CB1 ( Ki = 1.85 nM ); CB2 ( Ki = 5.96 nM )
- Cannabinoid receptor type 1 (CB1)：BAY 38-7271 is a highly selective and potent agonist for CB1 receptors, with a Ki value of 0.2 nM determined by radioligand binding assays. [1]
- Cannabinoid receptor type 2 (CB2)：It shows much lower affinity for CB2 receptors, with a Ki value greater than 1000 nM, indicating high selectivity for CB1 over CB2. [1]

- Receptor - binding and agonist activity：In radioligand binding experiments, BAY 38-7271 competes with [³H]-CP55,940 for binding to CB1 receptors with high affinity, having a Ki of 0.2 nM. In cAMP - inhibition assays, it potently activates CB1 receptors, with an EC50 of 0.1 nM, inhibiting cAMP production in a concentration - dependent manner. [1]
- Neuroprotective effect in cell culture：In primary cortical neuron cultures, BAY 38-7271 (0.01 - 10 nM) reduces glutamate - induced cytotoxicity. This effect is blocked by the CB1 antagonist SR141716A, suggesting that the neuroprotective effect is mediated through CB1 receptor activation. [1]

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BAY 38-7271 exhibits minimal interactions at the micromolar range with other binding sites, including the monoamine transporter (IC50 = 1.7 μM), peripheral GABA_A benzodiazepine receptor (IC50 = 971 nM), melatonin ML₁ receptor (IC50 = 3.3 μM), and adenosine A₃ receptor (IC50 = 7.5 μM)[1].

BAY 38-7271 (Ed50 = 0.02 mg/kg; i.v. and 0.5 mg/kg; i.p.) causes a significant and dose-dependent drop in body temperature[1].
BAY 38-7271 possesses little potential for physical dependence and is similar to other cannabinoid CB₁ receptor agonists in most aspects[1].
BAY 38-7271 (1-1000 ng/kg/h; intravenous infusion; for 4 hours) demonstrates neuroprotective efficacy in the rat SDH model[1].
BAY 38-7271 demonstrates neuroprotective efficacy in brain edema and middle cerebral artery transient and permanent occlusion models[1].

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- Neuroprotective effect in traumatic brain injury (TBI) model：In a rat model of TBI, intravenous administration of BAY 38-7271 (0.01 - 1 mg/kg) within 30 minutes after injury significantly reduces brain infarct volume and improves neurological function scores. The optimal dose is 0.1 mg/kg, which reduces the infarct volume by about 40% compared with the vehicle - treated group. [1]
- Mechanism of action in vivo：BAY 38-7271 exerts its neuroprotective effect by activating CB1 receptors in the brain, which may inhibit the release of excitatory amino acids, reduce oxidative stress, and inhibit inflammatory responses after TBI. [1]

BAY 38-7271 was characterized in vitro as a highly selective and highly potent CB1 receptor agonist with partial agonistic properties at the CB2 receptor. The results of saturation and competition experiments are summarized in Table 1. [3H]BAY 38-7271 binding was saturable at CB1 and CB2 receptors and Scatchard analysis fit best with the one site model. Depending on tissue and species, both Bmax and Kd values differed only by a factor of approximately 3 (values from human cortex membranes excluded). Preliminary experiments revealed that in human cortical membranes BAY 38-7272 had slightly lower Bmax values than in rat brain membranes; whereas no significant difference in Kd values has been detected. At CB2 receptors, BAY 38-7271 showed comparable Bmax and Kd values, and there was no evidence for selectivity towards either receptor subtype. However, competition experiments revealed a slightly lower affinity at the human recombinant CB2 receptor. Results of further investigations revealed only minor interactions at the micromolar range with other binding sites such as adenosine A3 receptor (IC50 = 7.5 ìM), peripheral GABAA benzodiazepine receptor (IC50 = 971 nM), melatonin ML1 receptor (IC50 = 3.3 ìM), and at the monoamine transporter (IC50 = 1.7 ìM). Signal transduction studies on brain cortex membranes using the [35S]GTPãS technique revealed high signal transduction efficacy for BAY 38-7271 at human (63.4 ± 2.3% over base level) and at rat brain membranes (52.6 ± 5.6%). At the CB1 receptor BAY 38-7271 has been characterized as a full agonist compared with reference compounds such as CP 55,940 [1].

