Toxins, cholera(CAS No. 9012-63-9)

Identification and Related Records

【Name】
Toxins, cholera
【CAS Registry number】
9012-63-9
【Synonyms】
Choleratoxin
Cholera toxins
Choleragen
Choleragenoid
Toxins, exo-, cholera
【Molecular Formula】
C22H29FO5 (Products with the same molecular formula)
【Molecular Weight】
0
【Inchi】
InChI=1S/C22H29FO5/c1-12-8-16-15-5-4-13-9-14(25)6-7-19(13,2)21(15,23)17(26)10-20(16,3)22(12,28)18(27)11-24/h6-7,9,12,15-17,24,26,28H,4-5,8,10-11H2,1-3H3/t12-,15+,16+,17+,19+,20+,21+,22+/m1/s1
【Canonical SMILES】
CC1CC2C3CCC4=CC(=O)C=CC4(C3(C(CC2(C1(C(=O)CO)O)C)O)F)C
【Isomers smiles】
C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@@]4([C@]3([C@H](C[C@@]2([C@]1(C(=
O)CO)O)C)O)F)C

Chemical and Physical Properties

【Melting Point】
262-264 deg C
【Solubilities】
Solubility in water (25 deg C): 10 mg/100 mL; sol in acetone, ethanol, chloroform
In water, 89.0 mg/L at 25 deg C
【Color/Form】
Crystals from ether
WHITE TO PRACTICALLY WHITE CRYSTALLINE POWDER
【Storage temp】
0-6°C
【Spectral properties】
Specific optical rotation: +77.5 deg at 25 deg C/D (dioxane)
IR: u 5108 (Coblentz Society spectral collection) /spectra converted from micrometers to wavenumbers/
【Computed Properties】
Molecular Weight:392.461063 [g/mol]
Molecular Formula:C22H29FO5
XLogP3:1.9
H-Bond Donor:3
H-Bond Acceptor:6
Rotatable Bond Count:2
Tautomer Count:9
Exact Mass:392.199902
MonoIsotopic Mass:392.199902
Topological Polar Surface Area:94.8
Heavy Atom Count:28
Formal Charge:0
Complexity:805
Isotope Atom Count:0
Defined Atom Stereocenter Count:8
Undefined Atom Stereocenter Count:0
Defined Bond Stereocenter Count:0
Undefined Bond Stereocenter Count:0
Covalently-Bonded Unit Count:1
Feature 3D Acceptor Count:5
Feature 3D Donor Count:3
Feature 3D Ring Count:4
Effective Rotor Count:3.4
Conformer Sampling RMSD:0.8
CID Conformer Count:2

Safety and Handling

【Safety Statements 】
A poison by intravenous route. Experimental reproductive effects. Mutation data reported. When heated to decomposition it emits acrid smoke and irritating vapors.
【HazardClass】
6.1
【Safety】

A poison by intravenous route. Experimental reproductive effects. Mutation data reported. When heated to decomposition it emits acrid smoke and irritating vapors.
RIDADR: 3172
HazardClass: 6.1
PackingGroup: I

