Macrolide;Toxoplasma

Treatment with spiramycin (24 hours; 1-1000 μM; T. gondii-infected HeLa cells and HeLa cells) decreases the cytotoxicity and exhibits anti-Toxoplasma gondii activity, with IC50 values of 189 μM for HeLa cells and 262 μM for T. gondii-infected HeLa cells[3].

Treatment with spiramycin (100 mg/kg; intraperitoneal injection; daily; for 4 days; female KM mice) decreases tachyzoites, hepatotoxicity, and greatly increases antioxidative effects. Treatment with piramycin also lessens the liver's granulomatous inflammation[3].

Cell Line: T. gondii infected HeLa cells and HeLa cells
Concentration: 1-1000 μM
Incubation Time: 24 hours
Result: Reduced the cytotoxicity.

Animal Model: 36 female KM mice with T.gondii[3]
Dosage: 100 mg/kg
Administration: Intraperitoneal injection; every day; for 4 days
Result: Tachyzoites were considerably fewer in number. decreased hepatotoxicity and markedly increased antioxidative benefits. Formation of cysts and granulomas was inhibited.

Absorption, Distribution and Excretion
Spiramycin is not completely absorbed. Oral bioavailability is 30-39%. Spiramycin is absorbed more slowly than erythromycin. Its pKa value is high (7.9), likely due to its high ionization in the acidic environment of the stomach. The fecal-biliary route is the primary route of excretion. The secondary route is the renal-urinary route. Spiramycin has a wide tissue distribution. Its volume of distribution exceeds 300 liters, and its concentrations in bones, muscles, respiratory tract, and saliva are higher than in serum. Spiramycin reaches higher concentrations in tissues such as the lungs, bronchi, tonsils, and sinuses. 80% of the administered dose is excreted via bile, making the fecal-biliary route the most important. Enterohepatic circulation may also occur. Only 4% to 14% of the administered dose is cleared via the renal-urinary route. Spiramycin is well absorbed in the human body after oral administration. In healthy young adult males, after oral administration of 15-30 mg/kg body weight, peak plasma concentrations are reached within 3-4 hours, with plasma concentrations ranging from 0.96-1.65 mg/L. Following intravenous administration (7.25 mg/kg body weight), a larger volume of distribution (Vdss 5.6 L/kg) was observed, indicating extensive tissue distribution. Biotransformation appears to be unimportant. Bile excretion is the primary route of excretion; only 7-20% of the oral dose is excreted in the urine. Spiramycin is known to achieve high tissue/serum concentration ratios in lung, prostate, and skin tissues. Spiramycin can cross the placenta and enter the fetus. After daily administration of 2 g of the antibiotic, the concentrations in maternal serum, umbilical cord blood, and placenta were 1.19 μg/mL, 0.63 μg/mL, and 2.75 μg/mL, respectively. When the maternal dose was increased to 3 g daily, these concentrations were 1.69 μg/mL, 0.78 μg/mL, and 6.2 μg/mL, respectively. Based on these results, the concentration ratio of umbilical cord blood to maternal serum was approximately 0.5. Furthermore, at these doses, the concentration of spiramycin in the placenta was approximately 2-4 times that in maternal serum. ...Spiramycin is secreted into milk. Infants nursed by mothers who received 1.5 g of spiramycin daily for three consecutive days had a serum spiramycin concentration of 20 μg/mL. This concentration exhibits antibacterial activity. Spiramycin is a macrolide antibiotic effective against most microorganisms isolated from the milk of mastitis-affected cows. This study investigated the distribution of spiramycin in plasma and milk after intravenous, intramuscular, and subcutaneous injections. Twelve healthy dairy cows were single-dose spiramycin injections at doses of 30,000 IU/kg via the three routes described above. Plasma and milk samples were collected after injection. The concentration of spiramycin in plasma was determined by high-performance liquid chromatography (HPLC), and the concentration of spiramycin in milk was determined using microbiological methods. Following intravenous administration, the mean residence time of spiramycin in breast milk (20.7 ± 2.7 h) was significantly longer than that in plasma (4.0 ± 1.6 h) (P < 0.01). The mean breast milk/plasma concentration ratio was calculated to be 36.5 ± 15 based on the area under the concentration-time curve. To determine the bioequivalence of the two extravascular administration routes, several pharmacokinetic parameters were investigated. Intramuscular or subcutaneous administration resulted in nearly 100% absorption, demonstrating bioequivalence to the extravascular route, although significant differences were observed in absorption rate, maximum plasma concentration, and time to peak concentration between the two routes. There was no difference in spiramycin excretion in breast milk between the two extravascular routes, but the latter was not bioequivalent in terms of maximum plasma concentration in breast milk. However, the two routes were bioequivalent for the duration during which spiramycin concentrations in breast milk exceeded the minimum inhibitory concentration (MIC) for various pathogens causing breast infections. Plasma protein binding ranged from 10% to 25%. Following oral administration of 6 million units, peak plasma concentration was 3.3 μg/mL 1.5 to 3 hours later; the half-life was approximately 5 to 8 hours. Even when plasma concentrations decreased to low levels, tissue concentrations remained high. For more complete data on the absorption, distribution, and excretion of spiramycin (13 in total), please visit the HSDB record page.
Metabolism/Metabolites
Spiramycin is metabolized less readily than some other macrolide antibiotics. Its metabolic processes have not been fully studied. It is primarily metabolized in the liver to its active metabolite. In cattle, a metabolite called neospiramycin, a norcarboxylic acid derivative, is produced. 14–28 days after administration, neospiramycin concentrations in muscle and kidneys were slightly higher than spiramycin; the concentrations of neospiramycin and spiramycin in muscle were approximately equal. Spiramycin is metabolized in the liver to its active metabolite; most is excreted via bile, and approximately 10% is excreted via urine.

