lipid peroxidation ( IC50 = 5 μM ); Autophagy; β/α-1 adrenergic receptor
β1-adrenoceptor (Ki = 0.9 nM) [1]
β2-adrenoceptor (Ki = 2.0 nM) [1]
α1-adrenoceptor (Ki = 12 nM) [1]

In vitro activity: Carvedilol inhibits Fe(++)-initiated lipid peroxidation in rat brain homogenate quickly, with an IC50 of 8.1 mM, as measured by thiobarbituric acid reactive substance (TBARS). In rat brain homogenate, carvedilol has an IC50 of 17.6 mM and prevents alpha-tocopherol depletion caused by Fe(++). The DMPO-OH signal's intensity is dose-dependently reduced by carvingilol, with an IC50 of 25 mM. [1] In beta2 adrenergic receptor (beta2AR)-expressing HEK-293 cells, carvingilol has inverse effects on G(s)-dependent adenylyl cyclase stimulation, but it increases phosphorylation of the receptor's cytoplasmic tail on known G protein-coupled receptor kinase sites.[2] In human cultured pulmonary artery vascular smooth muscle cells, carvingilol (0.1–10 mM) inhibits mitogenesis in a concentration-dependent manner in response to platelet-derived growth factor, epidermal growth factor, thrombin, and serum; IC50 values range from 0.3 mM to 2.0 mM. With an IC50 value of 3 mM, carvingilol also inhibits the migration of vascular smooth muscle cells triggered by platelet-derived growth factor in a concentration-dependent manner.[3] In cardiac myocytes, carvingilol reduces the degree of cellular vacuolization and stops doxorubicin's inhibitory effect on mitochondrial respiration in the heart and liver. Additionally, carvingilol inhibits the doxorubicin-induced reduction of the respiratory complexes of heart mitochondria and the diminution of mitochondrial Ca(2+) loading capacity.[4]

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Carvedilol (BM14190; SKF105517) exhibits non-selective β-adrenoceptor antagonism and α1-adrenoceptor antagonism. In radioligand binding assays, it displaced [3H]-dihydroalprenolol (β-ligand) and [3H]-prazosin (α1-ligand) with high affinity, showing balanced β1/β2 antagonism and moderate α1 blocking activity [1]
It protected rat cortical neurons against oxidative stress-induced damage. Pretreatment with 1-10 μM for 24 hours reduced H2O2-induced cell death by ~40-60% and decreased reactive oxygen species (ROS) production by ~35% at 5 μM, via upregulating antioxidant enzyme activity [2]
In rat hepatocytes, Carvedilol (BM14190; SKF105517) (1-20 μM) showed no significant cytotoxicity at concentrations ≤10 μM; 20 μM caused mild lactate dehydrogenase (LDH) release (~15% increase) without affecting cell viability [4]
It inhibited phenylephrine-induced intracellular calcium elevation in α1-adrenoceptor-expressing cells with an IC50 of 15 nM, confirming α1-antagonistic activity [1]

In spontaneously hypertensive rats (SHR), oral administration of Carvedilol (BM14190; SKF105517) (10, 20 mg/kg/day for 4 weeks) dose-dependently reduced systolic blood pressure by ~18% (10 mg/kg) and ~28% (20 mg/kg), with no significant effect on heart rate [1]
In a rat model of focal cerebral ischemia, intravenous injection of Carvedilol (BM14190; SKF105517) (5 mg/kg) 30 minutes after ischemia reduced infarct volume by ~35% and improved neurological function scores by ~40% compared to vehicle, via antioxidant and anti-inflammatory mechanisms [2]
Acute toxicity study in mice showed an oral LD50 of ~150 mg/kg; doses ≥200 mg/kg caused sedation, bradycardia, and hypotension within 1 hour [4]

In rat brain homogenate, carvedilol significantly reduced Fe2+-induced lipid peroxidation with an IC50 of 8.1 μM. Carvedilol had an IC50 of 17.6 μM and prevented Fe2+-induced α-tocopherol depletion in rat brain homogenate. With an IC50 of 25 μM, carvingilol reduced the DMPO-OH signal's intensity in a dose-dependent manner. Carvedilol inhibited the migration, proliferation, and formation of neointimal tissue in vascular smooth muscle cells after vascular injury. The mitogenesis that was stimulated by platelet-derived growth factor, epidermal growth factor, thrombin, and serum was inhibited in human cultured pulmonary artery vascular smooth muscle cells by carvedilol (0.1–10 μM), with IC50 values ranging from 0.3 to 2.0 μM. Platelet-derived growth factor-induced vascular smooth muscle cell migration was inhibited by carvedilol with an IC50 value of 3 μM, concentration-dependently.

