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PubMed1976

On the influence of concomitant food intake on sulfonamide bioavailability.

The influence of food intake on the bioavailability of a frequently used short-acting sulfonamide, sulfaisomidine (Elkosin), has been examined in eight healthy volunteers. The drug was administered as a single oral dose, both on an empty stomach and together with a standardized breakfast. Numerous venous blood samples were drawn for the first eight hours after ingestion of the drug, and the concentration of unmetabolized sulfonamide in serum was assessed by spectrophotometry. The observations indicate that concomitant food intake alters neither absorption rate, peak concentration, time to reach peak concentration, elimination rate, nor total amount of sulfonamide reaching the general circulation. Thus, the absorption of orally administered sulfaisodimidine is not at all affected by concomitant intake of food. This finding contrasts with previous observations on some other sulfonamides, and it may signify a therapeutic advantage of sulfaisodimidine. In addition, the amount absorbed showed only a little interindividual variation. This suggests that the use of standardized size and interval of sulfaisodimidine dosage can be recommended. The present findings emphasize that conclusions about the absorption of a certain drug should not be derived from studies with other, albeit chemically related, compounds.

Adolescent↗
PubMed2004

Chemical genetic screening identifies sulfonamides that raise organellar pH and interfere with membrane traffic.

Chemical genetics seeks to identify small molecules that afford functional dissection of cell biological pathways. Previous screens for small molecule inhibitors of exocytic membrane traffic yielded the identification and characterization of several compounds that block traffic from the Golgi to the cell surface as well as transport from the endoplasmic reticulum to the Golgi network [Feng et al. Proc Natl Acad Sci USA 2003;100:6469-6474; Yarrow et al. Comb Chem High Throughput Screen 2003;6:279-286; Feng et al. EMBO Reports 2004: in press]. Here, we screened these inhibitors for potential effects on endocytic membrane traffic. Two structurally related sulfonamides were found to be potent and reversible inhibitors of transferrin-mediated iron uptake. These inhibitors do not block endoplasmic reticulum-to-Golgi transport, but do disrupt Golgi-to-cell surface traffic. The compounds are members of a novel class of sulfonamides that elevate endosomal and lysosomal pH, down-regulate cell surface receptors, and impair recycling of internalized transferrin receptors to the plasma membrane. In vitro experiments revealed that the sulfonamides directly inhibit adenosine triphosphate (ATP) hydrolysis by the V-ATPase and that they also possess a potent proton ionophore activity. While maintenance of organellar pH is known to be a critical factor in both endocytosis and exocytosis, the precise role of acidification, beyond the uncoupling of ligands from their receptors, remains largely unknown. Identification of this novel class of sulfonamide inhibitors provides new chemical tools to better understand the function of organelle pH in membrane traffic and the activity of V-ATPases in particular.

Adenosine Triphosphatases↗
PubMed1998

Pharmacokinetics of sulfonamides and trimethoprim in the donkey (Equus asinus).

The body disposition of sulfadimidine (SDM), sulfadiazine (SDZ), sulfamethoxypyridazine (SMPZ) and a trimethoprim-sulfadimethoxine combination (TMP-SDMX) was investigated in the donkey. The four sulfonamides and TMP were injected intravenously at doses of 20 mg/kg (SDM, SDZ, SMPZ), 12.5 mg/kg (SDMX) and 2.5 mg/kg (TMP). The body clearance (ClB) of SDZ (1.70 +/- 0.14 ml/min/kg) was significantly higher than those of SDM (1.13 +/- 0.18 ml/min/kg), SMPZ (1.10 +/- 0.09 ml/min/kg) and SDMX (0.75 +/- 0.04 ml/min/kg). In contrast, the volume of distribution at steady state (Vss) was similar for the four sulfonamides (0.68 +/- 0.08 L/kg, 0.63 +/- 0.07 L/kg, 0.47 +/- 0.06 L/kg, and 0.46 +/- 0.05 L/kg for SDM, SDZ, SMPZ and SDMX, respectively). Both ClB and Vss were significantly higher for TMP (4.36 +/- 0.60 ml/min/kg and 2.71 +/- 0.86 L/kg) than for sulfonamides. Antipyrine ClB (3.49 +/- 0.35 ml/min/kg) and Vss (0.66 +/- 0.16 L/kg), determined in order to assess hepatic oxidative function and total body water volume, respectively, were either different from (ClB), or similar to (Vss), values calculated for sulfonamides. The results obtained were compared to those reported in horses.