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Biological Half-Life
Intravenous injection: Young adults (18 to 32 years): Approximately 4.5 to 6.2 hours. Older adults (73 to 85 years): Approximately 9.8 to 13.5 hours. Oral administration: 5.5 to 8 hours; Rectal administration in children: 8 hours.
The half-life of a 6 million oral dose is approximately 5 to 8 hours.

Toxicity Summary
Identification and Uses: Spiramycin is a macrolide antibiotic used to treat and control a variety of bacterial and mycoplasmal infections in animals. It is administered in animal feed as spiramycin embryate and via other routes of administration in the more soluble adipate form. It has also been used to treat protozoan infections such as cryptosporidiosis and toxoplasmosis. Human Exposure and Toxicity: Spiramycin has been reported to cause contact dermatitis in occupational settings. A man working in a feed mill developed allergic contact dermatitis after inhaling airborne spiramycin. The patient experienced recurrent eczematous lesions on exposed areas during work. Spiramycin has also been reported to cause hypersensitivity reactions. A 34-year-old woman developed nasal conjunctivitis and spasmodic cough after exposure to spiramycin powder at a pharmaceutical factory. The patient developed symptoms within hours of exposure and they persisted for several hours after leaving the workplace. A 35-year-old non-allergic maintenance engineer developed sneezing, coughing, and difficulty breathing after working in the pharmaceutical industry for a year. In an inhalation provocation test conducted in a hospital, gradually increasing the dose of spiramycin induced his symptoms and led to a delayed asthmatic reaction. In addition, two other cases of bronchial asthma induced by spiramycin were reported, both patients being pharmaceutical factory workers. After exposure to spiramycin powder at work, the patients developed cough, dyspnea, and asthma symptoms. Symptoms disappeared after 3 to 4 days of rest. Animal experiments: Two male and two female cynomolgus monkeys (Macaca fascicularis) were intravenously injected daily with 0, 240,000, 360,000, and 540,000 IU/kg body weight/day of spiramycin adipic acid, respectively, for 5 consecutive days. Excessive salivation occurred in all dose groups during the injection period. Several monkeys in the high-dose group and one monkey in the low-dose group experienced hypotonia and nausea/convulsions. All test animals showed no abnormalities in body weight, but food intake was reduced. The high-dose group showed a slight decrease in hemoglobin, red blood cell count, and hematocrit. In a short-term dietary study, rats were given a dose equivalent to 3900 mg/kg body weight for 13 consecutive weeks. The main effects observed were only decreased neutrophil counts and cecal dilatation in some medium- and high-dose groups. In another rat dietary study, animals were given a dose equivalent to 720 mg/kg body weight daily for one year. The only significant effect was weight loss in female rats receiving the high dose, while the relative weight of the liver, kidneys, and adrenal glands increased in rats in the high-dose groups (including both males and females). Glycogen depletion was observed in all dose groups, but not in the control group. In mongrel dogs, decreased spermatogenesis and testicular atrophy, along with kidney damage, were observed after 56 consecutive days of daily administration of 500 mg/kg body weight. In beagle dogs, oral administration of spiramycin equivalent to 150 mg/kg body weight daily for two years did not result in testicular damage, but degenerative changes were observed in other organs. In a mouse teratogenicity study, oral administration of up to 400 mg/kg body weight of spiramycin on days 5–15 of gestation had no effect on pregnancy outcomes. Intravenous injection of spiramycin adipic acid in rats during days 6-15 of gestation and in rabbits during days 6-19 of gestation at doses up to 84 mg/kg body weight/day had no effect on development; however, oral administration of 200 and 400 mg/kg body weight/day to rabbits caused cecal enlargement in the mothers. Twenty pregnant rats were divided into several groups and intravenously injected with 0, 90,000, 180,000, and 270,000 IU/kg body weight/day, respectively, during days 6-15 of gestation. The highest dose group showed transient (5 minutes) ataxia and tremor immediately after administration. The