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PubMed2006

Metabolism and effect of para-toluene-sulfonamide on rat liver microsomal cytochrome P450 from in vivo and in vitro studies.

AIM: To study the in vivo and in vitro metabolism and the effect of para-toluene-sulfonamide (PTS) on cytochrome P450 enzymes (CYP450). METHODS: Total CYP450 and microsome protein content were determined after iv pretreatment of rats with PTS. CYP-specific substrates were incubated with rat liver microsomes. Specific CYP isoform activities were determined by using HPLC. CYP chemical inhibitors added to the incubation mixture were used to investigate the principal CYP isoforms involved in PTS metabolism. The effect of PTS on CYP isoforms was investigated by incubating PTS with specific substrates. RESULTS: The groups treated with 33 and 99 mg/kg per d PTS, respectively, had a total CYP content of 0.66+/-0.17 and 0.60+/-0.12 nmol/mg. The K(m) and V(max) were 92.2 micromol/L and 0.0137 nmol/min per mg protein. CYP2C7, CYP2D1 and CYP3A2 might contribute to PTS metabolism in the rat liver. The inhibitory effects of sulfaphenazole and ketoconazole on PTS metabolism were shown to have a mixed mechanism, whereas PTS metabolism was inhibited noncompetitively by quinidine. PTS had little effect on the activities of the selected CYP isoforms. CONCLUSION: Generally speaking, it is relatively safe for PTS to be co-administered with other drugs. However, care should be taken when administering PTS with CYP inhibitors and the substrates of CYP2C, CYP2D and CYP3A.

Alcohol Oxidoreductases↗
PubMed1992

Indirect chiral separation and analyses in human biological fluids of the stereoisomers of a thienothiopyran-2-sulfonamide (TRUSOPT), a novel carbonic anhydrase inhibitor with two chiral centers in the molecule.

The indirect chiral separation of the four stereoisomers (1)-(4) of a novel carbonic anhydrase inhibitor with two chiral centers in the molecule is reported. The method is based on chemical derivatization of the secondary amino group of the inhibitor with chiral isocyanate, formation of diastereomeric urea derivatives, each with three chiral centers in the molecule, and their separation under nonchiral HPLC conditions. The attempts to separate racemic mixture (1) + (2) from its diastereomeric counterpart (3) + (4) under nonchiral conditions, and to separate enantiomers (1) and (2) directly on a chiral stationary phase (CSP) are also reported. The indirect method was utilized for the assessment of an in vivo inversion of configuration at either one or both chiral centers of the molecule of (1). Analyses of selected whole blood and urine samples from human subjects after multiple bilateral topical ocular dosing with (1) did not reveal the presence of any of the three possible stereoisomers (2)-(4) of (1) indicating that the inversion of configuration at neither one nor two chiral centers of (1) occurs in vivo.

Carbonic Anhydrase Inhibitors↗
PubMed2004

Accelerated solvent extraction and confirmatory analysis of sulfonamide residues in raw meat and infant foods by liquid chromatography electrospray tandem mass spectrometry.

This paper describes a new method for the rapid extraction and unequivocal confirmation of 13 sulfonamides (SAs) in raw meat and infant foods. The highly automated extraction procedure is based on accelerated solvent extraction followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) as a confirmatory analysis. After 1 g of food matrix was blended with 2 g of C18 as a solid support material, the mixture was packed into the extraction cell and the SAs were extracted with 10 mL of hot water at 160 degrees C and 100 atm; 100 microL of the extract was directly injected into the LC-MS system. The analytes were ionized in an electrospray interface operating in the positive ion mode and were identified by selecting two multireaction monitoring transitions, which guaranteed method specificity. Typical recoveries from crude meat and baby food samples ranged from 70 to 101% at a fortification level of 100 ppb, corresponding to the maximum residue limits established by the European Union and the U.S. Food and Drug Administration. The interday method precision was less than 8.5%, and the limits of detection were below 2.6 ppb. This study has taken matrix-induced suppression of ionization into account, by comparing standard and matrix-matched calibration curves. Four of the 13 monitored SAs have been detected in some baby foods and raw meat samples, bought from Roman supermarkets and butchers' shops, using the described methodology.