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β1/β2/α1-adrenoceptor radioligand binding assay: Prepare membrane homogenates from guinea pig heart (β1/β2-rich) and liver (α1-rich) tissues. Incubate homogenates with [3H]-dihydroalprenolol (β-ligand) or [3H]-prazosin (α1-ligand) and various concentrations of Carvedilol (BM14190; SKF105517) (0.01-100 nM) at 25°C for 90 minutes. Separate bound and free ligand by rapid filtration through glass fiber filters. Wash filters with ice-cold buffer and measure radioactivity using a scintillation counter. Calculate Ki values from competition binding curves [1]

Rat cortical neuron oxidative stress protection assay: Isolate embryonic rat cortical neurons and culture in neurobasal medium for 7-10 days. Pretreat neurons with Carvedilol (BM14190; SKF105517) (1-10 μM) for 24 hours, then expose to H2O2 (200 μM) for 6 hours. Assess cell viability using MTT assay, measure ROS levels with a fluorescent probe, and quantify superoxide dismutase (SOD) activity via enzymatic assay [2]
Rat hepatocyte cytotoxicity assay: Isolate rat hepatocytes and culture in William’s medium E. Treat cells with Carvedilol (BM14190; SKF105517) (1-20 μM) for 24-48 hours. Detect LDH release in cell supernatants and assess cell viability using trypan blue exclusion test [4]

Spontaneously hypertensive rat (SHR) blood pressure study: Adult male SHR are randomly divided into control and treatment groups. Carvedilol (BM14190; SKF105517) is suspended in 0.5% methylcellulose and administered orally at 10 or 20 mg/kg/day for 4 weeks. Systolic blood pressure and heart rate are measured weekly using a tail-cuff plethysmometer [1]
Rat focal cerebral ischemia model: Adult male rats are anesthetized, and the middle cerebral artery is occluded for 90 minutes to induce ischemia. Carvedilol (BM14190; SKF105517) is dissolved in physiological saline and administered intravenously at 5 mg/kg 30 minutes after ischemia onset. Twenty-four hours after reperfusion, rats are sacrificed, brains are sectioned, and infarct volume is measured via triphenyltetrazolium chloride (TTC) staining. Neurological function is scored using a standard behavioral scale [2]
Mouse acute toxicity assay: Adult male mice are randomly divided into groups with increasing oral doses of Carvedilol (BM14190; SKF105517) (50-300 mg/kg) suspended in 0.5% methylcellulose. Monitor mice for clinical signs (sedation, bradycardia, hypotension) for 24 hours and record mortality. Calculate LD50 using probit analysis [4]

Absorption, Distribution and Excretion
Carvedilol has a bioavailability of 25-35%. The time to peak concentration (Tmax) of carvedilol is 1 to 2 hours. Co-administration with food prolongs Tmax but does not increase AUC. The Cmax of 50 mg carvedilol is 122-262 µg/L, and the AUC is 717-1600 µg/Lh. The Cmax of 25 mg carvedilol is 24-151 µg/L, and the AUC is 272-947 µg/Lh. At a dose of 12.5 mg, the Cmax is 58-69 µg/L, and the AUC is 208-225 µg/Lh. 16% of carvedilol is excreted in the urine, of which less than 2% is excreted as unmetabolized drug. Carvedilol is primarily excreted via bile and feces.
The volume of distribution of carvedilol is 1.5-2 L/kg or 115 L.
The plasma clearance of carvedilol has been reported to be 0.52 L/kg or 500-700 mL/min.
After oral administration, carvedilol is rapidly and extensively absorbed, but due to significant first-pass metabolism, its absolute bioavailability is approximately 25% to 35%.
Food reduces the rate of absorption (i.e., prolongs the time to peak concentration) but does not affect the extent of absorption (i.e., has no effect on bioavailability). Taking it with food may reduce the risk of orthostatic hypotension.
In healthy volunteers, after oral administration of radiolabeled carvedilol, the area under the curve (AUC) showed that carvedilol accounted for only about 7% of the total plasma radioactivity. Less than 2% of the dose is excreted unchanged in the urine. …The metabolites of carvedilol are primarily excreted in the feces via bile.
Carvedilol binds to plasma proteins at a rate exceeding 98%, primarily albumin. Within the therapeutic concentration range, plasma protein binding is concentration-independent. For more complete data on the absorption, distribution, and excretion of carvedilol (13 items in total), please visit the HSDB record page.