【PackingGroup 】
I
【Transport】
3172
【Formulations/Preparations】
Parenteral Injection, for IM or IV use: 4 mg (of dexamethasone phosphate) per mL Dexmethasone Sodium Phosphate Injection (with benzyl alcohol 1%), (Abraxis), Dexamethasone Sodium Phosphate Injection ( with benzyl alcohol 1%), American Regent 10 mg (of dexamethasone phosphate) per mL Dexmethasone Sodium Phosphate Injection (preservative-free), (Abraxis). /Dexamethasone sodium phosphate/
Oral: Elixir 0.5 mg/5 mL Dexamethasone Elixir (with alcohol 5%), (Actavis), Dexamethasone Elixir (with alcohol 5%), (Morton Grove Pharmaceuticals) Solution: 0.5 mg/5 mL Dexamethasone Oral Solution, (Roxane). Solution, concentrate: 0.5 mg/0.5 mL Dexamethasone Intensol (with alcohol 30%), (Roxane). Tablets: 0.25 mg 0.5 mg Decadron (scored), (Merck); 0.75 mg Decadron (scored), (Merck); 1 mg Dexamethasone Tablets, (Roxane); 1.5 mg Dexpak Taperpak (available as 13-day mnemonic pack of 51 tablets), (ECR), Dexamethasone Tablets, (Par), Dexamethasone Tablets, (Roxane), Dexamethasone Tablets, (Par), Dexamethasone Tablets, (Roxane); 2 mg Dexamethasone Tablets, (Roxane); 4 mg Dexamethasone Tablets, (Par), Dexamethasone Tablets, (Roxane); 6 mg Dexamethasone Tablets, (Par), Dexamethasone Tablets, (Roxane).
Ophthalmic: Solution: 0.1% (of dexamethasone phosphate) Dexamethasone Sodium Phosphate Ophthalmic Solution, Bausch & Lomb).
Ophthalmic Suspension: 0.1% Maxidex (with benzalkonium chloride; viscous), (Alcon).
【Exposure Standards and Regulations】
The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl dexamethasone sodium phosphate approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Dexamethasone sodium phosphate/
The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl dexamethasone, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.
The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Dexamethasone-21-isonicotinate is included on this list. /Dexamethasone-21-isonicotinate/
The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Dexamethasone sodium phosphate is included on this list. /Dexamethasone Sodium Phosphate/
The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Dexamethasone is included on this list.
Oral dosage form new animal drugs. ... Dexamethasone powder is indicated in cases where cattle and horses require additional steroid therapy following its parenteral administration. The drug is used as supportive therapy for management or inflammatory conditions such as acute arthritic lameness, and for various stress conditions where corticosteroids are required while the animal is being treated for a specific condition. ... Federal law restricts this drug to use by or on the order of a licensed veterinarian. A withdrawal period has not been established for this product in preruminating calves. Do not use in calves to be processed for veal.
Oral dosage form new animal drugs. ... Dexamethasone bolus is indicated in cases where cattle and horses require additional steroid therapy following its parenteral administration. The drug may be used as supportive therapy for management of inflammatory conditions such as acute arthritic lamenesses, and for various stress conditions where corticosteroids are required while the animal is being treated for a specific condition. ... In treatment of dogs and cats as an anti-inflammatory agent. ... Federal law restricts this drug to use by or on the order of a licensed veterinarian.
Oral dosage form new animal drugs. ... Dexamethasone chewable tablets. ... Indications for use. Supportive therapy in nonspecific dermatosis and inflammatory conditions in dogs. ... Federal law restricts this drug to use by or on the order of a licensed veterinarian.
Implantation or injectable dosage form new animal drugs. Dexamethasone injection. ... The drug is indicated: (A) For the treatment of primary bovine ketosis and as an anti-inflammatory agent in cattle and horses; (B) As an anti-inflammatory agent in dogs and cats. ... Federal law restricts this drug to use by or on the order of a licensed veterinarian.
【Specification】

 Cholera Toxin (9012-63-9) is an oligomeric complex made up of six protein subunits: a single copy of the A subunit (part A), and five copies of the B subunit (part B). The two parts are connected by a disulfide bond. The three-dimensional structure of the toxin was determined using X-ray crystallography by Zhang et al. in 1995. The five B subunits—each weighing 12 kDa, and all coloured blue in the accompanying figure—form a five-membered ring. The A subunit has two important segments. The A1 portion of the chain (CTA1, red) is a globular enzyme payload that ADP-ribosylates G proteins, while the A2 chain (CTA2, orange) forms an extended alpha helix which seats snugly in the central pore of the B subunit ring.This structure is similar in shape, mechanism, and sequence to the heat-labile enterotoxin secreted by some strains of the Escherichia coli bacterium.

【Octanol/Water Partition Coefficient】
log Kow = 1.83
【Disposal Methods】
SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Use and Manufacturing

【Use and Manufacturing】
Methods of Manufacturing

Preparation: Muller et al., US 3007923 (1961 to Lab Franc Chimiother); Arth et al., DE 1113690 (1961 to Merck & Co.)

