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At least 379 records · Page 21Linked to original sources
PubMed1999

An Iron-Based Molecular Redox Switch as a Model for Iron Release from Enterobactin via the Salicylate Binding Mode.

The iron release mechanism from protonated ferric enterobactin [Fe(III)(enterobactinH(3))] via the salicylate binding mode was probed. For this purpose, a tripodal dodecadentate ligand incorporating three salicylamide (OO) and three bipyridine (NN) binding sites was synthesized as well as iron complexes thereof. It was shown that a ferric ion coordinates selectively to the hard salicylamides and a ferrous ion binds to the softer bipyridines. Upon reduction or oxidation, the iron translocates reversibly and intramolecularly from one site to the other, thus displaying switchlike properties. Both states were characterized by cyclic voltammetry and visible and Mössbauer spectroscopy. The Mössbauer spectrum for the ferric complex is fully consistent with that obtained by Pecoraro et al. upon lowering the pH of [Fe(III)(enterobactin)](3)(-) solutions (Pecoraro, V. L., et al. J. Am. Chem. Soc. 1983, 105, 4617), thus supporting the alternative iron release mechanism from enterobactin via the salicylate binding mode.

Journal Article↗
PubMed1991

Synthesis and in vitro evaluation of 2,3-dimethoxy-5-(fluoroalkyl)-substituted benzamides: high-affinity ligands for CNS dopamine D2 receptors.

A number of 2,3-dimethoxy-5-(fluoroalkyl)-N-[(1-ethyl-2- pyrrolidinyl)methyl]benzamides (with or without a 6-hydroxy group) were synthesized and evaluated as dopamine D2 receptor ligands. The parent acids were synthesized via the Claisen rearrangement of the appropriate O-allyl ethers, which were derived from o-vanillic acid or 2,3-dimethoxysalicylic acid. A decrease in reactivity was found to be characteristic of pentasubstituted benzoates, and difficulties were encountered with the introduction of fluorine onto the ethyl side chains. The (fluoroethyl)- and (fluoropropyl)salicylamides were 5 times more potent than the corresponding benzamides in inhibiting [3H]spiperone binding to the D2 receptor. These (fluoroalkyl)salicylamides are of potential value for in vivo positron emission tomography (PET) studies upon the basis of their relatively selective, high potency binding affinity for the D2 receptor.

Animals↗
PubMed2004

Design, synthesis, and biological evaluation of doxorubicin-formaldehyde conjugates targeted to breast cancer cells.

The anthracycline antitumor drug doxorubicin (DOX) has been utilized for decades as a broad-spectrum chemotherapeutic. Recent literature evidence documents the role of formaldehyde in the cytotoxic mechanism, and anthracycline-formaldehyde conjugates possess substantially enhanced activity in vitro and in vivo. Targeting a doxorubicin-formaldehyde conjugate specifically to cancer cells may provide a more efficacious chemotherapeutic. The design and 11-step synthesis of doxorubicin-formaldehyde conjugates targeted to the estrogen receptor, which is commonly overexpressed in breast cancer cells, are reported. The formaldehyde is incorporated in a masked form as an N-Mannich linkage between doxorubicin and salicylamide. The salicylamide triggering molecule, previously developed to release the doxorubicin-formaldehyde active metabolite, is tethered via derivatized ethylene glycols to an E and Z mixture of 4-hydroxytamoxifen. The targeting group, E/Z-4-hydroxytamoxifen, was selected for its ability to tightly bind the estrogen receptor and antiestrogen binding sites. The targeted doxorubicin-formaldehyde conjugates' estrogen receptor binding and in vitro growth inhibition were evaluated as a function of tether length. The lead compound, DOX-TEG-TAM, bearing a triethylene glycol tether, binds the estrogen receptor with a binding affinity of 2.5% relative to E/Z-4-hydroxytamoxifen and inhibits the growth of four breast cancer cell lines with 4-fold up to 140-fold enhanced activity relative to doxorubicin.

