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Kigelia africana plant is widely used as a herbal remedy in preventing the onset and the treatment of cancer-related infections. With the increase in the research interest of the plant, the specific chemical compound or metabolite that confers its anticancer properties has not been adequately investigated. The ethyl acetate and butanol fractions of the fruit extracts were evaluated by 2-(4,5-dimethylthiazol-2-yl)-3,5-diphenyl-2H-tetrazolium bromide assay against four different cell lines, with the ethyl acetate fraction having inhibition concentration values of 0.53 and 0.42 μM against Hep G2 and HeLa cells, respectively. More than 235 phytoconstituents were profiled using UHPLC-TOF-MS, while more than 15 chemical compounds were identified using GC-MS from the fractions. Molecular docking studies revealed that physostigmine, fluazifop, dexamethasone, sulfisomidine, and desmethylmirtazapine could favorably bind at higher binding energies of -8.3, -8.6, -8.2, and -8.1 kcal/mol, respectively, better than camptothecin with a binding energy of -7.9 kcal/mol. The results of this study showed that physostigmine interacted well with topoisomerase IIα and had a high score of pharmacokinetic prediction using absorption, distribution, metabolism, excretion, and toxicity profiles, thereby suggesting that drug design using physostigmine as a base structure could serve as an alternative against the toxic side effects of doxorubicin and camptothecin.

A graphene oxide-molybdenum disulfide (GO-MoS2) composite was synthesized and utilized as the highly efficient stationary phase of open-tubular capillary electrochromatography (OT-CEC). The characterization results indicated that GO-MoS2 composite was successfully synthesized. The GO-MoS2-coated capillary column was prepared by covalent immobilization method for the determination of seven sulfonamides. The baseline separation of seven sulfonamides was achieved by GO-MoS2-coated capillary column. The linear range was 0.05-100 μg/mL for sulfisomidine, sulfathiazole, sulfamerazine, phthalylsulfathiazole and sulfacetamide, 0.1-100 μg/mL for sulfamonomethoxine and sulfachloropyridazine with a satisfactory correlation coefficients (R2) > 0.9994. This developed OT-CEC method was successfully applied to determinate of seven sulfonamides in environmental water and milk samples with good recoveries of 85.77% - 109.10% and 80.03% - 109.97%, respectively. These results indicated that GO-MoS2-coated capillary column possessed good stability and repeatability.

Membrane bioreactors (MBRs) were shown contradictory results for the removal of antibiotics, such as sulfonamides (SAs), from wastewater in different studies, which highlighted the necessity for comprehensive investigation on removal mechanisms of sulfonamides in well-controlled lab-scale MBRs. In the present study, the removal performance of nine SAs by a lab-scale anaerobic/anoxic/oxic-membrane bioreactor (A1/A2/O-MBR) was studied at environmental relevant concentrations. The results showed that all the SAs were efficiently eliminated (93.9%-97.5%) in the A1/A2/O-MBR, much more efficiently than the previously reported MBR-based processes. The largest contribution to the total removal was made by the aerobic reactor (71.1%-85.3%) A small portion of SAs (7.1%-22.5%) were removed by anoxic reactor. Activated sludge in the A1/A2/O-MBR was harvested to conduct batch experiments to further study the removal and degradation kinetics of SAs under anaerobic, anoxic and aerobic conditions. The results indicated that only sulfisoxazole could be removed under anaerobic condition. Modest biodegradation of individual SAs (15-33%) was observed under anoxic condition. Under aerobic condition, most investigated SAs underwent an efficient and fast removal (68-77%) in 6h without a lag phase; while sulfisomidine and sulfamethazine were removed less efficiently (approximately 47% after 6h reaction). The aerobic and anoxic degradation of SAs fitted the first-order kinetics model well, and the obtained biodegradation rate constants (k1) were reliable to predict removal efficiencies of SAs in the anoxic and aerobic reactor of A1/A2/O-MBR based on their HRTs.

We found that sulfisomidine, a sulfonamide antibiotic, potently binds to the Piwi/Argonaute/Zwille (PAZ) domain of human Argonaute protein 2 and inhibits RNA interference (RNAi). To elucidate the effect on RNAi of strong affinity of the 3'-ends in small interfering RNA (siRNA) to the PAZ domain, chemically modified siRNAs bearing sulfisomidine at the 3'-end were synthesized.

