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PubMed2002

Allergic adverse reactions to sulfonamides.

Antimicrobial sulfonamides were the first antimicrobial agents used effectively to treat infectious diseases. However, because they may cause severe adverse drug reactions (ADRs) and because more effective agents have since been developed, sulfonamides now are used for only a few indications in specific groups, such as AIDS patients. Skin reactions, from benign rash to potentially lethal toxidermias, are the most frequent ADRs to sulfonamides. Other major ADRs include acute liver injury, pulmonary reactions, and blood dyscrasias. Although the mechanisms involved have not been fully elucidated, reactive metabolites appear to play a pivotal role. The hydroxylamine and nitroso metabolites of sulfamethoxazole, the most frequently used sulfonamide today, can bind covalently to proteins because of their chemical reactivity, resulting in the induction of specific adverse immune responses. Therefore, changes in the activity of metabolic and detoxification pathways are associated with a greater risk for developing allergic reactions to sulfonamides. Allergies to sulfonamides, particularly sulfamethoxazole (often used in combination with trimethoprim as co-trimoxazole), are more frequent in AIDS patients, but the reason for this increased risk is not fully understood. No valid tools are available to predict which patients have a greater risk for developing allergies to sulfonamides. Diagnosis is essential to avoid a possible evolution toward severe reactions and readministration of the offending drug. In patients who absolutely require further treatment, successful desensitization may be achieved.

Anti-Infective Agents↗
PubMedDate not supplied

Carbonic anhydrase inhibitors. Part 60(#). The topical intraocular pressure-lowering properties of metal complexes of a heterocyclic sulfonamide: influence of the metal ion upon biological activity.

Metal complexes of a sulfonamide possessing strong carbonic anhydrase (CA) inhibitory properties have been obtained from the sodium salt of the sulfonamide or from the free sulfonamide in the presence of ammonia, and the following metal ions: Mg(II); Zn(II); Mn(II); Cu(II); Co(II); Ni(II); Be(II); Cd(II); Pb(II); Al(III); Fe(III) and La(III). The original sulfonamide, 5-(3,4-dichlorophenylureido)-1,3,4-thiadiazole-2-sulfonamide and its complexes were assayed for in vitro inhibition of three CA isozymes, CA I, II and IV, some of which play a critical role in ocular fluid secretion. All these compounds (the sulfonamide and its metal complexes) behave as very powerful inhibitors against the three investigated CA isozymes. The parent sulfonamide possesses strong topical pressure lowering effects in rabbits when applied as a 1% solution directly into the eye, but some of its metal complexes, such as the Mg(II); Zn(II); Mn(II) and Cu(II) derivatives, lower intraocular pressure (IOP) in experimental animals much better. Ex vivo data showed a 98.5-99.9% inhibition of CA II and IV in ocular fluids and tissues of the rabbits treated with these agents, proving that the IOP lowering properties are due to CA inhibition. The influence of the different metal ions upon the efficiency of the obtained complexes as pressure lowering drugs are discussed, considering the possibility to design in this way more selective pharmacological agents from this class.

Administration, Topical↗
PubMed2004

Generic lanthanide fluoroimmunoassay for the simultaneous screening of 18 sulfonamides using an engineered antibody.

Sulfa antibiotics (sulfonamides) are used in veterinary and human medicine for therapeutic and prophylactic purposes. Veterinary use can result in foodstuffs derived from animals being contaminated with residual sulfonamides. Current sulfonamide-screening methods (mainly based on bacterial growth inhibition) are slow and inaccurate, since sensitivities of bacteria to different sulfonamides vary a lot. Therefore, a rapid immunoassay that was able to detect at least 18 different sulfonamides at the MRL level (100 microg/kg) from food samples in a single reaction was developed. The assay was reproducible and adequately accurate for screening purposes. The presence of sulfonamide metabolites did not cause major assay interference. We also demonstrated reliable detection of sulfonamides from a panel of meat, milk, and serum samples with the assay.

Animals↗
PubMed1977

Determination of ionization state by resonance Raman spectroscopy Sulfonamide binding to carbonic anhydrase.

