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PubMed1993

Bisubstrates: substances that interact with both, renal contraluminal organic anion and organic cation transport systems. II. Zwitterionic substrates: dipeptides, cephalosporins, quinolone-carboxylate gyrase inhibitors and phosphamide thiazine carboxylates; nonionizable substrates: steroid hormones and cyclophosphamides.

In order to test what chemical structure is required for a substrate to interact not only with the contraluminal organic anion (p-aminohippurate, PAH) transporter, but also with the organic cation (N1-methylnicotinamide, NMeN, or tetraethylammonium, TEA) transporter, the stop-flow peritubular capillary perfusion method was applied and app. Ki values were evaluated. Zwitterionic hydrophobic dipeptides not only interact with PAH but also with NMeN transport although with lower inhibitory potency (Ki,PAH = 0.2-1.4; Ki,NMeN 6-14 mmol/l). Amongst the zwitterionic cephalosporins, which all inhibit PAH transport, the amino cephalosporin analogue cefadroxil was identified to interact also with NMeN transport (Ki,PAH = 3.0, Ki,NMeN = 11.2 mmol/l). All zwitterionic naphthyridine and oxochinoline gyrase inhibitors tested inhibit NMeN transport with app. Ki,NMeN values between 1.2 mmol/l and 4.7 mmol/l; the naphthyridine analogues show a good inhibitory potency against PAH transport (Ki,PAH approximately 0.4 mmol/l), the piperazine-containing quinolone analogues have a moderate inhibitory potency (Ki,PAH = 1.1-2.5 mmol/l) and the piperazine-containing pipemidic acid did not inhibit PAH transport at all. Zwitterionic thiazolidine carboxylate phosphamides also interact with both transporters (app. Ki,PAH approximately 3.0; app. Ki,NMeN approximately 18.0 mmol/l). The nonionizable oxo- and hydroxy-group-containing corticosteroid hormones also interact with the two transporters. (a) An OH group in position 21 is necessary for interaction with the PAH transporter, but not for interaction with the TEA transporter. (b) Introduction of an OH group in position 17 alpha abolishes interaction with the TEA transporter, but has different effects with the PAH transporter. (c) Introduction of an OH group in position 6 abolishes interaction with both, the PAH and the TEA transporter. (d) A change of the side-group in position 11 of corticosterone from -OH to -H to = O enhances interaction with the PAH transporter but has no effect on the interaction with the TEA transporter. Nonionizable 4- or 5-androstene analogues inhibit both transporters with app. Ki between 0.16 mmol/l and 0.64 mmol/l, if the steroids are soluble in a concentration greater than 1 mmol/l. Nonionizable oxazaphosphorins with more than one chloroethyl group interact with the PAH transporter with app. Ki between 0.84 mmol/l and 4.9 mmol/l and with the NMeN transporter with app. Ki between 3.2 mmol/l and 18.7 mmol/l. Thus a substrate interacts with both transporters if it is sufficiently hydrophobic, possesses acidic and/or electron-attracting plus basic and/or electron-donating groups, or possesses several electron-attracting nonionizable groups (O, OH, Cl). A certain spatial arrangement of the interacting groups seems to be necessary.

Animals↗
PubMed1995

Monitoring pathological assembly of tau and beta-amyloid proteins in Alzheimer's disease.

This double-labelling confocal microscopy study of the neuropathology of Alzheimer's disease (AD) reports the use of a fluorescent dye, thiazin red, which has staining properties similar to thioflavin-S. Thiazin red fluorescence can be visualised selectively in the red channel, and we have used this property to compare it with the labelling seen using monoclonal antibody (mAb) 423, which detects tau protein C-terminally truncated at Glu-391, and mAb 4G8, which detects beta-amyloid protein. Thiazin red is shown to recognized the typical histopathological deposits associated with both proteins. However, not all deposits containing these proteins are stained. Specifically, diffuse beta-amyloid plaques and severely degraded extracellular tangles are unlabelled. Likewise a characteristic mAb 423-reactive granular plaque-like structure, typically present in cases with abundant extracellular tangels, is unlabelled by thiazin red. Such plaques can be shown to be continuous with the basal dendrites of degraded tangle-bearing pyramidal cells. These findings suggest that paired helical filaments (PHFs) continue to undergo degradation in the extracellular space, which is associated with loss of thiazin red binding sites, but preservation of mAb 423 immunoreactivity. This epitope appears to be characteristic of a stable core element of the PHF which is highly resistant to proteolysis. Compounds such as thiazin red with high affinity for beta-pleated protein structures can be used to monitor the state of pathological assembly of amyloidogenic protein species found in AD.