Biomedical Effects and Toxicity

【Pharmacological Action】
- Substances that reduce or suppress INFLAMMATION.
- Drugs used to prevent NAUSEA or VOMITING.
- Antineoplastic agents that are used to treat hormone-sensitive tumors. Hormone-sensitive tumors may be hormone-dependent, hormone-responsive, or both. A hormone-dependent tumor regresses on removal of the hormonal stimulus, by surgery or pharmacological block. Hormone-responsive tumors may regress when pharmacologic amounts of hormones are administered regardless of whether previous signs of hormone sensitivity were observed. The major hormone-responsive cancers include carcinomas of the breast, prostate, and endometrium; lymphomas; and certain leukemias. (From AMA Drug Evaluations Annual 1994, p2079)
- A group of CORTICOSTEROIDS that affect carbohydrate metabolism (GLUCONEOGENESIS, liver glycogen deposition, elevation of BLOOD SUGAR), inhibit ADRENOCORTICOTROPIC HORMONE secretion, and possess pronounced anti-inflammatory activity. They also play a role in fat and protein metabolism, maintenance of arterial blood pressure, alteration of the connective tissue response to injury, reduction in the number of circulating lymphocytes, and functioning of the central nervous system.
【Therapeutic Uses】
Anti-Inflammatory Agents, Steroidal; Antiemetics; Antineoplastic Agents, Hormonal; Glucocorticoids, Synthetic; Glucocorticoids, Topical
Nasal corticosteroids are used in some patients for prophylaxis of seasonal rhinitis. This form of therapy is generally reserved for patients who have consistently demonstrated a need for nasal corticosteroids to control seasonal rhinitis syndromes. Antihistamines and decongestants are considered primary therapies for this disorder. Dexamethasone nasal aerosol is less frequently used because its use results in a significantly higher incidence of systemic adverse effects with no additional benefit over other nasal corticosteroids. /NOT included in US product labeling/
Ophthalmic corticosteroids are indicated in the treatment of corticosteroid-responsive allergic and inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe. /Corticosteroids (Ophthalmic); Included in US product labeling/
Otic corticosteroids are indicated in the treatment of corticosteroid-responsive inflammatory disorders of the external auditory meatus such as: allergic otitis externa; infective otitis (treatment adjunct); (chronic eczematoid otitis externa or seborrheic otitis externa /NOT included in US product labeling/). Dexamethasone /is/ used in the treatment of these and other corticosteroid-responsive disorders of the external auditory meatus. /Included in US product labeling/
Dexamethasone is used principally as an anti-inflammatory or immunosuppressant agent. Because it has only minimal mineralocorticoid properties, the drug is inadequate alone for the management of adrenocortical insufficiency. If dexamethasone is used in the treatment of this condition, concomitant therapy with a mineralocorticoid is also required.
There is some evidence that short-term adjunctive therapy with IV dexamethasone may decrease the incidence of audiologic and/or neurologic sequelae in infants and children with Haemophilus influenzae meningitis and possibly may provide some benefit in patients with Streptococcus pneumoniae meningitis. The American Academy of Pediatrics (AAP) and other clinicians suggest that use of adjunctive dexamethasone therapy may be considered during the initial 2-4 days of anti-infective therapy in infants and children 6-8 weeks of age or older with known or suspected bacterial meningitis, especially in those with suspected or proven H. influenzae infection. If used, dexamethasone should be initiated before or concurrently with the first dose of anti-infective.
Dexamethasone regimens are used extensively for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy.
Adrenal corticosteroids were first reported in 1979 to have antiemetic effects during cancer chemotherapy. Since then considerable numbers of trials have been conducted to evaluate their activity alone and in combination with other agents. The majority of the research has centered on dexamethasone, although other corticosteroids have been studied. Dexamethasone as a single agent is superior to placebo and appears to be more effective than standard doses of prochlorperazine when administered with highly emetic agents. Dexamethasone is comparable to metoclopramide against moderately emetogenic agents and low dose cisplatin, but less effective than metoclopramide against highly emetic agents or high dose cisplatin. Dexamethasone improves the activity of prochlorperazine and metoclopramide and may reduce some of the side effects associated with the latter. [Cersosimo RJ, Karp DD; Pharmacotherapy 6 (3): 118-27 (1986)]
【Biomedical Effects and Toxicity】
Absorbed into aqueous humor, cornea, iris, choroid ciliary body, and retina. Systemic absorption occurs, but may be significant only at higher dosages or in extended pediatric therapy. /Corticosteroids (Ophthalmic)/
Dogs (mixed-breed) were administered dexamethasone alcohol or dexamethasone 21-isonicotinate as a solution iv or im (1 mg/kg bw), or dexamethasone 21-isonicotinate as a suspension im (0.1 or 1 mg/kg bw). Plasma concentrations were determined with HPLC up to 120 hours after treatment. The elimination half-life after iv administration was 120-140 minutes for both formulations. Following im administration, absorption was rapid with peak plasma concentrations at 30-40 minutes for both solutions. Bioavailability after im administration was 100% for dexamethasone alcohol but 40% for dexamethasone 21-isonicotinate. After im administration of dexamethasone 21-isonicotinate as a suspension, dexamethasone was not detected in plasma, suggesting a long absorption phase