Antineoplastic Agents↗
PubMed1985

Aspirin-sensitive asthma: abnormal platelet response to drugs inducing asthmatic attacks. Diagnostic and physiopathological implications.

The pathogenesis of aspirin-sensitive asthma remains unknown. Using a new model of platelet activation, initially described as a response of platelets to IgE antibody-dependent stimuli, this study was designed to test the hypothesis of a possible involvement of platelets in aspirin-sensitive asthma. Washed platelets from 35 aspirin-sensitive asthmatics showed an abnormal in vitro response to cyclooxygenase inhibiting nonsteroidal anti-inflammatory drugs (NSAIDs)--aspirin, indomethacin or flurbiprofen--characterized by the generation of a cytocidal supernatant and (14 patients explored) a burst of chemiluminescence; these drugs had no similar effect on platelets from 31 controls (p less than 0.0001). It was shown that the abnormal platelet response to NSAIDs was not mediated by IgE. In contrast to platelets, aspirin-sensitive asthmatic leukocytes generated neither cytocidal factors nor chemiluminescence in the presence of NSAIDs. Sodium salicylate and salicylamide, which, though structurally similar to aspirin, do not inhibit cyclooxygenase and are well tolerated by aspirin-sensitive asthmatics, did not activate their platelets to release cytocidal factors. Moreover, preincubation of platelets with sodium salicylate, salicylamide or prostaglandin endoperoxide PGH2, highly prevented their abnormal response to NSAIDs (greater than 80%; p less than 0.0001). Since several lipoxygenase inhibitors (NDGA, esculetin), including inhibitors of both cyclooxygenase and lipoxygenase (ETYA, BW755c), did not activate patient platelets and prevented the subsequent abnormal response to NSAIDs, it is suggested that the abnormal platelet activation by NSAIDs is not only the consequence of an inhibition of cyclooxygenase, but also involves generation of lipoxygenase metabolites of arachidonate. Besides, platelets from 4 aspirin-sensitive asthmatics undergoing aspirin desensitization were found to have completely lost their abnormal responsiveness to NSAIDs. These findings represent the first identification in aspirin-intolerant asthmatics of a specific abnormal cellular response to drugs inducing asthmatic attacks and open new perspectives into the pathogenesis, prevention and diagnosis of this disease. They also provide support to the concept of a role for platelets in asthma.

Adult↗
PubMed1996

[Drug induced hemolytic anemia associated with agranulocytosis].

A 27-year-old female was admitted to a hospital because of severe anemia (hemoglobin 4.9 g/dl) after taking PL (a drug for common cold consisted of Salicylamide, Acetaminophen, Caffeine and Promethazine methylene di-salicylate) and Cefadroxil (an oral antibiotic) for ten days. History and laboratory data leaded to a diagnosis of drug induced hemolytic anemia. 6 units of concentrated red blood cells were transfused and the suspected drugs were discontinued immediately. Though resolution of anemia and no further hemolysis were observed, progressive leukocytopenia developed since four days after the admission. Bone marrow aspiration revealed marked decrease of granulocytic series. The patient was transferred to our hospital and was isolated under laminar air-flow to prevent her from bacterial and fungal infections. She was treated with prednisolone and granulocyte-colony stimulating factor. She recovered from leukocytopenia in two weeks without suffering from any life-threatening infection. We extensively analyzed the suspected drugs and mechanism of hemolysis and granulocytopenia. Cefadroxil is turned out to be contributed to hemolysis by an immune complex mechanism. Cefadroxil and Salicylamide were suggested to be involved in granulocytopenia by the induction of antibodies against the leukocytes to which these drugs were bound. Thus Cefadroxil was regarded as a causative drug of both hemolysis and granulocytopenia. This case is of interest for analyzing drug-induced blood abnormality because it is very rare that two lineage of blood were injured by one drug at the same time as far as we know.

Adult↗
PubMed1992

A quantitative structure-activity relationship for some dopamine D2 antagonists of benzamide type.