Aged↗
PubMed2005

Synthesis and pharmacological profile of non-peptide vasopressin antagonists.

Recently we presented a series of 6-ethyl and 6-benzylthieno[2,3-b][1,4]thiazine derivatives with relaxing effects on vascular smooth muscle and terminal ileum. In this report the synthesis of further thieno[2,3-b][1,4]thiazine derivatives and related compounds with a thieno[2,3-b][1,4]thiazepine or thieno[3,2-b][1,4]thiazine ring system is described. The pharmacological effect of the agents was tested in isolated smooth (terminal ileum, pulmonary artery, aortic rings, myometrial strips) and heart (papillary muscle, spontaneously beating right atrium) muscle preparations of the guinea pig. Contractions were measured isometrically, and smooth muscle preparations were either precontracted with high K+ (60 or 90 mM KCl containing nutrient solution) or with agonists, while papillary muscles were electrically stimulated (1 Hz). The vasopressin antagonistic activity of the test compounds was tested in isolated papillary muscles in which the V1A-receptor subtype is located. The biphasic response to vasopressin was antagonized, dependent on the chemical structure of the test compound. Thieno[3,2-b][1,4]thiazines were more potent than thieno[2,3-b][1,4]thiazine and thieno[2,3-b][1,4]thiazepine compounds. In addition, substitution of a methyl substituted terminal benzyl ring instead of a phenyl- or dichlorobenzoyl moiety attenuated the vasopressin antagonistic effect.

Animals↗
PubMed1977

The analysis of some commercial dyes and Romamowsky stains by high-performance liquid chromatography.

High-performance liquid chromatography has been used to quantitate batch variations in commericial samples of thiazine dyes, thiazine eosinates, and Romanowsky-type blood stains. It has been observed that all the dyes and eosinates examined, only methylene blue chloride and thionin were reasonably free of their methylated, demethylated, or oxidized homologs. Large variations in composition were observed between most of the samples of each type examined. In several instances the labeled compound was a minority species. In one instance a dye was apparently mislabeled. Large compositional variation was found between various batches of Wright and Giemsa stains, whereas significant differences between the thiazine composition of these two stain types were minor. Very little compositional variation was observed between the lots of LARC stain examined. The thiazine composition of Ames stain was similar for the three lots examined. Ames stain, however, was found to contain several components of unknown composition which have been linked to degradation products formed when stains are aged in methanolic solution.

Chromatography, High Pressure Liquid↗
PubMed2006

Emerging antifungal azoles and effects on Magnaporthe grisea.

Derivatives of pyrazolo[1,5-a][1, 3, 5]triazine-2,4-dione,pyrazolo[1,5-c][1, 3, 5]thiadiazine-2-one, pyrazolo[3,4-d][1, 3]thiazine-4-one, and pyrazolo[3,4-d][1, 3]thiazine-4-thione were screened for antifungal activity against the causal agent of rice blast disease, Magnaporthe grisea. The compounds were tested at doses ranging from 10 to 200mugml(-1), using the commercial fungicide tricyclazole as reference compound. All triazine derivatives inhibited the growth and pigmentation of the mycelia less effectively than tricyclazole. The thiadiazine derivatives proved to be more effective than their triazine counterparts, but only 4-(butylimino)-7-methylpyrazolo[1,5-c][1,3,5]thiadiazine-2-one (2h) and 4-(cyclohexylimino)-7-methylpyrazolo[1,5-c][1,3,5]thiadiazine-2-one (2j) were more effective than tricyclazole. Pyrazolo[3,4-d][1,3]thiazine-4-one derivatives were active only at the highest doses, whereas members of the pyrazolo[3,4-d][1,3]thiazine-4-thione series inhibited fungal growth at the lowest concentrations used, at which tricyclazole had no effect. A dose-dependent mechanism might be responsible for this effect, with lipophilicity as the governing factor. Within a given set, the presence of a cyclohexyl or an n-butyl group generally increased antifungal activity, with respect to both growth inhibition and cell de-pigmentation of the mycelium, suggesting that a higher lipophilicity might improve transport inside the cells. SEM and TEM of M. grisea hyphae showed that treatment with the most active substance (2h) caused significant ultrastructural effects, particularly on the endomembrane system, suggesting a mechanism of action similar to that of most azole fungicides. Dissimilarities were also observed, with no alterations of the cell wall evident. In conclusion, several compounds showed greater inhibition than tricyclazole, and therefore provide useful new chemistry for control of M. grisea infections.

Antifungal Agents↗
PubMedDate not supplied

Realities of diagnosing Helicobacter pylori infection in clinical practice: a case for non-invasive indirect methodologies.

