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Effect of temperature on intestinal transfer and tissue uptake of sulfanilamide and aminopropyron in vitro.

The effect of temperature on the transfer and the tissue uptake of sulfanilamide and aminopropyron, an aminopyrine derivative, was investigated using the everted and the non-everted sacs of rat intestine. The M (mucosa) to S (serosa) transfer of sulfanilamide was slightly faster than reverse S-to-M in the ileum at the temperatures studied. Decreased transfer and tissue uptake of sulfanilamide with decreasing temperature were observed using both ileal everted and non-everted sacs. On the contrary, the M-to-S transfer of aminopropyron was slower than the S-to-M transfer in the ileum. The tissue uptake of aminopropyron was almost constant at any temperature in the ileal non-everted sac experiments, while a decreased transfer of aminopropyron was observed with a decrease in temperature. Similar results, like aminopropyron in the ileum, were obtained in the experiments of aminopropyron and sulfanilamide using the colonic sacs. It is concluded that a close relationship may exist between the directional superiority in the transfer and the temperature independency of the tissue uptake.

Aminopyrine↗

[Development of new antiepileptics. V. Pharmacological activity of some derivatives of sulfanilamide (author's transl)].

9 derivatives of sulfanilamide were tested for anticonvulsant properties against electroconvulsive shock in mice and rats and against pentylenetetrazole shock in mice. Reference standard in these tests was sulfanilamide. Their toxic, analgesic and sedative activities were also examined. The anticonvulsive activity of sulfanilamide could be enhanced by substitution of the phenyl ring with a halogen atom. Substitution of the sulfonamide group diminishes the anticonvulsant and increases the sedative activity of sulfanilamide. Detoxication of the basic substance by substitution of the aromatic amino group only little influences the anticonvulsant activity and may even enhance it. Of the tested substances, 1742 (3-chloro-4-phenacetamido-benzene-sulfonamide) exhibited the best anticonvulsant activity; slightly weaker was PB 311 (3-chloro-4-amino-benzene-sulfonamide). The ED50 for the activity against electroconvulsive shock of both substances was about 30 mg/kg p.o. in mice. The relationship between anticonvulsant activity and inhibition of the renal and cerebral carbonic anhydrase is discussed.

Analgesics↗

Antigenicity of sulfanilamide and its metabolites using fluorescent-labelled compounds.

In order to clarify the onset mechanisms of drug-induced allergies, three fluorescent-labelled compounds were synthesized by subjecting sulfanilamide (SA), a base compound for sulfonamides, and its active metabolites, i.e. sulfanilamide hydroxylamine and sulfanilamide nitroso, to dansylation using dansylchloride. In other words, 5-dimethylamino-N-(4-aminobenzyl)-naphthalenesulfonamide (DNS-4ABA), 5-dimethylamino-N-(4-hydroxylaminobenzyl)-1-naphthalenesulfonamide (DNS-4HABA) and 5-dimethylamino-N-(4-nitrosobenzyl)-1-naphthalenesulfonamide (DNS-4NSBA) were synthesized as model haptens. When analysed by HPLC, a conjugate of DNS-4HABA and glutathione (GSH) with nucleophilic amino acids had two peaks (P-1 and P-2). FAB-MS and 1H-NMR revealed that the DNS-4HABA-GSH conjugate consisted of sulphinamide and semimercaptal. The reactivity of GSH to DNS-4ABA, DNS-4HABA and DNS-4NSBA was quantified by HPLC using an oxidization system (horseradish peroxidase/H2O2). The results show that production of DNS-4NSBA-GSH-conjugate was four to eight times higher than that of DNS-4HABA-GSH conjugate, but that DNS-4ABA did not bind with GSH. Skin reactions were assessed using guinea pigs, and strong delayed erythema was seen with DNS-4NSBA, which bound most strongly with GSH, whereas weak delayed erythema was seen with DNS-4ABA, which did not bind with GSH. This suggests a correlation between GSH conjugate production and skin reactions. DNS-4HABA enzymatically bound with proteins in rat and guinea pig liver cytosol and microsomal fractions. The proteins that bound to DNS-4HABA were purified by HPLC and then subjected to N-terminal amino acid analysis. Ubiquitin (10 kDa) and fatty acid binding protein (30 kDa) were detected in the rat liver cytosol fraction; retinol-dehydrogenase (35 kDa) in the rat microsomal fraction; and glutathione-S-transferase B (mmu) (25 kDa) in the guinea pig liver cytosol fraction. When DNS-4HABA or DNS-4NSBA binds to proteins that play important roles in the body, unexpected adverse reactions may occur. Furthermore, by utilizing our technique using model compounds, it may be possible to identify the carrier proteins of various compounds, including pharmaceutical agents.

