Cytochrome P450db; K+ channel

For MES-SA cells, quinidine is cytotoxic and causes apoptosis [4]. 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]

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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]

Quinidine sulfate dihydrate affects the epilepsy threshold caused by PTZ [5]. DM/dextromethorphan (25 and 50 mg/kg) significantly increased PTZ- induced seizure threshold. dextromethorphan/quinidine (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]

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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]

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.

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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.

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).

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NMRI male mice (25-30 g) received quinidine (10, 20, and 30 mg/kg), DM (5, 10, 25, and 50 mg/kg) or DM/Q (10/20, 25/20, and 50/20 mg/kg), 30 min before the infusion of PTZ. ketamine (1 and 5 mg/kg), BD-1047 (2.5 and 5 mg/kg) or WAY-100635 (0.5 and 1 mg/kg) were administrated as pre-treatment 30 min before the selected dose of DM/Q. Seizures were induced by intravenous PTZ infusion. All data were presented as means ± S.E.M. One-way ANOVA test was used to determine statistical significance (p < 0.05).[5]

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In experiment 1 (including 11 groups), animals received different doses of quinidine (10, 20, and 30 mg/kg, i.p.), DM (5, 10, 25, and 50 mg/kg, i.p.) or DM/Q (5/20, 10/20, 25/20, and 50/20 mg/kg, i.p.) 30 min before determining PTZ-induced seizure threshold. Based on our experiments, quinidine at a dose of 20 mg/kg and DM at a dose of 10 mg/kg were used in later experiments.[5]

Absorption
The absolute bioavailability of quinidine sulfate is approximately 70%, but ranges from 45% to 100%. The incomplete bioavailability of quinidine sulfate is due to first-pass metabolism in the liver. In contrast, the absolute bioavailability of quinidine gluconate ranges from 70% to 80%, and the bioavailability of quinidine in gluconate is 1.03 relative to quinidine sulfate. The time to peak concentration (tmax) of quinidine sulfate extended-release tablets is approximately 6 hours, while that of quinidine gluconate is 3 to 5 hours. When taken with food, the peak plasma concentration of immediate-release quinidine sulfate is delayed by approximately 1 hour. Furthermore, drinking grapefruit juice may reduce the absorption rate of quinidine.
Elimination Pathway
Elimination of quinidine is primarily achieved through renal excretion of the unchanged drug (15% to 40% of total clearance) and hepatic biotransformation into various metabolites (60% to 85% of total clearance). When urine pH is below 7, approximately 20% of quinidine is present unchanged in the urine. However, this percentage decreases to about 5% as urine pH increases. Renal clearance of quinidine involves glomerular filtration and active tubular secretion, and is regulated by pH-dependent tubular reabsorption.
Volume of Distribution
The volume of distribution of quinidine in healthy young adults is 2-3 L/kg, in patients with congestive heart failure it is 0.5 L/kg, and in patients with cirrhosis it is 3-5 L/kg.
Clearance
The clearance of quinidine in adults is 3-5 mL/min/kg. In pediatric patients, the clearance of quinidine may be two to three times that of adults.
The volume of distribution of quinidine in healthy young adults is 2-3 L/kg, but may decrease to 0.5 L/kg in patients with congestive heart failure, while increasing to 3-5 L/kg in patients with cirrhosis. At concentrations of 2 to 5 mg/L (6.5 to 16.2 μmol/L), quinidine binds to plasma proteins (primarily α1-acid glycoprotein and albumin) at 80% to 88% in adults and older children, but is lower in pregnant women and may be as low as 50% to 70% in infants and newborns. Because α1-glycoprotein levels increase in stress responses, serum levels of total quinidine may be significantly elevated in cases such as acute myocardial infarction, even if serum levels of the free (active) drug may remain normal. Protein binding is also elevated in chronic renal failure, but it rapidly decreases to near or below normal levels when heparin is used for hemodialysis. It is almost completely absorbed after oral administration; the maximum effect occurs within 1–3 hours and lasts for 6–8 hours. Repeated administration within this interval can result in significant fluctuations in plasma concentrations. Intramuscular gluconate administration reaches peak effect within 30–90 minutes.
All administered compounds are excreted by the kidneys, with approximately 10-50% appearing in the urine as unmetabolized quinidine, which is excreted within 24 hours.
The bioavailability of oral quinidine is 70% to 80%, but varies from individual to individual and from formulation to formulation. Sulfate is rapidly absorbed within 60 to 90 minutes. Polygalacturonate reaches peak quinidine concentrations within 5 to 6 hours; gluconate has moderate gastrointestinal absorption (peak at 3-4 hours).