Four common refractory pharmaceuticals, diclofenac (DF), sulpiride (SP), sulfamethoxazole (SMX) and sulfisomidine (SIM) were detected in the Disc Tubular Reverse Osmosis (DTRO) concentrates with higher concentrations ranging from 0.85 to 11.57 μg/L from the local landfill. The effect of complex matrix of DTRO concentrates on the UV-Fenton degradation kinetics of DF, SP, SMX and SIM and their transformation products (TPs) were studied. All the four pharmaceuticals could be degraded more efficiently in the ultrapure water than that in the DTRO-concentrate matrix, which also had a significant negative effect on the kinetic constants of the degradation. Twenty-two out of forty-nine TPs were newly identified by HPLC-QTOF-MS and their peak-area evolution was presented. The main degradation pathways for four pharmaceuticals were identified. When assessing cytotoxicity by using HepG2 cells, there appeared to be an obvious toxicity-increase region for each of SP, SMX and SIM. Eleven TPs were identified as the potential toxicity-increase causing TPs by combination of the QSAR prediction, HepG2 cytotoxicity assessment and peak-area evolution of TPs. Therefore, UV-Fenton process was a promising method for the refractory pharmaceutical degradation even in the complex water matrix and choosing appropriate reaction parameters for the UV-Fenton could eliminate the cytotoxicity of the TPs.

A simple modification method was developed for the functionalization of amino terminated carbon nanotubes (CNT-NH2) by using isocyanates as modifiers via the nucleophilic addition reaction. Two types of functionalized magnetic carbon nanotubes (MCNT) were prepared through deposition of magnetic nanoparticles on CNT-NH2 and modification with different isocyanates. p-Tolyl-functionalized MCNT (Tol-MCNT) with better adsorption performance were selected as adsorbent for magnetic solid phase extraction (MSPE), which could extract sulfonamides (SAs) from various milk samples with a enrichment factor of about 30 after optimization. By combining the MSPE with liquid chromatography–high resolution mass spectrometry (LC–HRMS), a new method was developed. Both skimmed and whole milk samples of three brands were analyzed with this method, and 4 SAs including sulfadiazine, sulfisomidine, sulfamethazine and sulfameter were detected with the concentration from unquantifiable to 72 ng/L, which were all well below the maximum residue limits in milk according to the regulations of China and EU.

Sulfadiazine (SDA) and sulfisomidine (SFM) inclusion complexes with two cyclodextrins (α-CD and β-CD) are studied in aqueous as well as in solid state. The inclusion complexes are characterized by UV–visible, fluorescence, time correlated single photon counting, FTIR, DSC, PXRD and 1 H NMR techniques. The self assembled SDA/CD and SFM/CD inclusion complexes form different types of nano and microstructures. The self assembled nanoparticle morphologies are studied using SEM and TEM techniques. SDA/α-CD complex is formed hierarchal morphology, SDA/β-CD and SFM/β-CD complexes form the nanosheet self assembly. However, SFM/α-CD complex forms nanoporous sheet self assembly. van der Waals, hydrophobic and hydrogen bonding interaction play a vital role in the self assembling process.

The influence of food intake on the bioavailability of a frequently used short-acting sulfonamide, sulfaisodimidine (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.

Methodology is presented for identifying an unknown active (pharmaceutical) ingredient (AI) in a counterfeit drug product. A range of mass spectrometric techniques, i.e., accurate mass mass spectrometry, tandem mass spectrometry (MS/MS) and liquid chromatography/mass spectrometry (LC/MS), has been employed to determine the AI in a counterfeit Halfan™ suspension, an antimalarial drug. In particular, use of LockSpray accurate mass MS/MS allowed identification of parts of the molecule from fragments, hence limiting the number of possible elemental compositions for the nominal mass of 278 found for the AI in the counterfeit product. The analysis of the isotope pattern observed for the protonated molecule further reduced the number of possible elemental compositions. A literature search for readily commercially available compounds of molecular formula C12H14N4O2S suggested that the AI was either sulfamethazine or sulfisomidine. An LC/MS separation of those two compounds and reference MS/MS spectra obtained for sulfamethazine and sulfisomidine led to the conclusion that the AI in the counterfeit Halfan™ suspension is sulfamethazine, which is an antibacterial agent. Copyright © 2002 John Wiley & Sons, Ltd.

WOS: 000412328200009, Paraoxonase-1 (PON1) is an organophosphate hydrolyzer and antiatherogenic enzyme. Due to the PON1's crucial functions, inhibitors and activators of PON1 must be known for pharmacological applications. In this study, we investigated the in vitro effects of some sulfonamides compounds on human serum PON1 (hPON1). For this aim, we purified the hPON1 from human serum with high specific activity by using simple chromatographic methods, and after the purification processes, we investigated in vitro interactions between the enzyme and some sulfonamides (2-amino-5-methyl-1,3-benzenedisulfonamide, 2-chloro-4-sulfamoilaniline, 4-amino-3-methylbenzenesulfanilamide, sulfisoxazole, sulfisomidine, and 5-amino-2-methylbenzenesulfonamide). IC50, K-i values, and inhibition types were calculated for each sulfonamide. 2-amino-5-methyl-1,3-benzenedisulfonamide and 2-chloro-4-sulfamoilaniline exhibited noncompetitive inhibition effect, whereas 4-amino-3-methylbenzenesulfanilamide, sulfisoxazole, and sulfisomidine exhibited mixed type inhibition. On the other hand, 5-amino-2-methylbenzenesulfonamide showed competitive inhibition and so molecular docking studies were performed for this compound in order to assess the probable binding mechanism into the active site of hPON1.

