Angiotensin II receptor

By inhibiting the action of angiotensin, valsartan (CGP 48933), a synthetic non-peptide angiotensin II type 1 receptor antagonist, dilates blood vessels and lowers blood pressure. Ageing aortic endothelial cells exhibit a substantial reduction in AT1R expression when treated with valsartan[1]. Proinflammatory cytokines and TLR2 signaling are inhibited when valsartan is pretreated. Following alcohol consumption, the expression of AGTR1 is up-regulated, and valsartan pretreatment blocks this expression[2].

In rats with MI, valsartan (CGP 48933) dramatically reduces the expression of TGF-β/Smad, Hif-1α, and fibrosis-related protein. Comparing valsartan to saline and hydralazine, there is a considerable improvement in cardiac function, infarcted size, wall thickness, and myocardial vascularization of ischemic hearts[3]. A high-salt diet can cause hypertension, heart damage such fibrosis and inflammatory cell infiltration, suppression of aquaporin 1 and angiogenic factors, and other consequences that valsartan can partially reverse[4]. Valsartan is a potent antidepressant and anti-anxiety medication that can increase BDNF expression and hippocampus neurogenesis. Long-term valsartan administration (5–40 mg/kg/d, po) decreases immobility time in TST and FST, lengthens the time in the center of the field in OFT and the latency to eat in NSF, and enhances the preference for sucrose in SPT[5].

The aorta tissue or cell samples were homogenized in lysis buffer A (20 mM Tris-HCl, pH8.0, 150 mM NaCl, 1% Triton X-100, 2 mM EDTA, 1 mM phenylmethylsulfonyl fluoride, 20 μg/ml aprotinin, 10 μg/ml leupeptin, 20 mM ß-glycerophate, and 2 mM NaF) for 30 min. The homogenates were centrifugated and protein concentration was determined with BCA protein assay reagent kit (Piece Biotech Inc., Rockford, IL, USA). An equal amount of protein (20 μg/lane for most proteins, while 100 μg/lane for p-p38 and p-JNK detection) from each sample extract was loaded in a 12.5% SDS-PAGE gel for Electrophoresis, and electroblotted onto PDVF membrane. Membrane was blocked with 5% non-fat dried milk (in TBST) for 2 hrs at room temperature and then incubated with primary antibody overnight at 4°C Then, membrane was washed with TBST (10 min. ×3) and incubated with horseradish peroxidase-conjugated secondary antibodies for 1 hr at room temperature (All the antibodies were purchased from Cell Signaling Technology, Boston, MA, USA). After washing with TBST (10 min. ×3), the immunoblots were developed using an ECL Western blotting detection system (Amersham Pharmacia Biotech, Piscataway, NJ, USA) and recorded by exposure of the immunoblots to an X-ray film [1].

The aorta were cut into small pieces and fixed in 2.5% glutaraldehyde in 0.2 M cacodylate buffer (pH 7.4) at 4°C for 2 hrs, then washed in PBS. The materials were incubated in a 2% OsO4 solution, dehydrated in a series of increasing ethanol concentrations and propylene oxide, and finally were immersed in Spurr resin. Ultrathin sections (50 nm) were cut on a Leica ultracut UCT ultramicrotome (Leica Microsystems Inc, LKB-II, Wetzlar, Germany), mounted on copper grids, and examined under a JEM 1200EX transmission electron microscope [1].

Twenty young (or adult, 3-month-old) and 40 aged (18-month-old) male Wistar rats were purchased from the Department of Laboratory Animals, China Medical University. Animals were maintained at controlled temperature of 21°C and in a 12-hour day/night cycle. All the experimental procedures were approved by the Institutional Animal Care and Use Committee of China Medical University. Young or adult animals were used as control group. Aged animals were randomly divided into two groups: the ageing group and Valsartan group (n = 20 in each group). The control and the ageing animals had free access to water and standard rat chow. The valsartan group animals continually took valsartan (Novartis Pharma Stein AG; 30 mg/kg/day) in their drinking water for 6 months. The concentration of valsartan dissolved in the drinking water was determined based on the previously established rats drinking patterns [1].

