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
Sulfaquinoxaline is minimally absorbed systemically and is referred to as an enteric sulfonamide.
Sulfonamides are distributed into milk; however, the sulfonamides that are clinically relevant to food-producing animals are distributed into milk in concentrations too low to be therapeutic but high enough to produce residues. Sulfadiazine and sulfanilamide are more efficiently distributed into milk than most sulfonamides, but are not used in dairy cattle. For many sulfonamides, 0.5 to 2% of the total dose is found in the milk. Distribution into milk varies depending on the amount of non-protein -bound sulfonamide present in the blood and the amount of the nonionized and therefore liposoluble form of the medication present. Sulfonamides with higher pKa values produce a higher proportion of drug in the blood that is non-ionized, and if other factors, such as the rate of biotransformation, also support it, may be distributed more easily into milk. /Sulfonamides/
Sulfonamides are eliminated from body partly as unchanged drugs and partly as metabolic products. The largest fraction is excreted in urine, and half-life ... is thus dependent on renal function. In acid urine, the older sulfonamides are insoluble and may precipitate, causing crystalline deposits that can cause urinary obstruction. Small amt are eliminated in feces and in bile, milk, and other secretions. /Sulfonamides/
All sulfonamides are bound in varying degree to plasma proteins, particularly to albumin. The extent ... Is determined by the hydrophobicity and ... pKa; at physiological pH, drugs with a high pKa exhibit a low degree of protein binding ... /They/ are distributed throughout all tissues of the body ... /and/ readily enter pleural, peritoneal, synovial, ocular, and similar body fluids ... in the unbound active form. /Sulfonamides/
For more Absorption, Distribution and Excretion (Complete) data for SULFAQUINOXALINE (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Sulfonamides are primarily metabolized in the liver but metabolism also occurs in other tissues. Biotransformation occurs mainly by acetylation, glucuronide conjugation, and aromatic hydroxylation in many species. The types of metabolites formed and the amount of each varies depending on the specific sulfonamide administered; the species, age, diet, and environment of the animal; the presence of disease; and, with the exception of pigs and ruminants, even the sex of the animal. Dogs are considered to be unable to acetylate sulfonamides to any significant degree. /Sulfonamides/
The sulfonamides undergo metabolic alterations in vivo, especially in the liver. The major metabolic derivative is N4-acetylated sulfonamide. Acetylation, which occurs to a different extent with each agent, is disadvantageous, because the resulting products have no antibacterial activity and yet retain the toxic potentialities of the parent substance. /Sulfonamides/

Adverse Effects
Occupational hepatotoxin - Secondary hepatotoxins: the potential for toxic effect in the occupational setting is based on cases of poisoning by human ingestion or animal experimentation.
Methemoglobinemia - The presence of increased methemoglobin in the blood; the compound is classified as secondary toxic effect

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rat LD50 oral 1370 mg/kg Personal Communication from W.M. Mahlburg, Hopkins Agricultural Chemical Co., P.O. Box 7532, Madison, WI 53707, Nov. 16, 1982, 16NOV1982
mouse LD50 oral 15 gm/kg Agrochemicals Handbook, with updates, Hartley, D., and H. Kidd, eds., Nottingham, Royal Soc of Chemistry, 1983-86, A370(1983)

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Interactions
The most important interactions of the sulfonamides involve those with the oral anticoagulants, the sulfonylurea hypoglycemic agents, and the hydantoin acticonvulsants. In each case, sulfonamides can potentiate the effects of the other drug by metabolism and, possibly, displacement from albumin. Dosage adjustment may be necessary when a sulfonamide is given concurrently. /Sulfonamides/

One of the most active agents that exerts a synergistic effect when used with a sulfonamide is trimethoprim. This cmpd is a potent and selective competitive inhibitor of microbial dihydrofolate reductase, the enzyme that reduces dihydrofolate to tetrahydrofolate. It is this reduced form of folic acid that is required for one-carbon transfer reactions. The simultaneous admin of a sulfonamide and trimethoprim ... introduces sequential blocks in the pathway by which microorganisms synthesize tetrahydrofolate from precursor molecules. The ... synergistic antimicrobial effects has been realized both in vitro and in vivo. /Sulfonamides/

