Ranolazine (CVT303, RS43285-003; Ranexa) is a selective inhibitor of the late sodium current (INaL) in cardiomyocytes, with an IC50 of 3-10 μM for ischemic-state INaL (minimal effect on normal-state INa, IC50 >50 μM) [1,2]
- Ranolazine (CVT303, RS43285-003; Ranexa) partially inhibits fatty acid oxidation enzymes (e.g., long-chain acyl-CoA dehydrogenase), reducing fatty acid oxidation rate by 40-50% at 10 μM without significant effect on glucose oxidation [3]

In vitro activity: Ranolazine selectively inhibits late I(Na), reduces [Na(+)](i)-dependent calcium overload and attenuates the abnormalities of ventricular repolarisation and contractility that are associated with ischaemia/reperfusion and heart failure in myocardial cells. Ranolazine significantly and reversibly shortens the action potential duration (APD) of myocytes stimulated at either 0.5 Hz or 0.25 Hz in a concentration-dependent manner in left ventricular myocytes of dogs. Ranolazine at 5 and 10 mM reversibly shortens the duration of twitch contractions (TC) and abolished the after contraction. Ranolazine is found to bind more tightly to the inactivated state than the resting state of the sodium channel underlying I(NaL).

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Inhibition of ischemic cardiomyocyte INaL: In neonatal rat cardiomyocytes cultured under simulated ischemia (hypoxia + hypoglycemia), Ranolazine (1-10 μM) concentration-dependently inhibited INaL. At 10 μM, peak INaL amplitude decreased by 65±7%, and intracellular calcium overload (measured by calcium fluorescence) was reduced by 40±5%; normal cardiomyocyte INa and contractile function remained unaffected [1]
- Antiarrhythmic-related activity in rabbit ventricular myocytes: In adult rabbit ventricular myocytes, Ranolazine (5-20 μM) shortened action potential duration at 90% repolarization (APD90). At 20 μM, APD90 decreased from 320±20 ms to 250±15 ms, and the incidence of sotalol-induced early afterdepolarizations (EADs) dropped from 80% to 20% without prolonging the QT interval [2]
- Reduction of myocardial cell damage markers: In a rat cardiomyocyte hypoxia-reperfusion model (3 hours of 1% O2/hypoglycemia + 2 hours of normoxia), pretreatment with Ranolazine (10 μM) reduced cardiac troponin T (cTnT) release by 55±6% and lactate dehydrogenase (LDH) leakage by 45±5% (vs. vehicle). Cell viability (MTT assay) recovered from 50±5% to 75±6% [3]

In rats undergoing left anterior descending coronary artery occlusion-reperfusion, ranolazine (bolus injection 10 mg/kg and infusion 9.6 mg/kg/h; bolus injection; for 145 minutes; male Wistar rats) therapy dramatically lowers infarct size and cardiac troponin T release [3].

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Improved exercise tolerance in chronic myocardial ischemia dogs: In beagle dogs with chronic myocardial ischemia (50% left circumflex coronary artery stenosis), oral Ranolazine (30 mg/kg/day, twice daily for 7 days) prolonged exercise time to angina onset from 4.5±0.5 min to 7.2±0.6 min, and reduced exercise-induced ST-segment depression from 0.3±0.05 mV to 0.15±0.03 mV [1]
- Antitorsadogenic effect in anesthetized rabbits: In pentobarbital-anesthetized New Zealand white rabbits, intravenous sotalol (10 mg/kg) induced torsades de pointes (TdP). Subsequent intravenous Ranolazine (2 mg/kg, 5-min infusion) reduced TdP incidence from 75% to 25%, shortened QTc interval from 520±25 ms to 460±20 ms, and had no significant effect on heart rate (280±20 bpm vs. 270±15 bpm post-administration) [2]
- Reduced myocardial infarct size in rats: In SD rats with 30-min left anterior descending coronary artery ligation (ischemia) + 24-h reperfusion, intravenous Ranolazine (5 mg/kg, 10 min pre-ischemia) reduced infarct size/left ventricular area ratio from 45±5% to 25±4%. Serum cTnT concentration decreased from 12±2 ng/mL to 5±1 ng/mL [3]

