Imipramine (0.5-300 μM, 3 days) reduces the viability of HCT-116 cells [1]. Cell invasion (48 hours) and migration (7.5 hours) are inhibited by imipramine (20 μM) [1]. In U-87MG glioma cells, imipramine (50 μM, 0-240 min) suppresses the PI3K/Akt/mTOR signaling pathway [2]. In U-87MG glioma cells, imipramine (60 μM, 24 hours) promotes autophagy [2]. In HL-60 cells, imipramine (80 μM, 24 hours) causes apoptosis [3].

Imipramine (20 mg/kg intraperitoneally or 15 mg/kg orally; given daily for 24 days) attenuates neuroinflammatory signaling and reverses stress-induced social avoidance in mice [4].

Cell Viability Assay[1]
Cell Types: DLD-1, HCT-116 and SW-480
Tested Concentrations: 0.5-300 μM
Incubation Duration: 3 days
Experimental Results: Inhibition of cell viability, HCT-116 is more sensitive than DLD-1 and SW-480 .

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Cell migration assay[1]
Cell Types: SW-480, DLD-1 and HCT-116
Tested Concentrations: 20 μM
Incubation Duration: 7 hrs (hours)
Experimental Results: Significant migration inhibition was produced in all cell lines tested.

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Cell invasion experiment [1]
Cell Types: HCT-116
Tested Concentrations: 20 μM
Incubation Duration: 48 h
Experimental Results: Matrigel inhibits cell invasion.

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Western Blot Analysis[2]
Cell Types: U-87MG
Tested Concentrations: 50 μM
Incubation Duration: 0, 15, 30, 60, 120 and 240 minutes
Experimental Results: Significant time-dependent inhibition of phosphorylation of Akt (Ser473) and mTOR (Ser2481) The way. Also dephosphorylates p70 S6K, a downstream target of mTOR.

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Autophagy assay [2]
Cell Types: U-87MG
Tested Concentrations: 60 μM
Incubation Duration: 24 hrs (hours)
Experimental Results: Induction of autophagy is stimulated by redistribution of LC3 in U-87MG glioma cells. Autophagy d

Animal/Disease Models: Male C57BL/6 mice (6-8 weeks old) were subjected to RSD (repeated social defeat) and HCC (home cage control) [4]
Doses: 20 mg/kg or 15 mg/kg
Route of Administration: intraperitoneal (ip) injection or administered orally daily for 24 days.
Experimental Results: Reversed RSD-induced social avoidance behavior, Dramatically increased interaction time, and Dramatically diminished stress-induced IL-6 mRNA levels in brain microglia.

