Coccidia; antimicrobial

Sulfaquinoxaline (SQX) is an antimicrobial of the sulfonamides class. Usually employed in veterinary medicine, this contaminant of emerging concern has been found in superficial and groundwater and its consequences for the environment and human health are not completely known. In this study, SQX (C0 = 500 μg L-1, 1 L) degradation by an ozonation process at pH 3, 7, and 11 was evaluated. Ozonation was effective in degrading SQX: efficiency exceeding 99% was obtained applying an ozone dose of 2.8 mg L-1 at pH 3. Assays were performed according to a 22 design of experiments (DOE) with star points and three central points for statistical validity. Minimum and maximum levels were set at 3 and 11 for pH, and 0 and 11.5 mg L-1 for applied ozone dose. There was no significant interaction between these variables, and the pH value played the most important role in terms of contaminant degradation. In relation to toxicity, samples ozonated at pH 3 did not inhibit the luminescence of the bacteria, even though different intermediates were formed and identified by mass spectra. At pH 7, inhibition of luminescence remained almost constant (at around 30%) according to ozonation time or ozone dose. However, the hydroxyl radical, the major oxidant at pH 11, was responsible for the formation of toxic intermediates[2].

It was demonstrated by sulfaquinoxaline that until two days after the treatment was stopped, the concentration of all antibacterial drug residues was above the maximum residue limit (MRL) of 100 μg/kg [2].

The depletion times of enrofloxacin and its metabolite ciprofloxacin as well as sulfaquinoxaline and oxytetracycline were evaluated in broiler chickens that had been subjected to pharmacological treatment. The presence and residue levels of these drugs in muscle tissue were evaluated using an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method that was validated in this work. The results showed the presence of all antimicrobial residues; however, the presence of residues at concentrations higher than the drugs' maximum residue limit (MRL) of 100 μg kg-1 was found only during the treatment period for oxytetracycline and until two days after discontinuation of the medication for enrofloxacin, ciprofloxacin and sulfaquinoxaline. It was concluded that the residues of all antimicrobials were rapidly metabolized from the broiler muscles; after four days of withdrawal, the levels were lower than the limit of quantification (LOQ) of the method for the studied analytes[1].

Absorption, Distribution and Excretion
Sulfaquinoline is minimally absorbed systemically and belongs to the enteric-coated sulfonamide class. Sulfonamides are distributed into milk; however, the concentrations of sulfonamides clinically relevant to feed animals in milk are too low to achieve a therapeutic effect, but sufficient to leave residues. Sulfadiazine and sulfonamides are more readily distributed into milk than most sulfonamides, but they are not used in dairy cows. Many sulfonamides are present in milk at concentrations of 0.5% to 2% of the total dose. Distribution in milk depends on the levels of non-protein-bound sulfonamides in the blood and the levels of non-ionized (and therefore lipid-soluble) drugs. Sulfonamides with higher pKa values produce a higher proportion of non-ionized drugs in the blood and may be more readily distributed into milk if other factors, such as biotransformation rates, also support this. /Sulfonamides/ Sulfonamides are partially excreted unchanged and partially excreted as metabolites. Most are excreted in the urine, therefore the half-life depends on renal function. In acidic urine, older sulfonamides, insoluble in water, may precipitate, forming crystalline deposits that can lead to urinary tract obstruction. Small amounts of sulfonamides are excreted in feces, bile, breast milk, and other secretions. /Sulfonamides/
All sulfonamides bind to plasma proteins, especially albumin, to varying degrees. The degree of binding depends on the drug's hydrophobicity and pKa value. At physiological pH, drugs with high pKa values have low protein binding…they are distributed throughout all tissues…and readily enter pleural fluid, peritoneal fluid, synovial fluid, ocular fluid, and similar body fluids in their free active form. Sulfonamides
For more complete data on the absorption, distribution, and excretion of sulfaquinoxaline (8 types), please visit the HSDB record page.