intermediate dose group showed a slight but significant decrease in fetal weight, but all values were within the historical control range. No increase in fetal malformation was observed in this study. In one study, male rats were administered 30 mg/kg body weight/day for 8 consecutive days (route of administration unknown), and abnormalities in mitosis and meiosis were observed in spermatogonia. In in vitro mammalian cell forward mutation assays, in vitro cytogenetics assays, and mouse micronucleus assays, neither spiramycin adipic acid nor spiramycin enbranoate produced any adverse reactions. Protein Binding: Low protein binding (10-25%). Interactions: Macrolide antibiotics include natural members, prodrugs, and semi-synthetic derivatives. These drugs are effective against a variety of infections and are often used in combination with other drugs, thus potentially leading to pharmacokinetic interactions. Macrolides can inhibit hepatic drug metabolism by forming complexes and inactivating microsomal drug oxidases, and can also interfere with the gut microbiota through their antibacterial activity. Over the past 20 years, numerous reports have indicated that macrolide antibiotics may be a potential source of serious clinical drug interactions. However, different macrolide antibiotics vary in this regard, and not all macrolide antibiotics cause drug interactions. With the advent of many semi-synthetic macrolide antibiotics in recent years, they are now clearly classified into three categories in terms of drug interaction. The first class (e.g., tromethorphan, erythromycin) readily forms nitrosoalkanes, leading to inactive cytochrome P450 metabolite complexes. The second class (e.g., josamycin, fluerythromycin, roxithromycin, clarithromycin, miomycin, and midemycin) forms complexes to a lesser extent, rarely causing drug interactions. The last group (e.g., spiramycin, roxithromycin, dirithromycin, and azithromycin) does not inactivate cytochrome P450 or alter the pharmacokinetics of other compounds. The induction of cytochrome P450 and the formation of inhibitory cytochrome P450-iron-nitrosoalkane metabolite complexes in vivo or in vitro by macrolide antibiotics appears to be due to two important structural factors: the presence of a sterically unhindered and easily accessible N-dimethylamino group in the macrolide molecule, and the hydrophobicity of the drug. Tromethorphan is a potent inhibitor of hepatic microsomal enzymes and significantly reduces the metabolism of methylprednisolone, theophylline, carbamazepine, phenazine (antipyrine), and triazolam. Traromycin can cause ergot poisoning in patients taking ergot alkaloids and cholestatic jaundice in patients taking oral contraceptives. Erythromycin and its various prodrugs appear to have weak inhibitory effects on drug metabolism. However, case reports and controlled studies have shown that erythromycin may interact with theophylline, carbamazepine, methylprednisolone, warfarin, cyclosporine, triazolam, midazolam, alfentanil, disopyramide, and bromocriptine, thereby reducing drug clearance. In patients excreting large amounts of reduced digoxin metabolites, erythromycin also appears to increase digoxin bioavailability, possibly due to disruption of the gut microbiota responsible for the production of these compounds. These macrolide antibiotics suspected of being involved in drug metabolism should not be used concomitantly with other drugs known to be affected by their metabolism, or at least, concomitant use should be conducted under close patient monitoring.
It has been reported that plasma concentrations of levodopa decrease when used concomitantly with spiramycin. The authors report a case of a 21-year-old female patient with congenital long QT syndrome who experienced multiple episodes of syncope, at least one of which was caused by torsades de pointes (TDPT). This sudden complication was attributed to the concomitant use of spiramycin and mequinazon within 48 hours. Although these two drugs belong to two classes that can induce TDPT, they are not considered precipitating factors for TDPT. After discontinuation of both drugs, the patient's syncope completely resolved. During a two-year follow-up, the initial QTc interval was significantly shortened, but still longer than normal. This case highlights the potential risks of combined use of these two classes of drugs, especially in patients with congenital long QT syndrome.