Absorption, Distribution and Excretion
Rapidly and well absorbed (>95%) after oral administration. The primary site of absorption is the small intestine as the basic amine groups are ionized in the acidic environment of the stomach, preventing movement across tissues. Bioavailability ranges from 29-77% due to high inter-individual variability. Peak plasma concentration is usually attained 2-6 hours following oral administration. Absorption is unaffected by food.
Imipramine is primarily excreted in the urine with less than 5% present as the parent compound
Imipramine has a high apparent volume of distribution of 10-20 L/kg. The drug is known to accumulate in the brain at concentrations 30-40 times that in systemic circulation.
Imipramine has a mean clearance of 1 L/h/kg. Its active metabolite, desipramine has a mean clearance of 1.8 L/h/kg.
TRICYCLIC ANTIDEPRESSANTS ARE FAIRLY WELL ABSORBED AFTER ORAL ADMINISTRATION. ... ONCE ABSORBED /IT/ IS WIDELY DISTRIBUTED. ... ARE STRONGLY BOUND TO PLASMA PROTEIN AND TO THE CONSTITUENTS OF TISSUES./TRICYCLIC ANTIDEPRESSANTS
EXCRETION...IS RAPID... APPROX 40% OF DOSE OF RADIOACTIVE IMIPRAMINE APPEARS IN URINE IN 24 HR & TOTAL OF 70% DURING FIRST 72 HR. REMAINDER APPEARS IN FECES. SMALL PORTION...RECOVERED AS UNCHANGED DRUG OR AS ACTIVE DESMETHYL DERIV. LARGER PORTION...EXCRETED AS N-OXIDE OR AS NONCONJUGATED OR CONJUGATED 2-OH DERIV.
IN ANIMALS, PLACENTAL TRANSFER HAS BEEN OBSERVED WITH IMIPRAMINE & ITS DESMETHYL DERIVATIVE.
DISTRIBUTION OF IV ADMIN.../(14)C, IMIPRAMINE/ IN MICE...STUDIED USING WHOLE-BODY AUTORADIOGRAPHY. 5 MIN AFTER DOSING, HIGH UPTAKE OF (14)C OCCURRED IN BRAIN, MYOCARDIUM, LUNGS, ADRENALS & KIDNEYS, BUT (14)C IN BLOOD WAS LOW. IN 1 HR...(14)C /LEVELS/...HIGH IN SALIVARY GLANDS, INTESTINES, LIVER, GALL BLADDER, & URINARY BLADDER & 3 HR LATER...LARGELY CONFINED TO ORGANS CONCERNED WITH EXCRETION OF IMIPRAMINE...INTESTINES, LIVER, & KIDNEYS.
For more Absorption, Distribution and Excretion (Complete) data for IMIPRAMINE (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Imipramine is nearly exclusively metabolized by the liver. Imipramine is converted to desipramine by CYP1A2, CYP3A4, CYP2C19. Both imipramine and desipramine are hydroxylated by CYP2D6. Desipramine is an active metabolite. Minor metabolic pathways include dealkylation to form an imidodibenzyl product as well as demethylation of desipramine to didemethylimipramine and subsequent hydroxylation. Less than 5% of orally administered imipramine is excreted unchanged.
...STUDY OF METABOLISM OF IMIPRAMINE & ITS METABOLITES BY RAT LIVER MICROSOMES...REVEALED OPERATION OF 16 METABOLIC PATHWAYS, INCL N-DEMETHYLATION, AROMATIC HYDROXYLATIONS, SIDE-CHAIN DEALKYLATIONS, N-OXIDATION, N-OXIDE REDUCTION, & CONJUGATION REACTIONS.
IMIPRAMINE N-OXIDE & IMINODIBENZYL...IDENTIFIED AS ADDITIONAL URINARY METABOLITES IN MAN.
...METABOLIZED IN HUMANS BY N-DEMETHYLATION & BY HYDROXYLATION IN ONE OF THE AROMATIC RINGS OR IN ETHYLENE BRIDGE TO GIVE DESMONOMETHYLIMIPRAMINE (DMI) & DESDIMETHYLIMIPRAMINE (DDMI) & THE 2-HYDROXY & 10-HYDROXY DERIVATIVES OF IMIPRAMINE, DMI & DDMI, TOGETHER WITH THEIR GLUCURONIDE CONJUGATES.
IMIPRAMINE (HALF-LIFE, 16 HOURS) IS BIOTRANSFORMED TO THE ACTIVE METABOLITE, DESIPRAMINE (HALF-LIFE, 18 HOURS).
Imipramine has known human metabolites that include Imipramine N-glucuronide, Desipramine, and 2-Hydroxyimipramine.
Exclusively metabolized by the liver. Imipramine is converted in the liver by various CYP isoenzymes (e.g. CYP1A2, CYP2D6, CYP3A4, CYP2C9) to active metabolites desipramine and 2-hydroxydesipramine.
Route of Elimination: Approximately 40% of an orally administered dose is eliminated in urine within 24 hours, 70% in 72 hours. Small amounts are eliminated in feces via the biliary elimination.
Half Life: Imipramine - 8-20 hours; Desipramine (active metabolite) - up to 125 hours

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Biological Half-Life
Imipramine has a mean half life of 12 h. Its active metabolite, desipramine has a mean half life of 22.5 h.
IMIPRAMINE (HALF-LIFE, 16 HOURS)...

