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PubMed1994

Pharmacokinetics and pharmacodynamics of furosemide after intravenous and oral administration to spontaneously hypertensive rats and DOCA-salt-induced hypertensive rats.

The pharmacokinetics and pharmacodynamics of furosemide were investigated after intravenous (i.v.), 1 mg/100 g body weight, and oral administration, 2 mg per 100 g body weight, to spontaneously hypertensive rats (SHRs) and deoxycorticosterone acetate-salt-induced hypertensive rats (DOCA-salt rats). After i.v. administration, the 8 h urinary excretion of furosemide/g kidney (397 versus 572 micrograms) was significantly lower and the non-renal clearance (5.78 versus 3.94 ml min-1 kg-1) was significantly faster in SHRs of 16 weeks of age than in age-matched control Wistar rats. This suggested that the non-renal metabolism of furosemide could be faster in SHRs of 16 weeks of age than in age-matched control Wistar rats, and this could be supported by the significantly greater amount of 4-chloro-5-sulphamoyl anthranilic acid, a metabolite of furosemide, excreted in 8 h urine as expressed in terms of furosemide (11.1 versus 4.79% of the i.v. dose) in SHRs. It could also be supported at least in part by a study of liver homogenate; the amount of furosemide remaining per gram of liver after 30 min incubation of 50 micrograms of furosemide with the 9000g supernatant fraction of liver homogenate was significantly smaller (40.4 versus 43.7 micrograms) in SHRs of 16 weeks of age than in age-matched Wistar rats. The greater metabolic activity of furosemide in liver may also be supported by the result that the amount of hepatic cytochrome P-450 (0.7013 versus 0.5186 nmol/mg protein) and the weights of liver (3.52 versus 2.93% of body weight) were significantly greater in SHRs of 16 weeks of age than in age-matched Wistar rats. After i.v. administration of furosemide, the 8 h urine output (9.93 versus 16.5 ml) and 8 h urinary excretion of sodium (1.21 versus 2.05 mmol) and chloride (1.37 versus 2.17 mmol) per gram of kidney in SHRs of 16 weeks of age were lower than those in age-matched Wistar rats, this could be due to the significantly smaller amount of furosemide excreted in 8 h urine per gram of kidney. After oral administration, the pharmacokinetics and pharmacodynamics of furosemide were not significantly different between SHRs and the control Wistar rats of 16 weeks of age. After i.v. and oral administration of furosemide, there were no significant differences in the pharmacokinetics and pharmacodynamics between DOCA-salt rats and control SD rats of 16 weeks of age except for the significantly lower urinary excretion of potassium per gram of kidney in DOCA-salt rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMed1975

Biological properties of a new non-steroidal anti-inflammatory drug: etoclofene.

Etoclofene, the ethoxy methyl ester of N-(2,6-dichloro-m-tolyl)anthranilic acid, showed potent anti-inflammatory, anti-pyretic and peripheral analgesic activity in several experimental models of inflammation. There was no evidence of adrenal dependence or corticoid-like effects at effective and non-toxic dose levels. Etoclofene showed a low level of toxicity and was well tolerated in animals.

Analgesics↗
PubMed1977

Synthesis of certain 4-oxo-1.2.3.4-tetrahydroquinoline and benzazocine derivatives likely to possess analgesic activity.

Cyanoethylation of anthranilic acid afforded the N-cyanoethyl derivative which on treatment with ethanolic and methanolic hydrogen chloride yielded the corresponding diethyl and dimethyl esters respectively. Application of the Dieckmann's conditions to the N-acetyl derivatives of the two esters using sodium hydride and sodium ethoxide afforded different products. With the former, the expected products were obtained, while with the latter catalyst both esters furnished one and the same compound which was shown to be a benzazocine trione. The structure of the azocine was inferred from elemental analysis, spectroscopic data and formation of derivatives.

Analgesics↗
PubMed1988

Synthesis of some 1,2,4-triazine derivatives with potential biological activity.

6-Substituted benzyl-3-thioxo-1,2,4-triazin-5-ones 5a-e and the 4-amino derivatives 12c, e were prepared and converted into their corresponding 3-methylthio derivatives 6a-e and 13c, e, respectively of compounds 6a-e with primary and secondary amines gave the corresponding 3-amino-1,2,4-triazin-5-ones 7a-i and 8a, b. Cyclocondensation of compounds 6a-e and 13c, e with anthranilic acid was proved to give the corresponding triazino [3,2-b] quinazolindiones 9a-e and the 1-amino derivatives 11a, b.

Chemical Phenomena↗
PubMed2006

In vitro and in vivo evaluation of WK-X-34, a novel inhibitor of P-glycoprotein and BCRP, using radio imaging techniques.