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Approximately 90% of quinidine in plasma is bound to plasma proteins (α/acid glycoproteins and albumin).

The drug enters red blood cells and binds to hemoglobin; under steady state, the concentration of quinidine in plasma and red blood cells is approximately equal. Quinidine accumulates rapidly in most tissues except brain tissue, with a volume of distribution of 2-3 liters/kg. Quinidine 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 metabolized by the liver and excreted by the kidneys. Enterohepatic circulation does not significantly alter absorption kinetics, which is reflected in blood concentrations. PMID:7264866
Four hours after administration of sustained-release capsules (250 mg quinidine sulfate), the peak plasma concentration of quinidine was measured at 0.29 μg/mL, and it steadily decreased over the next 8 hours; while after administration of sustained-release tablets (300 mg quinidine sulfate), plasma concentrations remained essentially stable for 2-10 hours post-administration. Plasma concentrations in capsules were higher than in tablets in the later stages. Within 12 hours, the bioavailability of quinidine in capsules was 184% of that in 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.

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Metabolism/Metabolites
Quinidine is primarily metabolized in the liver by cytochrome P450 enzymes, particularly CYP3A4. The major metabolite of quinidine is 3-hydroxyquinidine, which has a larger volume of distribution than quinidine and an elimination half-life of approximately 12 hours. Non-clinical and clinical studies have shown that the antiarrhythmic activity of 3-hydroxyquinidine is approximately half that of quinidine; therefore, this metabolite is responsible for some of the adverse reactions observed with long-term quinidine use.
Lactate conjugates of quinidine and its 3-hydroxy metabolite were detected in a patient who committed suicide by overdose of quinidine. Quinidine is primarily metabolized in the liver, mainly through hydroxylation to produce 3-hydroxyquinidine and 2-quinidineone. Some metabolites possess antiarrhythmic activity. Approximately 10-50% of the dose is excreted unchanged in the urine within 24 hours (possibly via glomerular filtration). Quinidine metabolites include 3-hydroxyquinidine N-oxide, 2'-oxoquinidineone, desmethylquinidine, and quinidine N-oxide. Although there is considerable inter-individual variability in metabolism, at least in cases of quinidine-induced torsades de pointes, the metabolites do not appear to be involved in the formation of arrhythmias. Quinidine undergoes extensive oxidative metabolism in the liver… one of the metabolites, 3-hydroxyquinidine, has an almost equivalent ability to block cardiac sodium channels or prolong action potentials to quinidine. Most quinidine is cleared from the liver by the action of cytochrome P450 IIIA. Quinidine is metabolized in humans as 2'-hydroxyquinidine. /quinidine; from table/
Most urinary metabolites undergo hydroxylation at only one site, either on the quinoline ring or the quinine ring; small amounts of dihydroxy compounds have also been found. The metabolic rate and pathway of quinidine appear to vary from patient to patient.
Quinidine is primarily metabolized in the liver, via hydroxylation to 3-hydroxyquinidine and 2-quinidineone. These metabolites may be pharmacologically active. Approximately 10-50% of the dose is excreted unchanged in the urine over 24 hours (possibly through glomerular filtration). Quinidine
Known metabolites of quinidine include quinidine-N-oxide and 3-hydroxyquinidine.

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Biological half-life
The elimination half-life of quinidine in adults is 6-8 hours, and in pediatric patients it is 3-4 hours. The plasma half-life of quinidine in healthy individuals is typically 6–8 hours, but can be 3–16 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). Following intravenous administration, the plasma half-life is typically around 7 hours, but is prolonged in patients with chronic liver disease. The elimination half-life of quinidine in healthy individuals is 4 to 10 hours, with a typical mean 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 6–8 hours, but can be 3–16 hours or longer. In a study of patients with Plasmodium falciparum malaria, the drug's elimination half-life averaged 12.8 hours (range: 6.6–24.8 hours).