Resonance Raman (RR) spectroscopy has been used to study the ionization state of the sulfonamide, 4'-sulfamylphenyl-2-azo-7-acetamido-1-hydroxynaphthalene-3,-6-disulfonate (Neoprontosil), bound to carbonic anhydrase. The correlation of effects of pH and deuteration on the spectra of model compounds with these effects on the Neoprotosil spectrum allows us to assign spectral bands in the 900-1000 and 100-1200 cm-1 regions to the SO2NH2 group. Large shifts in these bands occur upon ionization of the sulfonamide. On the basis of the positions of bands in the enzyme complex, it was determined that the sulfonamide was bound to the enzyme as SO2NH2, rather than as SO2NH-. Rates of association and dissociation and the dissociation equilibrium constant were measured as a function of pH. The rate behavior for Neoprontosil is consistent with that observed for other sulfonamides and kdissoc/kassoc = kdissoc, suggesting a one-step binding mechanism. Since RR spectroscopy establishes that the final ionization state of the sulfonamide in the enzyme complex is SO2NH2, protonated sulfonamide must bind directly to basic form of the enzyme. These conclusions suggest that sulfonamides form "outer-space" complexes with metal at the enzyme active site.

Animals↗
PubMed1976

Resonance Raman studies in some carboni anhydrase-aromatic sulfonamide complexes.

Resonance Raman spectra of 4-sulfonamido -4'-dimethylaminoazobenzene, 4-sulfonamido-4'-hydroxyazobenzene, and 4-sulfonamideo-4' aminoazobenzene bound to various isoenzymes of carbonic anhydrase were obtained by exciting into the sulfonamide absorption bands in the 400-500-nm region. In this way it was possible to obtain vibrational spectra of the sulfonamides in the active site unmasked by contributions from the vibrational modes of the protein and H2O solvent. Direct evidence was obtained for the presence of -SO2NH- in the complex, and it was possible to eliminate hydrophobic bonding and twisting in the Ph--N==N--Ph bonds as sources of the observed spectral changes. No detectable differences were found in the spectra of 4-sulfonamido-4'-dimethylaminoazobenzene bound to human carbonic anhydrase B and C or between these and the spectra of the sulfonamide bound to bovine carbonic anhydrase or Co(II) human carbonic anhydrase B. A new band appears in the spectra of the bound sulfonamides, and this is interpreted in terms of a change in geometry about the sulfonamido sulfur atom. A possible explanation for this change in geometry is that the bound sulfonamide group closely mimics the transition state of the reactants in the reversible hydration of CO2. Sulfonamide binding at pH 12.0 was not detected in the resonance Raman spectrum. Sulfonamide replacement of CN- in the binding site occurred over a period of minutes and could be monitored in the resonance Raman spectra.

Animals↗
PubMed1993

Non-peptide angiotensin II receptor antagonists. 2. Design, synthesis, and biological activity of N-substituted (phenylamino)phenylacetic acids and acyl sulfonamides.