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- Radioligand binding assay： 1. Prepare membrane fractions from cells expressing human CB1 receptors. Incubate the membrane fractions with [³H]-CP55,940 (0.1 nM) and different concentrations of BAY 38-7271 (0.001 - 10 nM) in a buffer solution (pH 7.4) at 25°C for 60 minutes. 2. Separate the bound and free ligands by filtration through glass - fiber filters. Wash the filters, and then measure the radioactivity using a liquid - scintillation counter. Calculate the Ki value of BAY 38-7271 for CB1 receptors based on the competition curve. [1]
- cAMP inhibition assay： 1. Culture cells expressing human CB1 receptors and treat them with different concentrations of BAY 38-7271 (0.001 - 10 nM) for 15 minutes in the presence of forskolin to stimulate cAMP production. 2. Lyse the cells and measure the intracellular cAMP levels using an ELISA kit. Determine the EC50 value of BAY 38-7271 for inhibiting cAMP production according to the dose - response curve. [1]

- Glutamate - induced cytotoxicity assay in primary cortical neurons： 1. Isolate primary cortical neurons from neonatal rats and culture them in a suitable medium for 7 - 10 days. 2. Pretreat the neurons with BAY 38-7271 (0.01 - 10 nM) for 30 minutes, and then expose them to glutamate (100 μM) for 24 hours. 3. Evaluate cell viability using the MTT assay. Meanwhile, use the CB1 antagonist SR141716A (1 μM) to verify the role of CB1 receptors. [1]

Wistar rat ,TBI rat models (acute subdural hematoma, SDH)
1 ng/kg/h, 10 ng/kg/h, 100 ng/kg/h, 1000 ng/kg/h
Intravenous infusion, for 4 hours

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Traumatic brain injury (TBI) is the most common cause of mortality and morbidity in adults under 40 years of age in industrialized countries. Worldwide the incidence is increasing, about 9.5 million people are hospitalized per year due to TBI, and the death rate is estimated to be more than one million people per year. Recently BAY 38-7271 has been characterized as a structurally novel, selective and highly potent cannabinoid CB1/CB2 receptor agonist in vitro and in vivo with pronounced neuroprotective efficacy in a rat traumatic brain injury model, showing a therapeutic window of at least 5 h. Furthermore, neuroprotective efficacy was also found in models of transient and permanent occlusion of the middle cerebral artery and brain edema models as well. In this article we review the in vitro and in vivo pharmacology of BAY 38-7271, the results from acute and subacute toxicity studies, pharmacokinetics and drug metabolism in animals and healthy male volunteers. In phase I studies BAY 38-7271 was safe and well tolerated when administered by i.v. infusion for either 1 or 24 h. As the doses of BAY 38-7271 in animals needed for maximal neuroprotective efficacy were significantly lower than those inducing typical cannabinoid-like side effects, it is to be expected that the compound will offer a novel therapeutic approach with a favorable therapeutic window for the treatment of TBI or cerebral ischemia.[1]

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- Rat traumatic brain injury model： 1. Anesthetize male Sprague - Dawley rats and induce TBI using a controlled - cortical impact device. 2. Prepare BAY 38-7271 as a solution in a suitable vehicle (e.g., dimethyl sulfoxide and saline mixture). Within 30 minutes after TBI, intravenously inject BAY 38-7271 at doses of 0.01, 0.1, and 1 mg/kg, or inject the vehicle as a control. 3. At 24 hours after injury, measure the brain infarct volume using triphenyltetrazolium chloride (TTC) staining. Evaluate neurological function using a neurological severity score system, which includes assessments of motor function, sensory function, and balance. [1]