Hepatotoxicity
Long-term use of quinidine is associated with a lower incidence of elevated serum enzymes, which are usually mild, asymptomatic, and resolve spontaneously even without dose changes. However, there have been numerous reports of acute hypersensitivity reactions to quinidine, including liver involvement. These reactions typically occur 1 to 2 weeks after treatment, but can also occur within 24 hours of restarting quinidine or taking it again. Clinical manifestations include fatigue, nausea, vomiting, generalized muscle aches, arthralgia, and high fever. Early blood tests show elevated serum transaminase and alkaline phosphatase levels, as well as mild jaundice, which may persist for several days and worsen even after discontinuation of quinidine. The pattern of elevated serum enzymes is usually cholestatic or mixed. Skin rash is uncommon, and eosinophilia is not a typical symptom, although other signs of hypersensitivity (fever, arthralgia) are present. Autoantibodies are usually not detectable. Liver biopsy typically shows mild damage and small epithelioid granulomas, which are common in many organs in systemic hypersensitivity reactions. Quinine (the optical isomer of quinidine, primarily used as an antimalarial drug) can also cause similar clinical manifestations of liver injury. Reports of quinidine-induced liver injury are rare in recent years, possibly because quinidine is now rarely used.
Probability Score: A (Etiology of clinically confirmed liver injury).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
Limited information suggests that even with daily administration of up to 1.8 grams of quinidine by the mother, the concentration of quinidine in breast milk is very low and is not expected to have any adverse effects on breastfed infants, especially those older than 2 months. If this drug is used during lactation, exclusively breastfed infants should be closely monitored, and serum drug concentrations may need to be measured to rule out toxicity if there are any concerns.
◉ 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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Adverse Reactions
Occupational Hepatotoxicity - Secondary Hepatotoxicity: Potential toxic effects in occupational environments based on case studies of human ingestion or animal poisoning.
Skin Sensitizers - Substances that can induce allergic skin reactions.

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Protein Binding
At concentrations of 6.5 to 16.2 µmol/L, 80% to 88% of quinidine is bound to plasma proteins, primarily α1-acid glycoprotein and albumin. Binding rates are lower in pregnant women and may be as low as 50% to 70% in infants and newborns.