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Non-human toxicity values
Oral LD50 in rats: 3550 mg/kg
Intraperitoneal LD50 in rats: 575 mg/kg
Subcutaneous LD50 in rats: 1 g/kg
Intravenous LD50 in rats: 170 mg/kg
For more non-human toxicity values (complete data) for spiramycin (23 in total), please visit the HSDB record page.

[1]. Post-PKS tailoring steps of the spiramycin macrolactone ring in Streptomyces ambofaciens. Antimicrob Agents Chemother. 2013 Aug;57(8):3836-42.

[2]. Assessment of spiramycin-loaded chitosan nanoparticles treatment on acute and chronic toxoplasmosis in mice. J Parasit Dis. 2018 Mar;42(1):102-113.

[3]. Synthesis and Biological Evaluation of (+)-Usnic Acid Derivatives as Potential Anti-Toxoplasma gondii Agents. J Agric Food Chem. 2019 Aug 28;67(34):9630-9642.

Spiramycin is a macrolide antibiotic primarily acting as an inhibitor, active against Gram-positive cocci and bacilli, Gram-negative cocci, Legionella, Mycoplasma, Chlamydia, certain types of spirochetes, Toxoplasma gondii, and Cryptosporidium. Spiramycin is a 16-membered ring macrolide compound, first discovered in Streptomyces ambofaciens in 1952. Oral formulations have been available since 1955, and injectable formulations since 1987. Resistant bacteria include Enterobacteriaceae, Pseudomonas, and fungi. Spiramycin is a macrolide compound, initially discovered in Streptomyces ambofaciens, possessing antibacterial and antiparasitic activity. Although its exact mechanism of action is not fully elucidated, spiramycin may inhibit protein synthesis by binding to the 50S subunit of bacterial ribosomes. This drug can also prevent placental transmission of toxoplasmosis, and its mechanism may differ from the currently unclear mechanism. Drug Indications Macrolide antibiotics are used to treat various infections. Mechanism of Action The mechanism of action of macrolide antibiotics remains controversial. Spiramycin is a 16-membered ring macrolide antibiotic that binds to the bacterial 50S ribosomal subunit in a 1:1 apparent stoichiometry, thereby inhibiting ribosome translocation. This antibiotic effectively inhibits the binding of donor and acceptor substrates to the ribosome. Its primary mechanism of action is through stimulating the dissociation of peptidyl-tRNA from the ribosome during ribosome translocation. Therapeutic Uses Antibacterial drugs; anticoccidia drugs. ClinicalTrials.gov is a registry and results database that tracks human clinical studies funded by public and private institutions worldwide. This website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure being studied); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as NLM's MedlinePlus (for providing patient health information) and PubMed (for providing citations and abstracts of academic articles in the medical field). Spiramycin is indexed in this database.
Drug (Veterinary): Spiramycin is a macrolide antibiotic used to treat and control a variety of bacterial and mycoplasma infections in animals. Spiramycin is administered in animal feed in the form of emboside and in other routes of administration in the more soluble adipate form.
This study aims to evaluate the efficacy of spiramycin in preventing mother-to-child transmission of toxoplasmosis. Patients diagnosed with acute toxoplasmosis in early pregnancy (first trimester) who were positive for Toxoplasma gondii IgM antibodies (>0.65, ELISA, VIDAS) and IgG antibodies (>8 IU/ml), but with low IgG antibody affinity (<0.50, ELISA, Architet) were included in the diagnosis. These patients underwent amniocentesis at 19–21 weeks of gestation for Toxoplasma gondii DNA testing. Detailed ultrasound examinations were performed between 20–24 weeks of gestation, and both mother and fetus were followed up for at least one year. Of the 61 patients, 55 (90.2%) received spiramycin prophylaxis, while 6 (9.8%) refused. In the amniotic fluid obtained via amniocentesis at 19–21 weeks of gestation, 4 patients (6.6%) had positive Toxoplasma gondii PCR results. These 4 patients who refused spiramycin prophylaxis all had positive Toxoplasma gondii PCR results in their amniotic fluid (p < 0.01). Our results appear to support the use of spiramycin in pregnant patients with toxoplasmosis. Spiramycin is a macrolide antibiotic used similarly to erythromycin to treat infections caused by susceptible bacteria. It has also been used to treat protozoan infections such as cryptosporidiosis and toxoplasmosis.