Animals↗

Contamination of honey by the herbicide asulam and its antibacterial active metabolite sulfanilamide.

A number of antibacterial drugs (antibiotics) like sulfonamides, tetracyclines and streptomycin are used for the treatment of bacterial diseases in beehives. Yet, the finding of sulfanilamide residues in some 15 Swiss honeys out of some 350 samples could not be explained by such apicultural practice. Bees occasionally collect nectar from meadows treated with the herbicide asulam. Such honey is not only contaminated by asulam, but also by its degradation product sulfanilamide. This is the first report that the use of a herbicide causes the appearance of residues of an antibacterial active metabolite belonging to the category of sulfonamide drugs in food. The relevance of this finding lies in the fact that the use of the herbicide asulam might cause unacceptable residue levels of sulfanilamide in a product fbr human consumption.

Carbamates↗

The effect of antioxidants on the photolysis of aqueous sulfacetamide and sulfanilamide solutions.

Aqueous sulfacetamide and sulfanilamide solutions were photolyzed at pH 1-13 and in the presence of various antioxidants and a chelating agent (pH 7.0). The rate constants for the photodegradation of sulfacetamide and sulfanilamide were determined. Sodium metabisulfite and thiourea were the best antioxidants for the photostabilization of sulfacetamide and sulfanilamide solutions respectively. Sodium edetate is also an effective stabilizer in sulfacetamide solutions. The efficiency of the antioxidants on the basis of product distribution and the kinetic results is discussed.

Antioxidants↗

Synthesis of omega-(4-aminophenylsulfonamido)alkyl disulfides and thiosulfates and their activity against dihydropteroate synthetase from sulfanilamide-resistant Neisseria gonorrhoeae.

A series of omega-(4-aminophenylsulfonamido)alkyl disulfides and omega-(4-aminophenylsulfonamido)alkanethiosulfates was synthesized from the reaction of p-acetamidobenzenesulfanilyl chloride and either the aminoalkyl disulfide dihydrobromide or the aminoalkyl bromide hydrobromide followed by sodium thiosulfate. Several of the compounds showed inhibitory activity against dihydropteroate synthetase isolated from a sulfanilamide-resistant strain of Neisseria gonorrhoeae of the same order of activity as that of sulfanilamide. An increase in the hydrophobic nature of the sulfanilamide structure did not increase inhibitory activity against this enzyme.

Chemical Phenomena↗

Microcomputer-controlled determination of dissociation constants of sulfanilamides and stability constants of the related silver complexes.

As a contribution to the structure-activity relationship of silver sulfanilamide complexes, the pKa-values of thirteen sulfanilamides and the log K-values of their related silver compounds were determined using a microcomputer-controlled titrator which determines the silver ion concentration and hydrogen ion concentration in a combined measurement. Predictions on antibacterial effectiveness and the risk of sensitization reactions of some of the investigated silver sulfanilamides are made on the basis of the conditional stability constants computed from the pKa- and log K-values at pH = 7.4.

Chemical Phenomena↗

Portage transport of sulfanilamide and sulfanilic acid.