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Metabolism/Metabolites
Sulfonamides are primarily metabolized in the liver, but also occur in other tissues. In many species, biotransformation occurs primarily through acetylation, glucuronidation, and aromatic hydroxylation. The types of metabolites formed and the amount of each metabolite depend on the specific sulfonamide drug used; the animal's species, age, diet, and environment; and the presence of disease; even the animal's sex is irrelevant, except for pigs and ruminants. Dogs are considered to be almost incapable of acetylation of sulfonamide drugs to any degree. /Sulfonamides/
Sulfonamides undergo metabolic changes in the body, especially in the liver. The main metabolite is N4-acetylated sulfonamide. The degree of acetylation varies for each drug, but its disadvantage is that the resulting product lacks antibacterial activity while retaining the potential toxicity of the parent drug. /Sulfonamides/

Adverse Reactions
Occupational Hepatotoxicity - Secondary Hepatotoxicity: Potential toxic effects in occupational settings based on cases of human ingestion or animal studies.
Methemoglobinemia - Elevated levels of methemoglobin in the blood; this compound is classified as a secondary toxicity.
Oral LD50 in rats: 1370 mg/kg. Private Newsletter from WM Mahlburg (Hopkins Agrichemicals, P.O. Box 7532, Madison, 53707, Wisconsin), November 16, 1982.
Oral LD50 in mice: 15 g/kg. Handbook of Agrochemicals (with Updates), edited by D. Hartley and H. Kidd, Nottingham, Royal Society of Chemistry, 1983–86, A370 (1983).
Interactions
The most significant interactions involving sulfonamides involve interactions with oral anticoagulants, sulfonylurea hypoglycemic agents, and hydantoin vasomotor agents. In each case, sulfonamides can enhance the effects of other drugs through metabolism and possibly displacement from albumin. Dosage adjustments may be necessary when sulfonamides are taken concurrently. /Sulfonamides/
Trimethoprim is one of the most effective drugs that produce a synergistic effect when used in combination with sulfonamides. Trimethoprim is a potent and selective competitive inhibitor of microbial dihydrofolate reductase, which reduces dihydrofolate to tetrahydrofolate. Tetrahydrofolate is the reduced folate required for the single-carbon transfer reaction. Concomitant use of sulfonamides and trimethoprim… sequentially blocks the pathway by which microorganisms synthesize tetrahydrofolate from the precursor molecule. This synergistic antimicrobial effect has been demonstrated in vitro and in vivo. /Sulfonamides/
para-aminobenzoic acid (PABA) is the most important sulfonamide antagonist. Some local anesthetics, such as procaine, are esters of PABA and can antagonize these drugs in vitro and in vivo. /Sulfonamides/

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Sulfonamide resistance is increasingly serious… Although sulfonamides have been successfully used to treat meningococcal infections for many years, most group B and C Neisseria meningitidis isolated in the United States, as well as group A Neisseria meningitidis isolated in other countries, have developed resistance. The situation is similar with Shigella. Escherichia coli strains isolated from patients with urinary tract infections (community-acquired) are often resistant to sulfonamides.

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Drug Interactions
The most important interactions of sulfonamides include interactions with oral anticoagulants, sulfonylureas (hypoglycemic agents), and phenytoin (anticonvulsants). In each case, sulfonamides may enhance their effects through metabolism and by potentially displacing other drugs from albumin. Dosage adjustments may be necessary when sulfonamides are taken concurrently. Sulfonamides
Trimethoprim is one of the most effective drugs that produce a synergistic effect when used in combination with sulfonamides. Trimethoprim is a potent and selective competitive inhibitor of microbial dihydrofolate reductase, which reduces dihydrofolate to tetrahydrofolate. Tetrahydrofolate is the reduced folate required for the single-carbon transfer reaction. Concomitant administration of sulfonamides and trimethoprim... sequentially blocks the microbial pathway for the synthesis of tetrahydrofolate from precursor molecules. This synergistic antibacterial effect has been demonstrated in vitro and in vivo. Sulfonamides: Para-aminobenzoic acid (PABA) is the most important sulfonamide antagonist. Some local anesthetics, such as procaine, are esters of PABA and can antagonize these drugs in vitro and in vivo. /Sulfonamides/