Absorption, Distribution and Excretion
After one oral dose, the antihypertensive activity of valsartan begins within approximately 2 hours and peaks within 4-6 hours in most patients. Food decreases the exposure to orally administered valsartan by approximately 40% and peak plasma concentration by approximately 50%. AUC and Cmax values of valsartan generally increase linearly with increasing dose over the therapeutic dose range. Valsartan does not accumulate appreciably in plasma following repetitive administration.
Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites.
The steady-state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively.
Following intravenous administration, plasma clearance of valsartan is approximately 2 L/hour and its renal clearance is 0.62 L/hour (about 30% of total clearance).
Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. ... Following intravenous administration, plasma clearance of valsartan is about 2 L/hr and its renal clearance is 0.62 L/hr (about 30% of total clearance).
Absolute bioavailability for the capsule formulation is approximately 25% (range, 10-35%). Food decreases the area under the plasma concentration-time curve (AUC) and peak plasma concentration by approximately 40 and 50%, respectively.
Valsartan peak plasma concentration is reached 2 to 4 hours after dosing. Valsartan shows bi-exponential decay kinetics following intravenous administration, with an average elimination half-life of about 6 hours. Absolute bioavailability for Diovan is about 25% (range 10% to 35%). The bioavailability of the suspension is 1.6 times greater than with the tablet. With the tablet, food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%. AUC and Cmax values of valsartan increase approximately linearly with increasing dose over the clinical dosing range. Valsartan does not accumulate appreciably in plasma following repeated administration.
The steady state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin.
For more Absorption, Distribution and Excretion (Complete) data for VALSARTAN (6 total), please visit the HSDB record page.

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Metabolism / Metabolites
Valsartan undergoes minimal liver metabolism and is not biotransformed to a high degree, as only approximately 20% of a single dose is recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism.
Valsartan is known to be excreted largely as unchanged compound and is minimally metabolized in man. Although the only notable metabolite is 4-hydroxyvaleryl metabolite (4-OH valsartan), the responsible enzyme has not been clarified at present. The current in vitro studies were conducted to identify the cytochrome P450 (CYP) enzymes involved in the formation of 4-OH valsartan. Valsartan was metabolized to 4-OH valsartan by human liver microsomes and the Eadie-Hofstee plots were linear. The apparent Km and Vmax values for the formation of 4-OH valsartan were 41.9-55.8 microM and 27.2-216.9 pmol min(-1) mg(-1) protein, respectively. There was good correlation between the formation rates of 4-OH valsartan and diclofenac 4'-hydroxylase activities (representative CYP2C9 activity) of 11 individual microsomes (r = 0.889). No good correlation was observed between any of the other CYP enzyme marker activities (CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A). Among the recombinant CYP enzymes examined (CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, 3A5 and 4A11), CYP2C9 notably catalysed 4-hydroxylation of valsartan. For the specific CYP inhibitors or substrates examined (furafylline, diclofenac, S(+)-mephenytoin, quinidine and troleandomycin), only diclofenac inhibited the formation of 4-OH valsartan. These results showed that CYP2C9 is the only form responsible for 4-hydroxylation of valsartan in human liver microsomes. Although CYP2C9 is involved in valsartan metabolism, CYP-mediated drug-drug interaction between valsartan and other co-administered drugs would be negligible.
... Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism. ...
Valsartan has known human metabolites that include 4-hydroxy-valsartan.

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Biological Half-Life
After intravenous (IV) administration, valsartan demonstrates bi-exponential decay kinetics, with an average elimination half-life of about 6 hours.
Valsartan shows bi-exponential decay kinetics following intravenous administration, with an average elimination half-life of about 6 hours.
... In an investigation of pharmacokinetics and pharmacodynamics in normotensive male volunteers, valsartan was rapidly absorbed with the maximal plasma concentration occurring 2-3 hr after oral administration. The elimination half-life was about 4-6 hr, valsartan was poorly metabolized, and most of the drug was excreted via feces. ...