Animals↗
PubMedDate not supplied

Clinical findings in 40 dogs with hypersensitivity associated with administration of potentiated sulfonamides.

The purpose of this study was to summarize the clinical findings in 40 dogs with systemic hypersensitivity reactions associated with the administration of potentiated sulfonamides. Dogs ranged from 6 months to 14 years of age, with a mean of 5.7 +/- 3.2 years. Spayed female dogs were overrepresented (24 of 40, or 60% of the dogs), as were Samoyeds (3 of 40; 8%) and Miniature Schnauzers (5 of 40; 13%). Mean dosages of potentiated sulfonamides were 47.0 +/- 14.9 mg/kg/d (range, 23.4-81.4 mg/kg/d). The time from the 1st administration of the drug to the onset of the clinical signs of hypersensitivity ranged from 5 to 36 days, with a mean of 12.1 +/- 5.9 days. There was no relationship between either the dosage or type of sulfonamide given and the time to the onset of the clinical signs. Fever was the most common clinical sign observed (55% of the dogs); thrombocytopenia was 2nd (54%), and hepatopathy (28%) was 3rd. Neutropenia, keratoconjunctivitis sicca (KCS), hemolytic anemia. arthropathy, uveitis, skin and mucocutaneous lesions, proteinuria, facial palsy, suspected meningitis, hypothyroidism, pancreatitis, facial edema, and pneumonitis were also observed in some patients. Of 39 dogs with adequate follow-up, 30 (77%) recovered, whereas 8 (21%) either died or were euthanized, and 1 recovered clinically but had persistent increases in alanine aminotransferase (ALT) activity. Dogs with hepatopathy generally had a poorer prognosis (46% recovery) than dogs without hepatopathy (89% recovery; P = .0035). Sixty-three percent of the dogs with thrombocytopenia recovered, compared to 90% of the dogs without thrombocytopenia (P = .042). Recovery was not associated with sex, age, breed, or type of sulfonamide administered.

Alanine Transaminase↗
PubMed1976

Reevaluation of the disk diffusion method for sulfonamide susceptibility testing of Neisseria meningitidis.

Lack of correlation between quantitative minimal inhibitory concentration (MIC) determinations and disk diffusion susceptibility tests in our laboratory prompted a study to reevaluate the use of the disk diffusion test for sulfonamide susceptibility testing of Neisseria meningitidis. One hundred and sixty-three recent clinical isolates of N. meningitidis were examined for sulfonamide susceptibility by the agar dilution and disk diffusion methods. Optimal inocula for each of the tests were determined, and thereafter all disk diffusion tests were compared with quantitative MICs as determined by the agar dilution method using sulfadiazine and an inoculum of 10(6) colony-forming units (CFU)/ml. The clearest and most reproducible zone diameters were obtained with a 10(7)-CFU/ml inoculum in the disk diffusion test. There was complete correlation between the disk zone diameters for 300-mug disks of sulfadiazine and sulfathiazole and the agar dilution test MICs. All isolates with a zone diameter of <20 mm were resistant to sulfadiazine, whereas those with zone diameters of >/=30 mm were susceptible. False susceptible and false resistant readings were obtained with 300-mug sulfisoxazole disks. These data suggest that inocula and type of sulfonamide are critical factors in the disk diffusion test for meningococcal susceptibility testing. Sulfonamide disks are not interchangeable for susceptibility testing of meningococci.

Culture Media↗
PubMed1982

In vitro susceptibility of Gardnerella vaginalis and Bacteroides organisms, associated with nonspecific vaginitis, to sulfonamide preparations.

Recent reports suggest that anaerobic Bacteroides organisms are frequently found with Gardnerella vaginalis in nonspecific vaginitis. Specimens taken from 96 women with vaginal discharge were tested simultaneously for these organisms. G. vaginalis was found in 73% of the specimens, Bacteroides was found in 53%, and both organisms were found in 47%. Sulfonamides have been widely used in the successful treatment of vaginitis. Paradoxically, G. vaginalis is reported to be resistant, and it has been suggested that it could be the vehicle of the drugs which effects the cure. Little is known of the susceptibility of vaginal anaerobes to the sulfonamides. G. vaginalis and Bacteroides isolates were therefore tested in vitro against the individual excipients of sulfonamide tablets, and minimal inhibitory concentration tests were also performed against the three active drugs. The excipients had no effect on G. vaginalis, but Bacteroides strains were susceptible to the urea component. All strains of both organisms were susceptible to at least two of the three sulfonamides at high concentrations.