Toxicity Summary
IDENTIFICATION: Imipramine is a tricyclic antidepressant drug. Properties of the substance: Imipramine hydrochloride is a white or slightly yellow, odorless or almost odorless, crystalline powder. It is soluble in water, alcohol, chloroform, and acetone; practically insoluble in ether. Indications: Treatment of depression; nocturnal enuresis in children HUMAN EXPOSURE: Main risks and target organs: Affects the parasympathetic nervous system, central nervous system, and cardiovascular system. Summary of clinical effects: Early symptoms: mydriasis, blurred vision, dry mouth, tachycardia, hyperpyrexia, urinary retention, decreased intestinal peristalsis, and CNS excitation. Extrapyramidal symptoms may occur. Later more serious features: convulsions, coma, hypotension, arrhythmias, and cardiorespiratory arrest. The progression from being alert with mild symptoms to life-threatening toxic effects may be extremely rapid. Contraindications: Epilepsy, organic brain damage, urine retention, heart diseases, acute glaucoma. Hyperthyroidism and liver diseases are a relative contraindication. Routes of entry: Oral: Preferred route of administration. Parenteral: In the initial stages of treatment, if administration by mouth is impracticable or inadvisable imipramine may be given by intramuscular injection. Absorption by route of exposure: Oral: absorption occurs in the small intestine with little or no absorption in the stomach. Absorption is virtually complete (95%). The peak plasma concentration occurs 2 to 6 hours after administration. Food does not affect absorption, peak concentration or time to peak concentration. Large doses may be absorbed more slowly due to delayed gastric emptying and reduced peristalsis. Large amounts of imipramine, including intact pill fragments, have been recovered at autopsy. Parenteral: absorption appears to be complete since recovery of urinary metabolites is the same after either oral or parenteral administration. Distribution by route of exposure: Imipramine is lipophilic and therefore widely distributed in the body. Distribution is influenced by the degree of binding to plasma proteins. Plasma protein binding of imipramine ranges from 60 to 96%. Biological half-life by route of exposure: The half-life of imipramine is approximately 20 hours. Its active metabolite desipramine has a half-life of up to 125 hours. Metabolism: Imipramine is metabolised almost exclusively in the liver, undergoing oxidation by microsomal enzymes, followed by conjugation with glucuronic acid. Imipramine is mainly metabolised by demethylation to an active metabolite desipramine, and to a lesser extent by aromatic 2-hydroxylation to 2-hydroxyimipramine. Desipramine is metabolised by aromatic 2-hydroxylation to 2-hydroxydesimipramine. Quantitatively, hydroxylation is the most important intermediate metabolic pathway and it is the rate-limiting step for the elimination of imipramine and desimipramine. The greater plasma elimination half-life for desimipramine compared with imipramine may be due to a lower rate of hydroxylation. Both imipramine and desimipramine undergo substantial and highly variable first-pass metabolism, the extent of which is determined by oxidative phenotype. In Caucasians, there are slow and fast metabolizers: at least 6.5 to 10% of the population are slow metabolizers. First-pass metabolism of imipramine and desimipramine is reduced in slow metabolizers. Smoking, alcohol ingestion and other drugs may influence imipramine and desimipramine metabolism by altering the mixed function oxidase system: Smokers have lower steady-state levels of imipramine than non-smokers. Alcoholics were found to have a 3-fold greater intrinsic clearance of imipramine. Cimetidine increases the bioavailability of imipramine by 40 to 75%. Some drugs, such as haloperidol, disulfiram, and morphine, may prolong toxicity by inhibiting hydroxylation. Elimination by route of exposure: Less than 5% of an oral dose of imipramine is excreted unchanged in the urine. In patients with chronic renal failure, disproportionate increases in hydroxymetabolite concentration may occur. Mode of action: Toxicodynamics: Anticholinergic effects: increased heart rate. Quinidine-like effects on the heart due to slowing of sodium influx and potassium efflux, resulting in slowing of conduction and repolarization. Slowing of conduction notably occurs at the His-Purkinje portion of the atrioventricular conduction system resulting in prolongation of the PR- and QRS- intervals. Prolonged depolarization results in lengthening of the QT-interval. Peripheral receptor blockade may cause orthostatic hypotension. Pharmacodynamics: The probable mechanism of antidepressant activity is central inhibition of biogenic amine reuptake, predominantly affecting norepinephrine and serotonin. In addition to its central effects, imipramine is also a competitive antagonist at histamine H1 and H2 receptors. Interactions: Effect on imipramine itself: potentiation due to reduced hepatic metabolism by: neuroleptic drugs, methylphenidate, and certain steroids, including oral contraceptives. Reduced effect due to enhanced hepatic metabolism by barbiturates, certain other sedatives, and cigarette smoking. Effect of imipramine on other substances. Potentiates the effect of alcohol and probably other CNS depressants. Potentiates the anticholinergic effects of anticholinergic drugs used in the treatment of Parkinson's disease. Potentiates the effect of biogenic amines, such as norepinephrine, which are normally removed from their site of action by neuronal reuptake. Blocks the effects of indirectly acting amines, such as tyramine. Prevents the action of adrenergic neuron blocking agents such as guanethidine. Potentiates central nervous stimulation by amphetamine but blocks its peripheral effects. A particularly severe interaction occurs with concurrent administration of an MAO inhibitor and a tricyclic antidepressant. The resultant syndrome can include severe CNS toxicity, marked by hyperpyrexia, convulsions and coma. Main adverse effects: Antimuscarinic effects include dry mouth, a sour or metallic taste, epigastric distress, constipation, dizziness, tachycardia, palpitations, blurred vision and urinary retention. Paradoxically, excessive sweating. Weakness and fatigue. Older patients suffer more from dizziness, postural hypotension, constipation, delayed micturition, oedema, and muscle tremors. In approximately 10% of treated patients and in over 30% of patients over age 50, manic reactions, confusion, or delirium may occur. Extrapyramidal reactions are rare, though tremor is not unusual. A withdrawal syndrome, may occur in children, who experience gastrointestinal symptoms.
Imipramine works by inhibiting the neuronal reuptake of the neurotransmitters norepinephrine and serotonin. It binds the sodium-dependent serotonin transporter and sodium-dependent norepinephrine transporter preventing or reducing the reuptake of norepinephrine and serotonin by nerve cells. Depression has been linked to a lack of stimulation of the post-synaptic neuron by norepinephrine and serotonin. Slowing the reuptake of these neurotransmitters increases their concentration in the synaptic cleft, which is thought to contribute to relieving symptoms of depression. In addition to acutely inhibiting neurotransmitter re-uptake, imipramine causes down-regulation of cerebral cortical beta-adrenergic receptors and sensitization of post-synaptic serotonergic receptors with chronic use. This leads to enhanced serotonergic transmission.