Sulfanilic acid, in contrast to sulfanilamide, has poor in vitro antibacterial activity. Paradoxically, it has been shown to be a more effective inhibitor than sulfanilamide of dihydropteroic acid synthase. In order to circumvent the presumed permeability barrier to sulfanilic acid, advantage was taken of the technique of portage transport. Derivatives of the compound were prepared in which it was linked via its primary amino group to the alpha-carbon of glycine residues in di- and tripeptides. L-Alanyl-L-alanyl-L-2-[(4-sulfophenyl)amino]glycine proved to be 207 times more potent than sulfanilic acid and 8 times more active than either sulfanilamide or L-alanyl-L-alanyl-L-2-[[4-(aminosulfonyl)-phenyl]amino]glycine when tested against Escherichia coli. These findings confirm that the weak in vitro activity of sulfanilic acid is due to its limited ability to penetrate the bacterial membrane. They also emphasize the ability of portage transport to reveal therapeutic capability that had been attenuated by poor drug permeation.

Anti-Bacterial Agents↗

Cloning of the Bacillus subtilis sulfanilamide resistance gene in Bacillus subtilis.

A recombinant plasmid was constructed by ligation of chromosomal DNA from a sulfanilamide-resistant strain of Bacillus subtilis to the plasmid vector pUB110 which specifies neomycin resistance. Recombinant molecules generated in vitro were introduced into a B. subtilis recipient strain which carried the recE4 mutation, and selection was for neomycin-sulfanilamide-resistant transformants. A single colony was isolated containing the recombinant plasmid pKO101. This 6.3-megadalton plasmid simultaneously conferred resistance to neomycin and sulfanilamide when transferred into sensitive Rec+ or Rec- cells by either transduction or transformation.

Bacillus subtilis↗

[Effect of phenobarbital on sulfanilamide acetylation].

By using the "turned inside out bag" technique and brough tests with homogenates it was found that sulfanilamide is susceptible to acetylation in a larger measure than sulfocarbamide and sulfacylum natrium. In tests with isolated lengths of the small intestine phenobarbital (in doses of 25 mg/kg for 5 days) weakened acetylation of sulfanilamide and sulfocarbamide and did not change acetylation of sulfacylum natrium. Acetylation of all these three sulfanilamides in homogenates of the liver, blood and the small intestine mucosa did not change under the effect of phenobarbital.

Acetylation↗

[Effect of comprehensive therapy using antibiotics and sulfanilamide and stimulant preparations on natural body resistance in acute dysentery].

A total of 489 patients at the age of 18 to 74 with acute dysentery of medium severity without concomitant diseases were observed. The patients were subjected to combined therapy with the use of antibiotics, sulfanilamides and stimulants. The state of the patients' natural resistance was determined by the dynamics and levels of the bactericidal activity of lysozyme, blood serum complement as well as lysozyme and beta-lysine coprofiltrates. It was found that the use of tetracycline, furazolidone combinations with sulfanilamides and leukopoiesis-stimulating drugs had a favourable effect on the dynamics of the host natural resistance reduction. The reduction of the natural resistance in the patients treated with levomycetin in combination with sulfanilamides and stimulants was much slower than the clinical recovery.

Acute Disease↗

[Characterization of pancreatic beta cell receptors binding sulfanilamide drugs].

Analysis of pancreatic beta-cell receptors binding the sulfanilamide drugs widely used in therapy of type II diabetes, such as glibenclamide, glipizide, and gliclazide, showed that these drugs are characterized by excellent parameters of specific binding to these receptors. The receptors were tested for two parameters: number of binding sites and dissociation constant. Glibenclamide was the most active of the drugs we tested, the other two agents being less active. Binding of these agents was reversible. The problem of identification of the examined receptors of sulfanilamides with K(+)-ATP-sensitive channels, similarly active conductors of the information transported by the sulfanilamide drugs in the mechanism of insulin secretion, is discussed.

Animals↗

[Evaluation of the potential of chemotherapy of glanders caused by Pseudomonas mallei strains resistant to sulfanilamides and trimethoprim].

A sulfanilamide resistant strain Ts-5 of Pseudomonas mallei was isolated in the experiments on sulfazine therapy of malleus. The spectrum and level of the strain cross resistance to sulfanilamides and trimethoprim were studied. The frequency of the SurTrr mutants of P. mallei was determined. Efficient antibacterial drugs for the therapy of malleus caused by the sulfanilamide resistant strain are recommended.

Animals↗

Methemoglobinemia induced by topical vaginal sulfanilamide cream in a patient with cervical cancer: a case report.

