Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “THIAZINES”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 289 records · Page 16Linked to original sources
PubMed1995

In vivo pharmacological evaluation of two novel type II (inducible) nitric oxide synthase inhibitors.

Selective type II (inducible) nitric oxide synthase (NOS) inhibitors have several potential therapeutic applications, including treatment of sepsis, diabetes, and autoimmune diseases. The ability of two novel, selective inhibitors of type II NOS, S-ethylisothiourea (EIT) and 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), to inhibit type II NOS function in vivo was studied in lipopolysaccharide (LPS) treated rats. Type II NOS activity was assessed by measuring changes in plasma nitrite and nitrate concentrations ([NOx]). Both EIT and AMT elicited a dose-dependent and > 95% inhibition of the LPS-induced increase in plasma [NOx]. The ED50 values for EIT and AMT were 0.4 and 0.2 mg/kg, respectively. In addition, the administration of LPS and either NOS inhibitor resulted in a dose-dependent increase in animal mortality; neither compound was lethal when administered alone. Pretreatment with L-arginine (but not D-arginine) prevented the mortality, while not affecting the type II NOS-dependent NO production, suggesting the toxicity may be due to inhibition of one of the other NOS isoforms (endothelial or neuronal). Thus, although EIT and AMT are potent inhibitors of type II NOS function in vivo, type II NOS inhibitors of even greater selectivity may need to be developed for therapeutic applications.

Animals↗
PubMed1999

Salt-induced hypertension in Dahl salt-resistant and salt-sensitive rats with NOS II inhibition.

Although recent evidence suggests that reduced nitric oxide (NO) production may be involved in salt-induced hypertension, the specific NO synthase (NOS) responsible for the conveyance of salt sensitivity remains unknown. To determine the role of inducible NOS (NOS II) in salt-induced hypertension, we treated Dahl salt-resistant (DR) rats with the selective NOS II inhibitor 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT) for 12 days. Tail-cuff systolic blood pressures rose 29 +/- 6 and 42 +/- 8 mmHg in DR rats given 150 and 300 nmol AMT/h, respectively (P < 0.01, 2-way ANOVA) after 7 days of 8% NaCl diet. We observed similar results with two other potent selective NOS II inhibitors, S-ethylisourea (EIT) and N-[3-(aminomethyl)benzyl]acetamidine hydrochloride (1400W). Additionally, AMT effects were independent of alterations in endothelial function as assessed by diameter change of mesenteric arterioles in response to methacholine using videomicroscopy. We, therefore, conclude from these data that NOS II is important in salt-induced hypertension.

Amidines↗
PubMed1998

Role of inducible nitric oxide synthase in regulation of pulmonary vascular tone in the late gestation ovine fetus.

Nitric oxide (NO) produced by NO synthase (NOS) modulates fetal pulmonary vascular tone and contributes to the fall in pulmonary vascular resistance (PVR) at birth. Although the inducible (type II) NOS isoform is present in human and rat fetal lungs, it is uncertain whether type II NOS activity contributes to vascular NO production in the fetal lung. To determine whether type II NOS is present in the ovine fetal lung and to study the potential contribution of type II NOS on the regulation of basal PVR in the fetus, we measured the hemodynamic effects of three selective type II NOS antagonists: aminoguanidine (AG), 2-amino-5,6-dihydro-6-methyl-4H-1,3 thiazine (AMT), and S-ethylisothiourea (EIT). Studies were performed after at least 72 h of recovery from surgery in 19 chronically prepared fetal lambs (133+/-3 d; 147 d, term). Brief intrapulmonary infusions of AG (140 mg), AMT (0.12 mg), and EIT (0.12 mg) increased basal PVR by 82, 69, and 77%, respectively (P < 0.05). The maximum increase in PVR occurred within 20 min, but often persisted up to 80 min. These agents also increased mean aortic pressure but did not alter the pressure gradient between the pulmonary artery and aorta, suggesting little effect on tone of the ductus arteriosus. Acetylcholine-induced pulmonary vasodilation remained intact after treatment with selective type II NOS antagonists, but not after treatment with the nonselective NOS blocker, nitro-L-arginine. Using Northern blot analysis with poly(A)+ RNA, we demonstrated the presence of two mRNA transcripts for type II NOS (4.1 and 2.6 kb) in the fetal lung. We conclude that the type II NOS isoform is present in the ovine fetal lung, and that selective type II NOS antagonists increase PVR and systemic arterial pressure in the late-gestation fetus. We speculate that type II NOS may play a physiological role in the modulation of vascular tone in the developing fetal lung.

