence, syncope, coma, seizures, delirium; respiratory depression. Quinidine concentration may be helpful in diagnosis but not in clinical treatment. Contraindications: Hypersensitivity or idiosyncratic reaction to cinchona alkaloids; atrioventricular block or complete atrioventricular block; intraventricular block; loss of atrial activity; digitalis poisoning; myasthenia gravis and torsades de pointes. Precautions include: congestive heart failure, hypotension, kidney disease, liver failure; concurrent use of other antiarrhythmic drugs; elderly and lactating women. Route of Administration: Oral: Oral absorption is the most common cause of poisoning. Parenteral administration: Poisoning after intravenous administration is rare, but there have been reports of poisoning in patients receiving intravenous Quinidine for arrhythmia. Absorption routes: Oral: Quinidine is almost completely absorbed via the gastrointestinal tract. However, due to the first-pass effect in the liver, its absolute bioavailability is approximately 70% to 80% of the ingested dose and may vary depending on the patient and formulation. The peak plasma concentration time for Quinidine sulfate is 1 to 3 hours, for Quinidine gluconate it is 3 to 6 hours, and for Quinidine polygalacturonic acid it is approximately 6 hours. Sustained-release Quinidine can be absorbed continuously over 8 to 12 hours. Parenteral administration: Absorption of Quinidine after intramuscular injection can be unstable and unpredictable; the administered dose may not be completely absorbed, possibly due to drug precipitation at the injection site. Other studies have shown no difference in absorption rates between intramuscular and oral Quinidine. Drug distribution: Oral: Protein binding: Approximately 70% to 80% of the drug is bound to plasma proteins. Plasma protein binding is reduced in patients with chronic liver disease. Tissues: Quinidine concentrations in the liver are 10 to 30 times higher than in plasma. Quinidine levels in skeletal muscle, cardiac muscle, brain, and other tissues fall between these levels. The erythrocyte-plasma partition ratio is 0.82. Biological half-life determined by exposure route: Elimination half-life: The half-life is approximately 6 to 7 hours. The half-life is prolonged in chronic liver disease and in older adults. Congestive heart failure or renal failure does not appear to alter its half-life. Metabolism: 50% to 90% of Quinidine is metabolized in the liver to hydroxylated products. Metabolites include 3-hydroxyQuinidine, 2-oxoQuinidine, O-demethylQuinidine, and Quinidine-N-oxide. The major metabolite is 3-hydroxyQuinidine, which has similar effects to Quinidine and may partially explain the observed antiarrhythmic effects. The elimination kinetics of hydroxyQuinidine appear to be similar to those of Quinidine. Elimination determined by exposure route: Kidneys: The amount of drug excreted unchanged in urine varies considerably, but is approximately 17% of the administered dose. After administration of Quinidine, up to 50% of the dose (net drug + metabolites) is excreted in the urine within 24 hours. Renal excretion depends on urine pH, and the amount excreted is inversely proportional to urine pH. Renal insufficiency and congestive heart failure reduce excretion. Liver: 50% to 90% of the Quinidine dose is metabolized in the liver. Bile: Approximately 1% to 3% of Quinidine is excreted in the feces via bile. Breast milk: Quinidine is secreted into breast milk. Mechanism of action and toxicology: Quinidine reduces myocardial permeability to electrolytes (membrane stabilizer) and is a systemic cardiac depressant. It has a negative inotropic effect, inhibiting spontaneous diastolic depolarization, slowing conduction velocity, prolonging the effective refractory period, and increasing the electrical threshold. This leads to decreased myocardial contractility, impaired conduction (atrioventricular and intraventricular conduction), and decreased excitability, but may be accompanied by anomalous reentry mechanisms. Quinidine has anticholinergic and peripheral vasodilatory effects. The following progressive changes were observed in experimental studies: Electrocardiogram: bradycardia, prolonged PR interval, prolonged QT interval, widened QRS complex, and the appearance of ventricular voluntary rhythms, eventually progressing to ventricular arrest. Sometimes, the terminal event is ventricular fibrillation. Blood pressure gradually decreases. Blood pressure drops significantly when QRS widening occurs, and approaches zero when slow ventricular voluntary rhythms occur. Electrolyte abnormalities: decreased plasma potassium, sodium, and magnesium concentrations, and acidosis. Electrolytes: hypokalemia may occur, possibly related to intracellular potassium transport through direct effects on cell membrane permeability. Neurological symptoms: syncope and seizures may represent direct toxicity to the central nervous system or may be related to cerebral ischemia caused by circulatory or respiratory failure. Pharmacodynamics: Quinidine can slow the firing rate of normal and ectopic rhythmic pacemakers; increase the threshold for electrically induced arrhythmias; prevent ventricular arrhythmias; and prevent or terminate vortex fibrillation. Teratogenicity: Quinidine has been shown to cause minor cranial nerve damage in fetuses, even at doses far exceeding those required for treating arrhythmias. Drug Interactions: Several drug interactions have been reported. Quinidine has a synergistic effect with warfarin (lowering prothrombin levels). Quinidine can enhance the effects of non-depolarizing and depolarizing neuromuscular blocking agents. When used in combination with other antiarrhythmic drugs, Quinidine can enhance the cardiodepressant effects of these drugs. Amiodarone can increase blood Quinidine concentrations. Rifampin, anticonvulsants, nifedipine, and acetazolamide can decrease Quinidine concentrations. Antacids, cimetidine, verapamil, and amiodarone can increase Quinidine concentrations; terfenadine, astemizole, as well as thiazide diuretics and loop diuretics increase the risk of Quinidine toxicity. Quinidine can increase plasma concentrations of propafenone and digoxin. Major Adverse Reactions: Several adverse reactions have been reported during Quinidine treatment. Cardiovascular system: Hypotension; syncope following intravenous administration; arrhythmic effects: torsades de pointes; ECG: widened QRS interval; prolonged PR and QT intervals. Central nervous system: Quinidine poisoning: headache, fever, visual disturbances, mydriasis, tinnitus, nausea, vomiting, and rash. Gastrointestinal