The design, synthesis, and biological activity of a new class of highly potent non-peptide AII receptor antagonists derived from N-substituted (phenylamino)phenylacetic acids and acyl sulfonamides which exhibit a high selectivity for the AT1 receptor are described. A series of N-substituted (phenylamino)phenylacetic acids (9) and acyl sulfonamides (16) and a tetrazole derivative (19) were synthesized and evaluated in the in vitro AT1 (rabbit aorta) and AT2 (rat midbrain) binding assay. The (phenylamino)phenylacetic acids 9c (AT1 IC50 = 4 nM, AT2 IC50 = 0.74 microM), 9d (AT1 IC50 = 5.3 nM, AT2 IC50 = 0.49 microM), and 9e (AT1 IC50 = 5.3 nM, AT2 IC50 = 0.56 microM) were found to be the most potent AT1-selective AII antagonists in the acid series. Incorporation of various substituents in the central and bottom phenyl rings led to a decrease in the AT1 and AT2 binding affinity of the resulting compounds. Replacement of the carboxylic acid (CO2H) in 9c, 9d, and 9e with the bioisostere acyl sulfonamide (CONHSO2Ph) resulted in a (5-7)-fold increase in the AT1 potency of 16a (AT1 IC50 = 0.9 nM, AT2 IC50 = 0.2 microM), 16b (AT1 IC50 = 1 nM, AT2 IC50 = 2.9 microM), and 16c (AT1 IC50 = 0.8 nM, AT2 IC50 = 0.42 microM) and yielded acyl sulfonamides with subnanomolar AT1 activity. Incorporation of the acyl sulfonamide (CONHSO2Ph) for the CO2H of 9c not only enhanced the AT1 potency but also effected a marked increase in the AT2 potency of 16a (AT2 IC50 = 0.74 microM of 9c vs 0.2 microM of 16a) and made it the most potent AT2 antagonist in this study. Replacement of the CO2H of 9b with the bioisostere tetrazole resulted in 19 (AT1 IC50 = 15 nM) with a 2-fold loss in the AT1 and a complete loss in the AT2 binding affinity. (Phenylamino)phenylacetic acid 9c demonstrated good oral activity in AII-infused conscious normotensive rats at an oral dose of 1.0 mg/kg by inhibiting the pressor response for > 6 h. Acyl sulfonamides 16a-c displayed excellent in vivo activity by blocking the AII-induced pressor response for > 6 h after oral administration in conscious rats at a 3.0 mg/kg dose level. Both acyl sulfonamides 16a and 16c exhibited superior in vivo activity in rats compared to that of (phenylamino)phenylacetic acid 9c.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1989

Binding of sulfonamides to carbonic anhydrase: influence on distribution within blood and on pharmacokinetics.

Four new aromatic sulfonamides were synthesized and purified by standard techniques. Two were unsubstituted, primary sulfonamides and two possessed substituents on the sulfonamide nitrogen. The affinity of the inhibitors for the enzyme carbonic anhydrase was determined in terms of the inhibitory potency, which was found to be dependent on the presence of an unsubstituted sulfonamide group. Binding studies were performed in erythrocyte suspensions using a range of concentrations and the unbound, extracellular concentrations were determined by high-performance liquid chromatographic (HPLC) assay. The dissociation constant of binding and the total binding capacity of the erythrocytes were estimated by nonlinear regression using a two-site binding model. The affinity of the compounds for erythrocytes reflected their inhibitory potency against the enzyme. Binding to plasma proteins was more dependent on lipophilicity and pKa and was stronger for the substituted sulfonamides. Pharmacokinetic studies in rats showed that the unsubstituted sulfonamides with a high affinity for carbonic anhydrase in erythrocytes have longer half-lives and lower clearance values than the substituted sulfonamides which were more strongly bound to plasma proteins. However, comparison of unbound clearance values showed that the variations in molecular structure, which produced differences in carbonic anhydrase binding and in distribution, also produced variations in susceptibility to elimination processes.

Animals↗
PubMed1997

Structure-activity relationships between antibacterial activities and physicochemical properties of sulfonamides.

Relationships between the antimicrobial activities of sulfonamides and physicochemical properties including the acid dissociation constant (pKa) and the hydrophobicity constant (pi) were determined. The minimal inhibitory concentrations (MIC) of sulfonamides against Actinobacillus pleuropneumoniae, a gram-negative veterinary pathogen, were used. High performance liquid chromatography was applied for the determination of the electronic and hydrophobic parameters. Empirically determined relationships pointed out the dominant role of the degree of ionization on the antimicrobial activity. The data indicate that hydrophobic properties of sulfonamides, characterized by pi, are of minor importance for the in vitro antibacterial activity. Because of the restricted pKa range (4.9-7.7) it could not be established whether the relationship between pKa and activity was linear or bilinear. Whenever o,m-disubstituted sulfonamides were included correlations decreased substantially. Relationships based on multicompartment equilibrium models were derived and indicated a bilinear relation between pKa and MIC. Model-based equations showed that the antibacterial activity was governed by the extracellular ionic concentration of the sulfonamides whenever different intra and extracellular pH values were assumed in the equilibrium model. The antimicrobial activities of the sulfonamides against gram-positive organisms were also related to the degree of ionization of the sulfonamides in the agar medium.