Acetylcholine↗
PubMed1995

Profiles of the antinociceptive effect of R-84760, a selective kappa-opioid receptor agonist, in the formalin test in mice.

The antinociceptive effect of a selective kappa-opioid receptor agonist R-84760, (3R)-3-(1-pyrrolidinylmethyl)-4-[(1S)-5,6-dichloro-1-indancarbo nyl]- tetrahydro-1,4-thiazine hydrochloride, in the second phase of the formalin test, a model of tonic pain, was examined in mice. R-84760 had a 2700 times more potent antinociceptive effect than morphine. The effect of R-84760 was antagonized by subcutaneously administered nor-binaltorphimine, a kappa-selective opioid receptor antagonist. Both intracerebroventricularly and intrathecally administered nor-binaltorphimine partially antagonized the antinociceptive effect of R-84760. Intrathecally administered phentolamine, an alpha-adrenoceptor antagonist, attenuated and desipramine, a noradrenaline reuptake inhibitor, augmented the antinociceptive effect of R-84760. Intrathecally administered noradrenaline attenuated the nociceptive response in the second phase of the formalin test. Intrathecally administered (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), an N-methyl-D-aspartate (NMDA)-receptor antagonist, reduced and threo-beta-hydroxyaspartate, a reuptake inhibitor of glutamate, augmented the second phase nociceptive response. However, R-84760 did not influence the intrathecally injected NMDA-induced nociceptive response. These results suggest the following: R-84760 produces an extremely potent antinociceptive effect against tonic pain through the kappa-opioid receptors; the sites of action of subcutaneously administered R-84760 are the supraspinal and spinal loci in the central nervous system; and a part of the mechanism of the antinociceptive effect of R-84760 is activation of the descending noradrenergic pathway.

Analgesics↗
PubMed2003

Pathodynamics of nitric oxide production within implanted glioma studied with an in vivo microdialysis technique and immunohistochemistry.

Nitric oxide (NO) is thought to be a mediator in many of the processes of malignant brain tumor progression. We examined NO production in the brain of normal conscious, freely moving rats with or without implanted C6 glioma. Both nitrite (NO(2)(-)) and nitrate (NO(3)(-)) in the dialysates of the two groups were measured using an in vivo microdialysis technique. The mean concentration of NO(2)(-) in the glioma group was two-times higher than that in the control group (P<0.01). Concentrations of both NO(2)(-) and NO(3)(-) in the glioma and control groups decreased following intraperitoneal injection of N(G)-nitro-L-arginine methyl ester (L-NAME), a non-selective inhibitor of NO synthase (NOS). NO production was also significantly suppressed in the glioma group, but not the control group, by intraperitoneal injection of 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), a selective inhibitor of inducible NOS (iNOS). On immunohistochemical examination, diffuse iNOS-positive cells were located within glioma tissue. ED1-positive cells (microglia/macrophages) were intermingled between glioma cells on double immunostaining. These results indicate that the basal level of NO production in the glioma group is higher than that in the control group and that the increased NO production was continuously induced by iNOS-expressing cells in glioma.

Animals↗
PubMed1977

The degradation of Romanowsky-type blood stains in methanol.