Phenolic compounds are prevalent as toxins or environmental pollutants, but they are also widely used as drugs for various purpose including anticancer agent. A novel biphenolic compound, bis(2-hydroxy-3-tert-butyl-5-methylphenyl)methane (GERI-BP002-A) was isolated from the fermentation broth ofAspergillus fumigatus F93 previously, and it has revealed cytotoxicity against human solid tumor cells. Its effective doses that cause 50% inhibition of cell growthin vitro against non-small cell lung cancer cell A549, ovarian cancer cell SK-OV-3, skin cancer cell SK-MEL-2 and central nerve system cancer cell XF498 were 8.24, 10.60, 8.83, 9.85 μg/ml respectively. GERI-BP002-A has also revealed cytotoxicity against P-glycoprotein-expressed human colon cancer cell HCT15 and its multidrug-resistant subline HCT15/CL02, and its cytotoxicity was not affected by P-glycoprotein. We have also tested cytotoxicities of structurally related compounds of GERI-BP002-A such as diphenylmethane, 1,1-bis(3,4-dimethylphenyl)ethane, 2,2-diphenylpropane, 2-benzylpyridine, 3-benzylpyridine, 4,4′-di-tert-butylphenyl, bibenzyl, 2,2′-dimethylbibenzyl,cis-stilbene,trans-stilbene, 3-tert-butyl-4-hydroxy-5-methylphenylsulfide, sulfadiazine and sulfisomidine for studying of structure and activity relationship, and from these data we could suppose that hydroxyl group of GERI-BP002-A conducted important role in its cytotoxicity.

Much attention has recently been devoted to the fate and effects of pharmaceuticals in the water cycle. Removal of antibiotics in effluents by photo-treatment or biodegradation is a topic currently under discussion. Degradation and removal efficiencies of sulfisomidine (SUI) by photodegradation and aerobic biodegradability were studied. SUI behavior was monitored during photodegradation (150 W medium-pressure Hg-lamp) photocatalysis (catalyst Titanium dioxide). Also an aerobic bacterial degradation test from the OECD series (Closed Bottle test (CBT, OECD 301 D), was performed.The primary elimination of SUI was monitored. Structures of photo-degradation products were assessed by chromatographic separation on a C18 column with ultraviolet detection at 270 nm and ion trap mass spectrometry. The results demonstrate that SUI is not readily biodegradable in CBT. Photo catalysis was more is effective than photolysis. SIU underwent photodegradation and several SUI photoproducts were identified. Accordingly, the photodegradation pathway of SUI was postulated. When reaching the aquatic environment SIU and its photo products can constitute a risk to the environment.

The residues of sulfonamides (SAs) in the foods of animal origin are of the major concern because they are harmful to the consumer's health and could induce pathogens to develop resistance. Rapid and efficient determination methods are urgently in need. A quantitative high performance liquid chromatography method (HPLC) and a confirmative liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the simultaneous determination of 18 sulfonamides such as sulfamidinum, sulfanilamide, sulfisomidine, sulfadiazine, sulfapyridine, sulfathiazole, sulfamerazine, sulfadimidine, sulfamethoxypyridazine, sulfamethoxydiazine, sulfisoxazole, sulfachloropyridazine, sulfamethoxazole, sulfamonomethoxine, sulfadoxine, sulfaclozine, sulfadimethoxine, sulfaquinoxaline in the muscles, livers and kidneys of swine, bovine and chicken were developed and validated. The sample preparation procedures included a pressurized liquid extraction (PLE) with acetonitrile conducted at elevated temperature (70°C) and pressure (1400 psi). After clean-up with hydrophilic-lipophilic balance cartridge, the extraction solution was concentrated and analyzed by HPLC and LC-MS/MS analysis. 18 SAs were separated by the HPLC with a Zorbax SB-Aq-C18 column and the mobile phase of methanol/acetonitrile/1% acetic acid with a gradient system. The wavelength of UV for the HPLC detection was set at 285 nm. The LC-MS/MS analysis was achieved with a Hypersil Golden column and the mobile phase of acetonitrile and 0.1% formic acid aqueous solution with two gradient systems. The Limits of detection (LOD) and the limits of quantitation (LOQ) were 3 μg/kg and 10 μg/kg, respectively, for both of the HPLC and LC-MS/MS. Linearity was obtained with an average coefficient of determination (R) higher than 0.9980 over a dynamic range from the LOQ value up to 5000 μg/kg. The recoveries of the methods range from 71.1% to 118.3% with the relative standard derivation less than 13%. The peaks of interest with no interferences were observed throughout the chromatographic run. The sample pretreatment provided efficient extraction and cleanup that enables a sensitive and rugged determination of 18 SAs, the obtained results revealed that PLE, in comparison with other sample preparation methods applied, has significantly higher efficacy for SAs isolation from animal tissues.