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Drug Warnings
The most common adverse reaction is gastrointestinal discomfort. Transient paresthesia has been reported during injectable administration.
Spiramycin is a 16-membered macrolide antibiotic that has been used clinically for 15 years with few serious associated toxicities. Gastrointestinal discomfort is usually mild, and no changes in gastrointestinal motility have been observed in either experimental or human studies, unlike other macrolide antibiotics such as erythromycin. Allergic reactions are uncommon, mainly manifesting as transient skin rashes. Although liver injury is a potential complication of treatment with most macrolide antibiotics, there is currently no conclusive evidence that spiramycin causes hepatitis, and unlike most other macrolide antibiotics, biochemical, pharmacokinetic, and clinical studies have clearly demonstrated that spiramycin does not interact with other drugs.
...Allergic reactions to macrolide antibiotics are extremely rare, and there is very little literature on related diagnostic tests. Recently, we treated 21 patients suspected of having an allergic reaction to multiple macrolide antibiotics (mainly manifesting as urticaria). We performed skin prick and intradermal tests on these patients using injectable spiramycin and erythromycin. Of the 21 patients, 17 underwent provocation testing under close hospital monitoring. ...Only 3 patients had positive provocation test results, thus confirming a true allergy (to spiramycin allergy). Their skin tests for both tested macrolide antibiotics were positive. ...Therefore, most macrolide antibiotic hypersensitivity reactions are diagnosed through provocation testing.
We recently reported two cases of neonates experiencing QT interval prolongation and cardiac arrest after treatment with spiramycin (a macrolide antibiotic widely used for toxoplasmosis prevention). In this study, we evaluated the potential risk of this drug on ventricular repolarization and fatal arrhythmias in 8 newborns requiring toxoplasmosis prevention. Electrocardiograms (ECGs) and echocardiograms were recorded during spiramycin treatment (350,000 IU/kg/day) and after discontinuation. No significant differences were found between two ECG recordings in a control group of eight age- and sex-matched healthy newborns. The QT interval (QTc) after heart rate correction was prolonged during spiramycin treatment compared to after discontinuation (448 ± 32 ms vs 412 ± 10 ms, +9%, p=0.021). QTc dispersion (QTcmax-min, the difference between the longest and shortest QTc values in 12 different leads) was also higher during spiramycin treatment (60 ± 32 ms vs 34 ± 8 ms, +76%, p=0.021), primarily due to the significant prolongation of the longest QTc interval (QTcmax). Compared to six newborns who did not exhibit drug-induced symptoms, two newborns who experienced cardiac arrest after treatment initiation showed significantly increased QTc interval and QTc dispersion. During treatment, seven out of eight newborns developed a rare abnormality of thickening of the left ventricular posterior wall, resembling lesions in patients with congenital long QT syndrome. This abnormality disappeared after drug discontinuation. Therefore, antibiotic treatment with spiramycin in the neonatal period may induce QT interval prolongation and increased QT dispersion. When this effect on ventricular repolarization is more pronounced, it may promote the occurrence of torsades de pointes and lead to cardiac arrest.