Overexpression of the multidrug resistance proteins P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) results in treatment failure of many malignancies including ovarian cancer. Dual inhibition of Pgp and BCRP may restore the sensitivity of resistant cells to anticancer drugs. We report the synthesis and characterization of a novel anthranilic-acid based Pgp and BCRP modulator, WK-X-34. In vitro inhibition of Pgp activity was evaluated using 99mTc-Sestamibi and daunorubicin accumulation in Pgp overexpressing human ovarian cancer cells (A2780/Adr) and its sensitive counterpart (A2780/wt). Interaction with BCRP was examined with a mitoxantrone-efflux assay in BCRP-overexpressing MCF7/mx cells, with flow cytometry. Interactions with the multidrug resistance associated proteins (MRP) were evaluated in transfected MRP1, MRP2 and MRP3 cell lines, using a 5-CFDA efflux assay. In vivo 99mTc-Sestamibi imaging of human ovarian cancer xenografts was used to evaluate the in vivo efficacy of WK-X-34 in mice. Daunorubicin accumulation in A2780/Adr cells was inhibited by WK-X-34 at nanomolar concentrations (IC50: 82.1 +/- 6 nM). WK-X-34 inhibited mitoxantrone accumulation in BCRP-overexpressing cells at micromolar concentrations (IC50 = 26.5 +/- 4.6 microM), whereas WK-X-34 did not significantly alter 5-CFDA accumulation in MRP transfected cells. In vivo, uptake of 99mTc-Sestamibi was significantly increased in A2780/Adr xenograft tumors, brain and intestine (AUCs(0-4h) 136%, 147% and 138%; p < 0.05) in mice dosed with WK-X-34 (20 mg/kg i.p.). WK-X-34 selectively modulates Pgp and BCRP in vitro and in vivo in multidrug resistant ovarian cancer cells, and thus may have potential utility in the treatment of multidrug resistant tumors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

A mass spectrometric investigation on the possible role of tryptophan and 7-hydroxytryptophan in melanogenesis.

The activity of tyrosinase and peroxidase + H2O2 in promoting melanogenesis from tryptophan (Trp) and 7-hydroxytryptophan (7-HTP) has been investigated. The reaction samples have been drawn at different reaction times and analysed by MALDI mass spectrometry. The data obtained showed that tryptophan undergoes, under tyrosinase and peroxidase action, an oligomerization process mainly due to the reaction of anthranilic acid (AA) and Trp. However, analysing the UV and fluorescence data, it is seen that the oligomers cannot belong to the melanin pattern, but their possible role in melanogenesis is not to be excluded. Once it reacts with the two enzymes, 7-hydroxytryptophan leads to dark brown products, indicating its possible role in melanin production. In contrast to what was observed in the case of 5-hydroxytryptophan, for which oligomers were constituted by 5-hydroxytryptophan (5-HTP) and 5-hydroxytryptamine (5-HT) units, the MALDI data indicate a sharply different behaviour for 7-HTP. In fact, in the case of 5-hydroxytryptophan, oligomerization takes place through the formation of 5-hydroxytryptamine and the oligomerization products are due to mixed 5-HTP-5-HT oligomers. In the case of 7-hydroxytryptophan, the formation of 7-hydroxytryptamine (7-HT) is also observed, but it does not seem to play any role; the only oligomerization products formed are due to the reaction of 7-hydroxytryptophan and AA. The data so obtained indicate that 7-hydroxytryptophan acts like an effective melanin precursor in the presence of both tyrosinase and peroxidase + H2O2.

Agaricales↗
PubMed1977

Fluorescence properties of glafenine.

The fluorescence properties of glafenine are partly caused by the anthranilic acid nucleus of the molecule. Correlations are made between fluorescence capacities and UV absorbance. Analytical determinations can be carried out in different solvents, e.g., ether, benzene, and ethanol. Linearity of the emission intensity with the concentration, limiting detectable sample concentrations, and Stokes shifts are reported.

Glafenine↗
PubMed1978

New spectrophotofluorometric assay for probenecid.

A new spectrophotofluorometric assay for probenecid is presented based on conversion of the drug to a fluorescent anthranilic acid derivative. The assay is especially applicable with "clean" biological fluids such as cerebrospinal fluid and offers severalfold greater sensitivity than the commonly used UV method.

Animals↗
PubMed1992

Mass spectrometry of DNA mixtures by laser ablation from frozen aqueous solution.

We report time-of-flight mass spectra of test mixtures of six single-stranded DNA segments. The segments range in size from 8 to 60 nucleotides (molecular weight range 2413 to 18,602 Da). The best mass spectra were obtained by pulsed laser ablation of thin frozen films of an aqueous solution of the mixture from an oxidized copper substrate. These mass spectra are dominated by the molecular-ion peak for each DNA segment, and show little evidence of fragmentation, peak broadening or cluster formation. In contrast, mass spectra obtained using UV laser ablation from an anthranilic acid matrix yield broad peaks with evidence of fragmentation, and DNA segments longer than 26 nucleotides are difficult to detect.