A method is described for the determination of the residual sulfisomidine and its metabolite, N4-acetylsulfisomidine, in swine muscle, kidney, liver and plasma by high performance liquid chromatography. Sulfisomidine and N4-acetylsulfisomidine were extracted from the swine tissues with acetonitrile, followed by alumina column clean-up procedure, and analyzed using a reversed-phase C18 column (250×4.6mm id), with UV detection at 270nm and a mobile phase of 10mM phosphate buffer (pH 5.6)-acetonitrile (92:8; v/v). The average recoveries of sulfisomidine and N4-acetylsulfisomidine from swine tissues fortified with 0.lμg/g were ranged from 83.2 to 91.3%, 88.6 to 99.5%, respectively. The detection limits were 0.01μg/g for each drug. The applicability of the method was demonstrated by determining concentration of sulfisomidine and metabolite in tissues from swine administrated with sulfisomidine.

To investigate whether dogs are able to excrete acetylated drugs by active transport, the plasma kinetics and renal excretion of the N4-acetyl metabolites of sulphasomidine and sulphadimethoxine were studied in the beagle dog after a rapid intravenous bolus injection. Two doses of N4-acetylsulphasomidine (1050 and 105 mg) and one dose of N4-acetylsulphadimethoxine (472 mg) were administered on separate occasions. The renal clearance (CLR) was as follows: N4-acetylsulphasomidine (1050 mg) 34 mL min−1; N4-acetylsulphasomidine (105 mg) 28 mL min−1; and N4-acetylsulphadimethoxine (472 mg) 24 mL min−1. CLR was higher than expected on the basis of the measured glomerular filtration rate, indicating that the N4-acetyl metabolites may be excreted by the renal tubules by active tubular transport. Saturation of the excretion process of N4-acetylsulphasomidine occurred with a transport maximum of 930 ± 190 μg min−1 and a Michaelis-Menten constant of 37 ± 10 μg mL−1. It may be concluded that the dog renal organic anion transport system is able to secrete acetylated sulphonamides.

A thermospray high-performance liquid chromatographic-mass spectrometric (LC-MS) method has been developed for the analysis of sulfonamides such as sulfachlorpyridazine, sulfadiazine, sulfadimethoxine, sulfadimidine, sulfadoxine, sulfamerazine, sulfamethoxazole, sulfamethoxypyridazine, sulfamonomethoxine, sulfaquinoxaline, sulfathiazole and sulfisomidine. The LC separation was carried out on a TSK-gel ODS-80TM by using 0.05 M ammonium acetate (pH 4.5)- acetonitrile (7 : 3) as the mobile phase, at a flow rate of 0.8 ml/min. The vaporizer temperature was set to 155°C and ion source block temperature to 280°C. The mass spectra obtained from sulfonamides were very simple, with base peaks corresponding to protonated molecular ions MH+. The calibration curve for sulfadimidine was rectilinear from 0.2 to 20 ng with the detection limit by selected ion monitoring (SIM) was about 100 pg. Similar results were obtained with other sulfonamides. An excellent correlation between the results of the thermospray LC-MS method and HPLC method was obtained (γ=0.981).

Most drugs taken by the mother reach breast milk and are ingested by the nursing infant. Most of the drugs are detected in breast milk at low concentrations, so breastfeeding by women taking these drugs is possible. The effect of some drugs on the nursing infant is unknown and further studies are needed. Some drugs may achieve significant infant plasma concentrations and may be unsafe for the infant. In these cases the infant should be carefully monitored for any clinical side effects and whenever observed, breastfeeding should be discontinued. Despite the confirmed benefits of breastfeeding, there are certain drugs which are absolutely contraindicated; in these cases interruption of breastfeeding is necessary. This review summarises the current scientific knowledge on compatibility of drugs with breastfeeding, focusing on drugs that are contraindicated and of which use in breastfeeding remains controversial.

A simple and sensitive photometric method for the trace determination of 1-naphthylamine has been worked out. The method is based on the coupling reaction of the determinand in acidic medium with diazotized sulfisomidine, to form a purplish violet water-soluble mono azo dye that shows maximum absorption at 540 nm with a molar absorptivity of 4.47 x 10(4) l mol(-1) cm(-1). Beer's law is obeyed over the concentration range 5-70 mug of 1-naphthylamine in a final volume of 25 ml, i.e. 0.2-2.8 p.p.m. with a relative error of -0.7 to +1.7% and a relative standard deviation of 0.35-4.2%, depending on the concentration level. Moreover, the method does not require either temperature control or solvent extraction. Interferences due to foreign species have been examined. The developed method has been applied to the determination of 1-naphthylamine in river water and sea water.