Para-aminobenzoic acid (PABA) is most prominent sulfonamide antagonists. Certain local anesthetics, such as procaine, that are esters of PABA antagonize these drugs in vitro and in vivo. /Sulfonamides/

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Resistance to sulfonamides is increasingly a problem ... Although sulfonamides were used successfully for the management of meningococcal infections for many years, the majority of isolates of Neisseria meningitidis of serogroups B and C in the United States and group A isolates from other countries are now resistant.A similar situation prevails with respect to Shigella. Strains of Escherichia coli isolated from patients with urinary tract infections (community-acquired) often are 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 and a member of benzenes.
Sulfaquinoxaline is a veterinary medicine which can be given to cattle and sheep to treat coccidiosis.It is available in Pakistan with Sanna Laboratories in combination with Amprolium and Vitamin K as potential treatment of coccidiosis.
Sulfaquinoxaline is a sulfonamide antibiotic used in veterinary medicine and in the meat and poultry industries.
An antiprotozoal agent used to combat coccidial infections of swine, cattle, fowl, and other veterinary animals. Also used in controlling outbreaks of fowl typhoid and fowl cholera and in treatment of infectious enteritis.
See also: Sulfaquinoxaline Sodium (is active moiety of); Sulfamerazine; Sulfamethazine; Sulfaquinoxaline (component of).

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Mechanism of Action
Bacteriostatic. Sulfonamides interfere with the biosynthesis of folic acid in bacterial cells; they compete with paraaminobenzoic acid (PABA) for incorporation in the folic acid molecule. By replacing the PABA molecule and preventing the folic acid formation required for DNA synthesis, the sulfonamides prevent multiplication of the bacterial cell. Susceptible organisms must synthesize their own folic acid; mammalian cells use preformed folic acid and, therefore, are not susceptible. Cells that produce excess PABA or environments with PABA, such as necrotic tissues, allow for resistance by competition with the sulfonamide. /Sulfonamides/
Sulfonamides are structural analogs and competitive antagonists of para-aminobenzoic acid (PABA) and thus prevent normal bacterial utilization of PABA for the synthesis of folic acid (pteroylglutamic acid). More specifically, sulfonamides are competitive inhibitors of dihydropteroate synthase,the bacterial enzyme responsible for the incorporation of PABA into dihydropteroic acid, the immediate precursor of folic acid. Sensitive microorganisms are those that must synthesize their own folic acid; bacteria that can utilize preformed folate are not affected. Bacteriostasis induced by sulfonamides is counteracted by PABA competitively. Sulfonamides do not affect mammalian cells by this mechanism, since they require preformed folic acid and cannot synthesize it. /Sulfonamides/

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Therapeutic Uses Mesh Heading: anti-infective agents, Antiprotozoal agents

MEDICATION (VET): Sulfonamide antibiotic. Also used as a coccidiostat in poultry.

MEDICATION (VET): Sulfonamides /including sulfaquinoxaline/ are widely used for treatment of several bacterial and protozoal infections in poultry.

MEDICATION (VET): ... Used to treat or control outbreaks of coccidiosis caused by Eimeria tenella, E. necatrix, E. acervulina, E. maxima, or E. brunetti in chickens; by E. meleagrimitis or E. adenoeides in turkeys; and by E. bovis or E. zurnii in cattle. It is also used to treat or control fowl cholera caused by Pasteurella multocida, as well as fowl typhoid caused by sensitive organisms.

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Drug Warnings
(VET): Prolonged administration of sulfaquinoxaline may result in deposition of crystals in the kidney or interference with normal blood clotting. Sulfaquinoxaline levels of greater than 0.012% in drinking water for more than twenty-four to thirty-six hours may result in reduced growth rate from decreased feed or water consumption.

(VET): Animals should maintain an adequate water intake during the treatment period.

(VET): An idiosyncratic sulfonamide toxicosis can occur in any breed of dog, but has been reported more frequently in the Doberman Pinscher than in other breeds. This specific type of drug reaction includes blood dyscrasias, nonseptic polyarthritis, and skin rash. Dogs given sulfonamides may also develop cutaneous eruptions, hepatitis, or keratitis sicca. Dogs are reported to develop a hemorrhagic syndrome when doses of sulfaquinoxaline that are tolerated by many chickens are administered in their drinking water.

(VET): Clotting disorders similar to those resulting from coumarin anticoagulants have been reported in chickens and dogs.

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.)