Animals↗
PubMed2002

Application of TLC-densitometry, first-derivative UV-spectrophotometry and ratio derivative spectrophotometry for the determination of dorzolamide hydrochloride and timolol maleate.

Three methods are described for the simultaneous determination of dorzolamide hydrochloride (DORZ) and timolol maleate (TIM) in ophthalmic solutions. The first method is based on application of thin layer chromatographic separation of both drugs followed by the densitometric measurements of their spot areas. After separation on silica gel GF(254) plates, using methanol-ammonia 25% (100:1.5 v/v) as the mobile phase, the chromatographic zones corresponding to the spots were scanned at 253 and 297 nm, respectively. The calibration function was established in the ranges of 2-18 microg for DORZ and 0.5-4.5 microg for TIM. The second method depends on first derivative ultraviolet spectrophotometry, with zero-crossing measurement method. The first derivative values D(1) at 250.2 and 312.5 nm were selected for the assay of DORZ and TIM, respectively. Calibration graphs follow Beer's law in the range 10-64 and 2.5-16 microg ml(-1), respectively. The third method is based on ratio first derivative spectrophotometry. The signals in the first derivative of the ratio spectra at 244 and 306.2 nm were selected to determine DORZ and TIM in the mixture and calibration graphs are linear in the range of 5-40 and 5.0-17.5 microg ml(-1), respectively. The proposed methods were successfully applied to the determination of these compounds in synthetic mixtures and in pharmaceutical preparations. The proposed methods are simple, rapid and suitable for quality control application.

Antihypertensive Agents↗
PubMed2001

Matrix solid-phase dispersion extraction and high-performance liquid chromatographic determination of residual sulfonamides in chicken.

Simultaneous determination of the six sulfonamides (SAs) sulfadiazine, sulfadimidine, sulfamonomethoxine, sulfamethoxazole, sulfadimethoxine and sulfaquinoxaline in chicken using matrix solid-phase dispersion (MSPD) with neutral aluminium oxide as an MSPD sorbent and high-performance liquid chromatography (HPLC) is presented. In the present MSPD, six SAs could be isolated by only one step, elution with a 70% (v/v) aqueous ethanol solution, without the sorbent conditioning and the sorbent-tissue matrix washing. For the HPLC determination, a LiChrospher 100 RP-8 and a mixture of 1% acetic acid solution (pH 3.0, in water)-acetonitrile-N,N-dimethylformamide (78:22:5, v/v/v) as the mobile phase with a photodiode array detector were used. Average recoveries were greater than 87.6% with relative standard deviations between 0.5 and 8.6%. The total time and amount of solvent required for the analysis of one sample were <1.5 h and <12 ml, respectively.

Animals↗
PubMed2005

[Determination of residual sulfonamides in meat by high performance liquid chromatography with solid-phase extraction].

A method was developed for determining residual sulfonamides (SAs) such as sulfamethazine (SM2), sulfamonomethoxine (SMM), sulfamethiazole (SMZ), sulfadimethoxine (SDM) and sulfaquinoxaline (SQ) in pork and chicken using solid-phase extraction (SPE) and high performance liquid chromatography (HPLC) with a photodiode array detector. The samples were extracted with ethyl acetate. An NH2 column was used for clean up. For the HPLC determination, an Intersil ODS-2 column was used with a mixture of methanol-acetonitrile-water-acetic acid (2: 2: 9: 0.2, v/v) as the mobile phase. The detection limits (S/N = 3) were 3 microg/kg for SM2, SMM and SMZ, and 7 microg/kg for SDM and SQ. The quantitation limits (S/N = 10) were 10 microg/kg for SM2, SMM and SMZ, and 25 microg/kg for SDM and SQ. The linear ranges were 30 - 5 000 microg/L for SM2, SMM and SMZ, and 60 - 5 000 microg/L for SDM and SQ. The recoveries were between 73.2% and 97.3% with the relative standard deviations between 2.5% and 11.6% originated from the spiked level of 50 microg/kg.