Bacteroides↗
PubMed1987

Organization of two sulfonamide resistance genes on plasmids of gram-negative bacteria.

The organization of two widely distributed sulfonamide resistance genes has been studied. The type I gene was linked to other resistance genes, like streptomycin resistance in R100 and trimethoprim resistance in R388 and other recently isolated plasmids from Sri Lanka. In R388, the sulfonamide resistance gene was transcribed from a promoter of its own, but in all other studied plasmids the linked genes were transcribed from a common promoter. This was especially established with a clone derived from plasmid R6-5, in which transposon mutagenesis showed that expression of sulfonamide resistance was completely dependent on the linked streptomycin resistance gene. The type II sulfonamide resistance gene was independently transcribed and found on two kinds of small resistance plasmids and also on large plasmids isolated from clinical material.

Cloning, Molecular↗
PubMed1997

Mechanism of sulfonamide resistance in clinical isolates of Streptococcus pneumoniae.

The genetic basis of sulfonamide resistance in six clinical isolates of Streptococcus pneumoniae was demonstrated to be 3- or 6-bp duplications within sulA, the chromosomal gene encoding dihydropteroate synthase. The duplications all result in repetition of one or two amino acids in the region from Arg58 to Tyr63, close to but distinct from the sul-d mutation, a duplication previously reported in a resistant laboratory strain (P. Lopez, M. Espinosa, B. Greenberg, and S. A. Lacks, J. Bacteriol. 169:4320-4326, 1987). Six sulfonamide-susceptible clinical isolates lacked such duplications. The role of the duplications in conferring sulfonamide resistance was confirmed by transforming 319- or 322-bp PCR fragments into the chromosome of a susceptible recipient. Two members of a clone of serotype 9V, one susceptible and one resistant to sulfonamide, which are highly related by other criteria, were shown to have sulA sequences that differ in 7.2% of nucleotides in addition to the duplication responsible for resistance. It is postulated that horizontal gene exchange has been involved in the acquisition (or loss) of resistance within this clone. However, five of the six resistant isolates have distinct duplications and other sequence polymorphisms, suggesting that resistance has arisen independently on many occasions.

Amino Acid Sequence↗
PubMed2002

Sulfonamide resistance in Haemophilus influenzae mediated by acquisition of sul2 or a short insertion in chromosomal folP.

Determinants of sulfonamide resistance were investigated in clinical isolates of Haemophilus influenzae from the United Kingdom and Kenya. The mechanism of sulfonamide resistance in H. influenzae has not previously been reported. Eight isolates requiring at least 1,024 microg of sulfamethoxazole per ml for inhibition carried the sul2 gene, a common mediator of acquired sulfonamide resistance in enteric bacteria. In other isolates with similarly high levels of resistance, the chromosomal gene encoding dihydropteroate synthase, folP, was found to carry an insertion of 15 bp together with other missense mutations relative to folP of H. influenzae strain Rd RM118 (MIC, 8 microg/ml); the folP sequence was identical in all seven such isolates investigated, although they represented three different strains by restriction pattern analysis. The 15-bp insertion was absent in isolates inhibited by sulfamethoxazole at 2 to 64 microg/ml (although these exhibited considerable divergence in folP sequence) and in highly resistant isolates carrying sul2. Transformation with a 599-bp fragment of folP containing the insertion but no other differences conferred high-level resistance on a recipient strain, confirming the role of the insertion. Other amino acid substitutions in dihydropteroate synthase may modulate the level of sulfonamide inhibition in susceptible isolates and those with more moderate levels of resistance. The two mechanisms of resistance, mediated by sul2 and modified folP, were detected in isolates from both the United Kingdom and Kenya.

Anti-Bacterial Agents↗
PubMed1976

R-factor-mediated resistance to sulfonamides by a plasmid-borne, drug-resistant dihydropteroate synthase.

Evidence was found for the existence of an episome-specified variant of the enzyme dihydropteroate synthase involved in folic acid formation. Since the plasmid-borne enzyme showed a decreased susceptibility for sulfonamide inhibition and was transferable together with resistance to this drug, it is proposed that diploidy for the target enzyme in some cases could be the mechanism of R-factor-mediated resistance to sulfonamides. Two types of evidence were obtained. One was the rescue from temperature sensitivity of bacterial mutants with a lesion in the chromosomal dihydropteroate synthase by the R factor R1dr19 mediating sulfonamide resistance. The other evidence was found by the determination of dihydropteroate forming activity in extracts from R(-) and R(+) bacteria. Cells harboring R1dr19 were found to contain an enzyme activity which was far less susceptible to sulfonamide inhibition than the corresponding activity from R(-) cells.