Actinobacillus pleuropneumoniae↗
PubMed2004

In vitro inhibition effects of some new sulfonamide inhibitors on human carbonic anhydrase I and II.

A new series of aromatic and heterocyclic sulfonamides, including six new derivatives, 2-(3-cyclohexene-1-carbamido)-1,3,4-thiadiazole-5-sulfonamide (CCTS), 4-(3-cyclohexene-1-carbamido) methyl-benzenesulfonamide (CCBS), 2-(9-octadecenoylamido)-1,3,4-thiadiazole-5-sulfonamide (ODTS), 2-(4,7,10-trioxa-tetradecanoylamido)-1,3,4-thiadiazole-5-sulfonamide (TDTS), 2-(coumarine-3-carbamido)-1,3,4-thiadiazole-5-sulfonamide (COTS) and 2-(8-methoxycoumarine-3-carbamido)-1,3,4-thiadiazole-5-sulfonamide (MCTS), has been investigated. These sulfonamides were assayed for inhibition of human carbonic anhydrase I (hCA-I) and human carbonic anhydrase II (hCA-II) which were purified by affinity chromatography.

Carbonic Anhydrase I↗
PubMed2001

Comparison of clindamycin phosphate vaginal cream with triple sulfonamide vaginal cream in the treatment of bacterial vaginosis.

BACKGROUND: Triple sulfonamide vaginal cream has been used to treat bacterial vaginosis for many years. There are few studies in which triple sulfonamide cream has been compared with newer regimens. GOAL: To compare the efficacy and safety of clindamycin phosphate vaginal cream with that of triple sulfonamide vaginal cream in the treatment of bacterial vaginosis. STUDY DESIGN: In this double-blind, randomized multicenter study, nonpregnant women 16 years of age or older with symptomatic bacterial vaginosis were assigned to receive either 2% clindamycin phosphate vaginal cream or triple sulfonamide vaginal cream for 7 days. Follow-up visits were conducted 5 to 10 days and 25 to 39 days after completion of treatment. RESULTS: Clinical cure or improvement at 25 to 39 days was noted in 55 (69.6%) of 79 assessable participants who received clindamycin vaginal cream and in 33 (41.8%) of 79 women who received triple sulfonamide vaginal cream (P < 0.0001). Most of the difference between the treatment groups was noted in women with a history of bacterial vaginosis. Among women without a history of bacterial vaginosis, clindamycin and triple sulfonamide creams had similar efficacy. Evaluation of Gram-stained vaginal smears correlated with clinical outcome. Most patients in both treatment groups reported an improvement in symptoms. No significant difference was observed between the treatment groups in the incidence of adverse events. CONCLUSION: Clindamycin 2% vaginal cream is more effective than triple sulfonamide vaginal cream in the treatment of bacterial vaginosis.

Administration, Intravaginal↗
PubMed2006

Difference in risks of allergic reaction to sulfonamide drugs based on chemical structure.

BACKGROUND: The chemical structure of sulfonamide antibiotics and sulfonamide nonantibiotics can affect the potential for adverse reactions. OBJECTIVE: To assess whether differences in chemical structure of the various sulfonamide drugs influence the risk of allergic events. METHODS: A case-control study was conducted among patients with diabetes mellitus (DM) using data from the General Practice Research Database. Cases were defined as patients with a diagnosis of hypersensitivity or allergic reaction. The date of the last event was the index date. Controls were matched on practice, type of DM, and index date. Current use of sulfonamides was defined as use in a 14 day time window before the index date. Sulfonamides were classified according to the presence/absence of an N1 substituent (N1(+)/(-)) and/or an arylamine (N4(+)/(-)). Conditional logistic regression was used to estimate strength of association and expressed as odds ratios and 95% confidence intervals. RESULTS: Overall, current use of N1(+) N4(+) sulfonamide drugs was associated with the outcome (adjusted OR 3.71; 95% CI 1.40 to 9.81). Current use of N1(+) N4(-) and N1(-) N4(-) sulfonamide drugs was also associated with the occurrence of allergic reactions, although not as strongly: adjusted OR 2.48 (95% CI 2.12 to 2.89) and 2.07 (95% CI 1.74 to 2.46), respectively. Sex and age seemed to be effect modifiers. There was no clear evidence for effect modification by immune disease state. CONCLUSIONS: Although we did not identify major differences between the groups, we believe that this approach is an innovative manner to examine adverse drug reactions by using chemical structure instead of therapeutic drug classes to classify exposure.