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Non-human toxicity values
Rats oral LD50 >1 g/kg
Mice oral LD50 15 g/kg

[1]. Evaluation of the Presence and Levels of Enrofloxacin, Ciprofloxacin, Sulfaquinoxaline and Oxytetracycline in Broiler Chickens after Drug Administration. PLoS One. 2016 Nov 15;11(11):e0166402.
[2]. Influence of pH and ozone dose on sulfaquinoxaline ozonation. J Environ Manage. 2017 Jun 15;195(Pt 2):224-231

Therapeutic Uses
MeSH Title: Anti-infectives, Antibiotics for Animals
Veterinary Drugs: Sulfonamide antibiotics. Also used as anticoccidial drugs for poultry.
Veterinary Drugs: Sulfonamides (including sulfaquinoline) are widely used to treat a variety of bacterial and protozoan infections in poultry.
Veterinary Drugs: ...used to treat or control outbreaks of coccidiosis caused by Eimeria tenella, E. necatrix, E. acervulina, E. maxima, or E. brunetti in chickens; outbreaks of coccidiosis caused by E. meleagrimitis or E. adenoeides in turkeys; and outbreaks of coccidiosis caused by E. bovis or E. zurnii. It is also used to treat or control fowl cholera caused by Pasteurella multocida and fowl typhoid caused by susceptible bacteria. For more complete data on the therapeutic uses of sulfaquine (14 in total), please visit the HSDB records page.

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Drug Warnings
(Veterinarian): Prolonged use of sulfaquine may lead to kidney crystal deposits or interfere with normal blood clotting. Sulfaquine concentrations in drinking water exceeding 0.012% for more than 24 to 36 hours may result in reduced feed or water intake, thus slowing growth.
(Veterinarian): Animals should be kept well-hydrated during treatment.
(Veterinarian): Specific sulfonamide poisoning can occur in any breed of dog, but Doberman Pinschers have been reported to have a higher incidence than other breeds. This specific type of drug reaction includes blood disorders, non-infectious polyarthritis, and rashes. Dogs given sulfonamides may also develop rashes, hepatitis, or dry keratitis. Hemorrhagic syndrome has been reported in dogs when many doses of sulfaquine that chickens can tolerate are added to their drinking water. (Veterinarian): Chickens and dogs have been reported to exhibit coagulation disorders similar to those caused by coumarin anticoagulants. For more complete data on drug warnings for sulfaquine (11 in total), please visit the HSDB records page.

C14H12N4O2S

300.336

300.068

C, 55.99; H, 4.03; N, 18.66; O, 10.65; S, 10.67

59-40-5

Sulfaquinoxaline sodium salt;967-80-6;Sulfaquinoxaline-d4;1329652-02-9

5338

Minute crystals

1.5±0.1 g/cm3

557.0±52.0 °C at 760 mmHg

247-2480C

290.7±30.7 °C

0.0±1.5 mmHg at 25°C

1.718

1.58

2

6

3

21

442

0

C1=CC=C2C(=C1)N=CC(=NS(=O)(=O)C3=CC=C(C=C3)N)N2

NHZLNPMOSADWGC-UHFFFAOYSA-N

InChI=1S/C14H12N4O2S/c15-10-5-7-11(8-6-10)21(19,20)18-14-9-16-12-3-1-2-4-13(12)17-14/h1-9H,15H2,(H,17,18)

Benzenesulfonamide, 4-amino-N-2-quinoxalinyl-

SQ 40; sulfaquinoxaline; 59-40-5; Sulfabenzpyrazine; Sulphaquinoxaline; Sulfaline; Avicocid; Sulquin; Ursokoxaline; SQXAI3-17254

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.)