The oxidative demethylation of Romanowsky-type stains in methanol has been examined quantitatively with respect to its effect upon the staining of blood smears. Spectral changes in bound dye, observed through two color filters, have been measured for the nuclei and cytoplasm of segmented neutrophils and monocytes utilizing the LARC automated differential analyzer. Stain decomposition in methanol results in a large loss in staining intensity with little change in color. The loss in intensity has been correlated with the observed spectral changes in the degraded stain. High-performance liquid chromatographic analysis of degraded stain samples has shown the products of methanolic degradation to be different from those obtained in aqueous polychroming reactions. To maintain a stain of defined thiazine dye composition and thus defined staining properties, refrigeration is recommended.

Blood Cells↗
PubMed2001

Spleen damage in endotoxaemic mice: the involvement of nitric oxide.

The association between Escherichia coli endotoxin-induced organ damage and nitric oxide-related mechanisms was investigated in the spleen of male Swiss albino mice (20-40 g) by using (1) Pt/Ir electrochemical sensor connected to an amperometric detection system (NO-501, InterMedical Co., Japan), (2) nitrotyrosine immunohistochemistry, (3) conventional light microscopy and (4) immunoblotting techniques in parallel. 1 h before endotoxin injection, animals were pretreated with either nitric oxide synthase inhibitor, L-N(G)-nitroarginine methyl ester (L-NAME, 20 mg kg(-1), i.p.) or inducible nitric oxide synthase expression inhibitor, dexamethasone (5 mg kg(-1), i.p.) or the inhibitor of murine inducible nitric oxide synthase in vivo, 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT, 1 mg kg(-1), i.p.). 5 h after endotoxin treatment, electrochemically detected concentration of nitric oxide was significantly elevated (nM, endotoxin: 716.6 +/- 178.2, n = 10 vs saline: 209.4 +/- 127.8, n = 9, P = 0.0312, unpaired Student's t-test) and remained so throughout the 30 min monitorization period. Neither dexamethasone nor AMT blocked the endotoxin-induced overproduction of nitric oxide indicating that the enhanced inducible nitric oxide synthase activity cannot be the only explanation. When dexamethasone and L-NAME combination was used to block both the constitutive and the inducible isoforms, nitric oxide production was virtually abolished, indicating a significant contribution from the constitutive isoform of nitric oxide synthase. The results of nitrotyrosine immunohistochemistry and the conventional light microscopy were also in agreement with the amperometric method while immunoblotting revealed the expression of both the endothelial and the inducible isoforms of nitric oxide synthase were induced endotoxaemic animals. Thus, conclude that endotoxin-induced splenic damage in endotoxaemia can be explained by enhanced production of nitric oxide due to the induction of both endothelial and inducible nitric oxide synthases while causal relationship and the roles of other deleterious mediators such as oxygen-derived free radicals are yet to be established.

Animals↗
PubMed2003

Progesterone production in bovine luteal cells treated with drugs that modulate nitric oxide production.

The aim of this study was to investigate the influence of nitric oxide (NO) donors (S-nitroso-L-acetyl penicillamine, spermine-NO complex and sodium nitroprusside) and NO synthase inhibitors (N(omega)-nitro-L-arginine methyl ester, N(omega)-nitro-l-arginine, and (+/-)-2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine) on progesterone production by dispersed bovine luteal cells cultured for 24 h. All NO donors inhibited progesterone production and increased nitrite or nitrate concentration in the medium in a dose-dependent manner. Secretion of progesterone was reduced to 75% (P < 0.01), 56% (P < 0.001) and 37% (P < 0.001) by S-nitroso-L-acetyl penicillamine; to 65% (P < 0.001), 45% (P < 0.001) and 33% (P < 0.001) by spermine-NO complex and to 77% (P < 0.05), 74% (P < 0.01) and 54% (P < 0.001) by sodium nitroprusside treatments at concentrations of 10(-5), 10(-4) and 10(-3) mol l(-1), respectively, compared with the concentration of this hormone measured in cells cultured in medium alone. NO synthase inhibitors decreased significantly (P < 0.05) nitrite or nitrate concentration and increased progesterone secretion with different potency at different doses. Significant increases in progesterone production were observed after N(omega)-nitro-L-arginine methyl ester treatment at a concentration of 10(-5) mol l(-1) and 10(-4) mol l(-1), and after N(omega)-nitro-l-arginine administration at a concentration of 10(-6) mol l(-1) (P < 0.01) and 10(-5) mol l(-1) (P < 0.05), compared with the concentration of this hormone measured in control cells. The results indicate that both NO donors and NO synthase inhibitors regulate steroidogenesis in cultured bovine luteal cells from days 10 to 14 of the oestrous cycle; however, the degree of progesterone inhibition by NO donors and stimulation by NO synthase inhibitors was dependent on the drug used.