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Toxicity Overview
Identification: Quinidine is a class IIa antiarrhythmic drug. Source: Quinidine is the D-isomer of quinine. Quinidine is an alkaloid, possibly derived from various cinchona trees. Cinchona bark contains 0.25% to 3.0% quinidine. Quinidine can also be prepared from quinine. Quinidine is a powder or white crystal, odorless, and bitter. Quinidine bisulfate is a colorless and odorless crystal with a bitter taste. Quinidine gluconate is a white powder, odorless, and bitter. Quinidine polygalacturonic acid is a powder. Quinidine sulfate is a white powder or odorless crystal with a bitter taste. 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 cause central nervous system symptoms. Clinical Overview: Symptoms of poisoning usually appear within 2–4 hours of ingestion, but the timing 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, convulsions, delirium. Respiratory depression. Quinidine concentration may be helpful for diagnosis but is of no clinical significance. 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. Injection Administration: Intravenous toxicity is rare, but has been reported in patients receiving intravenous quinidine for arrhythmia. Absorption Routes: Oral: Quinidine is almost completely absorbed from 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. Injection 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 (by Route of Administration): Oral: Protein Binding: Approximately 70%–80% of the drug is bound to plasma proteins. Plasma protein binding is reduced in patients with chronic liver disease. Tissue: Quinidine concentrations in the liver are 10–30 times higher than in plasma. Quinidine levels in skeletal muscle, cardiac muscle, brain, and other tissues fall between these two ranges. The erythrocyte-plasma partition ratio is 0.82. Biological half-life (by route of administration): Elimination half-life: Approximately 6–7 hours. The elimination half-life is prolonged in patients with chronic liver disease and the elderly. Congestive heart failure or renal failure does not appear to alter the elimination half-life. Metabolism: 50%–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 similar to those of quinidine. Elimination via exposure: Renal: The amount excreted unchanged in urine varies considerably, but is approximately 17% of the administered dose. Up to 50% of the quinidine dose (original + metabolites) is excreted in the urine within 24 hours after administration. Renal excretion depends on urine pH. Excretion 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 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 negative inotropic effects; inhibits spontaneous diastolic depolarization; slows conduction; prolongs the effective refractory period; and increases 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. In experimental studies, the following progressive changes were observed: Electrocardiogram: bradycardia, prolonged PR interval, prolonged QT interval, widened QRS complex, and the appearance of ventricular voluntary rhythms, eventually developing into ventricular arrest. Sometimes, the terminal event is ventricular fibrillation. Blood pressure gradually decreases. Blood pressure drops significantly when QRS widening occurs; blood pressure approaches zero when slow ventricular voluntary rhythms appear. Electrolyte abnormalities: decreased plasma potassium, sodium, and magnesium concentrations, accompanied by acidosis. Electrolytes: hypokalemia may occur, possibly related to the drug's direct effect on cell membrane permeability, leading to intracellular potassium ion transport. Neurological symptoms: syncope and seizures may represent the drug's direct toxic effects on 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 cyclonic flutter. 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 both non-depolarizing and depolarizing neuromuscular blocking agents. The cardiac depressant effect of quinidine is enhanced when used in combination with other antiarrhythmic 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 may occur after intravenous administration; arrhythmic effects: torsades de pointes ventricular tachycardia; ECG: widened QRS interval; prolonged PR and QT intervals. Central nervous system: Cinchona 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 observed. 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 enhanced 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 (caused by ventricular arrhythmias such as torsades de pointes) and gastrointestinal disturbances caused by cinchona poisoning. Course, prognosis, and cause of death: The typical course of quinidine poisoning is dominated by cardiovascular disturbances, usually appearing within 2 to 4 hours after exposure, but may not appear until 12 hours after exposure (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 due to cardiac arrest caused by cardiac cessation or electromechanical dissociation, and in rare cases, ventricular fibrillation. Systematic description of clinical manifestations: Cardiovascular: 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 caused by atrioventricular block may occur. Hypotension and shock: Hypotension caused by peripheral vasodilation is common. In severe poisoning, cardiogenic shock is usually observed, accompanied by elevated central venous pressure, which is related to decreased myocardial contractility. 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. Symptomatic poisoning patients invariably exhibit ECG changes: repolarization abnormalities, T-wave depression, U-wave elevation, QT and PR interval prolongation, QRS complex widening (>0.08 seconds), and atrioventricular block. Torsades de pointes (TDPT) may cause syncope. Chronic: ECG changes (including repolarization abnormalities, T-wave depression, and QT interval prolongation) are common features during quinidine treatment. Syncope is associated with transient TDPT, occurring in 1% to 8% of quinidine-treated patients. The occurrence of TDPT is not related to plasma quinidine concentration, but QT interval prolongation increases its incidence. Respiratory system: Acute: Respiratory depression or apnea is primarily associated with severe cardiac disturbances such as shock or ventricular arrhythmias. Pulmonary edema with normal pulmonary capillary wedge pressure has been reported after suicide attempts. 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; administration of quinidine shortly after the neuromuscular blockade has been lifted may lead to a relapse of respiratory paralysis. 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: Quinidine has been reported to cause hepatotoxicity, manifested by elevated serum transaminase, lactate dehydrogenase, and alkaline phosphatase levels, and cholestasis. Kidneys: Acute: No direct nephrotoxicity has been reported. Acute renal failure associated with cardiogenic shock may occur. Dermatology: Chronic: Quinidine use can cause skin lesions, including rash, photosensitivity, and lichen planus. Eyes, Ears, Nose, and Throat: Local Effects: Acute: Cinchona poisoning is rare in acute poisoning. Toxic doses may cause toxic amblyopia, scotomas, and color vision impairment. Chronic: Chronic 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 common. Special Risks: Pregnancy: Long-term use of quinidine may cause cranial nerve damage in the fetus, even at doses much higher than those required to treat arrhythmias. A newborn of 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. Lactation: Long-term use of quinidine: Quinidine concentrations in breast milk are slightly lower than serum concentrations. The dose 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. Identification: Quinidine is a class II antiarrhythmic drug. Source: Quinidine is the D-isomer of quinine. Quinidine is an alkaloid that may be derived from various cinchona species. Cinchona bark contains 0.25% to 3.0% quinidine. Quinidine is also derived 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 cause central nervous system symptoms. Clinical Manifestations Overview: Symptoms of poisoning usually appear within 2–4 hours after ingestion, but the time of onset may vary depending on the quinidine salt and formulation. Symptoms may include cardiac arrhythmias (especially in patients with coexisting 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 for diagnosis but is of no clinical benefit. 