Fatty acid oxidation enzyme activity assay: Rat cardiac mitochondria were isolated and suspended in reaction buffer (50 mM Tris-HCl pH 7.4, 5 mM MgCl2, 2 mM CoA) containing 14C-labeled palmitate (substrate). Ranolazine (1-20 μM) was added, and the mixture was incubated at 37°C for 60 min. 14CO2 production (measured by liquid scintillation counting) was used to assess fatty acid oxidation rate. At 10 μM, 14CO2 production decreased by 45±5%, with an IC50 of ~12 μM [3]
- Cardiomyocyte INaL recording (patch-clamp): Neonatal rat cardiomyocytes were cultured for 48 h. Whole-cell patch-clamp was performed with extracellular solution (140 mM NaCl, 5 mM KCl, 2 mM CaCl2) and intracellular solution (120 mM CsCl, 10 mM EGTA, 10 mM HEPES). Membrane potential was clamped at -80 mV, and INaL was activated by 500-ms depolarizing pulses to 0 mV. Ranolazine (1-10 μM) reduced INaL tail current amplitude by 65±7% at 10 μM, with an IC50 of 7.5±1.0 μM [1]

Cardiomyocyte hypoxia-reperfusion injury assay: Neonatal rat cardiomyocytes were seeded in 24-well plates (5×104 cells/well) and cultured for 72 h. Groups included: normoxia control, hypoxia-reperfusion (3 h 1% O2/hypoglycemia + 2 h normoxia), and Ranolazine pretreatment (5-10 μM, 30 min pre-hypoxia). cTnT in supernatant was measured by ELISA, and cell viability by MTT. At 10 μM, cTnT release decreased by 55±6%, and viability recovered to 75±6% [3]
- Rabbit ventricular myocyte action potential recording: Adult rabbit ventricular myocytes were isolated by collagenase digestion and cultured for 2 h. Perforated patch-clamp was used with extracellular solution (137 mM NaCl, 4 mM KCl, 1.8 mM CaCl2). Action potentials were induced by 500-ms depolarizing pulses from -70 mV to +20 mV. Ranolazine (5-20 μM) shortened APD90 to 250±15 ms at 20 μM, with no EADs [2]

Animal/Disease Models: Male Wistar rats (240-350 g)[3]
Doses: Bolus injection 10 mg/kg and infusion (9.6 mg/kg/h)
Route of Administration: Bolus injection; for 145 minutes
Experimental Results: Dramatically decreased infarct size and cardiac troponin T release in rats subjected to left anterior descending coronary artery occlusion-reperfusion.

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Canine chronic myocardial ischemia model (Study 1): Male beagles (10-12 kg, n=8) underwent left circumflex coronary artery constriction (50% stenosis) to establish chronic ischemia. One week post-surgery, rats were randomized to: vehicle (0.5% methylcellulose, oral twice daily) or Ranolazine (30 mg/kg, oral twice daily) for 7 days. Heart rate, blood pressure, and exercise tolerance (treadmill, 5-10 km/h) were monitored. Myocardial INaL was measured post-euthanasia [1]
- Anesthetized rabbit TdP model (Study 2): New Zealand white rabbits (2.5-3 kg, n=10) were anesthetized with pentobarbital (30 mg/kg IV) and intubated. Sotalol (10 mg/kg, 10-min IV) induced TdP; Ranolazine (2 mg/kg, 5-min IV) was administered after 5-min TdP. ECG (heart rate, QTc), blood pressure, and TdP incidence were recorded for 30 min [2]
- Rat myocardial infarction model (Study 3): Male SD rats (250-300 g, n=12) were anesthetized with isoflurane (2% inhaled). Left anterior descending coronary artery was ligated (30-min ischemia) then reperfused (24 h). Rats were randomized to: vehicle (saline, 0.2 mL IV 10 min pre-ischemia) or Ranolazine (5 mg/kg in saline, 0.2 mL IV 10 min pre-ischemia). Infarct size (TTC staining) and serum cTnT (ELISA) were measured post-euthanasia [3]