Aged↗
PubMed2004

Antiviral sulfonamide derivatives.

The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anti-carbonic anhydrase, diuretic, hypoglycemic, antithyroid and anticancer activity among others. A large number of structurally novel sulfonamide derivatives have ultimately been reported to show substantial antiviral activity in vitro and in vivo. The review summarizes recent classes of sulfonamides and related sulfonyl derivatives disclosed as effective such agents. Thus, at least some HIV protease inhibitors used clinically (amprenavir) or compounds in advanced clinical trials (tipranavir, TMC-126, TMC-114, etc.) possess sulfonamide moieties in their molecules, whereas a very large number of other derivatives are constantly being synthesized and evaluated in order to obtain compounds with less toxicity or activity against drug-resistant viruses. Several non nucleoside HIV reverse transcriptase or HIV integrase inhibitors containing sulfonamide groups were also reported. Another approach to inhibit the growth of retroviruses, including HIV, targets the ejection of zinc ions from critical zinc finger viral proteins, which has as a consequence the inhibition of viral replication in the absence of mutations leading to drug resistance phenotypes. Most compounds with antiviral activity possessing this mechanism of action incorporate in their molecules primary sulfonamide groups. Finally, some small molecule chemokine antagonists acting as HIV entry inhibitors also possess sulfonamide functionalities in their scaffold.

Animals↗
PubMed2001

A rapid assay for detecting sulfonamides in tissues of slaughtered animals.

Governments regulate antimicrobial residues in slaughtered animals with surveillance programs for detecting drugs in food-producing animals. Although initial screening bioassay systems are recognized for their sensitivities to antimicrobial drug groups, none are sensitive to sulfonamides at or near the maximum residue levels (MRLs) in the Codex Alimentarious. We have developed a sulfonamide-sensitive rapid assay using Bacillus stearothermophilus inoculated PM indicator agar containing bromcresol purple and trimethoprim, where the end point is a combination of color change in the agar and zone of microbial growth inhibition around the sampling disk. Five sulfonamides, plus 16 other antimicrobial drugs were tested in standard concentrations in water, bovine kidney, and ground beef. Sulfonamides were detected at concentrations near the MRLs, and they were presumptively identified using para-aminobenzoic acid. The rapid assay was extremely sensitive to beta-lactams that were presumptively identified using penase. The system also was sensitive to tetracyclines, aminoglycosides, and macrolides, of which tetracyclines and gentamicin were identified using enzyme-linked immunosorbent assay (ELISA). In trials on slaughterhouse tissues submitted for testing in Ontario's meat surveillance program, the rapid assay identified twofold the number of positive kidneys and threefold the number of positive diaphragm samples compared to a standard microbiological inhibition test (MIT) currently approved. Fifty-three of 471 carcasses were sulfonamide positive with the rapid assay, while no sulfonamides were detected with the MIT. ELISA and thin-layer chromatography were used on selected samples to confirm the rapid assay sulfonamide presumptive results.

Animals↗
PubMed1989

Diagnosis of sulfonamide hypersensitivity reactions by in-vitro "rechallenge" with hydroxylamine metabolites.