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; concomitant use of other antiarrhythmic drugs. Use with caution in the elderly and breastfeeding women. Route of administration: Oral: Oral absorption is the most common cause of poisoning. Parenteral administration: Poisoning after intravenous injection is rare, but has been reported in patients receiving intravenous quinidine for arrhythmias. Absorption route: Oral: Quinidine is almost completely absorbed from the gastrointestinal tract. However, due to the first-pass effect of the liver, its absolute bioavailability is approximately 70% to 80% of the ingested dose and may vary depending on the patient and formulation. The time to peak plasma concentration 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 is continuously absorbed over 8 to 12 hours. Parenteral administration: After intramuscular injection, quinidine absorption may 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 (by route of exposure): Oral: Protein binding: Approximately 70%–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 10–30 times higher than in plasma. Concentrations in skeletal muscle, myocardium, brain, and other tissues fall between these levels. The erythrocyte-plasma partition ratio is 0.82. Biological half-life (by route of exposure): Elimination half-life: The half-life is approximately 6–7 hours. The elimination half-life is prolonged in patients with chronic liver disease and the elderly. Congestive heart failure or renal failure does not appear to alter the elimination half-life. Metabolism: 50%–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 via exposure: Kidneys: The amount excreted unchanged in urine varies considerably, but is approximately 17% of the administered dose. Up to 50% of the quinidine dose (unchanged + metabolites) is excreted in the urine within 24 hours after administration. Renal excretion depends on urine pH. Excretion 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 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 negative inotropic effects; inhibits spontaneous diastolic depolarization; slows conduction; prolongs the effective refractory period; and increases 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 have been observed in experimental studies: Electrocardiogram: bradycardia, prolonged PR interval, prolonged QT interval, widened QRS complex, and the appearance of ventricular voluntary rhythms, eventually developing into 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 appear. Electrolyte abnormalities: decreased plasma potassium, sodium, and magnesium concentrations, and acidosis. Electrolytes: Hypokalemia may occur, possibly due to the drug's direct effect on cell membrane permeability, leading to intracellular potassium transport. Neurological symptoms: Syncope and seizures may represent direct toxicity of the drug to the central nervous system, or may be related to cerebral ischemia caused by circulatory or respiratory failure. Pharmacodynamics: Quinidine slows the firing rate of normal and ectopic pacemakers; it increases the threshold for electrically induced arrhythmias; it prevents ventricular arrhythmias; and it can 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. The cardiac depressant effect of quinidine is enhanced when used in combination with other antiarrhythmic drugs; amiodarone can increase the concentration of quinidine in the blood. Rifampin, anticonvulsants, nifedipine, and acetazolamide can decrease quinidine concentrations. Antacids, cimetidine, verapamil, and amiodarone can increase quinidine concentrations. Terfenadine, astemizole, thiazides, and loop diuretics increase the risk of quinidine poisoning. Quinidine can increase plasma concentrations of propafenone and digoxin. Major adverse reactions: Several adverse reactions have been reported during quinidine treatment. Cardiovascular system: Hypotension after intravenous administration; syncope; arrhythmogenic effects: torsades de pointes; ECG: widened QRS interval; prolonged PR and QT intervals. Central nervous system: Cinchona 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 rashes may occur. Hematologic system: Thrombocytopenia (immune response) has been observed. 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 may show: decreased T waves; prolonged QT and QRS intervals; atrioventricular block; ventricular arrhythmias (torsades de pointes). Neurological symptoms: tinnitus, drowsiness, syncope, coma, convulsions, blurred vision, and diplopia. Respiratory symptoms: hypoventilation and apnea. Cardiotoxicity may be enhanced if other cardiotoxic drugs (antiarrhythmic drugs, tricyclic antidepressants) are ingested concurrently. Parenteral exposure: Symptoms appear more rapidly after intravenous administration. Chronic Poisoning: Ingestion: The most relevant symptoms of chronic poisoning include: ECG abnormalities; syncope due to ventricular arrhythmias (torsades de pointes) and cinchona poisoning; gastrointestinal disturbances. Course, Prognosis, and Causes of Death: The typical course of quinidine poisoning is dominated by cardiovascular disturbances, usually appearing within 2 to 4 hours of exposure, but may occur as late as 12 hours (even later with sustained-release formulations). Symptoms can last 24 to 36 hours. Patients who survive 48 hours after acute poisoning are likely to recover. Death may be due to cardiac arrest or electromechanical dissociation, and in rare cases, ventricular fibrillation. Systematic Description of Clinical Effects: Cardiovascular: 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 often occurs, accompanied by elevated central venous pressure, which is related to decreased myocardial contractility. Cardiac arrest may occur, possibly related to electromechanical dissociation, ventricular arrhythmias, or cardiac arrest. 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 caused by 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 and occurs in 1% to 8% of patients treated with quinidine. The occurrence of torsades de pointes ventricular tachycardia 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 sometimes occur. Chronic: Cinchona poisoning. Delirium has been reported. Peripheral Nervous System: Chronic: Quinidine can enhance the neuromuscular blocking effects of certain skeletal muscle relaxants; administration of quinidine shortly after the recovery of neuromuscular blockade may lead to relapse of respiratory paralysis. Autonomic Nervous System: Acute: Quinidine has anticholinergic effects. However, this effect is usually limited to the vagus nerve. Skeletal and smooth muscle: 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), alkaline phosphatase levels, and cholestasis. Kidney: Acute: No direct nephrotoxicity has been reported. Acute renal failure associated with cardiogenic shock may occur. Skin: Chronic: Skin lesions associated with quinidine use include rash, photosensitivity, and lichen planus. Eyes, ears, nose, and 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 symptoms such as headache, tinnitus, dizziness, dilated pupils, blurred vision, double vision, photophobia, deafness, and corneal deposits. Hematologic system: Chronic: Immune thrombocytopenic purpura and hemolytic anemia have been reported. Immune system: Chronic: Quinidine may cause various immune-mediated reactions: thrombocytopenia, hemolytic anemia, angioedema, rash, and 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 far exceeding those required for treating arrhythmias have been shown to cause fetal cranial nerve damage. A pregnant woman took quinidine throughout her pregnancy, and her newborn had the same serum quinidine concentration as the mother. The infant's electrocardiogram was normal, and no evidence of teratogenicity was found. Breastfeeding: Long-term breastfeeding: Quinidine concentrations in breast milk are slightly lower than serum concentrations. The dose of quinidine ingested by an infant drinking 1 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/ International Programme for Chemical Safety; Toxic Information Monograph: Quinidine (PIM 463) (1990) Available as of April 7, 2009 at: https://www.inchem.org/pages/pims.html