Dihydropteroate Synthase↗
PubMed1983

Plasmid-borne sulfonamide resistance determinants studied by restriction enzyme analysis.

The relationship between sulfonamide resistance genes carried on different plasmids was investigated by restriction enzyme analysis and DNA-DNA hybridization. The results showed that sulfonamide resistance mediated by different plasmids is determined by the production of at least two different types of drug-resistant dihydropteroate synthase. Plasmids pGS01, pGS02, and R22259, found in bacteria isolated from patients in Swedish hospitals, contained identical sulfonamide resistance genes, which were also identical to those of plasmids R1, R100, R6, and R388. These latter plasmids, which have been well studied in different laboratories, were originally from clinical isolates from different parts of the world. Two other clinically isolated plasmids, pGS04 and pGS05, were shown to contain sulfonamide resistance determinants of a completely different type.

DNA Restriction Enzymes↗
PubMed1971

Inhibition by sulfonamides of the candidacidal activity of human neutrophils.

Sulfonamides reduced substantially the ability of normal human neutrophils to kill strains of Candida albicans and Candida tropicalis, and impaired to a lesser extent their activity against Staphylococcus aureus 502A and Serratia marcescens. Sulfonamides also inhibited (a) iodination of Candida cells by normal neutrophils; (b) candidacidal activity in cell-free systems containing purified human myeloperoxidase, hydrogen peroxide, and potassium iodide; and (c) accumulation of molecular iodine in analogously constructed cell-free systems. In contrast to these effects on reactions catalyzed by myeloperoxidase, sulfonamides exerted relatively little effect on the levels of microbicidal activity manifested by human neutrophils that lacked myeloperoxidase. Sulfonamides appear to influence the function of human neutrophils predominantly by interfering with myeloperoxidase-mediated pathways. Certain basic and clinical implications of these data are discussed.

Candida↗
PubMed1989

Binding of sulfonamides to erythrocytes and their components.

Binding of zonisamide, a new antiepileptic sulfonamide derivative, was examined to human erythrocytes, their lysate and their carbonic anhydrase by centrifugation for cells or by ultrafiltration for the others. Scatchard plots revealed that the binding to intact and lysed cells was composed of high- and low-affinity components and that to carbonic anhydrase, of the high-affinity component alone. Parameters for high-affinity binding were similar in all three preparations and those for low-affinity binding were similar in the former two preparations. Dissociation constants for these bindings to erythrocytes were smaller than the dissociation constant for serum albumin. These results may explain the concentration of sulfonamides in red cells, and suggest the participation of cellular protein component(s) in addition to previously known carbonic anhydrase in the binding. Acetazolamide, sulthiame, zonisamide, hydrochlorothiazide and sulfanilamide inhibited carbonic anhydrase in a non-competitive manner to different extents. The Ki values of these sulfonamides were of the order of 0.1--0.2 of their respective Kd values determined by ultrafiltration, suggesting that under the present conditions, physicochemical interactions between sulfonamides and carbonic anhydrase primarily occur at common sites that affect the activity of the enzyme.

Erythrocytes↗
PubMed2000

The synthesis and human FP receptor binding affinity of 13,14-dihydro prostaglandin F1alpha sulfonamides: potential treatments for osteoporosis.

A novel class of saturated prostaglandin F2alpha sulfonamide analogs have been synthesized and evaluated in the human FP receptor binding assay for potential use in the treatment of osteoporosis. These compounds have been modified at the C1 carboxylic acid moiety and at the C16-C20 region of the prostaglandin. Based on the structure-activity relationships, it was found that at C1, the aryl sulfonamide analogs possessed greater affinity for the hFP receptor when compared to alkyl sulfonamides. When the sulfonamide was introduced into the C16-C20 region (omega chain) of the prostaglandin, a significant reduction in binding was observed. These results are discussed within the framework of a proposed model for the human FP receptor.

Dinoprost↗
PubMed1992

Comparison of the inhibitory effect of sulfamonomethoxine and other sulfonamides on capsule formation of Bordetella bronchiseptica.