A rapid, sensitive and selective high-performance liquid chromatographic method is described for simultaneous determination of eight sulfa drugs in meat and meat products using pre-column derivatization with fluorescamine. The drugs are sulfisomidine, sulfadiazine, sulfamerazine, sulfadimidine, sulfamonomethoxine, sulfamethoxazole, sulfadimethoxine and sulfaquinoxaline. The method includes blender extraction of 3-g samples with choloroform, partition with 3 M hydrochloric acid, derivatization with fluorescamine at pH 3.0 and subsequent high-performance liquid chromatographic analysis on a C 18 column with fluorescence detection at an excitation wavelength of 405 nm and an emission wavelength of 495 nm. The drugs were separated with a mobile phase of acetonitrile-2% acetic acid (3:5) at 55°C. The average recovery from samples fortified at 0.1 ng/g was 92.6% with a coefficient of variation of 6.2%. The detection limit was 0.01 ng/g for sulfaquinoxaline and 0.005 ng/g for the other seven drugs. The method was field-tested in a survey of 37 samples including beef (five), pork (seven), chicken (seven), ham (five), sausage (eight), bacon (two) and roast beef (three). Sulfadimidine was detected in one port sample at the level of 0.295 ng/g and in ham at 0.178 ng/g.

The influence of gestation on the pharmacokinetics of four sulphonamides was studied in goats before, during and after pregnancy. Similar doses were given as intravenous boluses of 50 mg kg-1 each. Results were compared with those of non-pregnant goats to eliminate seasonal effects. With sulphadimidine elimination was mainly apparently first-order. In gestating goats the mean residence times decreased and mean plasma clearance rates increased with sulphadimidine during pregnancy, but this effect was continued after kidding at least until the end of May. The same happened with sulphadimethoxine, but sulphisomidine was not affected. In contrast to the other sulphonamides the mean residence time of sulphadoxine showed a maximum in February in gestating goats, while mean plasma clearance remained constant during and after pregnancy, at a lower level than in September. The mean plasma clearance of sulphadoxine decreased significantly from September to February in the non-pregnant control goats. In May five of six control goats and two of six goats which had kidded showed capacity-limited elimination against only two control goats in the foregoing experiments. With sulphadoxine one animal in the gestation group, but not the same one in each experiment, showed capacity-limited elimination against one, four and three in the control group in December, February and May, respectively. Distribution volumes increased significantly during and after pregnancy with sulphisomidine and sulphadimethoxine. A decrease in distribution volumes was seen in control goats with sulphadimidine, sulphisomidine and sulphadoxine, but was only significant for sulphadoxine. The pregnant uterus could not be recognised as an extra compartment, either in distribution volume nor in the pharmacokinetic model.(ABSTRACT TRUNCATED AT 250 WORDS)

The suction blister technique was used for pharmacokinetic studies with sulfonamides and trimethoprim. Blisters produced by suction (-0.3 kg/cm2) for 1.5 h contained approximately 0.15 ml fluid with a protein content of 40-50% of that in plasma, the main protein fractions being present in the same ratio as in plasma. 2 g sulfaisodimidine was given as bolus injection, i.v. infusion or orally to groups of 4 volunteers. The peak blister fluid concentrations after oral administration (120 +/- 18 mmol/l) was only marginally lower than the concentrations after i.v. infusion (122 +/- 28 mmol/l) and i.v. bolus injections (134 +/- 37 mmol/l). The total drug blister fluid concentration started to decrease before the plasma level was reached. However the relative concentration increased from 53% of that in plasma at 8 h to 66% at 12 h after drug administration. Considering the protein binding of the drugs, the interstitial fluid levels of free drug were presumably higher than the plasma level after 8 h. Comparison of drug concentrations in blisters produced before and after the drugs were given showed higher concentrations in the latter for the first 2-6 h. However, after 8-12 h the concentrations of the drugs in the two types of blisters were similar. The suction blister method produces blisters of uniform size. The drug concentrations in different experiments showed the coefficient of variation for blister fluid concentrations to be no greater than for plasma levels. The consistent results of the standardized suction blister method makes this method useful for studying drug penetration to extravascular compartments in humans.

We aimed to clarify the relationship between drug dissociation (sulphisomidine) and its direct transport from the nasal cavity to the cerebrospinal fluid (CSF). Rat nasal cavities were perfused in a single pass system with buffers (pH 5·5, 6·5, 7·4, 8·7 and 9·4). Plasma and CSF were collected and the concentration of sulphisomidine was measured. Nasal clearance increased with the increase in the un-ionized fraction of the drug. The ratio of the drug concentration in CSF to that in the nasal perfusion fluid (the index of the degree of the drug transport from the nasal cavity to CSF), was changed in accordance with the un-ionized fraction of drug. These results show that both the nasal absorption and the drug transport conform to the pH partition theory.