tract: Nausea, vomiting, diarrhea, and colic have been reported. Liver: Granulomatous hepatitis or hepatitis with centrilobular necrosis. Skin: Drug fever and photosensitive rash may occur. Hematologic system: Thrombocytopenia (immune reaction) has been reported. Clinical manifestations: Acute poisoning: Ingestion: The severity of Quinidine poisoning is related to cardiotoxicity. Symptoms usually appear within 2 to 4 hours and may include: Cardiovascular symptoms: hypotension, cardiogenic shock, cardiac arrest. Electrocardiogram (ECG) may show: decreased T waves; prolonged QT and QRS intervals; atrioventricular block; ventricular arrhythmias (torsades de pointes). Neurological symptoms: tinnitus, drowsiness, syncope, coma, seizures, blurred vision, and diplopia. Respiratory symptoms: hypoventilation and apnea. Cardiotoxicity may be exacerbated if other cardiotoxic drugs (antiarrhythmic drugs, tricyclic antidepressants) are ingested concurrently. Parenteral exposure: Symptoms appear more quickly after intravenous administration. Chronic poisoning: Ingestion: The most relevant symptoms of chronic poisoning are: ECG abnormalities; syncope due to ventricular arrhythmias (torsades de pointes) and cinchona poisoning; gastrointestinal disturbances. Course, prognosis, and cause of death: The typical course of Quinidine poisoning is dominated by cardiovascular disturbances, usually appearing within the first 2 to 4 hours, but may not appear until 12 hours after exposure (and even later with extended-release formulations). Symptoms can last 24 to 36 hours. Patients who survive 48 hours after acute poisoning are likely to recover. Death may be caused by cardiac arrest due to cardiac cessation or electromechanical dissociation, and in rare cases by ventricular fibrillation. Systemic description of clinical manifestations: Cardiovascular system: Acute: Cardiovascular symptoms are the main feature of Quinidine poisoning. Tachycardia caused by anticholinergic effects usually occurs in the early or moderate stages of poisoning. In severe poisoning, bradycardia due to atrioventricular block may occur. Hypotension and shock: Hypotension due to peripheral vasodilation is common. In severe poisoning, cardiogenic shock with elevated central venous pressure, which is associated with decreased myocardial contractility, usually occurs. Cardiac arrest may occur, which may be related to electromechanical dissociation, ventricular arrhythmias, or cardiac cessation. Arrhythmias are common and may include: atrioventricular block, ventricular voluntary rhythms, ventricular tachycardia and ventricular fibrillation, and torsades de pointes. In symptomatic poisoning, ECG changes are consistently present: repolarization abnormalities, T-wave depression, U-wave elevation, QT and PR interval prolongation, QRS complex widening (>0.08 seconds), and atrioventricular block. Syncope due to torsades de pointes may occur. Chronic: ECG changes (including repolarization abnormalities, T-wave depression, and QT interval prolongation) are common features during Quinidine treatment. Syncope is associated with transient torsades de pointes, occurring in 1% to 8% of Quinidine-treated patients. The occurrence of torsades de pointes is not related to plasma Quinidine concentration, but QT interval prolongation increases its likelihood. Respiratory system: Acute: Respiratory depression or apnea is mostly associated with severe cardiac disturbances, such as shock or ventricular arrhythmias. Cases of pulmonary edema with normal pulmonary capillary wedge pressure following suicide attempts have been documented. Nervous System: Central Nervous System: Acute: Drowsiness, delirium, coma, and seizures may occur without cardiac symptoms. However, heart failure should always be considered when central nervous system symptoms are present. Cinchona poisoning may occur occasionally. Chronic: Cinchona poisoning. Delirium has been reported. Peripheral Nervous System: Chronic: Quinidine can enhance the neuromuscular blocking effects of certain skeletal muscle relaxants, and relapse of respiratory paralysis may occur if Quinidine is administered shortly after the neuromuscular blockade has been lifted. Autonomic Nervous System: Acute: Quinidine has anticholinergic effects. However, this effect is usually limited to the vagus nerve. Skeletal and Smooth Muscles: Chronic: An elevated serum skeletal muscle enzyme level has been reported in a male patient treated with Quinidine. Gastrointestinal Tract: Acute: Nausea and vomiting may occur. Chronic: Gastrointestinal toxicity (nausea, vomiting, diarrhea, and colic) is the most common side effect of Quinidine. Liver: Chronic: Hepatotoxicity has been reported, manifested as elevated serum transaminase, lactate dehydrogenase (LDH), and alkaline phosphatase levels, and cholestasis. Kidneys: Acute: No direct nephrotoxicity has been reported. Acute renal failure associated with cardiogenic shock may occur. Skin: Chronic: Skin lesions are associated with Quinidine use, including rash, photosensitivity, and lichen planus. Eyes, Ears, Nose, Throat: Local effects: Acute: Cinchona poisoning is rare in acute cases. Toxic doses may cause toxic amblyopia, scotomas, and color vision impairment. Chronic: Long-term cumulative overdose may lead to cinchona poisoning: A patient who took Quinidine for two years has been reported to experience headache, tinnitus, dizziness, mydriasis, blurred vision, diplopia, photophobia, deafness, and corneal deposits. Hematologic system: Chronic: Immune thrombocytopenic purpura and hemolytic anemia have been reported. Immune System: Chronic: Quinidine may cause a variety of immune-mediated reactions: thrombocytopenia, hemolytic anemia, angioedema, rash, fever. Metabolism: Acid-Base Imbalance: Acute: Metabolic acidosis may occur in severe poisoning with shock. Fluid and Electrolyte Imbalance: Acute: Hypokalemia is commonly observed. Special Risks: Pregnancy: Chronic: Quinidine doses significantly higher than those required for treating arrhythmias have been shown to cause cranial nerve damage in the fetus. A newborn born to a pregnant woman who took Quinidine throughout her pregnancy had the same serum Quinidine concentration as the mother. The infant's electrocardiogram was normal, and there was no evidence of teratogenicity. Breastfeeding: Long-term: Quinidine concentrations in breast milk are slightly lower than serum concentrations. The amount of Quinidine ingested by an infant per liter of breast milk is lower than the therapeutic dose. However, breastfeeding is not recommended because Quinidine may accumulate in the immature liver of newborns. /Quinidine/