Toxicity Summary
IDENTIFICATION AND USE: Valsartan is a white to practically white fine powder that is formulated into oral tablets. Valsartan is an angiotensin II type 1 (AT1) receptor antagonist. It is used in the management of hypertension. Valsartan is also used to treat heart failure or left ventricular dysfunction after acute myocardial infarction. HUMAN EXPOSURE AND TOXICITY: The most likely manifestations of overdosage include hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. Depressed levels of consciousness, circulatory collapse and shock have been reported. The use of valsartan during pregnancy is contraindicated. While use during the first trimester does not suggest a risk of major anomalies, use during the second and third trimester may cause teratogenicity and severe fetal and neonatal toxicity. Fetal toxic effects may include anuria, oligohydramnios, fetal hypocalvaria, intrauterine growth restriction, prematurity, and patent ductus arteriosus. Anuria-associated anhydramnios/oligohydramnios may produce fetal limb contractures, craniofacial deformation, and pulmonary hypoplasia. Severe anuria and hypotension, resistant to both pressor agents and volume expansion, may occur in the newborn following in utero exposure to valsartan. ANIMAL STUDIES: There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for up to two years. Also, valsartan had no adverse effects on fertility of male or female rats and no teratogenic effects were observed when valsartan was administered to pregnant mice and rats. However, significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed in studies in which parental rats were treated with valsartan at oral, maternally toxic (reduction in body weight gain and food consumption) doses during organogenesis or late gestation and lactation. In rabbits, maternal toxic doses resulted in fetal resorptions, litter loss, abortions, and low fetal body weight as well as maternal mortality. Mutagenicity assays did not reveal any valsartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella (Ames) and E coli, a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with Chinese hamster ovary cells, and a rat micronucleus test.

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Hepatotoxicity
Valsartan has been associated with a low rate of serum aminotransferase elevations (
Likelihood score: D (Possible rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Milk levels after the lowest dose of the combination of valsartan and sacubitril (Entresto) are very low. If the highest recommended maternal dosage (6 times greater) produces proportionate milk levels, they would likely still be quite low. Valsartan is unlikely to affect the nursing infant.
◉ Effects in Breastfed Infants
Two women taking sacubitril 24 mg and valsartan 26 mg (Entresto) did not observe any symptoms in their breastfed infants. Their extent of breastfeeding was not reported.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Valsartan is highly bound to serum proteins (95%), mainly serum albumin.

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Interactions
Concurrent use of valsartan and warfarin did not affect the pharmacokinetics of valsartan or the anticoagulant effect of warfarin.
Concomitant use of potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene), potassium supplements, or potassium-containing salt substitutes with valsartan may result in increased hyperkalemic effects and, in patients with heart failure, increases in serum creatinine concentration.
Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists, including Diovan. Monitor serum lithium levels during concomitant use.
Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on Diovan and other agents that affect the RAS.
For more Interactions (Complete) data for VALSARTAN (11 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Marmoset gavage >1000 mg/kg (approximate)
LD50 Rat gavage >2000 mg/kg (approximate)

[1]. Valsartan ameliorates ageing-induced aorta degeneration via angiotensin II type 1 receptor-mediated ERK activity. J Cell Mol Med. 2014 Jun;18(6):1071-80.

[2]. Valsartan blocked alcohol-induced, Toll-like receptor 2 signaling-mediated inflammation in human vascular endothelial cells. Alcohol Clin Exp Res. 2014 Oct;38(10):2529-40.

[3]. Novel mechanism of cardiac protection by valsartan: synergetic roles of TGF-β1 and HIF-1α in Ang II-mediated fibrosis after myocardial infarction. J Cell Mol Med. 2015 Aug;19(8):1773-82.

[4]. Cardioprotective effect of valsartan in mice with short-term high-salt diet by regulating cardiac aquaporin 1 and angiogenic factor expression. Cardiovasc Pathol. 2015 Jul-Aug;24(4):224-9.

[5]. Valsartan reverses depressive/anxiety-like behavior and induces hippocampal neurogenesis and expression of BDNF protein in unpredictable chronic mild stress mice. Pharmacol Biochem Behav. 2014 Sep;124:5-12.