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Pharmacodynamics
The absolute bioavailability of oral spiramycin is typically between 30% and 40%. After oral administration of 1 gram, peak serum drug concentrations range from 0.4 to 1.4 mg/L.

C43H74N2O14

843.0527

842.513

C, 61.26; H, 8.85; N, 3.32; O, 26.57

8025-81-8

8025-81-8;24916-52-7 (III);67724-08-7 (Embonate);68880-55-7 (adipate);

5289394

White to off-white solid powder

1.2±0.1 g/cm3

913.7±65.0 °C at 760 mmHg

506.4±34.3 °C

0.0±0.6 mmHg at 25°C

1.550

3.06

4

16

11

59

1370

19

O1[C@@]([H])(C([H])([H])[H])[C@@]([H])([C@@]([H])([C@@]([H])([C@@]1([H])O[C@]1([H])[C@]([H])([C@@]([H])(C([H])([H])C(=O)O[C@]([H])(C([H])([H])[H])C([H])([H])C([H])=C([H])C([H])=C([H])[C@@]([H])([C@]([H])(C([H])([H])[H])C([H])([H])[C@]1([H])C([H])([H])C([H])=O)O[C@@]1([H])C([H])([H])C([H])([H])[C@@]([H])([C@]([H])(C([H])([H])[H])O1)N(C([H])([H])[H])C([H])([H])[H])O[H])OC([H])([H])[H])O[H])N(C([H])([H])[H])C([H])([H])[H])O[C@]1([H])C([H])([H])[C@@](C([H])([H])[H])([C@@]([H])([C@@]([H])(C([H])([H])[H])O1)O[H])O[H] |c:39,43|

ACTOXUHEUCPTEW-AQKFJFIXSA-N

InChI=1S/C43H74N2O14/c1-24-21-29(19-20-46)39(59-42-37(49)36(45(9)10)38(27(4)56-42)58-35-23-43(6,51)41(50)28(5)55-35)40(52-11)31(47)22-33(48)53-25(2)15-13-12-14-16-32(24)57-34-18-17-30(44(7)8)26(3)54-34/h12-14,16,20,24-32,34-42,47,49-51H,15,17-19,21-23H2,1-11H3/b13-12+,16-14+/t24-,25-,26-,27-,28+,29+,30+,31-,32+,34+,35+,36-,37-,38-,39+,40+,41+,42+,43?/m1/s1

2-[(4R,5S,6S,7R,9R,10R,11E,13E,16R)-6-{[(2S,3R,4R,5S,6R)-5-{[(2S,5S,6S)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy}-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-10-{[(2R,5S,6R)-5-(dimethylamino)-6-methyloxan-2-yl]oxy}-4-hydroxy-5-methoxy-9,16-dimethyl-2-oxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde

HSDB-7027; Rovamycin; HSDB7027; HSDB 7027

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)

DMSO : 100~157 mg/mL ( 118.62~186.22 mM )
Ethanol : ~157 mg/mL

Solubility in Formulation 1: ≥ 2.5 mg/mL (2.97 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 (2.97 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 (2.97 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: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (2.97 mM)

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