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].

The maximum residue limit (MRL) of 100 μg/kg was not reached by any antibacterial drug residues until two days after the treatment was stopped, as demonstrated by the quantities of sulfaquinoxaline sodium salt [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. Sulfonamide resistance is becoming 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.

[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.

4-Amino-N-(2-quinoxalinyl)benzenesulfonamide is a sulfonamide compound belonging to the benzene family. Sulfaquinoxaline is a veterinary drug used to treat coccidiosis in cattle and sheep. In Pakistan, Sanna Laboratories manufactures sulfaquinoxaline in combination with amproli and vitamin K as a potential treatment for coccidiosis. Sulfaquinoxaline is a sulfonamide antibiotic used in veterinary medicine and the meat and poultry processing industry. It is an antimicrobial agent used to treat coccidiosis in pigs, cattle, poultry, and other veterinary animals. It is also used to control outbreaks of fowl typhoid and fowl cholera, and to treat infectious enteritis. See also: sulfaquinoxaline sodium (its active ingredient); sulfadiazine; sulfadiazine; sulfaquinoxaline (ingredient). Mechanism of Action: Antibacterial agent. Sulfonamides interfere with the biosynthesis of folate in bacterial cells; they compete with para-aminobenzoic acid (PABA) for the synthetic sites of folate molecules. Sulfonamides inhibit bacterial cell proliferation by displacing the PABA molecule, preventing the formation of folic acid required for DNA synthesis. Susceptible bacteria must synthesize folic acid themselves; mammalian cells utilize pre-formed folic acid and are therefore insensitive to sulfonamides. Cells producing excessive PABA or PABA-containing environments, such as necrotic tissue, can develop resistance by competing with sulfonamides. Sulfonamides are structural analogs and competitive antagonists of para-aminobenzoic acid (PABA), thus preventing bacteria from normally utilizing PABA to synthesize folic acid (pteroylglutamate). More specifically, sulfonamides are competitive inhibitors of dihydropteroate synthase, the enzyme in bacteria responsible for incorporating para-aminobenzoic acid (PABA) into dihydropteroate (a direct precursor of folic acid). Susceptible microorganisms are those that must synthesize folic acid themselves; bacteria that can utilize pre-formed folic acid are unaffected. The antibacterial effect of sulfonamides can be competitively antagonized by para-aminobenzoic acid. Sulfonamides do not affect mammalian cells through this mechanism because they require pre-formed folic acid, which they cannot synthesize themselves. /Sulfonamides/

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Therapeutic Uses MeSH Title: Anti-infectives, Antiprotozoal Drugs
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 in chickens caused by Eimeria tenella, Eimeria necrotic, Eimeria spurulenta, Eimeria giant, or Eimeria brucellae; outbreaks of coccidiosis in turkeys caused by Eimeria turkeyensis or Eimeria adenocarcinoma; and outbreaks of coccidiosis in cattle caused by Eimeria bovis or Eimeria zurni. It is also used to treat or control fowl cholera caused by Pasteurella multocida, and fowl typhoid caused by susceptible bacteria.

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Drug Warnings
(Veterinarian): Long-term use of sulfaquinone may lead to kidney crystal deposits or interfere with normal blood clotting. Sulfaquinone concentrations exceeding 0.012% in drinking water for more than 24 to 36 hours may cause 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 particular type of drug reaction includes blood cachexia, non-infectious polyarthritis, and rashes. Dogs taking sulfonamides may also develop rashes, hepatitis, or dry keratitis. Hemorrhagic syndrome has been reported in dogs when many doses of sulfaquinone, which chickens can tolerate, are added to their drinking water.
(Veterinarian): Chickens and dogs have been reported to have symptoms similar to those caused by coumarin anticoagulants.

C14H11N4NAO2S

322.32

322.05

C, 52.17; H, 3.44; N, 17.38; Na, 7.13; O, 9.93; S, 9.95

967-80-6

Sulfaquinoxaline;59-40-5

3693427

Light yellow to yellow solid powder

551.1ºC at 760 mmHg

>296ºC (dec.)

287.1ºC

4.268

1

6

3

22

448

0

WXUQBKOBXREBBX-UHFFFAOYSA-N

InChI=1S/C14H11N4O2S.Na/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;/q-1;+1

sodium;(4-aminophenyl)sulfonyl-quinoxalin-2-ylazanide

SULFAQUINOXALINE SODIUM; 967-80-6; Sulfaquinoxaline sodium salt; sodium sulfaquinoxaline; Sulfaquinoxaline (sodium salt); Benzenesulfonamide, 4-amino-N-2-quinoxalinyl-, monosodium salt; UNII-21223EPJ40; sodium;(4-aminophenyl)sulfonyl-quinoxalin-2-ylazanide;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

DMSO : ~100 mg/mL (~310.25 mM)
H2O : ~1 mg/mL (~3.10 mM)

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.)