STUDY OBJECTIVE: To determine whether differences in in-vitro detoxification of sulfonamide-reactive metabolites can be detected among the lymphocytes from controls, patients with sulfonamide hypersensitivity reactions, and patients with nonhypersensitivity reactions to the sulfonamide agents. DESIGN: In-vitro toxicity assay on lymphocytes. SETTING: Clinics for adverse drug reactions in an adult and pediatric tertiary care center. PATIENTS: Peripheral blood lymphocytes were obtained from 46 normal volunteers and 76 patients referred to the clinic for assessment of adverse drug reactions to sulfonamide agents. Thirty-one patients had clinical histories consistent with a diagnosis of hypersensitivity reaction, whereas 45 patients had clinical histories felt to be inconsistent with a diagnosis of hypersensitivity reaction. INTERVENTIONS: Lymphocytes were assayed with tetrazolium to determine toxicity from the hydroxylamine of sulfamethoxazole. MEASUREMENTS AND MAIN RESULTS: The lymphocytes from patients with a history of hypersensitivity reactions showed markedly increased toxicity across a tenfold-concentration toxicity-concentration curve compared with those from controls and patients with a history of nonhypersensitivity reactions. These differences were highly significant (P less than 0.01). No difference was found between the toxicity shown by the lymphocytes from controls and that shown by the lymphocytes from patients with a history of nonhypersensitivity reactions. CONCLUSIONS: Metabolic differences in the production and detoxification of reactive metabolites of sulfonamide agents are important determinants of hypersensitivity reactions to these agents. These results suggest that the hydroxylamine derivative of sulfamethoxazole may be a reactive metabolite mediating these reactions. Sulfonamide hydroxylamines are useful in the diagnosis and study of the pathogenesis of hypersensitivity reactions to sulfonamide agents.

Adult↗
PubMed1998

The inhibition of bovine carbonic anhydrase by saccharin and 2- and 4-carbobenzoxybenzene sulfonamide.

The present work demonstrates that the high-activity zinc metalloenzyme, carbonic anhydrase (CA II) from bovine erythrocytes is inhibited by the cyclic sulfimide, saccharin, and 2- and 4-carbobenzoxybenzene sulfonamide. A spectrophotometric method was employed to monitor the enzymatically catalyzed hydrolysis of p-nitrophenyl acetate by following the increase in absorbance at 410 nm which accompanies p-nitrophenoxide/p-nitrophenol formation. The more rapid enzymatic hydration of CO2 was monitored by using a stopped-flow spectrophotometer as well as by a modified colorimetric method of Wilbur and Anderson. The studies show that, at a given molar ratio of inhibitor to enzyme, the degree of inhibition of the enzymaic hydration of CO2 and hydrolysis of p-nitrophenyl acetate by the inhibitory compounds is essentially the same. Kinetic analyses were made at 25.0 degrees at pH 6.5 (MES buffers), pH 6.9 (HEPES buffers) and pH 7.9 (HEPES buffers) with ionic strength regulated by the addition of appropriate quantities of sodium sulfate. Lineweaver-Burk plots were used to evaluate apparent inhibition constants for each of the three inhibitors. For all the inhibitors studied, inhibition appears to be mixed (competitive/noncompetitive). For saccharin in the presence of sodium sulfate, the extent of inhibition is considerably decreased. It was found for the three inhibitors that the inhibitory potency decreases with increasing pH, and that the inhibitory potency is extremely sensitive to the shape of these rather closely related molecules. For example, apparent inhibition constants for the enzymatic hydrolysis of p-nitrophenyl acetate at pH 6.9 were Ki (saccharin) = 0.20 mM, Ki (2-carbobenzoxybenzene sulfonamide) = 0.54 mM and Ki (4-carbobenzoxybenzene sulfonamide) = 1.6 microM. For the enzymatic hydration of CO2 at pH 6.9, 0.10 mM saccharin caused 50% inhibition while 7.0 nM 4-carbobenzoxybenzene sulfonamide resulted in 50% inhibition. The results suggest that sulfonamide inhibition is caused by formation of a monodentate ligand at the zinc ion of the enzyme active site and that the more linear 4-carbobenzoxybenzene sulfonamide is better able to enter a conical enzyme active site than is 2-carbobenzoxybenzene sulfonamide or saccharin.

Algorithms↗
PubMed1992

Sulfonamide residues in eggs.