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Effects during pregnancy and lactation
◉ Overview of use during lactation
Limited information suggests that low concentrations of Quinidine in breast milk, even when taken daily by the mother up to 1.8 g, are not expected to have any adverse effects on breastfed infants, especially those older than 2 months. If a breastfeeding woman uses this medication, the exclusively breastfed infant should be closely monitored, and serum drug concentration testing may be performed if necessary to rule out toxicity.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Interactions
In more than 90% of patients undergoing digitalisization, Quinidine administration leads to an increase in plasma concentrations of this glycoside. The degree of concentration change is proportional to the dose of Quinidine; the average change is approximately two-fold. The initial action of Quinidine may be due to its displacement of digoxin from its binding site in tissues. Certain drugs, such as phenobarbital or phenytoin sodium, may significantly shorten the duration of action of Quinidine by accelerating its clearance. Nitroglycerin can cause severe orthostatic hypotension in patients taking Quinidine. Quinidine is a weakly basic drug, primarily excreted by the kidneys; its biological half-life may be prolonged if urine pH is elevated. Carbonic anhydrase inhibitors, sodium bicarbonate, and thiazide diuretics can all increase urine pH, thereby increasing the lipid solubility of Quinidine and renal tubular reabsorption, prolonging its therapeutic effect. Slow intravenous administration of Quinidine (300 mg) can cause a relapse of the paralysis induced by succinylcholine (40 mg, intravenous). Quinidine may enhance or cause a relapse of the neuromuscular effects of tubocurarine. /Quinidine/
For more complete data on interactions of Quinidine sulfate (30 types), please visit the HSDB record page.