Animals↗
PubMed1979

The effect of a plasmid on growth and survival of E. coli.

We studied the growth characteristics of a pair of Escherichia coli strains, isogenic apart from the possession of a nonconjugative plasmid. There was no difference between the two strains when they were grown separately. In mixed culture, a second slow phase of growth that normally occurred following the end of rapid exponential growth, was absent from the plasmid-carrying strain. This resulted in a considerable decrease in the proportion of the cells that carried the plasmid after overnight incubation. The effect of different conditions of growth is reported. The plasmid-carrying strain survived extended incubation (150 days at 37 degrees C) as well as did the plasmid free strain separately. In a mixture, the proportion of plasmid-carrying cells declined rapidly, and none was detected after 100 days.

Cell Division↗
PubMed2006

Synthesis and selected reactions of a bicyclic sultam having sulfur at the apex position.

A practical synthesis of the bicyclic dienyl sultam 9 has been developed. The viable route involved several key steps. Of these, ring-closing metathesis represented by the conversion of 19 to 20 had to be implemented in advance of the assembly of other rings such as is present in 15. Product 20 was used as the template for more advanced framework construction, as in 16. The second double bond was best introduced by a bromination-dehydrobromination sequence, the 2-fold loss of HBr being achieved most reliably by the use of tetra-n-butylammonium fluoride in CH2Cl2 or DMSO. The direct irradiation of 9 gave rise to the endo-oriented cyclobutene derivative 30. The title diene is not a ready participant in Diels-Alder reactions. When heated with endo-bornyltriazolinedione in ethyl acetate solution, conversion to a 1:1 mixture of 33 and its diastereomer occurred as confirmed by X-ray crystallographic analysis. From the mechanistic perspective, this transformation constitutes an interesting example of a stereocontrolled and regioselective [2+2] cycloaddition followed by a vinylcyclobutane-cyclohexene rearrangement. Products 30 and 33 constitute examples of strained sulfonamides featuring a norbornyl-like structural component.

Journal Article↗
PubMedDate not supplied

Contact allergy to colour developing agents. Analysis of test preparations, bulk chemicals and tank solutions by high-performance liquid chromatography.

Colour developing agents which are derivatives of p-phenylenediamine can cause contact allergy. This study was done to perform if the observed simultaneous test reactions between different colour developing agents could be explained by common contaminants, reaction products or impurities. High-performance liquid chromatography (HPLC) was used for the separation of p-phenylenediamine, 1,4-benzoquinone, hydroquinone, Metol and the colour developing agents CD-2, CD-3 and CD-4. The stability in water solutions and in petrolatum mixtures was examined for the last three substances. Samples of test preparations drawn at different stages of guinea pig maximization tests (GPMT) with colour developing agents were analysed, as well as patch test preparations for clinical use and tank solutions from developer machines. No contaminants or reaction products in common were shown in the bulk chemicals, tank solutions or test preparations of CD-2, CD-3 and CD-4. These findings and the GPMT studies imply that the simultaneous test reactions reflect cross-sensitization. The colour developing agents were stable in petrolatum mixtures, but unstable in water solutions. Therefore, fresh solutions for intradermal induction and petrolatum mixtures for topical induction and challenge were used in the final GPMT's.

Animals↗
PubMed1991

Excavations in drug chirality: 1. Cyclothiazide.