Analysis of Variance↗
PubMed1975

[Tomizine--a new inhibitor of folate metabolism enzymes possessing an antitumor activity].

In the experiments on enzymic systems functioning in the metabolism of folic acid and on transplantable tumors in animals the preparation thomizine (chlorohydrate 4-methoxy-6-aminopyrimido (4,5-b) (1,4) thiazine) was worked out. Thomizine, as well as the known antimetabolite of folic acid-methotrexate, suppresses the activity of dihydrofolate reductase, but contrary to it suppresses FAP enzymic system, inhibiting aminopterin in the organism. Thomizine differes from methotrexate by another spectrum of antitumor effect, selective suppression of the tumor tissue growth, compared with the normal in vitro, it does not inhibit leucopoiesis, shows less toxicity and insignificant cumulative properties.

Aminopterin↗
PubMed1987

The role of oxygen radicals in dye-mediated photodynamic effects in Escherichia coli B.

Photosensitive dyes representative of the thiazines, xanthenes, acridines, and phenazines mediated phototoxicity in Escherichia coli B. The observed phototoxicity was sensitizer-, light-, and oxygen-dependent and is therefore a photodynamic effect. Hydroxyl radical scavengers conferred protection against the photodynamic action of all of the representative dyes. The extent of protection was dependent on the concentration of scavenger and on the in vitro reactivity of the scavenger with the hydroxyl radical. Exogenous superoxide dismutase and catalase partially protected the cells against the dye-mediated phototoxicity, and prior induction of intracellular superoxide dismutase and catalase by growth in glucose minimal medium containing manganese and paraquat substantially protected E. coli B against the photodynamic action of all of the dyes examined. Combinations of protective treatments against the phototoxicity of all four classes of dyes, including superoxide dismutase and catalase preinduction and addition of extracellular superoxide dismutase and catalase or the addition of hydroxyl radical scavengers, provided nearly complete protection against the oxygen-dependent component of dye-mediated lethality. E. coli B grown in glucose minimal medium containing manganese and photosensitive dyes induced manganese superoxide dismutase. The extent of induction was correlated with the dyes' ability to photooxidize NADH in vitro. Thus, oxygen radicals are primarily responsible for the oxygen-dependent toxicity of the photosensitive dyes examined, and one adaptive response of E. coli B to a dye-mediated oxidative threat is to induce superoxide dismutase.

Acridines↗
PubMedDate not supplied

Effects of R-84760, a selective kappa-opioid receptor agonist, on nociception, locomotion and respiration in rats.

The effects of R-84760 [(3R)-3-(1-pyrrolidinylmethyl)-4-[(1S)-5,6-dichloro-l-indancarb onyl] tetrahydro-1,4-thiazine hydrochloride] on nociception, locomotion and respiration were examined in rats. R-84760 induced a potent antinociceptive effect in the formalin test. The potency was 930 and 1500 times higher than that of U-50488 and morphine, respectively, when injected subcutaneously. Intracerebroventricular and intrathecal injection, as well as subcutaneous administration of naloxone antagonized the antinociceptive effect of R-84760, suggesting the sites of action of R-84760 were at the spinal and supraspinal levels. R-84760 disturbed the rotarod performance at doses 16 times higher than those needed for antinociception. R-84760 did not affect the arterial blood Pco2, Po2 and pH at a supramaximal dose for antinociception.