[1]. Class I antiarrhythmic agents: quinidine, procainamide and N-acetylprocainamide, disopyramide.

[2]. Quinidine-induced inhibition of the fast transient outward K+ current in rat melanotrophs. Br J Pharmacol. 1991 Jul;103(3):1807-13.

[3]. Quinidine inhibits in vivo metabolism of amphetamine in rats: impact upon correlation between GC/MS and immunoassay findings in rat urine. J Anal Toxicol. 1990 Sep-Oct;14(5):311-7.

[4]. Hydrocinchonine, cinchonine, and quinidine potentiate paclitaxel-induced cytotoxicity and apoptosis via multidrug resistance reversal in MES-SA/DX5 uterine sarcoma cells. Environ Toxicol. 2011 Aug;26(4):424-31.

[5]. Effect of dextromethorphan/quinidine on pentylenetetrazole- induced clonic and tonic seizure thresholds in mice. Neurosci Lett. 2020 Jun 11;729:134988.

Quinidine sulfate is the sulfate form of Quinidine, an alkaloid with antimalarial and antiarrhythmic (class Ia) activity. Quinidine sulfate exerts its antimalarial activity primarily by binding to heme polymers (heme crystals) in the acidic food vacuoles of Plasmodium, thereby inhibiting further polymerization by heme polymerase. This leads to the accumulation of toxic heme, ultimately resulting in the death of the Plasmodium. Quinidine sulfate exerts its antiarrhythmic effect by inhibiting the influx of sodium ions into cells during phase 0 of the myocardial action potential, thus slowing impulse conduction through the atrioventricular node, reducing the rate of phase 0 depolarization, and prolonging the refractory period. Quinidine sulfate also reduces the slope of phase 4 depolarization of Purkinje fibers, thereby slowing cardiac conduction velocity and reducing cardiac automaticity. Quinidine is an optical isomer of quinine, extracted from cinchona bark and similar plants. This alkaloid inhibits the excitability of myocardial and skeletal muscle by blocking sodium-potassium currents on cell membranes. It prolongs cellular action potentials and reduces cardiac automaticity. Quinidine also blocks muscarinic receptors and alpha-adrenergic neurotransmission.
See also: Quinidine (containing the active moiety).

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Mechanism of Action
In experimental animals, Quinidine exhibits a very significant atropine-like effect, blocking the effects of vagal stimulation or acetylcholine. …It also has alpha-adrenergic blocking effects. This causes vasodilation and activates sympathetic efferent activity through baroreceptors. The cholinergic blockade and β-adrenergic enhancement induced by Quinidine can jointly increase sinus heart rate and enhance atrioventricular node conduction. Quinidine can cause severe sinoatrial node suppression in patients with sick sinus syndrome…Quinidine can increase sinus heart rate through cholinergic blockade or reflexive enhancement of sympathetic activity. Therapeutic concentrations of Quinidine…reduce the firing frequency of the Plugin's fibers in the myocardium through direct action…reducing the phase 4 depolarization slope and shifting the threshold voltage toward zero. Quinidine…increases the diastolic current threshold of atrial and ventricular myocardium and Purkinje fibers…and also increases the fibrillation threshold of atrial and ventricular myocardium. Quinidine…reentrant arrhythmias can be eliminated by Quinidine. It acts on the effective refractory period, responsiveness, and conduction. For example, when ventricular premature beats are caused by reentry through the Purkinje fiber rings, unidirectional block can be converted to bidirectional block, thus preventing reentry. Quinidine…For more complete data on the mechanism of action of Quinidine sulfate (9 types), please visit the HSDB record page.