Base Sequence↗
PubMed1984

Lack of in vivo and in vitro genotoxicity with the nonsteroid, antiinflammatory agent sodium meclofenamate.

Sodium meclofenamate (Meclomen), CI-583, is an anthranilic acid salt developed as a nonsteroidal, antiinflammatory agent. A multitest battery of short-term tests was employed to characterize the genotoxic and mutagenic potential of the compound by measuring point mutations in bacteria, induction of sister-chromatid exchange, chromosome aberrations, and gene mutations in mammalian cells in vitro. In vitro assays included metabolic activation. The in vivo assay was for chromosome aberrations in bone marrow cells from rats. At toxicity-limited doses for each assay, no activity was detected in the bacterial or mammalian cell mutation assays, and sister-chromatid exchange frequencies were not increased over control rates. When sodium meclofenamate was evaluated in vitro, chromosome aberrations were induced under metabolic activation in CHO cells. Chromosome aberrations and clastogenic activity were not demonstrated after oral administration of Meclomen to male rats. It was concluded that sodium meclofenamate does not possess overt mutagenic potential under these conditions. The activity seen in vitro with CHO cells after metabolic activation did not correlate with the results from the other tests and was attributed to the formation of reactive metabolites not present or formed in in vivo systems.

Animals↗
PubMed1993

A high throughput fluorogenic substrate for interstitial collagenase (MMP-1) and gelatinase (MMP-9).

Two members of the matrix metalloproteinase family of enzymes, interstitial collagenase and 92-kDa gelatinase, have been implicated in the pathogenesis of rheumatoid arthritis and tumor metastasis. In order to characterize the activities of these enzymes, we have developed a fluorogenic peptide substrate which is efficiently hydrolyzed by both enzymes. This substrate was developed based on the addition of the fluorescent tag, N-methyl-anthranilic acid (Nma), to several previously synthesized substrates that had been evaluated with respect to their turnover by interstitial collagenase. One substrate, Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys-(Nma)-NH2, had favorable solubility characteristics, was > 98% quenched, and produced a single cleavage product, Dnp-Pro-Cha-Gly, with a high fluorescence yield with both interstitial collagenase and 92-kDa gelatinase. Since the assay depends on measurement of increases in fluorescence, the position of the Nma group also proved to be important for optimization of the fluorescence signal. The assay is free from interference by organomercurial compounds and the cleavage product has excitation and emission spectra compatible with filters commonly available on commercial plate readers. The assay has been adapted to a 96-well format and provides a rapid screening protocol for the evaluation of inhibitors of these enzymes.

Amino Acid Sequence↗
PubMed1999

Tryptanthrins and other tryptophan-derived agonists of the dioxin receptor.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related environmental pollutants exert most of their adverse effects via the aryl hydrocarbon or dioxin receptor (AhR). While most potent agonists of the AhR are of synthetic origin, an increasing number of natural compounds is now recognized as receptor agonists. Our findings demonstrate that some tryptanthrin derivatives biosynthesized in incubations of Candida lipolytica with tryptophan and anthranilic acid or its derivatives activate the AhR measured as induction of cytochrome P4501A1 mRNA and protein in rat hepatocytes in primary culture. The specificity of the inducing effect of tryptanthrins was demonstrated in gel retardation experiments in Hepa-1 mouse hepatoma cells using an oliogonucleotide comprising the sequence of the dioxin-responsive element. Furthermore, unidentified AhR agonists were formed in incubations of rat feces with a minimal medium supplemented with tryptophan. It is suggested that the receptor may be part of a defense system protecting higher organisms from secondary tryptophan-derived metabolites formed by the microflora of the host or its environment.

Animals↗
PubMed1984

Thiol-dependent passive K/Cl transport in sheep red cells: IV. Furosemide inhibition as a function of external Rb+, Na+, and Cl-.