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Toxicity Data
LD50: 355 to 682 mg/kg (oral, rat).

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Interactions
A PARTICULARLY SEVERE, BUT RARE, INTERACTION HAS BEEN NOTED FOLLOWING THE CONCURRENT ADMINISTRATION OF AN MAO /MONOAMINE OXIDASE/ INHIBITOR AND A TRICYCLIC ANTIDEPRESSANT. /TRICYCLIC ANTIDEPRESSANTS/
...INTERACTIONS INCL POTENTIATION OF CENTRAL DEPRESSANT DRUGS, BLOCKADE OF ANTIHYPERTENSIVE EFFECTS OF GUANETHIDINE, & AUGMENTATION OF PRESSOR EFFECTS OF SYMPATHOMIMETIC AMINES. INTERACTIONS WITH THYROID PREPN, METHYLPHENIDATE, & PHENOTHIAZINES, ALL OF WHICH MAY ENHANCE...EFFECT... /TRICYCLIC ANTIDEPRESSANTS/
CHRONIC ADMIN OF EITHER IMIPRAMINE OR DESMETHYLIMIPRAMINE SIGNIFICANTLY INCR THE CARDIOTOXICITY OF DIGOXIN...
THEY /TRICYCLIC COMPOUNDS/ POTENTIATE THE EFFECTS OF ANTIHISTAMINICS; ANTIMUSCARINICS, AND OTHER CENTRAL NERVOUS SYSTEM DEPRESSANTS... /TRICYCLIC ANTIDEPRESSANTS/
For more Interactions (Complete) data for IMIPRAMINE (26 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 250 mg/kg
LD50 Rat ip 79 mg/kg
LD50 Rat sc 250 mg/kg
LD50 Rat iv 15900 ug/kg
For more Non-Human Toxicity Values (Complete) data for IMIPRAMINE (8 total), please visit the HSDB record page.

[1]. New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells. Exp Mol Med. 2020 Feb;52(2):281-292.

[2]. The tricyclic antidepressant imipramine induces autophagic cell death in U-87MG glioma cells. Biochem Biophys Res Commun. 2011 Sep 23;413(2):311-7.

[3]. The antidepressants imipramine, clomipramine, and citalopram induce apoptosis in human acute myeloid leukemia HL-60 cells via caspase-3 activation. J Biochem Mol Toxicol. 1999;13(6):338-47.

[4]. Imipramine attenuates neuroinflammatory signaling and reverses stress-induced social avoidance. Brain Behav Immun. 2015 May;46:212-20.

[5]. Evidence for an imipramine-sensitive serotonin transporter in human placental brush-border membranes. J Biol Chem. 1989 Feb 5;264(4):2195-8.