BACKGROUND: Methemoglobinemia is a rare disorder most commonly associated with the ingestion or topical application of an offending exogenous agent. The clinical consequences of acute methemoglobinemia can be devastating and include lethargy, headache, and dyspnea and, as methemoglobin concentrations rise, respiratory depression, confusion, seizures, and even death. CASE: Here we present a case of acute methemoglobinemia induced by exposure to topical vaginal sulfanilamide cream in a 36-year-old woman with a FIGO stage IIIB squamous cell cervical carcinoma. CONCLUSION: Although methemoglobinemia associated with topical anesthetics has been well documented, to our knowledge this is the first reported case of methemoglobinemia induced by exposure to topical sulfanilamide cream. Although patients undergoing intracavitary radiation treatment for cervical cancer are at risk for cyanosis due to the development of deep vein thromboses and pulmonary embolism, methemoglobinemia should be suspected in the setting of acute cyanosis with a normal arterial oxygen pressure.

Administration, Topical↗

Polymorphism of sulfanilamide: (II) Stability hierarchy of alpha-, beta-, and gamma-forms from energy calculations by the atom-atom potential method and from the construction of the p, T phase diagram.

PURPOSE: Sulfanilamide trimorphism was chosen as a model system for comparison between stability hierarchies obtained from lattice-energy calculations with those deduced from the relative locations of the sublimation curves of polymorphs in the sulfanilamide p, T diagram. METHODS: The atom-atom potential (AAP) method was used for lattice-energy calculations. The p, T diagram was constructed by using crystallographic and thermodynamic data for alpha-, beta-, and gamma-forms, and by assigning the temperatures of the experimentally observed phase transitions to triple points involving the vapour phase. RESULTS: The hierarchy obtained with the AAP method (E alpha > or = E gamma > > E beta) differs only slightly from that deduced from the positions of the sublimation curves (p gamma > p alpha > p beta) in the p, T diagram at room temperature. No stable phase region was found for form alpha. Thus it is really monotropic. CONCLUSIONS: Provided enthalpy and volume changes at the transitions are accurate enough, it is possible to draw a p, T diagram that accounts for the stability hierarchy of polymorphs.

Crystallography↗

Measurement of nitric oxide levels in the red cell: validation of tri-iodide-based chemiluminescence with acid-sulfanilamide pretreatment.

The tri-iodide-based chemiluminescence assay is the most widely used methodology for the detection of S-nitrosothiols (RSNOs) in biological samples. Because of the low RSNO levels detected in a number of biological compartments using this assay, criticism has been raised that this method underestimates the true values in biological samples. This claim is based on the beliefs that (i) acidified sulfanilamide pretreatment, required to remove nitrite, leads to RSNO degradation and (ii) that there is auto-capture of released NO by heme in the reaction vessel. Because our laboratories have used this assay extensively without ever encountering evidence that corroborated these claims, we sought to experimentally address these issues using several independent techniques. We find that RSNOs of glutathione, cysteine, albumin, and hemoglobin are stable in acidified sulfanilamide as determined by the tri-iodide method, copper/cysteine assay, Griess-Saville assay and spectrophotometric analysis. Quantitatively there was no difference in S-nitroso-hemoglobin (SNOHb) or S-nitroso-albumin (SNOAlb) using the tri-iodide method and a recently described modified assay using a ferricyanide-enhanced reaction mix at biologically relevant NO:heme ratios. Levels of SNOHb detected in human blood ranged from 20-100 nM with no arterial-venous gradient. We further find that 90% of the total NO-related signal in blood is caused by erythrocytic nitrite, which may partly be bound to hemoglobin. We conclude that all claims made thus far that the tri-iodide assay underestimates RSNO levels are unsubstantiated and that this assay remains the "gold standard" for sensitive and specific measurement of RSNOs in biological matrices.

Albumins↗

Multicenter comparison of clotrimazole vaginal tablets, oral metronidazole, and vaginal suppositories containing sulfanilamide, aminacrine hydrochloride, and allantoin in the treatment of symptomatic trichomoniasis.