The effect of the loop diuretic furosemide (4-chloro-N-furfuryl-5-sulfamoyl-anthranilic acid) on the thiol-dependent, ouabain-insensitive K(Rb)/Cl transport in low K+ sheep red cells was studied at various concentrations of extracellular Rb+, Na+ and Cl-. In Rb+-free NaCl media, 2 X 10(-3) M furosemide inhibited only one-half of thiol-dependent K+ efflux. In the presence of 23 mM RbCl, however, the concentration of furosemide to produce 50% K+ efflux inhibition (IC50) was 5 X 10(-5) M. In Rb+ containing NaCl media, the inhibitory effect of 10(-3) M furosemide was equal to that caused by NO-3 replacement of Cl- in the medium. The apparent synergistic action of furosemide and external Rb+ on K+ efflux was also seen in the ouabain-insensitive Rb+ influx. A preliminary kinetic analysis suggests that furosemide binding alters both maximal K+(Rb+) transport and apparent external Rb+ affinity. In the presence of external Rb+, Na+ (as compared to choline) exerted a small but significant augmentation of the furosemide inhibition of K+(Rb+) fluxes. There was no effect of Cl- on the IC50 value of furosemide. As there is no evidence for coupled Na+K+ cotransport in low K+ sheep red cells, furosemide may modify thiol-dependent K+(Rb+)/Cl flux or Rb+ (and to a slight degree Na+) modulate the effect of furosemide.

Animals↗
PubMed1994

Inhibition of interferon-gamma and interleukin-2 production from lymphocytes stimulated with food antigens by an anti-allergic drug, Tranilast, in patients with food-sensitive atopic dermatitis.

N(3',4'-dimethoxycinnamoyl) anthranilic acid (Tranilast) inhibits antibody-mediated hypersensitivity reactions, and is an effective drug for patients with bronchial asthma or allergic rhinitis. Interferon-gamma (IFN-gamma) production of ovalbumin (OA)-stimulated peripheral blood mononuclear cells (PBMCs) from hen's egg-sensitive patients with atopic dermatitis (AD) was significantly higher than those of healthy controls. Tranilast inhibited this IFN-gamma production. Moreover, interleukin-2 (IL-2) production of OA-stimulated PBMCs from hen's egg-sensitive patients with AD was also inhibited by Tranilast. Our results suggest that Tranilast can be used to the patients with food sensitive AD.

Anti-Allergic Agents↗
PubMed1993

Two phorbol ester receptor affinities in partially transformed human urothelial cells and decrease of receptor binding in desensitized cells.

The presence of specific binding sites for phorbol esters was studied in a transformed but non-tumorigenic human urothelial cell line HCV-29 by assay of specific binding of 3H-phorbol-12,13-dibutyrate (3H-PDBu) to intact living cells. 3H-PDBu bound specifically to HCV-29 cells in a saturable and competitive manner. Scatchard plot analysis of specific binding yielded a curved plot consistent with two binding sites with Kd of 11 nM and 102 nM, respectively. At saturation the corresponding PDBu binding capacities (Bmax) were 8.8 pmol/10(6) cells (5.2 x 10(6) molecules bound per cell) and 2.8 pmol/10(6) cells (1.7 x 10(6) molecules bound per cell). 3H-PDBu binding was displaced by biologically active phorbol ester tumor promoters such as 12-O-tetradecanoylphorbol-13-acetate (TPA) and mezerein, but not by tumor promoters such as L-tryptophan, anthranilic acid and sodium saccharin. In cells desensitized by pretreatment with 1 microgram/ml (2 microM) TPA or PDBu for 24 h the level of binding was reduced to 28% of the level in non-exposed cells. The ability of desensitized cells to bind 3H-PDBu was gradually restored within 5-6 days. At the same time the cells became sensitive to the morphological alteration induced by PDBu. This suggests that desensitization of HCV-29 cells is due to a decreased receptor-ligand binding capacity probably associated with down regulation of the phorbol ester receptors.

Caenorhabditis elegans Proteins↗
PubMed1988

Mast cell degranulation and its inhibition by an anti-allergic agent tranilast. An electron microscopic study.

Degranulation of IgE-sensitized rat mast cells by antigen was studied quantitatively in vitro and in vivo by electron microscopy. The inhibition of this degranulation by an anti-allergic drug, N-(3,4-dimethoxycinnamoyl)anthranilic acid (Tranilast), was also examined both in vitro and in vivo. In the in vitro study using peritoneal mast cells, alteration of the granules, cavity formation by fusion of the perigranular membrane and granule discharge due to fusion of the cavity membrane with the cell membrane were observed and were accompanied by histamine release. Scanning electron microscopy disclosed the extrusion of smooth, round bodies from pores formed on the cell surface. In the in vivo study of passive cutaneous anaphylaxis (PCA), the characteristic features of mast cell degranulation were obvious 5 min after the injection of antigen; leakage of dye increased progressively from 5 to 30 min but was not found at 6 h. From quantitative analysis of the substructure of mast cells, it was demonstrated that degranulation of IgE-sensitized mast cell induced by antigen was achieved by sequential exocytosis both in vitro and in vivo. Tranilast inhibited these changes to a remarkable extent and it was concluded that the inhibition of mast cell degranulation by this drug might play an important role in anti-allergic treatment.

Animals↗