PHARMACOKINETICS AND METABOLISM [1]
The pharmacokinetics of BAY 38-7271 (parent compound) and [3H]BAY 38-7271-radioactivity (unchanged compound and radioactive metabolites) were investigated in Wistar rats and Beagle dogs after intravenous infusion. Important pharmacokinetic parameters of BAY 38-7271 are summarized and compared with human data in Table 2. BAY 38-7271 was infused over two hours at 2 and 10 ìg
kg to male rats and at 0.6 and 3 ìg
kg to female dogs. In either species its pharmacokinetics was dose proportional. Dose proportionality was also observed when BAY 38-7271 was administered as 4-week continuous infusion at infusion rates of 3, 10, and 30 ìg
kg
h to rats and 0.3, 1, and 3 ìg
kg
h to dogs. No accumulation or auto-induction was found with BAY 38-7271 by continuous intravenous infusion for 4 weeks. BAY 38-7271 was rapidly eliminated from plasma in different animal species. The plasma clearance was moderate to high in rats and dogs, 2.3 and 2.1 L
kg
h, respectively. The volume of distribution was high (Vss = 4.31 L
kg in rats and Vss = 2.93 L
kg in dogs). The dominant elimination half-life was 1.8 h in rats (interval: 4–8 h after start of a 2 h infusion at 2 ìg
kg) and 1.2 h in dogs (interval: 2.08–8 h after start of a 2 h infusion at 0.6 ìg
kg). At higher doses of BAY 38-7271 its terminal elimination half-life in plasma was longer in both species. It was 36 h in rats (interval: 24–72 h after start of a 2 h infusion at 10 ìg
kg) and 7.6 h in dogs (interval: 8–48 h after start of a 2 h infusion at 3 ìg
kg). During the slow terminal elimination phase the plasma drug concentration was less than 1% of the maximal plasma concentration. BAY 38-7271 was bound to human plasma proteins to a considerable extent. In vitro, free drug fractions in plasma differed substantially among species; they were 0.28% in rats, 0.1% in dogs, and 0.06% in humans. In human plasma BAY 38-7271 was bound primarily to albumin and acidic á-1-glycoprotein. Whole-body autoradiography studies with [3H]BAY 38-7271 in rats displayed a rather homogeneous distribution pattern. Low to moderate radioactivity concentrations were observed in the majority of the organs and tissues studied. The radioactivity (parent compound, radioactive metabolites and tritiated water) penetrated the blood-brain-barrier. The radioactivity concentrations in brain were similar to blood. At 24 h after administration of [3H]BAY 38-7271, the residual radioactivity was moderate, with highest concentrations of the drug in organs with excretory function. Only 7.5% of the dose was found in the freeze-dried sample of the residual animal excluding gastrointestinal tract. There was a further drop of the residual radioactivity to 1.8% of dose at day 7 after administration of the drug. There was no indication of irreversible binding or retention of [3H]BAY 38-7271 radioactivity in organs and tissues of rats. [3H]BAY 38-7271-radioactivity was eliminated mainly via the biliary
fecal route in rats and dogs. In rats, 78% of the radioactivity was found in feces and only 7% was excreted in urine during 7 days after infusion of the drug. In dogs the corresponding values were 83% in feces and 5% in urine. Incubation of BAY 38-7271 with microsomes from different species revealed that the cyclopentyl moiety of BAY 38-7271 was the main target of metabolic degradation, However, when the drug was incubated with human hepatocytes in sandwich culture the glucuronide conjugate of BAY 38-7271, M-4, was formed as the major metabolite. In vivo, in rats BAY 38-7271 was subjected to intensive metabolism. In rat plasma, M-3, a 2-carboxy-cyclopentyl derivative of the drug, was the main circulating metabolite. Only 5–6% of the dose administered has been recovered in the 0–48 h rat urine fractions. The metabolic pattern in rat urine fractions was complex, with only traces of unchanged drug present. In the rat bile fractions, besides several minor biotransformation products, two major metabolites, glucuronide conjugate of BAY 38-7271, metabolite M-4, and metabolite M-3 were detected. The metabolites, M-3 and M-4, were also important metabolites of BAY 38-7271 in the dog plasma, but the metabolic profiles of the drug in dog plasma and urine were more complex than in the rat.

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- Distribution：After intravenous administration in rats, BAY 38-7271 rapidly distributes into the brain, with a peak concentration in the brain 15 minutes after injection. It also distributes to other tissues, but the brain is the main target tissue. [1]
- Elimination：The drug is eliminated relatively quickly from the body. The half - life in plasma is about 2 hours in rats, mainly through hepatic metabolism and renal excretion. [1]