Crl:SD(CD)BR rats were administered a single im dose of 9 ug, (1,2,4-3H)-dexamethasone/kg bw. Radioactivity was measured up to 96 hours after administration in plasma (pre- and post-freeze dried), urine, feces and expired air. Tritium exchange was measured in stored urine. Highest plasma levels were observed 6 hours after dosing (3.7 ug equivalents/g), declining rapidly thereafter to 0.15 ug equivalents/g. Within 24 hours 41% of the radioactivity was excreted in the urine. After 96 hours a mean of 44% of the radio-activity was excreted. Tritium exchange was observed both in plasma and urine. Following freeze-drying, the mean loss of radioactivity 96 hours after dosing was 87% and 37% in plasma and urine, respectively
Male Wistar albino rats were administered 0.23 umol (1,2-3H) dexamethasone/kg bw, ip. Urine and feces were collected up to 4 days after treatment. Within 96 hours 74% of the dose was excreted, 30% in the urine and 44% in the feces
Four hours after the sc administration to pigs of (1,2-3H)-dexamethasone-21-trimethylacetate, less than 1% of total plasma radioactivity was extractable as unchanged (3)H-dexamethasone-21-acetate. The plasma concentration of dexamethasone was highest (about 3 ng/ml) at 4 hours, declining rapidly to about 0.5 ng/ml at 24 hours, and slowly thereafter. Measurable amounts of dexamethasone (>0.2 ng/mL) were still present at day 5
Sixty-five guinea pigs were divided into three groups. In the first group, the drug application protocol used an intra-abdominal dose of 0.5% dexamethasone 4 mg x kg(-1). In the second group, an intratympanic application dose of 0.5% dexamethasone 150 uL was used. The third group was the control group. The concentrations of dexamethasone in inner ear perilymph were determined by high-pressure liquid chromatography. The perilymph concentration-time curves of dexamethasone conformed to a one-compartment open model after an intra-abdominal application. The Cmax was 0.927 +/- 0.008 mg x l(-1), the Tmax 1.47 +/- 0.04 h, the T(1/2K) 2.92 +/- 0.056 hr, the AUC 5.533 +/- 0.05 mg x hr x l(-1), the T(1/2Ka) 0.47 +/- 0.024 hr. After an intratympanic application, the perilymph concentration-time curves of dexamethasone also conformed to a one-compartment open model. The Cmax was 0.201 +/- 0.006 mg x l(-1), the Tmax 0.117 +/- 0.06 hr, the AUC 0.868 +/- 0.004 mg x hr x l(-1), the T(1/2K) 2.918 +/- 0.089 hr, the T(1/2Ka) 0.161 +/- 0.009 hr. Compared to the intra-abdominal application, the intratympanic application resulted in similar levels of inner ear perilymph drug concentrations in 30 min. Dexamethasone can penetrate the blood-labyrinthine barrier after intra-abdominal application. Dexamethasone can enter into perilymph after intratympanic application. Under the condition of the study, the intratympanic application resulted in a similar level of inner ear perilymph drug concentrations compared to the intra-abdominal application in 30 min. [Liu HJ et al; ORL J Otorhinolaryngol Relat Spec 68 (2): 93-8 (2006)] PubMed Abstract
Elimination: Renal /Dexamethasone sodium phosphate/
Rapidly and extensively absorbed from the nasal mucosa; readily absorbed from the gastrointestinal mucosa. /Dexamethasone sodium phosphate/
/Dexamethasone/ is distributed into breast milk.
Absorbed into aqueous humor, cornea, iris, choroid, ciliary body, and retina. Systemic absorption occurs, but may be significant only at higher dosages or in extended pediatric therapy. /Corticosteroids, ophthalmic/
Oral: Rapidly and almost completely absorbed. Parenteral: Intramuscular: Freely soluble esters (sodium phosphate, sodium succinate) - Rapidly absorbed. Poorly soluble derivatives (acetate, acetonide, diacetate, hexacetonide, tebutate) - Slowly but completely absorbed. Local: Freely soluble esters - Less rapidly absorbed than with intramuscular injection. Poorly soluble derivatives - Slowiy but completely absorbed. /Corticosteroids (glucocorticoid effects - systemic)/

Environmental Fate and Exposure Potential

【Environmental Fate/Exposure Summary】
TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 240(SRC), determined from a log Kow of 1.83(2) and a regression-derived equation(3), indicates that dexamethasone is expected to have moderate mobility in soil(SRC). Volatilization of dexamethasone from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.2X10-8 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Dexamethasone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 8.9X10-14 mm Hg(SRC), determined from a fragment constant method(5). Biodegradation data for dexamethasone were not available(SRC, 2007).
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 240(SRC), determined from a log Kow of 1.83(2) and a regression-derived equation(3), indicates that dexamethasone is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 7.2X10-8 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(6), an estimated BCF of 14(SRC), from its log Kow(2) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data for dexamethasone were not available(SRC, 2007).
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), dexamethasone, which has an estimated vapor pressure of 8.9X10-14 mm Hg at 25 deg C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase dexamethasone may be removed from the air by wet or dry deposition(SRC). Dexamethasone contains chromophores that absorb at wavelengths >290 nm(3) and therefore may be susceptible to direct photolysis by sunlight(SRC).

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