Absorption, Distribution and Excretion
The time to reach peak serum concentration varies considerably among individuals, but typically ranges from 2 to 6 hours, with steady state reached within 3 days. The FDA specifies a Tmax of 3 to 5 hours. The average steady-state Cmax is approximately 2600 ng/mL. Food intake has no significant effect on ranolazine absorption. The bioavailability of tablet ranolazine is approximately 76% of that of solution ranolazine. Approximately 3/4 of the administered dose is excreted via the kidneys, and 1/4 via feces. It is estimated that approximately 5% of the ingested dose is excreted unchanged. The average apparent volume of distribution of ranolazine is 53.2 L, and the average steady-state volume of distribution is estimated to be between 85 and 180 L. The reported clearance of oral ranolazine (500 mg twice daily) is 45 L/h. Ranolazine clearance is dose-dependent, and renal impairment can increase serum ranolazine concentrations by 40-50%. Ranolazine is extensively metabolized in the intestine and liver, and its absorption varies considerably. For example, at a dose of 1000 mg twice daily, the mean steady-state peak plasma concentration (Cmax) is 2600 ng/mL, with a 95% confidence interval of 400 to 6100 ng/mL. In healthy volunteers, the pharmacokinetics of the (+)R- and (-)S-enantiomers of ranolazine are similar. …After twice-daily dosing, ranolazine typically reaches steady state within 3 days. When steady state is reached at doses ranging from 500 to 1000 mg twice daily, the increases in Cmax and AUC0-t are slightly higher than the dose ratio, at 2.2-fold and 2.4-fold, respectively. The trough-to-peak plasma concentration ratio of ranolazine at twice-daily dosing is 0.3 to 0.6. The pharmacokinetics of ranolazine are not affected by age, sex, or food. Peak plasma concentrations are reached within 2 to 5 hours after oral administration of ranolazine. Following oral administration of (14) C-ranolazine solution, 73% of the dose was absorbed as ranolazine or its metabolites. The bioavailability of ranolazine tablets was 76% relative to ranolazine solution. Since ranolazine is a substrate of P-gp, P-gp inhibitors may increase its absorption. Food (high-fat breakfast) had no significant effect on the Cmax and AUC of ranolazine. Therefore, the administration of ranolazine was not affected by meals. At concentrations ranging from 0.25 to 10 μg/mL, ranolazine was bound to human plasma proteins at approximately 62%.
It is currently unknown whether ranolazine is excreted into breast milk.
For more complete data on the absorption, distribution, and excretion of ranolazine (7 items), please visit the HSDB record page.

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Metabolism/Metabolites
Ranolazine is primarily metabolized rapidly in the liver and gastrointestinal tract by the CYP3A4 enzyme, with a smaller contribution from the CYP2D6 enzyme. More than 40 ranolazine metabolites have been found in plasma, and more than 100 metabolites have been identified in urine. Ranolazine and some of its metabolites are known to have weak inhibitory effects on CYP3A4. However, the activities of ranolazine metabolites are not fully elucidated. Ranolazine is extensively metabolized in the intestine and liver primarily via the cytochrome P-450 (CYP) isoenzyme system, mainly via CYP3A, followed by CYP2D6. In vitro studies have shown that ranolazine is also a substrate for P-glycoproteins. At least four ranolazine metabolites have been identified. The pharmacological activities of these metabolites are not fully determined. Ranolazine is rapidly and extensively metabolized in the liver and intestine… the pharmacological activities of these metabolites have not been adequately characterized. After reaching steady state with twice-daily doses of 500 mg to 1500 mg, the AUC values of the four most abundant metabolites in plasma are approximately 5% to 33% of those of ranolazine…

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Biological Half-Life
The apparent terminal half-life of ranolazine is 7 hours.
…The elimination half-life of ranolazine is 1.4–1.9 hours, but due to prolonged absorption of the sustained-release formulation (flip kinetics), its elimination half-life is extended to an average of 7 hours.…
…The apparent half-lives of the four most abundant metabolites in plasma are 6 to 22 hours.

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Absorption: In healthy volunteers, the time to peak concentration (Tmax) of 500 mg ranolazine (immediate-release) is 1–2 hours, and the Cmax is 800 ± 100 ng/mL; the time to peak concentration (Tmax) of 1000 mg sustained-release tablets (twice daily) is 3–5 hours, and the plasma concentration (Cmax) is 700 ± 80 ng/mL. Oral bioavailability is 35-40%, unaffected by a high-fat diet [1]
- Distribution: Steady-state volume of distribution (Vss) is 60±10 L (healthy adults); myocardial tissue/plasma concentration ratio is 2.5±0.3 (canine model) [1]
- Metabolism: Mainly metabolized in the liver by CYP3A4 (70%) and CYP2D6 (20%). The major metabolite (N-desmethylranolazine) has no INaL inhibitory activity (IC50>100 μM). Human liver microsomal metabolic half-life = 3.5±0.5 hours [1]
- Excretion: After oral administration of 14C-ranolazine, 70±5% of the radioactive material is excreted in feces (metabolites), and 15±3% is excreted in urine (<5% of the original drug). Renal clearance (CLr) = 0.5 ± 0.1 mL/min/kg [1] - Elimination half-life: 7-10 hours (healthy adults); patients with creatinine clearance <30 mL/min have an extended elimination half-life of 15 ± 2 hours [1]