Analgesia↗
PubMed1999

Synthesis and antitumor activity of some new substituted quinolin-4-one and 1,7-naphthyridin-4-one analogs.

The synthesis of some new analogs of quinolin-4-one and 1,7-naphthyridin-4-one is described. The prepared compounds were tested for their in vitro antitumor and cdc2 kinase or cdc25 phosphatase inhibitory activity. Compound ethyl 7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de][2,3-b]pyrido-1,4-thiazine-6-carboxylate (6b) showed antitumor activity against CNS SNB-75, breast T-47D, and lung NCI-H522 cancer cell lines with GI50 values of 8.3, 17.6, and 22.7 microM, respectively. Meanwhile, the compounds ethyl 4-oxo-8-phenylthio-1H,4H-quinoline-3-carboxylate (11a) and 4-oxo-8-phenylthio-1H,4H-1,7-naphthyridine-3-carboxylic acid (12b) have proved to be cdc25 phosphatase inhibitors at IC50 values of 11 and 5 microM, respectively.

Antineoplastic Agents↗
PubMed1978

Hydrolysis of cephalosporins in strongly acid medium.

The hydrolysis of cephalexin, cephalothin and cephaloridine in strongly acid medium (10--25% sulfuric acid) at high temperature (approximately 100 degrees C) was studied. The hydrolysis proceeds with a high rate (10--15 min are necessary for complete hydrolysis) and results in definite products with low mol.-wt. The hydrolysis under such hard conditions affects the side chain in 3-position, in some cases the C--N bond in the amido group in 7-position, and leads to a total cleavage of the beta-lactam ring, giving thiazine compounds. The reaction products were identified using IR and UV spectral data, thin-layer and gas chromatography, and some characteristic reactions of functional groups. The results of the investigation were used for development of photometric procedures for determination of cephalosporins.

Cephalexin↗
PubMed1988

Condensation of DNA in situ in metaphase chromosomes induced by intercalating ligands and its relationship to chromosome banding.

Interactions of certain intercalating cationic ligands with nucleic acids result in the formation of products that undergo condensation and agglomeration; this transition in solution can be monitored by light-scatter measurements. In the present study, using such intercalators as the antitumor drug mitoxantrone or fluorochromes acridine orange and quinacrine, we induced condensation of DNA in situ in Chinese hamster chromosomes. The in situ products scattered light and could be detected by darkfield- or phase-contrast microscopy. In the darkfield the complexes had a characteristic granular appearance and often generated a banding pattern on the chromosomes. In contrast, condensation of DNA in situ by the nonintercalating polyvalent cations (Co3+, spermine4+), while enhancing the chromosome's image contrast, did not produce the granular products or the banding. The condensation of free DNA, single or double stranded, natural or synthetic, the latter of various base composition and configuration, was also measured in solution. The condensation in solution and in situ was observed at similar concentrations of the respective ligands. The intercalating dye ethidium bromide, which did not condense DNA in solutions of moderate and high ionic strength, also did not generate the granular products or banding on chromosomes. The data also show that both base composition and configuration are important factors in determining the sensitivity of DNA to condensation by particular intercalating ligands. The studies suggest that the phenomenon of DNA condensation by intercalating dyes, which shows a high degree of specificity with respect to primary and secondary structures of DNA, may be associated with mechanisms of chromosome banding induced by the intercalating thiazine dyes in Giemsa staining or by quinacrine. Observation of chromosome banding based on light-scatter detection in darkfield microscopy allows the study of interactions between DNA and the ligands that neither fluoresce nor generate colored products. This principle of chromosome "counter-staining" can be explored by flow cytometry.

Acridine Orange↗