There is a great deal of current interest in the role and importance of chirality in the development of new drugs, but little attention is being paid to the stereochemistry of older drugs. Indeed, many older chiral drugs were introduced without adequate information on their stereochemical identity or composition. We have examined one such drug, the antihypertensive diuretic agent cyclothiazide. Standard sources of drug information and the research literature do not provide data on the stereochemical composition of clinically used cyclothiazide, although scattered reports indicate that the drug may consist of "several stereoisomers." Inspection of the chemical structure of the drug, 6-chloro-3,4-dihydro-3-(5-norbornen-2-yl)-2H-1,2,4-benzothiadiazin e-7- sulfonamide 1,1-dioxide, shows that it can exist as eight stereoisomers that may form four racemates. Using synthesis, fast-atom-bombardment mass spectrometry, gas-liquid chromatography, chiral and nonchiral high-performance liquid chromatography, and nuclear magnetic resonance spectroscopy, we determined that pharmaceutical cyclothiazide is in fact a mixture of the eight stereoisomers in the form of the four racemates. The two racemates with endo configuration at the norbornene moiety predominate over the exo racemates, and small but significant differences in isomer distribution between different batches of the drug were observed. We urge that in studies of older drugs the stereochemical details be considered.

Antihypertensive Agents↗
PubMed2005

Enhancement of dissolution rate of valdecoxib using solid dispersions with polyethylene glycol 4000.

The aim of the present study was to enhance the dissolution rate of valdecoxib using its solid dispersions (SDs) with polyethylene glycol (PEG) 4000. The phase solubility behavior of valdecoxib in the presence of various concentrations of PEG 4000 in water was obtained at 37 degrees C. The solubility of valdecoxib increased with increasing amount of PEG 4000 in water. Gibbs free energy (deltaG(zero)tr) values were all negative, indicating the spontaneous nature of valdecoxib solubilization, and they decreased with increase in the PEG 4000 concentration, demonstrating that the reaction conditions became more favorable as the concentration of PEG 4000 increased. The SDs of valdecoxib with PEG 4000 were prepared at 1:1, 1:2, 1:5, and 1:10 (valdecoxib: PEG 4000) ratio by melting method. Evaluation of the properties of the SDs was performed by using dissolution, Fourier-transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), X-ray diffraction (XRD), and scanning electron microscopy (SEM) studies. The SDs of valdecoxib with PEG 4000 exhibited enhanced dissolution rate of valdecoxib, and the rate increased with increasing concentration of PEG 4000 in SDs. Mean dissolution time (MDT) of valdecoxib decreased significantly after preparation of SDs and physical mixture with PEG 4000. The FTIR spectroscopic studies showed the stability of valdecoxib and absence of well-defined valdecoxib-PEG 4000 interaction. The DSC and XRD studies indicated the amorphous state of valdecoxib in SDs of valdecoxib with PEG 4000. The SEM pictures showed the formation of effective SDs of valdecoxib with PEG 4000, since well-defined changes in the surface nature of valdecoxib, SDs, and physical mixture were observed.

Algorithms↗
PubMed1971

Changes in the drug resistance of Staphylococcus aureus in a non-hospital population during a 20-year period.

The antibiotic resistance of Staphylococcus aureus isolated in Bristol from primary skin sepsis and nasal carriers outside hospital was recorded between 1949 and 1969. The proportion of penicillinase-forming strains rose to about 60% but resistance to other antibiotics remained un-common except for a peak about 1957, due to the spread of multiresistant phage-type 80 staphylococci. Reasons are discussed for the failure of other multiresistant staphylococci to increase outside hospital.Recently isolated strains from inside and outside hospital were tested with sulphonamide and trimethoprim. All were sensitive to trimethoprim but 5% of non-hospital strains and 40% of hospital strains were resistant to sulphonamide. It is suggested that sulphonamide-resistant staphylococcal infections should not be treated with sulphonamide-trimethoprim mixtures because of the risk of breeding trimethoprim-resistant strains.

Carrier State↗
PubMed1996

Nitric oxide synthase in cat brain: cofactors--enzyme-substrate interaction.