In two series of experiments lasting 3 days each, laying hens were medicated with sulfonamides via the drinking water. In the first experiment 8 laying hens were given sulfaquinoxaline (SQ) at a dose rate of 400 mg/l, while in the second trial 16 laying hens received a 3:5:5 sulfonamide mixture containing sulfaquinoxaline (SQ), sulfadimidine (SDI) and sulfamerazine (SMN), at a dose of 390 mg/l. According to the water consumption data, the hens' daily sulfonamide intake was 53.6 and 56.9 mg/kg body mass, respectively. Eggs laid during and in the first 10 days after the treatment were collected and assayed for sulfonamide residues by spectrophotometry. The detection limit of the method was 0.16 mg/l and the recovery percentage was between 70 and 80%. Sulfonamide was found to appear already in eggs laid after the first day of treatment. The absorption half-life of the drug was 0.4-0.6 day in the egg-white and 0.93-1.08 day in the egg-yolk. Peak drug level in the egg-white was measured on the last day of medication, while in the egg-yolk within 3 days after the end of treatment. The residue measured in the yolk was 13-16% of that found in the egg-white. Acetylated sulfonamide could be measured in the yolk for 3 days after the treatment: its level reached 15%. On the basis of the elimination rate, complete elimination of sulfonamides requires at least 5.2-7.4 days. Therefore, observance of the generally accepted withdrawal time of 10 days is indispensable.

Animals↗
PubMed1996

Demonstration of synergistic effects of sulfonamides and dihydrofolate reductase/thymidylate synthase inhibitors against Neospora caninum tachyzoites in cultured cells, and characterization of mutants resistant to pyrimethamine.

OBJECTIVE: To examine the efficacies of combinations of 7 sulfonamides and 5 dihydrofolate reductase/thymidylate synthase (DHFR/TS) inhibitors against tachyzoites of Neospora caninum in cultured cells. Mutant tachyzoites that were resistant to pyrimethamine were produced and examined for resistance to other DHFR/TS inhibitors. DESIGN AND PROCEDURES: After 5 days of treatment, a cell culture flask lesion-based assay was used to determine efficacies of combinations of sulfonamides and DHFR/TS inhibitors against N caninum tachyzoites and to evaluate the sensitivity of pyrimethamine-resistant mutants of N caninum to test agents. Cultured cells that were infected with the appropriate strains of N caninum and treated or not treated (controls) with test agents were examined. Mutations were induced by chemical mutagenesis with N-methyl-N'-nitro-N-nitrosoguanidine or by selection for growth in permissive concentration of pyrimethamine. RESULTS: Synergism was detected for combinations of pyrimethamine, ormetoprim, trimethoprim, or diaveridine with the sulfonamides. Methotrexate did not have improved efficacy when combined with sulfonamides. Two mutants were produced that were resistant to pyrimethamine. Both mutants were resistant to other DHFR/TS inhibitors. Both mutants remained resistant to pyrimethamine in the absence of continuous exposure to the agent, indicating that the induced resistance was stable. Synergism was detected for combinations of DHFR/TS inhibitors and sulfonamides against these pyrimethamine-resistant mutants. CONCLUSIONS: Combinations of suboptimal concentrations of sulfonamides with suboptimal concentrations of DHFR/TS inhibitors results in improved efficacy of the agents in a cell culture assay. Stable resistance to pyrimethamine can be induced in N caninum tachyzoites by use of chemical mutagenesis or by selection. CLINICAL RELEVANCE: In vitro evidence indicated that combination treatment, using sulfonamides and DHFR/TS inhibitors, may be effective in treating neosporosis.

Animals↗
PubMed2026

The Role of In Vivo, In Vitro and Pharmacogenomic Diagnostic Approaches to Sulfonamide Allergy.

Sulfonamide antibiotics are commonly reported as a medication allergy, presenting as both immediate IgE-mediated reactions and delayed hypersensitivity reactions ranging from benign cutaneous eruptions to severe cutaneous adverse reactions. Sulfonamide antibiotics have retained importance as treatment for multiple indications and are especially relevant in immunocompromised patients wherein use is indicated for prevention of opportunistic infections. Sulfonamide antibiotic allergy labels may lead to inappropriate avoidance of other "sulfur"-containing medications, because cross-reactivity is unlikely between antibiotic and nonantimicrobial sulfonamides. In this review, we discuss the typical presentation of sulfonamide antibiotic hypersensitivity reactions. We also review risk stratification tools and current in vivo procedures and experimental in vitro evaluation methods. Lastly, we will provide an update on emerging pharmacogenomics data associated with sulfonamide medication adverse reactions.

Humans↗