A procedure was developed for simultaneous determination of 21 synthetic antibacterials in fish and meat products by high performance liquid chromatography with a photodiode array detector. The antibacterials were extracted with acetonitrile-0.2% metaphosphoric acid (7:3), followed by liquid-liquid partition with dichloromethane. High performance liquid chromatography was carried out on a TSK-gel ODS-80Ts column using gradient elution with acetonitrile-sodium dihydrogenphosphate. The recoveries of antibacterials from fish and meat products spiked at 1.0μg/g were over 70% except in the cases of sulfisomidine and carbadox. The detection limits were 0.05-0.10μg/g for each antibacterial except thiamphenicol (0.25μg/g).

A simplified method was developed for the detection of residual tetracyclines and sulfa drugs in honey by microbiological assay. A honey sample was homogenized in 0.01M di-Na EDTA McIlvaine buffer (pH 4.0) and centrifuged. The supernatant was mixed well with chloroform and centrifuged. The chloroform layer was evaporated to dryness and the residue was dissolved in phosphate buffer (pH 8.0) to prepare fraction A. The aqueous layer was passed through a Sep-pak C18 cartridge column. The Sep-pak C18 cartridge column was washed with water and absorbed antibacterial agents were eluted with methanol. The eluate was evaporated to dryness, and the residue was dissolved in phosphate buffer (pH 4.5) to prepare fraction B.Fractions A and B contained sulfa drugs and tetracyclines, respectively. The pulp disk method with Bacillus subtilis ATCC 6633 and Bacillus cereus var. mycoides ATCC 11778 as test organisms was employed for the assay of sulfa drugs and tetracyclines. As little as 0.05μg/g (oxytetracycline), 0.01μg/g (chlortetracycline) or 0.1μg/g (sulfa drugs) was detectable.Thin layer chromatographic identification was performed for positive test solutions. The test solution A was spotted on an aluminum oxide plate (Merck 5550) and a silica gel plate (Merck 5553), then developed in chloroform-methanol (7:3) and ethyl ether-chloroform-n-butanol (5:1:1), respectively. The test solution B was spotted on a cellulose plate (Merck 5552), which was developed in n-butanol saturated with water. Rf values were determined by bioautography with B. subtilis and B. cereus as the test organisms. Microbioautography was suitable for separation and identification of sulfa drugs and tetracyclines in honey. We used this method to identify sulfa drugs and tetracyclines detected in 22 samples out of 297 commercial honeys. It was found that 8 specimens contained oxytetracycline, 12 specimens chlortetracycline, 1 specimen sulfadimethoxine, and 1 specimen sulfisomidine.

A simple and selective method for the simultaneous determination of sulfadiazine (SDZ), sulfadimidine (SDD), sulfadimethoxine (SDMX), sulfadoxine (SDOX), sulfamerazine (SMR), sulfamethoxazole (SMXZ), sulfamonomethoxine (SMMX), sulfaquinoxaline (SQ), sulfathiazole (STZ), and sulfisomidine (SID) in meat has been developed by high performance liquid chromatography (HPLC) with photodiode array detection.The drugs were extracted from meat with 0.2% metaphosphoric acid-methanol (2:1), followed by a Baker C18 clean-up procedure. The HPLC separation was carried out on a TSK-gel ODS 80TM (150×4.6mm i. d. ) using 0.05M sodium dihydrogenphosphate (pH 4.5)-acetonitrile (2:1) as the mobile phase, with a flow rate of 0.5ml/min, and monitored with a photodiode array detector. The recoveries of drugs from meats fortified at 0.5μg/g were 74.2-89.9%. The limits of detection were 0.05μg/g for each drug. SDD was found in 10 samples of imported pork meat (11.1%) at levels in the range of 0.05-1.05μg/g. SDMX was found in 1 sample of domestic pork meat (2.2%).

The effects of sulphonamides (SA) and of trimethoprim (TMP) on the growth rates ofEscherichia coli have been established for the drugs both alone and in combination. When combined, the action of SA and TMP is synergistic, i. e. more than additive and more than equivalent. The maximum possible synergistic effect of SA-TMP combinations onE. coli is, according to the results with bacterial growth kinetic studies, obtained with rather small concentrations of SA or TMP. In these studies the TMP concentration (significantly below the minimum plasma level) was kept constant while the SA concentration was varied and vice versa. The same optimal potentiation was achieved. An “antagonistic” effect of high SA concentration on the synergistic effect of the combination and a reduction of the inhibitory effect of TMP has also been observed. According to the results of the bacterial growth kinetics obtained withE. coli and the pharmacokinetic data presented, it seems justified to consider especially the pharmacokinetic parameters of SA and TMP derivatives for an optimal choice of the drug combination rather than the highest inhibitory activity of the single drugs. The sulphonamides being discussed are sulphamethylisoxazole (sulphamethoxazole), sulphadimethyloxazole, sulphabenzene, 4-sulpha-2,6-dimethyl-pyrimidine (sulphisomidine) and 2-sulphapyrimidine (sulphadiazine).