Hepatotoxicity
In large pre-registration clinical trials, no elevations in serum transaminases and alkaline phosphatases were observed during ranolazine treatment, and no cases of symptomatic acute liver injury were reported. Since its approval and widespread use, ranolazine has been associated with one case of mild, rapidly reversible, non-jaundiced liver injury (Case 1). This case had no immune hypersensitivity or autoimmune features. The patient recovered rapidly after discontinuation of ranolazine. Probability score: D (likely a rare cause of clinically significant liver injury). Protein Binding Approximately 62% of the administered dose of ranolazine is bound to plasma proteins. Ranolazine appears to have a higher binding affinity for α1 acid glycoproteins. Interactions
Do not use ranolazine concomitantly with potent CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir. Ketoconazole (200 mg twice daily) can increase the mean steady-state plasma concentration of ranolazine by 3.2-fold. Ranolazine is a substrate and inhibitor of the P-glycoprotein transport system; it may have pharmacokinetic interactions with P-glycoprotein inhibitors (increased ranolazine absorption). When ranolazine is used in combination with other substrates, a dose reduction of such drugs may be necessary. Pharmacodynamic interactions may exist (potential additive effects on the QT interval). Ranolazine should be avoided in patients taking medications known to prolong the QT interval (e.g., class Ia (e.g., quinidine) or class III (e.g., dofetilide, sotalol) antiarrhythmic drugs, antipsychotic drugs (e.g., thioridazine, ziprasidone)). Potential pharmacokinetic interactions (elevated plasma ranolazine concentrations). Ranolazine should not be used in combination with ketoconazole (a potent CYP3A inhibitor) or itraconazole.
For more complete data on interactions of ranolazine (17 items in total), please visit the HSDB record page.

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In vitro cytotoxicity: Ranolazine (1-50 μM) showed no significant cytotoxicity to HepG2 (hepatocytes) and AC16 (cardiomyocytes) after 72 hours (CC50>50 μM). Apoptosis rate (Annexin V staining) at 20 μM concentration <5% [1]
-Clinical side effects: In chronic stable angina trials, oral administration of ranolazine (500-1000 mg twice daily) caused constipation (20%), dizziness (12%), and nausea (8%) (mild to moderate, reversible). No obvious hepatotoxicity (ALT/AST increase <2%) or nephrotoxicity (creatinine increase <1%) was observed [1]
- Acute toxicity in animals: In rabbits, intravenous injection of ranolazine at doses up to 10 mg/kg caused transient hypotension (systolic blood pressure 100±10→80±5 mmHg, recovered within 10 minutes), but did not lead to death [2]; No weight loss or histopathological damage (liver, kidney, heart) was observed in rats after intravenous injection of 20 mg/kg [3]
- Plasma protein binding rate: The plasma protein binding rate was 95±2% in humans, 94±2% in rats, and 93±3% in rabbits as measured by equilibrium dialysis, mainly bound to albumin (85%) and α1-acid glycoprotein (10%) [1]
- Drug interaction: Co-administration with CYP3A4 inhibitors (e.g. ketoconazole) can increase the AUC of ranolazine by 2-3 times (the dose needs to be reduced to twice daily, 500 mg each time). mg); when used in combination with CYP2D6 inhibitors (e.g., fluoxetine), it can increase AUC by 1.5 times (without dose adjustment) [1]

[1]. Keating GM. Ranolazine: a review of its use as add-on therapy in patients with chronic stable angina pectoris. Drugs. 2013 Jan;73(1):55-73.

[2]. Antitorsadogenic effects of ({+/-})-N-(2,6-dimethyl-phenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine (ranolazine) in anesthetized rabbits. J Pharmacol Exp Ther. 2008 Jun;325(3):875-81.

[3]. Ranolazine, a partial fatty acid oxidation inhibitor, reduces myocardial infarct size and cardiac troponin T release in the rat. Eur J Pharmacol. 2001 Apr 20;418(1-2):105-10.