Therapeutic Uses
Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents
Diovan is an angiotensin II receptor blocker (ARB) indicated for: treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. /Included in US product labeling/
Diovan is an angiotensin II receptor blocker (ARB) indicated for: reduction of cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction. /Included in US product labeling/
Diovan is an angiotensin II receptor blocker (ARB) indicated for: treatment of heart failure (NYHA class II-IV); Diovan significantly reduced hospitalization for heart failure. /Included in US product labeling/
For more Therapeutic Uses (Complete) data for VALSARTAN (6 total), please visit the HSDB record page.

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Drug Warnings
/BOXED WARNING/ WARNING: FETAL TOXICITY. When pregnancy is detected, discontinue Diovan as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Diovan as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimesters of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Diovan, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Diovan for hypotension, oliguria, and hyperkalemia.
Angiotensin II (A-II) is the main effector of the renin-angiotensin system. A-II functions by binding its type 1 (AT1) receptors to cause vasoconstriction and retention of sodium and fluid. Several AT1 receptor antagonists-a group of drugs collectively called "sartans"-have been marketed during the past few years for treatment of hypertension and heart failure. At least 15 case reports describe oligohydramnios, fetal growth retardation, pulmonary hypoplasia, limb contractures, and calvarial hypoplasia in various combinations in association with maternal losartan, candesartan, valsartan, or telmisartan treatment during the second or third trimester of pregnancy. Stillbirth or neonatal death is frequent in these reports, and surviving infants may exhibit renal damage. The fetal abnormalities, which are strikingly similar to those produced by maternal treatment with angiotensin-converting enzyme (ACE) inhibitors during the second and third trimesters of pregnancy, are probably related to extreme sensitivity of the fetus to the hypotensive action of these drugs. ...
Valsartan is distributed into milk in rats. It is not known whether valsartan is distributed into human milk. Discontinue nursing or the drug because of potential risk in nursing infants.
For more Drug Warnings (Complete) data for VALSARTAN (21 total), please visit the HSDB record page.

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Pharmacodynamics
Valsartan inhibits the pressor effects of angiotensin II with oral doses of 80 mg inhibiting the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan. In multiple-dose studies in hypertensive patients, valsartan had no notable effects on total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid. **Hypotension** Excessive hypotension was rarely seen (0.1%) in patients with uncomplicated hypertension treated with valsartan alone. In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur. This condition should be corrected prior to administration of valsartan, or the treatment should start under close medical supervision. Caution should be observed when initiating therapy in patients with heart failure. Patients with heart failure given valsartan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients. If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. **Impaired Renal Function** Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on valsartan. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on valsartan. **Hyperkalemia** Some patients with heart failure have developed increases in potassium. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of valsartan may be required.

C24H29N5O3

435.52

435.227

C, 66.19; H, 6.71; N, 16.08; O, 11.02

137862-53-4

Sacubitril/Valsartan;936623-90-4;Valsartan-d9;1089736-73-1;Valsartan-d3;1331908-02-1;Valsartan-d8;1089736-72-0;(Rac)-Valsartan-d9; 137862-53-4; 149690-05-1 (sodium)

60846

White to off-white solid

1.2±0.1 g/cm3

684.9±65.0 °C at 760 mmHg

116-117°C

368.0±34.3 °C

0.0±2.2 mmHg at 25°C

1.587

4.75

2

6

10

32

608

1

O([H])C([C@]([H])(C([H])(C([H])([H])[H])C([H])([H])[H])N(C(C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H])=O)C([H])([H])C1C([H])=C([H])C(C2=C([H])C([H])=C([H])C([H])=C2C2N=NN([H])N=2)=C([H])C=1[H])=O

ACWBQPMHZXGDFX-QFIPXVFZSA-N

InChI=1S/C24H29N5O3/c1-4-5-10-21(30)29(22(16(2)3)24(31)32)15-17-11-13-18(14-12-17)19-8-6-7-9-20(19)23-25-27-28-26-23/h6-9,11-14,16,22H,4-5,10,15H2,1-3H3,(H,31,32)(H,25,26,27,28)/t22-/m0/s1

(S)-3-methyl-2-(N-{[2-(2H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl]methyl}pentanamido)butanoic acid

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 (5.74 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), suspension 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 (5.74 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 3: 10 mg/mL (22.96 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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