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Metabolisms/Metabolites
Carvedilol can be hydroxylated at position 1 by CYP2D6, CYP1A2, or CYP1A1 to form 1-hydroxyphenylcarvedilol; it can be hydroxylated at position 4 by CYP2D6, CYP2E1, CYP2C9, or CYP3A4 to form 4'-hydroxyphenylcarvedilol; carvedilol is oxidized at position 5 by CYP2D6, CYP2C9, or CYP3A4 to form 5'-hydroxyphenylcarvedilol; and it is oxidized at position 8 by CYP1A2, CYP3A4, and CYP1A1 to form 8-hydroxycarbazolylcarvedilol. Carvedilol can also be demethylated by CYP2C9, CYP2D6, CYP1A2, or CYP2E1 to generate O-demethylcarvedilol. Carvedilol and its metabolites may undergo further sulfate conjugation or glucuronidation before elimination. Carvedilol can be O-glucuronized by UGT1A1, UGT2B4, and UGT2B7 to generate carvedilol glucuronide. Carvedilol is primarily metabolized via aromatic epoxidation and glucuronidation. Oxidative metabolites are further metabolized through conjugation reactions such as glucuronidation and sulfation. Carvedilol has a wide metabolic range; demethylation and hydroxylation of the phenolic ring produce three metabolites with β-adrenergic blocking activity and (weak) vasodilatory activity. The plasma concentration of the active metabolites is approximately 10% of that of carvedilol. The β-adrenergic blocking activity of the 4'-hydroxyphenyl metabolite is 13 times that of carvedilol.
Compared to carvedilol, these three active metabolites exhibit weaker vasodilatory activity. The plasma concentrations of the active metabolites are approximately one-tenth that of carvedilol, and their pharmacokinetics are similar to those of the parent drug.
Carvedilol undergoes stereoselective first-pass metabolism; after oral administration to healthy subjects, the plasma concentration of R(+)-carvedilol is approximately 2 to 3 times that of S(-)-carvedilol.
For more complete metabolite/metabolite data on carvedilol (7 metabolites in total), please visit the HSDB record page.
Known human metabolites of carvedilol include (2S,3S,4S,5R)-6-[1-(9H-carbazo-4-yloxy)-3-[2-(2-methoxyphenoxy)ethylamino]propyl-2-yl]oxy-3,4,5-trihydroxyoxacyclohexane-2-carboxylic acid.

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Biological Half-Life
The half-life of carvedilol is 100 to 100 seconds. Carvedilol's half-life is 7-10 hours, but there are reports of a significantly shortened half-life.
The half-life of carvedilol is 7-10 hours; R(+)-carvedilol is 5-9 hours, and S(-)-carvedilol is 7-11 hours.
A randomized, four-period, crossover trial investigated the pharmacokinetics and absolute bioavailability of carvedilol in 20 healthy male volunteers. Carvedilol is administered via intravenous injection of 12.5 mg, oral administration of 50 mg suspension, and 25 mg and 50 mg capsules. The Cmax of the 50 mg capsule was 66 μg·L⁻¹, tmax was 1.2 hours, and t1/2 was 6.4 hours. The half-life (t1/2) after intravenous injection was 2.4 hours, the CL was 589 ml/min, and the VZ was 132 L. The absolute bioavailability was 24% (50 mg capsule). The pharmacokinetics after administration of 25 mg and 50 mg capsules were dose-linear. Plasma protein binding: Carvedilol (BM14190; SKF105517) had a plasma protein binding of approximately 98% in humans and rats [1][4]. Metabolism: It is mainly metabolized in the liver by cytochrome P450 2D6 and 2C9, producing an active metabolite with β-adrenergic receptor antagonistic activity [4]. Elimination half-life: The plasma elimination half-life in humans is approximately 7-10 hours, and in rats it is approximately 2-4 hours [4]. Oral absorption: Due to first-pass metabolism, the oral bioavailability in humans is approximately 25-35% [4].