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Therapeutic Use
Veterinary Drug: Among the 6 antiarrhythmic drugs tested, Quinidine sulfate did not protect against canine-induced arrhythmias.…It is effective for the short-term and long-term treatment of supraventricular and ventricular arrhythmias. Quinidine…In fact, Quinidine is usually administered orally only, but in special cases it can also be injected intramuscularly or intravenously. The usual oral dose of Quinidine sulfate is 200 to 300 mg three to four times daily. It is indicated for patients with atrial or ventricular premature beats or for maintenance therapy. For the treatment of paroxysmal ventricular tachycardia, higher doses and/or more frequent dosing may be used for a short period. Quinidine is primarily used for prophylactic treatment to maintain normal sinus rhythm restored after conversion to atrial fibrillation and/or atrial flutter by other methods. This drug is also used to prevent recurrence of paroxysmal atrial fibrillation, paroxysmal atrial tachycardia, paroxysmal atrioventricular junctional rhythm, paroxysmal ventricular tachycardia, and atrial or ventricular premature beats. For more complete data on the therapeutic uses of Quinidine sulfate (7 types), please visit the HSDB record page. Drug Warnings Syncope or sudden death has occasionally occurred in patients taking Quinidine. This may be due to excessively high plasma Quinidine concentrations or concomitant digoxin poisoning. Quinidine
Patients with long QT syndrome or those who respond significantly to low concentrations of Quinidine appear to be particularly prone to syncope or sudden death and should not be treated with this drug. Quinidine
High plasma concentrations of the drug can cause adverse reactions in any patient. Due to the low treatment rate of Quinidine, close monitoring is required for every patient taking this drug. Quinidine
Quinidine should be used with extreme caution, or even avoided altogether, in patients with incomplete atrioventricular block, as it may lead to complete atrioventricular block and cardiac arrest. Intramuscular or intravenous administration of Quinidine is particularly dangerous in patients with atrioventricular block, absence of atrial activity, and extensive myocardial damage. For patients requiring high doses of antiarrhythmic drugs to control ventricular arrhythmias, risk factors such as hypokalemia, hypoxemia, and acid-base imbalances must be eliminated.
For more complete data on drug warnings for Quinidine sulfate (24 in total), please visit the HSDB record page.

2[C20H24N2O2].H2O4S

746.912

746.335

50-54-4

Quinidine hydrochloride monohydrate;6151-40-2;Quinidine (15% dihydroquinidine);56-54-2;Quinidine sulfate dihydrate;6591-63-5;Quinidine polygalacturonate;27555-34-6;Quinidine gluconic acid;7054-25-3;Quinidine-d3;1267657-68-0;

441326

Occurs as fine, needle-like, white crystals which frequently cohere in masses or as a fine, white powder.

495.9ºC at 760mmHg

212ºC

253.7ºC

6.65

4

12

8

53

538

8

O[C@@H](C1=CC=NC2=CC=C(OC)C=C12)C3N4CC(C=C)C(CC4)C3.O[C@@H](C5=CC=NC6=CC=C(OC)C=C56)C7N8CC(C=C)C(CC8)C7.O=S(O)(O)=O

RONWGALEIBILOG-VCSAERELSA-N

InChI=1S/2C20H24N2O2.H2O4S/c2*1-3-13-12-22-9-7-14(13)10-19(22)20(23)16-6-8-21-18-5-4-15(24-2)11-17(16)18;1-5(2,3)4/h2*3-6,8,11,13-14,19-20,23H,1,7,9-10,12H2,2H3;(H2,1,2,3,4)/t2*13-,14-,19+,20-;/m00./s1

(S)-[(2R,4S,5R)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol;sulfuric acid

Quinidine sulfate; Quinidine sulphate; Quinidine sulfate anhydrous; Quinitex; Quinicardine; 50-54-4; sk-Quinidine sulfate; Quinidine sulfate (salt);

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)