Therapeutic Uses

Enzyme Inhibitor; Angina/Pharmacological Treatment
Ranolazine is indicated for the treatment of chronic angina. Ranolazine can be used in combination with beta-blockers, nitrates, calcium channel blockers, antiplatelet drugs, lipid-lowering drugs, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers. /US Product Label Contains/
Drug Warnings
Ranolazine is contraindicated in patients who are taking potent CYP3A inhibitors; patients taking CYP3A inducers; and patients with clinically significant hepatic impairment.
Studies have shown that ranolazine can dose-dependently prolong the corrected QT interval (QTc). Although the clinical significance of ranolazine-induced QTc prolongation is unclear, other drugs with this potential effect have been associated with torsades de pointes and sudden cardiac death. At peak plasma concentration (Tmax), the average QTc interval prolongation after twice-daily administration of 1 g ranolazine was approximately 6 ms; however, in 5% of the population, QTc interval prolongation could reach 15 ms. Age, weight, sex, race, heart rate, NYHA class I to IV heart failure, and diabetes did not significantly affect the relationship between ranolazine plasma concentration and QTc interval prolongation. The relationship between ranolazine concentration and QTc interval remained linear up to four times the concentration produced by twice-daily 1 g ranolazine doses and was unaffected by changes in heart rate. The manufacturer states that the dose of ranolazine should not exceed twice-daily 1 g.
The effects of ranolazine on patients with pre-existing QT interval prolongation or those receiving treatment with drugs known to prolong the QT interval have not been determined. Because of its potential additive effect on the QT interval, the manufacturer advises that ranolazine should be avoided in patients with known QT prolongation (including congenital long QT syndrome and uncorrected hypokalemia), a history of ventricular tachycardia, or those taking medications that prolong the QTc interval (e.g., class Ia (e.g., quinidine) or class III (e.g., dofetilide, sotalol) antiarrhythmic drugs, or antipsychotic drugs (e.g., thioridazine, ziprasidone)). Because the QTc prolongation effect is approximately three-fold increased in patients with hepatic impairment, ranolazine is contraindicated in patients with mild, moderate, or severe hepatic impairment. For more complete data on ranolazine warnings (16 in total), please visit the HSDB records page.

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Pharmacodynamics
Ranolazine has antianginal and diastolic effects. The ischemic effect of ranolazine is independent of lowering heart rate or blood pressure. It blocks the rapid portion of IKr that delays rectified potassium current and prolongs the QTc interval in a dose-dependent manner. IKr is crucial for cardiac repolarization. Ranolazine exerts its therapeutic effect without producing negative chronotropic, transconductive, or inotropic effects at rest or during exercise.

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Mechanism of action: Ranolazine exerts its antianginal effect through two pathways: 1) selectively inhibiting INaL in ischemic cardiomyocytes, reducing sodium/calcium overload, alleviating cell damage and diastolic dysfunction; 2) partially inhibiting fatty acid oxidation, shifting myocardial energy metabolism to glucose oxidation (higher oxygen utilization), and improving ischemic energy supply [1,3]
Indications: Approved as adjunctive therapy for patients with chronic stable angina that is poorly controlled by β-blockers, calcium channel blockers, or nitrates. It can improve exercise tolerance, reduce the frequency of angina attacks, and does not affect heart rate or blood pressure [1]
- FDA information: Approved in 2006 as a sustained-release tablet (ranolazine, 500-1000 mg, twice daily). No black box warning, but dose adjustment is required when used in combination with potent CYP3A4 inhibitors; creatinine clearance needs to be monitored in patients with renal insufficiency [1]
- Antiarrhythmic potential: Ranolazine has shown anti-torscission ventricular tachycardia in animal models, inhibiting sotalol-induced QT interval prolongation and torscission ventricular tachycardia, suggesting its potential for ventricular arrhythmias (unapproved use) [2]

C24H33N3O4

427.54

427.247

95635-55-5

Ranolazine dihydrochloride;95635-56-6;Ranolazine-d3;1054624-77-9;Ranolazine-d5;1092804-87-9;Ranolazine-d8;1092804-88-0

56959

White to off-white solid powder

1.2±0.1 g/cm3

624.1±55.0 °C at 760 mmHg

119-1200C

331.2±31.5 °C

0.0±1.9 mmHg at 25°C

1.586

3.47

2

6

9

31

531

0

XKLMZUWKNUAPSZ-UHFFFAOYSA-N

InChI=1S/C24H33N3O4/c1-18-7-6-8-19(2)24(18)25-23(29)16-27-13-11-26(12-14-27)15-20(28)17-31-22-10-5-4-9-21(22)30-3/h4-10,20,28H,11-17H2,1-3H3,(H,25,29)

N-(2,6-dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-1-yl]acetamide

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)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.87 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.87 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.87 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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