Therapeutic Uses
Adrenergic Uptake Inhibitors; Antidepressive Agents, Tricyclic
EFFECTIVE IN DEPRESSIVE SYNDROMES, PARTICULARLY THOSE ASSOC WITH MANIC-DEPRESSIVE & INVOLUTIONAL PSYCHOSES... /HYDROCHLORIDE/
2-HYDROXYIMIPRAMINE-HCL INHIBITED UPTAKE OF NOREPINEPHRINE & SEROTONIN BY RAT CEREBROCORTICAL SYNAPTOSOMES TO SAME EXTENT AS PARENT DRUGS.
METHODS OF TREATMENT OF ENURESIS IN CHILD ARE PRESENTED INCL IMIPRAMINE.
For more Therapeutic Uses (Complete) data for IMIPRAMINE (8 total), please visit the HSDB record page.

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Drug Warnings
BECAUSE OF POSSIBLE CONGENITAL MALFORMATIONS ASSOC WITH USE OF THIS DRUG.../IT/ SHOULD NOT BE USED DURING FIRST TRIMESTER OF PREGNANCY. /IMIPRAMINE HYDROCHLORIDE/
TRICYCLIC COMPD ARE CONTRAINDICATED IN PT WITH CONGESTIVE HEART FAILURE, ANGINA PECTORIS, & PAROXYSMAL TACHYCARDIA; ALSO, THEY SHOULD BE USED WITH CAUTION IN PATIENTS WITH URINARY RETENTION, GLAUCOMA, DIABETES, IMPAIRED LIVER FUNCTION, ASTHMA, AND A HISTORY OF CONVULSIVE SEIZURES. /TRICYCLIC ANTIDEPRESSANTS/
OCCASIONAL PT WILL SHOW PHYSICAL DEPENDENCE ON TRICYCLIC ANTIDEPRESSANTS, WITH MALAISE, CHILLS, CORYZA, & MUSCLE ACHES FOLLOWING ABRUPT DISCONTINUATION OF HIGH DOSES OF IMIPRAMINE.
ALTHOUGH MOST FATAL CASES...HAVE OCCURRED AFTER INGESTION OF MORE THAN 1.5 G ... DEATH HAS BEEN REPORTED AFTER AS LITTLE AS 500 TO 750 MG AND RECOVERY HAS BEEN REPORTED AFTER INGESTION OF 5.4 G. /IMIPRAMINE HYDROCHLORIDE/
For more Drug Warnings (Complete) data for IMIPRAMINE (33 total), please visit the HSDB record page.

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Pharmacodynamics
Imipramine is a tricyclic antidepressant with general pharmacological properties similar to those of structurally related tricyclic antidepressant drugs such as amitriptyline and doxepin. While it acts to block both, imipramine displays a much higher affinity for the serotonin reuptake transporter than for the norepinephrine reuptake transporter. Imipramine produces effects similar to other monoamine targeting antidepressants, increasing serotonin- and norepinephrine-based neurotransmission. This modulation of neurotransmission produces a complex range of changes in brain structure and function along with an improvement in depressive symptoms. The changes include increases in hippocampal neurogenesis and reduced downregulation of this neurogenesis in response to stress. These implicate brain derived neurotrophic factor signalling as a necessary contributor to antidepressant effect although the link to the direct increase in monoamine neurotransmission is unclear. Serotonin reuptake targeting agents may also produce a down-regulation in β-adrenergic receptors in the brain.

C19H24N2

280.4073

316.17

113-52-0

Imipramine-d4 hydrochloride;61361-33-9;Imipramine;50-49-7;Imipramine-d6;65100-45-0;Imipramine-d3 hydrochloride;112898-42-7

3696

White to off-white solid powder

1.041g/cm3

403.1ºC at 760mmHg

168-1700C

179.7ºC

6.6E-06mmHg at 25°C

4.742

0

2

4

21

291

0

BCGWQEUPMDMJNV-UHFFFAOYSA-N

InChI=1S/C19H24N2/c1-20(2)14-7-15-21-18-10-5-3-8-16(18)12-13-17-9-4-6-11-19(17)21/h3-6,8-11H,7,12-15H2,1-2H3

3-(5,6-dihydrobenzo[b][1]benzazepin-11-yl)-N,N-dimethylpropan-1-amine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

DMSO : ≥ 100 mg/mL (~315.59 mM)
H2O : ~62.5 mg/mL (~197.24 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.89 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 25.0 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: ≥ 2.5 mg/mL (7.89 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 25.0 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: ≥ 2.5 mg/mL (7.89 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 60 mg/mL (189.35 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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