Binary mixtures of sulfisomidine and lactose particles were suspended in chloroform and were agglomerated with buffered sodium phosphate solutions (pH7.4). The agglomerate particles at 1.5min residence time were fractionated by sieves at six levels according to the particle size. The content ratio of sulfisomidine of the each fraction to the original feed powder was determined. The significant variance of the content ratio with the particle size of the agglomerates was found, which strongly depended on the particle size of lactose and the mixing ratio of sulfisomidine.With increasing the particle size of lactose and decreasing the mixing ratio of sulfisomidine, the content ratio in the agglomerate with over size (+12mesh) decreased, which indicates that the larger lactose particles are included more in the agglomerate with increasing the particle number of lactose in the system. The content variation disap Peared gradually when the agglomerate particles growing in the course of agitating the suspension. This suggests that the more preferential adhesion may occure between the larger lactose and sulfisomidine particles, leading to the formation of the agglomerate enriched with lactose.

The extended Hildebrand solubility approach is used to estimate the solubility of sulfonamides in binary and ternary solvent systems. The solubility of sulfisomidine in the binary solvent, dioxane-water, shows a bell-shaped profile with a solubility maximum well above the ideal solubility of the drug. This is attributed to solvation of the drug with the dioxane-water solvent, and indicates that the solute-solvent interaction energy (W) is larger than the geometric mean (delta 1 delta 2) of regular solution theory. The solubilities of sulfadiazine, sulfisomidine, sulfathiazole, and sulfamethoxazole were determined in mixtures of dimethylacetamide, glycerol, and water, and the solubility profiles were well reproduced by use of the extended Hildebrand solubility approach. Since the solubility parameter (delta 1 = 11) of the solvent (dimethylacetamide) was approximately equal to the solubility parameters of the sulfonamides, and because of the powerful solvating power of dimethylacetamide, the solubility profiles did not exhibit peaks as observed for sulfisomidine in dioxane-water. When sulfisomidine was dissolved in a ternary mixture, i.e., butyl acetate (delta 1 = 8.5), dimethylacetamide (delta 1 congruent to 11), and methanol (delta 1 = 14.5), a spike was produced in the solubility profile at the solubility parameter of dimethylacetamide. This sharply peaked profile suggests that the two branches be treated as separate solubility curves, which are then independently well reproduced by the extended Hildebrand solubility approach. None of the four sulfonamides yielded log-linear relationships in the ternary mixtures.

28 non-pregnant women were treated with conventional doses of sulphasomidine or sulphalene for acute urinary tract infections caused by Escherichia coli. Both preparations were found to be effective in simple cystitis infection with sulphonamide-sensitive organisms. Also, both were found to exert a selective pressure favouring sulphonamide-resistant E. coli in the faecal flora.

A method for the determination of the level of Streptococcus mutans in saliva samples was developed. The method was a modification of a previously described technique based on the a

Summary Following bile duct ligation (DL) or bilateral nephrectomy (NX), phenol red accumulation in kidney or liver tissue, respectively, is reduced in rats of different ages. This is in contrast to in vivo experiments showing a compensatory increase of renal or hepatic excretion of phenol red in adult rats after DL or NX, respectively. The present study was performed to clarify this discrepancy. Three possible reasons were taken into consideration: 1. competition between accumulation of phenol red and bilirubin or bile acids; 2. influence of humoral factors occurring in serum of DL-rats on accumulation capacity; 3. changes of phenol red binding in homogenate of the kidney cortex or liver tissue after DL or NX. Ad 1. There exist inhibitory effects of bilirubin and cholic acid on phenol red accumulation. This inhibition is a competitive as well as a toxic one, apparently caused by a reduction of intracellular phenol red binding. Similar results have been obtained in in vivo experiments. During continuous infusion of bilirubin both renal and hepatic excretion of phenol red is significantly diminished. Ad 2. Incubation of tissue slices of control animals in serum of DL-rats does not indicate the existence of humoral factors reducing accumulation of phenol red after DL. Only in adult rats the plasma protein binding of phenol red is reduced after DL; in 10-day-old rats the binding capacity of the proteins for the dye is unchanged after DL. Ad 3. In young animals the phenol red binding on tissue homogenate is significantly reduced after DL or NX in kidney or liver; binding capacity of adult rats' tissue homogenate is unchanged after both operations. It can be concluded that renal and hepatic excretion capacity cannot be increased within a few hours after these blocking operations and obviously a functional reserve of the transport mechanisms does not exist.