BACKGROUND: The current, arbitrarily defined gold standard for the diagnosis of H. pylori infection requires histologic examination of two specially stained antral biopsy specimens. However, routine histology is potentially limited in general clinical practice by both sampling and observer error. The current study was designed to examine the diagnostic performance of invasive and non-invasive H. pylori detection methods that would likely be available in general clinical practice. METHODS: The diagnostic performance of rotating clinical pathology faculty using thiazine staining was compared with that of an expert gastrointestinal pathologist in 38 patients. In situ hybridization stains of adjacent biopsy cuts were also examined by the expert pathologist for further comparison. Receiver operator characteristic (ROC) analysis was performed to evaluate whether the diagnostic performance of the expert pathologist differed depending upon the histologic method employed. A similar analysis was made to evaluate the diagnostic performance of pathology trainees relative to the expert. In the absence of an established invasive gold standard, non-invasive testing methods (rapid serum antibodies, formal Elisa antibodies and carbon-14 urea breath testing) were evaluated in 74 patients by comparison with a gold standard defined using a combination of diagnostic tests. RESULTS: Using either rapid urease testing of biopsy specimens or urea breath testing as the gold standard for comparison, the diagnostic performance of the rotating clinical pathology faculty was inferior to that of the expert gastrointestinal pathologist especially with regard to specificity (e.g., 69 percent for the former versus 88 percent, with the latter relative to rapid urease testing). Although interpretation of in situ hybridization staining by the expert appeared to have an even higher specificity, ROC analysis failed to show a difference. The mean ROC areas for thiazine and in situ hybridization staining for trainee pathologists relative to the expert were 0.88 and 0.94, respectively. In untreated patients, urea breath testing had a sensitivity and specificity of 100 percent as compared with thiazine staining with a sensitivity of 83 percent and a specificity of 97 percent. Post-therapy, breath testing had a sensitivity of 100 percent but a specificity of only 86 percent as compared with invasive testing with a sensitivity and specificity of 100 percent. Rapid serum antibody testing and formal Elisa antibody testing agreed in 93 percent of cases (Kappa 0.78) with the rapid test being correct in three of the four disagreements. CONCLUSIONS: The current study illustrates a number of realities regarding H. pylori diagnosis. There is no diagnostic gold standard in general clinical practice. Accurate interpretation of specially stained slides is a learned activity with a tendency towards overdiagnosis early on. Urea breath testing is likely to be the diagnostic method of choice for untreated patients in general clinical practice although antibody testing is almost as accurate. Rapid antibody tests are at least as accurate as formal Elisa antibody tests. Urea breath testing is useful for confirming cure after therapy, but false-positive results may occur in some patients.

Biopsy↗
PubMed1983

Topo-optical reactions and polarization optical analysis of human lymphocytes.

The latent birefringence of lymphocyte membranes of various species may readily be studied and analysed by various topo-optical reactions. The membranes of glutaraldehyde-fixed and PBS-washed lymphocytes show continuous birefringence with thiazine- and quinoline dyes. According to polarization optical analysis thiazine dye-stained cells are radially positive, whereas quinoline dye-stained cells are radially negative spherites, i.e. thiazine dye molecules are in a perpendicular, quinoline dye molecules in a parallel orientation relative to the membrane surface. These findings suggest that in lymphocyte membranes glycoproteins are primarily responsible for the topo-optical reactions. The actual conformational state of the glycoprotein components is a decisive factor not only in dye binding but also in the orientation of dye molecules. Heparin treatment directs attention to an important interaction between heparin and membrane glycoproteins. With the aid of the critical electrolyte concentration (CEC) technique we were able to demonstrate an ultrastructural differences between human erythrocyte and human lymphocyte membranes. After this procedure the birefringence of erythrocyte membranes was lost, whereas that of lymphocyte membranes did not change. There were no differences between the topo-optical reactions of T and B lymphocytes.

Cell Membrane↗
PubMed1979

[Topo-optical reactions on the membrane of the human red cell ghost (author's transl)].

Previous studies have proved that the thiazin dyes toluidine blue, azure A, azure B, 1.9-dimethyl methylene blue and the quinolin dyes N,N'-diethylpseudoisocyanine chloride, N,N'-6,6'-dichlorpseudoisocyanine chloride are suitable for topo-optical reaction on the membrane of the red blood cells. In the present study the applicability of the thiazin and quinolin dyes on the membrane of the human red cell ghost was examined. Optical analysis revealed that the thiazin dyes are bound in radial position to the membrane, while the quinolin dyes are bound parallel to the membrane's plane.

Coloring Agents↗