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

[2]. Class I antiarrhythmic agents: quinidine, procainamide and N-acetylprocainamide, disopyramide. Pharmacol Ther. 1983;23(2):179-91.

[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 is an optical isomer of quinine, extracted from cinchona bark and similar plants. This alkaloid inhibits the excitability of cardiac and skeletal muscle by blocking sodium-potassium currents on cell membranes. It prolongs cellular action potentials and reduces automaticity. Quinidine also blocks muscarinic receptors and α-adrenergic neurotransmission.
See also: Quinidine (note moved to); Quinidine sulfate (note moved to).

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In summary, the results of this study indicate that the addition of quinidine enhances the anticonvulsant effect of low-dose dexamethasone but weakens the anticonvulsant effect of high-dose dexamethasone. Our results suggest that the effect of dexamethasone/quinidine on seizures is due to increased dexamethasone concentration, consistent with previously reported FDA-approved dexamethasone/quinidine ratios that increase the ratio of dexamethasone to dextromethorphan. Meanwhile, we used ketamine, WAY-100635, or BD-1047 to demonstrate that NMDA receptors, sigma-1 receptors, and 5-HT1A receptors are involved to some extent in the central effects of DM/Q on epileptic seizure activity. [5]

2(C20H24N2O2).H2O4S.2[H2O]

405.50

782.356

6591-63-5

Quinidine hydrochloride monohydrate;6151-40-2;Quinidine (15% dihydroquinidine);56-54-2;Quinidine sulfate;50-54-4;Quinidine polygalacturonate;27555-34-6;Quinidine gluconic acid;7054-25-3;Quinidine-d3;1267657-68-0

656862

Typically exists as solid at room temperature

992.5ºC at 760 mmHg

212-214 °C (dec.)(lit.)

554ºC

275 ° (C=2, 0.1mol/L HCl)

6.521

6

14

8

55

538

8

C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@H](C3=C4C=C(C=CC4=NC=C3)OC)O.C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@H](C3=C4C=C(C=CC4=NC=C3)OC)O.OS(=O)(=O)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 dihydrate; 6591-63-5; Quinidine sulfate; Quinidine sulfate hydrate; Cin-Quin; Quinidex Extentabs; quinidine sulphate dihydrate; MFCD00149346;

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.)