Nitric oxide, derived from L-arginine by the enzyme nitric oxide synthase, is an activator of the soluble guanylate cyclase and a cellular messenger. This work demonstrates that, in cat brain, the neuronal constitutive nitric oxide synthase activity is a) NADPH/calcium dependent, b) independent upon exogenous calmodulin in crude brain supernatant, c) significantly enhanced by exogenous FAD and tetrahydrobiopterin (Vmax: 118 instead of 59.4 pmol of citrulline formed .mg of prot.-1 min-1, d) inhibited by calcium chelators and calmodulin antagonist, and e) present in several neuroanatomical structures. Moreover, the Km value for L-arginine was of 11 microM instead of 41 microM in the presence of FAD and tetrahydrobiopterin in the incubation mixture, thus demonstrating that these cofactors are able to stabilize the enzyme-substrate interactions.

Animals↗
PubMed1981

Effect of various diuretics on lipid peroxidation in rat renal cortical mitochondria and in the supernatant.

Effect of various diuretics of lipid peroxidation in rat kidney cortical mitochondria and in the supernatant (11,000 x g) was studied. Mersalyl (mercurial diuretic) markedly stimulated the lipid peroxidation in mitochondria and in the supernatant at a concentration of 1 mM, and metolazone (sulfonamide derivative, 1 mM) stimulated only that in the supernatant. Mersalyl-induced lipid peroxidation was markedly inhibited by several classical radical scavengers such as sodium diethyldithiocarbamate, 2,6-di-tert-butylphenol and N,N'-diphenyl-p-phenylenediamine, but metolazone-induced lipid peroxidation was not inhibited by these scavengers. The addition of superoxide dismutase to the reaction mixture inhibited the mersalyl-induced lipid peroxidation, but did not inhibit the peroxidation by metolazone or ascorbate. These results suggest that lipid peroxidation by mersalyl is mediated by free radicals or superoxide anion, which were probably produced by mersalyl, and the mercurial diuretics-induced nephrotoxicity may be due to the lipid peroxidation in the kidney.

Animals↗
PubMed2006

Multiwalled carbon nanotubes as sorbent for on-line coupling of solid-phase extraction to high-performance liquid chromatography for simultaneous determination of 10 sulfonamides in eggs and pork.

The sulfonamides (SAs) have been widely used as effective chemotherapeutics and growth promoters in animals' feeding, but their residues could be a potential danger to human health due to their carcinogenic potency and possible antibiotic resistance. Development of a simple and sensitive method for the determination of SAs residues in food of animal origin, therefore, is of great significance. An on-line solid-phase extraction (SPE) method using multiwalled carbon nanotubes as sorbent coupled with high-performance liquid chromatography (HPLC) for simultaneous determination of 10 sulfonamides (SAs) in eggs and pork was developed. The adsorptive potential of carbon nanotubes for solid-phase extraction of sulfonamides was investigated for the first time in the present paper. To on-line interface solid-phase extraction with HPLC, a conventional sample loop on the six-port injector valve of the HPLC was replaced by a preconcentration column packed with carbon nanotubes. The analytes in water solution were preconcentrated onto the preconcentration column and subsequently eluted with mobile phase of methanol-water (22:78). The developed on-line solid-phase extraction method for HPLC permitted the current HPLC separation and the next preconcentration proceeded in parallel, and thus allows one determination finished within 35 min. The RSD of 10 SAs for nine replicate measurements of a standard mixture of 1 microgl(-1) were in the range of 2.5-7.8%. The method was applied to the determination of trace sulfadiazin (SDZ), sulfamerazine (SMR), sulfadimidine (SDMD), sulfathiazole (STZ), sulfamoxol (SMO), sulfamethizole (SMT), sulfamethoxypyridazine (SMP), sulfachlorpyridazine (SCP), sulfadoxin (SDX) and sulfisoxazole (SIA) in eggs and pork. The results indicated that the proposed method was simple, cost-effective and sensitive.