The inhibitory effect of sulfamonomethoxine and other sulfonamides on the capsule formation of sulfonamide-resistant Bordetella bronchiseptica was investigated. All the sulfonamides having MeO(-OCH3) groups inhibited the capsule formation of B. bronchiseptica. Strong inhibition was obtained with sulfamonomethoxine. Inhibition was not seen with sulfonamides having no MeO groups.

Bacterial Capsules↗
PubMed2005

Test-plot studies on runoff of sulfonamides from manured soils after sprinkler irrigation.

Three test-plot series have been performed to gather information on runoff of sulfonamides from manured arable and grassland after sprinkler irrigation. To prepare test slurries with defined aged residues, liquid bovine manure was fortified with sulfadiazine, sulfadimidine, and sulfamethoxazole and stored short-term. After test-slurry application, the arable land was treated by soil cultivation before irrigation, and the manured grassland was irrigated directly with 50 mm h(-1) for 2 h. The runoff suspensions were sampled at 5- to 10-min intervals, separated into aqueous phase and suspended matter and residue analyzed. Higher runoff emissions were found from manured grassland plots. The discharge volumes ranged from 106 to 252 L and the total runoff emissions ranged from 13 to 28% of sulfonamides applied initially. Within the first 20 min of the irrigation period that represented a rainfall of 17 mm, emissions, on average, were 4%. The loads of sulfonamides predominantly occurred in the runoff water. The only emissions via suspended matter, on average, were 0.02%. On arable land, however, the runoff was reduced by soil cultivation. Discharge volumes and sulfonamide emissions were 36 to 128 L and 0.1 to 2.5%, respectively. Despite the high-intensity sprinkler irrigation, major emissions did not occur until a 60-min delay.

Agriculture↗
PubMed2005

Surface runoff and transport of sulfonamide antibiotics and tracers on manured grassland.

Despite their common use in animal production the environmental fate of the veterinary sulfonamide antibiotics after excretion is only poorly understood. We performed irrigation experiments to investigate the transport of these substances with surface runoff on grassland. Liquid manure from pigs treated with sulfadimidine was spiked with sulfadiazine, sulfathiazole, the herbicide atrazine (2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine), and the conservative tracer bromide and spread onto eight plots. Four plots received the same amounts of the spiked substances in aqueous solution (controls). Apart from the application matrix we varied the time between application and irrigation. Manure increased the runoff volume up to six times compared with the controls. It seemed that manure enhanced the runoff by sealing the soil surface. On manured plots the relative antibiotic concentrations in runoff were higher than on the controls, reaching an average of 0.3% (sulfadiazine), 0.8% (sulfathiazole), and 1.4% (sulfadimidine) of the input concentrations after a 1-d contact time. The corresponding values on the controls were 0.16% for sulfadiazine and 0.08% for sulfathiazole. After 3 d, the maximum values on the manured plots were even higher, whereas they had fallen below the limit of quantification on the controls. As a consequence, the sulfonamide losses were 10 to 40 times larger on the manured plots. The relative mobility of the sulfonamides on the control plots followed the trend expected from their chromatographic separation but the opposite was found on the manured plots. Hence it is important to consider explicitly the physical and chemical effects of manure when assessing the environmental fate of sulfonamides.

Animal Husbandry↗
PubMed2004

COX-2 selective inhibitors, carbonic anhydrase inhibition and anticancer properties of sulfonamides belonging to this class of pharmacological agents.

The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anti-carbonic anhydrase, diuretic, hypoglycaemic, antithyroid, protease inhibitory and anticancer activity among others. A recently developed class of pharmacological agents incorporating primary sulfamoyl moieties in their molecule is constituted by the COX-2 selective inhibitors, with at least two clinically used drugs, celecoxib and valdecoxib. Another drug of this class, rofecoxib, does not contain sulfonamide moieties, but the isosteric and isoelectronic methylsulfone group. It was recently shown that the sulfonamide COX-2 selective inhibitors (but not the methylsulfone ones) also act as nanomolar inhibitors of several isozymes of the metallo-enzyme carbonic anhydrase (CA), some of which are strongly involved in tumourigenesis. In consequence, the potent anticancer effects of the sulfonamide COX-2 selective inhibitors and the much weaker such effects of rofecoxib, reported ultimately by many researchers, may be explained by the contribution of CA inhibition to such processes in addition to COX-2 inhibition.

Animals↗