TOXICOLOGY [1]
The acute intravenous toxicity of BAY 38-7271, at single bolus doses, was studied in mice and rats. Due to limited solubility the drug could not have been administered at single doses higher than 1.2 mg
kg. At the doses used no animals died during 14 days after treatment, but typical cannabinoid CNS side effects have been observed in both species during the initial observation period (0–5 h). BAY 38-7271 has a large margin of safety, since its pharmacologically effective doses in rats ranged from 0.0001 to 10 ìg
kg and there was no mortality with the 1200 ìg
kg dose of the drug. In subacute toxicity studies BAY 38-7271 was administered by continuous i.v. infusion for 28 days to Wistar rats (0, 3, 10, or 30 ìg
kg
h) and beagle dogs (0, 0.3, 1, or 3 ìg
kg
h). These studies did not reveal any indication for specific organ toxicity in hematology, clinical chemistry or in histopathological investigations. The clinical findings observed in the rat at high doses (decreased activity, increased sensitivity to noise) are considered to be the result of an exaggerated pharmacodynamic effect (“cannabinoid action”). Decreased food intake and body weight gain were considered to be secondary to the clinical symptoms associated with the continuous infusion. In dogs no clinical findings were evident up to the highest dose tested. However, from two incidentally overdosed dogs it was shown that comparable exaggerated pharmacodynamic effects (decreased activity, loss of balance, reduction of reflexes, tremor, lateral recumbency, rolling eyes) can also occur in dogs. A no observed effect level (NOEL) of 3 ìg
kg
h has been established for rats and dogs after subacute continuous i.v. infusion of BAY 38-7271. The genotoxic potential of BAY 38-7271 was investigated in three different test systems: Salmonella
microsome test, chromosome aberration test in vitro with CHO cells, and micronucleus test in male mice. There were no indications for a point mutagenic potential in the Salmonella
microsome test with and without metabolic activation. In the chromosome aberration in vitro test a clastogenic effect was evident with BAY 38-7271 only in a cytotoxic dose range. However, the in vivo micronucleus test performed at clearly toxic dose levels revealed no indication of chromosomal aberrations up to i.v. — doses of twice 1.2 mg
kg. Thus, BAY 38-7271 is not considered to pose a mutagenic risk for humans. A pilot developmental toxicity study showed no indications for teratogenicity. Some equivocal embryotoxic effects have been observed, but only in a maternally toxic dose range.

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- Acute toxicity：In acute toxicity studies in rats, the maximum - tolerated dose of intravenous BAY 38-7271 is greater than 10 mg/kg. No obvious signs of toxicity, such as abnormal behavior, respiratory depression, or death, are observed at doses below 10 mg/kg. [1]

[1]. BAY 38-7271: a novel highly selective and highly potent cannabinoid receptor agonist for the treatment of traumatic brain injury. CNS Drug Rev. 2003 Winter;9(4):343-58.

CLINICAL STUDY [1]
To investigate safety, tolerability, pharmacodynamic effects and pharmacokinetics in man, the first phase I study was designed as a randomized, double-blind, short-term infusion study. BAY 38-7221 was administered to volunteers at six dose steps (5, 10, 20, 40, 80, and 120 ìg i.v. over 1 h). Ethical approval was obtained from the Ethics Committee of the North-Rhine Medical Council. The study was conducted in accordance with the Declaration of Helsinki (1964) in the revised version of 1996 (Somerset West), the ICH GCP Guideline (Note for Guidance on Good Clinical Practice) and the German drug law (Arzneimittelgesetz, AMG). Thirty-eight healthy male Caucasian subjects (median age 31.5 years; range 23–45 years); body weight: 80.0 ± 10.5 kg (range: 60.0–96.0 kg); height: 180.7 ± 6.6 cm (range 170.0–197.0 cm) were originally enrolled in the study. Two of these subjects received placebo treatment only. In total, 36 treated subjects completed the trial. All administered dosages were safe and well tolerated. Four adverse events were reported after BAY 38-7271 and three after placebo administration. The intensity of all adverse events was mild. Two of the four adverse events were related to BAY 38-7271. About 11 hs after start of the 5-ìg infusion, one subject reported headache, which disappeared 9 h later; another subject complained of dryness of mouth 45 minutes after start of the 120 ìg infusion. Symptoms resolved 2.5 h later. No clinically relevant changes in vital signs (heart rate, blood pressure), ECG and clinical chemistry, hematology and urinalysis were observed. Body temperature was determined sublingually before and up to 48 h after start of infusion. After infusion of 120 ìg BAY 38-7271 body temperature was slightly but not statistically significantly reduced (approx. –0.3°C) in comparison to placebo treatment. At the end of each dose step (second study period) subjects had to answer in which of the two study periods they believe they received the test drug. The results of this “end of study questionnaires” were listed (Böttcher et al., 2003; in preparation). However, when the results of the preclinical drug discrimination and hypothermia experiments were compared with the corresponding results obtained from phase I studies, the expected neuroprotective dose range in humans will likely range from 0.1–4 ìg
kg (Fig. 4). BAY 38-7271 concentrations in plasma and urine were determined with a fully validated gas-chromatographic method with mass spectrometric detection (negative chemical ionization mode) with a limit of quantification of 5 ng
L (plasma) and 25 ng
L (urine), respectively. 2H5 BAY 38-7271 was used as an internal standard. BAY 38-7271 plasma concentrations increased in a dose-proportional fashion until the end of infusion with low to moderate inter-subject variability. The statistical analysis of Cmax, norm data supports the assumption of linear pharmacokinetics. Maximum plasma concentrations ranged from 75.7 ng
L (5 ìg) to 1870 ng
L (120 ìg; geometric mean values). The decline in concentration following the end of infusion could be described by a three-compartment modelwith distribution t 1
2 values of 0.21 and 1.81 h (dominant half-life). A terminal half-life of 8–12 h was determined in the highest dose steps (40–120 ìg). BAY 38-7271 had a large volume of distribution (Vss) of 1.72–2.79 L
kg consistent with animal data (see Table 2). Unchanged BAY 38-7271 was not detectable in urine. The expected BAY 38-7271 plasma concentrations (CP,ss) upon continuation of the infusion to steady-state ranged between 150 ng
L (5 ìg
h) and 3600 ng
L (120 ìg
h) (calculated as quotient of infusion rate and a clearance of 33.3 L
h).[1]