Sodium was measured in rat pancreatic islet exposed to tolbutamide, glipizide, diazoxide or sulfisomidine. When added to a medium with physiologically balanced cations these sulphonamides induced a significant rise of the islet content of sodium. The insulin-releasing compounds, tolbutamide and glipizide, had effects opposite to those of the hyperglycemic diazoxide in counteracting the increase of sodium obtained with removal of K+. The tolbutamide-induced increase in sodium was reversed to a decrease when Ca2+ was omitted from the incubation medium. The increase of sodium, which was also seen with non-hypoglycemic sulphonamides, is itself not sufficient for initiating insulin release. However, it may well represent an important mechanism contributing to the secretory response initiated by Ca2+ entry into the sulfonylurea-depolarized beta-cell.

Aqueous slurries or ammonium solutions of sulfiso-rnidine containing various kinds of binder, i.e. acacia, gelatin, carboxymethylcellulose, methylcellulose or poly-vinylpyrrolidone were spray dried using a centrifugal wheel atomizer. The spray-dried products were found by scanning electron microscopy observation to be agglomerated or encapsulated. The products prepared from the aqueous slurries were microcapsules coated with a smooth film, whilst the products from ammonium solutions were agglomerates with porous agglomerating crusts on their surfaces. Micromeritic properties such as, particle diameter, flow and packing properties, etc. were investigated. Infrared absorption spectra confirmed that the spray-dried ammonium sulfisomidine was converted to the non-salt form during drying. X-ray diffraction patterns were obtained to investigate the crystalline forms and to determine the degree of crystallinity of spray-dried sulfisomidine. Solubilities of the products were measured in distilled water an...

The relation of absorption sites of sulfonamides administered orally in uncoated tablets to their solubilities and dissolution rates was studied. Eight sulfonamides, sulfisomidine, sulfamethoxypyridazine, sulfamethizole, sulfamethoxazole, sulfisoxazole, sulfamonomethoxine, sulfaphenazole and sulfadimethoxine, were tested to determine their solubilities, dissolution rates and absorption rates following oral administration to humans. As a marker of gastric emptying time, the lag time of the urinary excretion of total salicylate was determined after the concurrent administration of enteric tablets of aspirin. A new parameter, RAAS (Relative Amount Absorbed in the Stomach) is proposed in order to represent the relative amount absorbed in the stomach region. RAAS values showed good correlations with the solubilities and dissolution rates of sulfonamides determined by means of the Sartorius solubility simulator with continuous pH change under non-sink conditions. It was concluded that : 1) The critical value of the solubility which distinguishes drugs according to their absorption sites, stomach or intestine, is about 3 mg/ml in 0.1 N HCl at 37° when 1 g of the drug is administered to humans orally with 200 ml of water after overnight fasting. 2) A drug having a solubility larger than the critical value can reasonably be tested for dissolution rate in an acidic medium, and a drug having a solubility less than the critical value should be tested under neutral conditions after pretreatment in acidic conditions.

Sulfisomidine, sulfamethomidine, sulfadimethoxine and their corresponding N4-acetyl derivatives were administered to man. The percentages of acetylation and deacetylation and those of protein binding, the half-lives of elimination and the apparent and true renal clearance values were measured. No acetylation phenotype could be demonstrated in these compounds. Methoxy substitution in the N1-pyrimidine group of sulfisomidine affects predominantly the renal clearance value and mechanism of the parent compound but has no influence on the renal clearance of the N4-acetyl derivatives.

イオン会合性試薬を用いる医薬品の吸光光度定量法の一環として,ベンゾジアゼピン系医薬品であるメタゼパムをそのままの形で,サルファ剤であるスルフイソミジンをp-メチルベンジル誘導体とし定量する方法を検討した。方法は,メタゼパムは抽出溶媒にクロロホルム,イオン会合性試薬としてエリオグリーンBを用いpH4.10でイオン会合体を抽出し波長637nmを用いて吸光度を測定した。スルフイソミジンはα-クロロ-p-キシレンを用いてp-メチルベンジル誘導体とした後,ジクロロメタンで抽出しイオン会合性試薬としてトロペオリンOOを用いpH2.56でイオン会合体を形成後,ジクロロメタン相を酸性にし波長543nmを用いて吸光度を測定した。又本法によればメタゼパムの定量においてクロキサゾラム,ニトラゼパム,オキサゼパム,ジアゼパムはモル比で約4倍共存していても,スルフイソミジンの定量においてスルファジメトキシン,スルファメトキサゾール,スルファメチゾールはモル比で約5倍共存していても全く妨害を示さなかった。

The extended Hildebrand approach for predicting solubilities of crystalline compounds in solvent mixtures was tested using tolbutamide, acetohexamide, and sulfisomidine in mixed solvents consisting of hexane-absolute ethanol and 95% (v/v) ethyl alcohol-aqueous buffer. The solubility of these drugs was determined at 25 +/- 0.2 degrees and then back-calculated using the adhesive energy term, W, to account for solute-solvent interaction. Solubilities were predicted within 13% for tolbutamide, 31% for acetohexamide, and 43% for sulfisomidine, and with considerably better accuracy in most solvent mixtures.