BACKGROUND AND OBJECTIVES: Trichomonas vaginalis is a common vaginal pathogen. Oral metronidazole is the drug of choice for the treatment of trichomoniasis. Oral metronidazole, however, may cause unpleasant side effects and is contraindicated during the first trimester of pregnancy. In vitro studies and preliminary clinical data have suggested that intravaginal clotrimazole may be effective against this pathogen. GOALS: To compare the efficacy of clotrimazole vaginal tablets, oral metronidazole, and vaginal suppositories containing sulfanilamide, aminacrine, and allantoin (AVC suppositories) in the treatment of women with symptomatic trichomoniasis. STUDY DESIGN: In a multicenter, open-label trial conducted in 1982 and 1983, 168 symptomatic women with microscopically evident vaginal trichomoniasis were randomized to receive any of 2 g of metronidazole as a single oral dose, two 100-mg clotrimazole vaginal tablets once a day for 7 days, or vaginal suppositories containing 1.05 g of sulfanilamide, 14 mg of aminacrine hydrochloride, and 140 mg of allantoin (AVC suppositories) twice a day for 7 days. Wet mounts and cultures were repated at 1 to 2 and 4 to 6 weeks after completion of treatment. RESULTS: The number of patients who had positive cultures after treatment were 40/45 (88.9%) in the clotrimazole group, 35/43 (81.4%) in the AVC suppository group, and 9/45 (20%) in the metronidazole group (P < 0.001). All treatments were associated with a reduction in reported symptoms. Oral metrohidazole was more effective in reducing symptoms than either of the topical preparations. Adverse events, mostly mild or moderate in severity, were reported by 7 (14.6%) of 48 patients who had received oral metronidazole and 4 (7.8%) of 51 women who used AVC suppositories. There were no adverse events reported by the 50 women who used clotrimazole vaginal tablets. CONCLUSIONS: Oral metronidazole was more effective in eradicating T. vaginalis than clotrimazole vaginal tablets or AVC vaginal suppositories. All three regimens reduced symptoms; oral metronidazole was more effective in reducing symptoms than either topical preparation.

Administration, Intravaginal↗

Pneumocystis jiroveci dihydropteroate synthase polymorphisms confer resistance to sulfadoxine and sulfanilamide in Saccharomyces cerevisiae.

Failure of anti-Pneumocystis jiroveci prophylaxis with sulfa drugs is associated with mutations within the putative active site of the fungal dihydropteroate synthase (DHPS), an enzyme encoded by the multidomain FAS gene. This enzyme is involved in the essential biosynthesis of folic acid. The most frequent polymorphisms are two mutations leading to two amino acid changes ((55)Trp-Arg-(57)Pro to (55)Ala-Arg-(57)Ser), observed as a single or double mutation in the same P. jiroveci isolate. In the absence of a culture method for P. jiroveci, we studied potential resistance to sulfa drugs conferred by these polymorphisms by using Saccharomyces cerevisiae as a model. Single or double mutations identical to those observed in the DHPS domain of the P. jiroveci FAS gene were introduced by in vitro site-directed mutagenesis into alleles of the S. cerevisiae FOL1 gene, which is the orthologue of the P. jiroveci FAS gene. The mutated alleles were integrated at the genomic locus in S. cerevisiae and expressed by functional complementation in a strain with a disrupted FOL1 allele. The single mutation (55)Trp to (55)Ala conferred resistance to sulfanilamide, whereas the single mutation (57)Pro to (57)Ser conferred resistance to both sulfanilamide and sulfadoxine. Both single mutations also separately conferred hypersensitivity to sulfamethoxazole and dapsone. The resistance to sulfadoxine is consistent with epidemiological data on P. jiroveci. The double mutation (55)Trp-Arg-(57)Pro to (55)Ala-Arg-(57)Ser conferred on S. cerevisiae a requirement for p-aminobenzoate, suggesting reduced affinity of DHPS for this substrate. This characteristic is commonly observed in mutated DHPS enzymes conferring sulfa drug resistance from other organisms. However, the double mutation conferred hypersensitivity to sulfamethoxazole, which is not in agreement with epidemiological data on P. jiroveci. Taken together, our results suggest that the DHPS polymorphisms observed in P. jiroveci confer sulfa drug resistance on this pathogen.

Alleles↗