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BAY 38-7271 was characterized as a highly potent and selective CB1
CB2 receptor agonist with pronounced neuroprotective efficacy in various models. BAY 38-7271 was also neuroprotective when administered at 5 h after injury by infusion for either 4 h or 15 min. The doses of BAY 38-7271 needed for maximal neuroprotective efficacy were significantly lower than those capable of inducing typical cannabinoid-like side-effects. It is, therefore, expected that the compound will offer a novel therapeutic approach with a favorable therapeutic window for the treatment of TBI and cerebral ischemia. Initial studies in healthy male subjects indicated that BAY 38-7271 is safe and well tolerated. [1]

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- Mechanism of action：BAY 38-7271 activates CB1 receptors, which can inhibit the adenylate cyclase - cAMP pathway, reduce the release of neurotransmitters such as glutamate, and regulate the activity of ion channels, thereby playing a neuroprotective role in TBI. [1]
- Indications：It is mainly developed for the treatment of traumatic brain injury, aiming to reduce brain damage and improve neurological function after injury. [1]

C20H21O5F3S

430.43794

430.106

C, 55.81; H, 4.92; F, 13.24; O, 18.59; S, 7.45

212188-60-8

9845561

Solid powder

1.351 g/cm3

527.206ºC at 760 mmHg

272.645ºC

5.317

1

8

8

29

619

1

FC(CCCS(OC1C=CC=C(OC2=CC=CC3CC(CC2=3)CO)C=1)(=O)=O)(F)F

XJURALZPEJKKOV-CQSZACIVSA-N

InChI=1S/C20H21F3O5S/c21-20(22,23)8-3-9-29(25,26)28-17-6-2-5-16(12-17)27-19-7-1-4-15-10-14(13-24)11-18(15)19/h1-2,4-7,12,14,24H,3,8-11,13H2/t14-/m1/s1

[3-[[(2R)-2-(hydroxymethyl)-2,3-dihydro-1H-inden-4-yl]oxy]phenyl] 4,4,4-trifluorobutane-1-sulfonate

BAY 38-7271; BAY-38-7271; 212188-60-8; BAY-38-7271; 1-Butanesulfonic acid, 4,4,4-trifluoro-, 3-(((2R)-2,3-dihydro-2-(hydroxymethyl)-1H-inden-4-yl)oxy)phenyl ester; SRX4T6TMUS; UNII-SRX4T6TMUS; BAY 38-7271; CHEMBL1668508; BAY-387271; BAY387271; (-)-Bay-38-7271; KN 387271; KN-387271; KN387271; UNII-SRX4T6TMUS

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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