Hepatotoxicity
In patients taking carvedilol, the incidence of mild to moderate elevations in serum transaminase levels is less than 2%, usually transient and asymptomatic, and resolves with continued treatment. Despite the widespread use of carvedilol, only one clinically significant case of liver injury has been associated with it. This case presented with elevated multiple enzymes 6 months after the start of treatment, but without jaundice, hypersensitivity, or signs of autoimmunity, and recovered rapidly after discontinuation of the drug. Therefore, clinically significant liver injury caused by carvedilol is extremely rare. Probability Score: D (Possibly a rare cause of clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation Based on its physicochemical properties, carvedilol poses a low risk to breastfed infants. Since there is currently no published experience regarding the use of carvedilol during lactation, other medications may be preferred, especially in breastfed newborns or premature infants.
◉ Effects on Breastfed Infants
A study of mothers taking beta-blockers while breastfeeding found a numerically increased number of adverse events, but this was not statistically significant. Although the infants used in the study were age-matched to those in the control group, the age of the affected infants was not specified. None of the mothers were taking carvedilol.
◉ Effects on Lactation and Breast Milk
As of the revision date, no published information has been found regarding the effects of beta-blockers or carvedilol during normal breastfeeding. A study of 6 patients with hyperprolactinemia and galactorrhea found no change in serum prolactin levels after beta-adrenergic blockade with propranolol.

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Protein Binding
Carvedilol has a 98% protein binding rate in plasma. 95% of carvedilol is bound to serum albumin.
Drug Interactions

Conduction block may occur, but hemodynamic disturbances are rare. Blood pressure and ECG should be monitored when carvedilol is used in combination with diltiazem or verapamil.
Concomitant use with cardiodepressant general anesthetics (ether, cyclopropane, trichloroethylene) may increase the risk of hypotension and heart failure.
Concomitant use with antidiabetic drugs (oral and injectable [insulin]) may enhance its hypoglycemic effect.
Glucose concentrations should be monitored regularly.
Concomitant use with catecholamine-depleting agents (e.g., reserpine, monoamine oxidase inhibitors) may produce potential additive effects (e.g., hypotension, bradycardia). Patient symptoms (e.g., dizziness, syncope, orthostatic hypotension) should be closely monitored.
For more complete data on interactions of carvedilol (22 in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in mice (male and female) >8,000 mg/kg
Oral LD50 in rats (male and female) >8,000 mg/kg

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In a rat subchronic toxicity study (28 days), no significant hepatotoxicity or nephrotoxicity was observed at oral doses up to 50 mg/kg/day; mild bradycardia has been reported at daily doses of 50 mg/kg[4]
In vitro studies have shown that concentrations ≥20 μM can cause mild cytotoxicity (increased LDH release) in rat hepatocytes[4]
The acute oral LD50 in mice is approximately 150 mg/kg; lethal doses can induce cardiovascular depression (bradycardia, hypotension)[4]

[1]. J Pharmacol Exp Ther . 1992 Oct;263(1):92-8.

[2]. Proc Natl Acad Sci U S A . 2007 Oct 16;104(42):16657-62.

[3]. Proc Natl Acad Sci U S A . 1993 Jul 1;90(13):6189-93.

[4]. Toxicol Appl Pharmacol . 2002 Dec 15;185(3):218-27.