Animals↗
PubMed2005

[IOP in rabbits after instillation of a mixture of the antiglaucomatic Cosopt and the aminoacid L-argininin HCL into the conjunctival sac].

OBJECTIVE: The article documents results of experiments focused to influence the physiological IOP values after application of the COSOPT eye drops (double combination of bbb-blocker and carbonic anhydrase inhibitor), aminoacid 10% L-arginin.HCl and their mixture in rabbits. METHODS: COSOPT followed by 10% L-arginin.HCl and mixture of 10% L-arginin.HCl with COSOPT was instilled weekly into the left conjunctival sac of 5 adult rabbits (females of the New Zealand White species). The IOP and pupilar diameter were measured in 5, 15, 30, 60, 120, 180, 240 min. and 24 hours after instillation. The right eye was used as control. RESULTS: The antiglaucomatic COSOPT no significantly decreased the rabbit IOP during 24 hours (mean value 1.85 %) in vivo. The aminoacid 10% L-arginin.HCl achieved significant decrease of the IOP: the mean value was 16.03% reaching maximum in 60th and 180th min. After instillation of the 10% L-arginin.HCl and COSOPT mixture in the IOP showed significant decrease with mean value of 9,64% (except values in 5th min. and 24th hour). Compared with control eye, the major decrease of the IOP was measured in 240th min. (mean value 17.98%). However even in 24 hours after instillation the IOP was not reaching the values of the control eye, shoving also the IOP decrease. CONCLUSION: We assume that in a double combination of antiglaucomatics in COSOPT a new substance was created. This substance interacted in vitro with the aminoacid 10% L-arginin.HCl resulting in a new "bio-antiglaucomatis" better penetrating into the target area. This new substance was responsible for more significant decrease after the mixture application compared with COSOPT alone. The presence of aminoacid can slow down the undesirable effect of the antiglaucomatics together with the possible neuroprotection.

Animals↗
PubMed2001

Discovery of a new efficient chiral ligand for copper-catalyzed enantioselective Michael additions by high-throughput screening of a parallel library.

A combinatorial library of 125 chiral Schiff base ligands 5 was synthesized with the use of solution-phase parallel synthesis and solid-phase extraction (SPE) techniques to scavenge excess reagents and reaction by-products and avoid chromatography. The synthetic methodology coupled five N-Boc-protected beta-amino sulfonyl chlorides 1a-e with five different amines 2f-j to give 25 N-Boc sulfonamides 3, which were in turn deprotected and coupled with five salicylaldehydes 4p-t to give 125 ligands 5 in good yields and of sufficient purity to be used in ligand-catalyzed reactions. These ligands were tested in the copper-catalyzed conjugate addition of dialkyl zinc to cyclic and acyclic enones. A multisubstrate high-throughput screening of the library was performed with an equimolar mixture of 2-cyclohexenone and 2-cycloheptenone (9 and 10, respectively, 0.2 mmol total), with 5.5 mol% ligand 5 (0.011 mmol) and 5 mol% Cu(OTf)2 (OTf= OSO2CF3) (0.010 mmol) in 1:1 toluene/ hexane at - 20 degrees C. From the screening of the library, 5bhr was identified as the best ligand, which yielded 3-ethylcyclohexanone (12) and 3-ethylcycloheptanone (13) in 82% and 81% ee, respectively, and complete conversions. Under optimized conditions (2.75 mol% 5bhr, 2.5 mol% copper(i) triflate, toluene as reaction solvent), improved results were obtained for 12 (90% ee, 93% yield) and for 13 (91% ee, 95% yield). Selected ligands 5 were also tested in the addition of Me2Zn to 2-cyclohexenone (9, ee up to 79%), of Et2Zn to 2-cyclopentenone (11, ee up to 80%) and to acyclic enones 16 and 17 (ee up to 50%).

Journal Article↗