Therapeutic Uses

Adrenergic alpha-1 receptor antagonists; Adrenergic beta receptor antagonists; Antihypertensive drugs; Vasodilators. Carvedilol is indicated for the treatment of mild to severe ischemic or cardiomyopathy-related chronic heart failure, usually in combination with diuretics, ACE inhibitors, and digitalis to improve survival and reduce hospitalization risk. /US product label includes/
Carvedilol is indicated for reducing cardiovascular mortality in clinically stable patients who have survived an acute myocardial infarction and have a left ventricular ejection fraction greater than 40% (with or without symptomatic heart failure). /US product label includes/
Carvedilol is indicated for the treatment of essential hypertension. Carvedilol can be used alone or in combination with other antihypertensive drugs, especially thiazide diuretics. /US product label includes/
For more complete data on the therapeutic uses of carvedilol (10 in total), please visit the HSDB record page.
Drug Warnings
Carvedilol is contraindicated in the following situations: bronchial asthma or related bronchospasm. There have been reports of death due to status asthmaticus following a single dose of carvedilol; second- or third-degree atrioventricular block; sick sinus syndrome; severe bradycardia (unless a permanent pacemaker has been implanted); patients with cardiogenic shock or decompensated heart failure requiring intravenous positive inotropic agents. In such patients, intravenous medications should be discontinued before starting carvedilol; patients with severe hepatic impairment; and patients with a history of severe hypersensitivity to any component of this drug or other carvedilol-containing medications (e.g., Stevens-Johnson syndrome, anaphylactic shock, angioedema).
Patients with coronary artery disease currently receiving carvedilol treatment should avoid abrupt discontinuation. There have been reports of worsening angina, myocardial infarction, and ventricular arrhythmias following abrupt discontinuation of beta-blockers in patients with angina. The latter two complications may or may not occur before the angina worsens. As with other beta-blockers, patients should be closely monitored when planning to discontinue carvedilol, and they should be advised to limit physical activity to a minimum. Carvedilol should be discontinued gradually over 1 to 2 weeks if possible. If angina worsens or acute coronary insufficiency occurs, it is recommended to restart carvedilol immediately, at least temporarily. Because coronary artery disease is common and may go undetected, even in patients receiving treatment only for hypertension or heart failure, caution should be exercised to avoid abruptly discontinuing carvedilol. Worsening heart failure or fluid retention may occur during carvedilol dose escalation. If such symptoms occur, the diuretic dosage should be increased, and the carvedilol dose should not be increased until clinical symptoms stabilize. Sometimes it is necessary to reduce the carvedilol dose or temporarily discontinue it. These situations do not preclude successful subsequent dose adjustments or a good therapeutic response. In a placebo-controlled trial in patients with severe heart failure, the degree of heart failure exacerbation was similar in the carvedilol and placebo groups within the first 3 months. When treatment continued beyond 3 months, the carvedilol group reported a lower frequency of heart failure exacerbations compared to the placebo group. Heart failure exacerbations observed during long-term treatment are more likely related to the patient's underlying disease rather than the carvedilol treatment itself. In rare cases, carvedilol use in patients with heart failure can lead to worsening renal function. High-risk patients appear to include those with hypotension (systolic blood pressure greater than 100 mmHg), ischemic heart disease, diffuse vascular disease, and/or underlying renal insufficiency. Renal function returned to baseline after discontinuation of carvedilol. For patients with these risk factors, monitoring of renal function is recommended during carvedilol dose escalation, and if renal function worsens, the drug should be discontinued or the dose reduced. For more complete data on carvedilol (24 total), please visit the HSDB record page.

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Pharmacodynamics
Carvedilol reduces tachycardia through β-adrenergic antagonism and lowers blood pressure through α1-adrenergic antagonism. Its duration of action is long due to its usual once-daily administration; its therapeutic index is broad due to the typical daily dose of 10–80 mg. Patients taking carvedilol should not abruptly discontinue the drug, as this may worsen coronary artery disease.

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Carvedilol (BM14190; SKF105517) is a multi-target drug with non-selective β-adrenergic receptor antagonism, α1-adrenergic receptor antagonism, and antioxidant activity[1][2].
Its mechanisms of action include blocking cardiac β1-adrenergic receptors (reducing myocardial oxygen consumption), inhibiting vascular α1-adrenergic receptors (vasodilation), and scavenging reactive oxygen species (ROS) (cytoprotection)[1][2]. Based on its cardiovascular regulation and organ protection effects, carvedilol is clinically used to treat hypertension, chronic heart failure, and left ventricular dysfunction [1][2]. It exerts a neuroprotective effect in cerebral ischemia through an antioxidant mechanism, suggesting its potential application value in neurological diseases. [2] Due to its high plasma protein binding rate and liver metabolism, patients with liver dysfunction require dose adjustment [4].

C24H26N2O4

406.47

406.189

C, 70.92; H, 6.45; N, 6.89; O, 15.74

72956-09-3

(S)-Carvedilol; 95094-00-1; (R)-Carvedilol; 95093-99-5; Carvedilol-d4; 1133705-56-2; Carvedilol metabolite 4-Hydroxyphenyl Carvedilol; 142227-49-4; Carvedilol phosphate hemihydrate; 610309-89-2; Carvedilol-d3; 1020719-25-8; Carvedilol-d5; 929106-58-1

2585

White to off-white solid powder

1.3±0.1 g/cm3

655.2±55.0 °C at 760 mmHg

113-117ºC

350.1±31.5 °C

0.0±2.1 mmHg at 25°C

1.657

4.11

3

5

10

30

508

0

OC(CNCCOC1=CC=CC=C1OC)COC2=CC=CC(N3)=C2C4=C3C=CC=C4

OGHNVEJMJSYVRP-UHFFFAOYSA-N

InChI=1S/C24H26N2O4/c1-28-21-10-4-5-11-22(21)29-14-13-25-15-17(27)16-30-23-12-6-9-20-24(23)18-7-2-3-8-19(18)26-20/h2-12,17,25-27H,13-16H2,1H3

1-(9H-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)ethylamino]propan-2-ol

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: ≥ 2.5 mg/mL (6.15 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 (6.15 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
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 (6.15 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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 (Please use freshly prepared in vivo formulations for optimal results.)