A quantitative structure-activity relationship (QSAR) for some 6-methoxybenzamides having 1-ethyl-2-pyrrolidinylmethyl side chains with respect to the inhibition of [3H]spiperone binding is established using the PLS method. An experimental design approach to select the training set compounds is demonstrated. The established relationship between structure and in vitro activity indicates the dominating influence of the substituents in the 3-position as well as the importance of (S)-configuration in the side chain. A methoxy substituent in the 5-position is also beneficiary for high activity. Both salicylamides and non-salicylamides could be accommodated in the analysis, which supports the notion of a common binding site in the receptor.

Benzamides↗
PubMed1977

Antiproliferative activity of anti-inflammatory drugs in two mammalian cell culture lines.

The nonsteroid anti-inflammatory drugs inhibited cell proliferation when added to rat hepatoma and human fibroblast cultures. The inhibition was reversible; normal growth resumed when the cultures were washed free of drug. Protein and nucleic acid synthesis, as measured by isotope incorporation was also reduced, although this reduction was probably a reflection of the decrease in cell numbers. An exception was that, in low concentration, the salicylate drugs, salicylamide, salicylic acid and aspirin, stimulated protein and nucleic acid synthesis, but in high concentrations (greater than 1 mM) they inhibited culture growth as well as protein and nucleic acid synthesis. Pharmacologically inactive derivatives, such as m-hydroxybenzoic acid and gentisic acid, were not inhibitory in concentrations up to 5 mM. The order of potency in inhibiting culture growth, meclofenamate greater than indomethacin greater than salicylamide greater than phenylbutazone greater than phenacetin greater than aspirin = salicylic acid, was similar to that reported for their anti-inflammator activity and their ability to inhibit prostaglandin synthesis. The antiproliferative activity of these drugs may, in part, account for their anti-inflammatory and toxic actions in vivo.

Animals↗
PubMed1995

[Iontophoresis in the treatment of pain].

UNLABELLED: The objective has been to verify the effectiveness of iontophoresis in alleviating conditions of pain by means of a computer-assisted search of the pertinent literature. The search was performed with the aid of the Medline database (1984 bis 1993) and reference lists (studies from 1954). SELECTION CRITERIA: all clinical trials performed with at least one control group as well as all experimental studies conducted within the same period. The selection criteria were met by 10 experimental and 15 clinical studies. The studies were categorized by substance group. The following groups of substances were applied (experimentally/clinically): local anaesthetics (0/6), non steroidal anti-inflammatory drugs (2/3), vinca-alkaloids (1/2), corticosteroids (3/1), morphine (0/1), iodide (4/1) and fluoride (0/1). Both short-term effects (lidocaine, procaine, flufenamic acid, morphine) and long-term effects (benzocaine-salicylamide, diclofenac, Mobilat, vinca-alkaloids, dexamethasone-lidocaine, iodide, fluoride) were studied. Comparisons were made against placebo iontophoresis (lidocaine, procaine, flufenamic acid, diclofenac, Mobilat, vinca-alkaloids, dexamethasone-lidocaine, morphine, fluoride), solely topical administration (procaine, benzocaine-salicylamide, flufenamic acid), placebo administration without current (procaine, flufenamic acid), and other methods (lidocaine, iodide). With one single exception (lidocaine), none of the studies included groups without treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1976

Improved transport apparatus for examining diffusion of drugs across isolated tissues and synthetic membranes.

A three-compartment diffusion apparatus that can accommodate synthetic as well as small isolated biological membranes such as rat intestine was developed and tested. The diffusion of drug from two outer donor cells into a central recipient cell allows for more membrane surface exposure and greater sensitivity in assaying as compared with previously published techniques. Reproducibility values for the synthetic membrane were equivalent to those obtained in more elaborate designs, while the reproducibility for biological membranes compared favorably with everted gut preparations and a similar diffusion apparatus. The clearance, per square centimeter of membrane, of salicylamide at pH 7.4 and 37 degrees was 0.288 ml/hr/cm2, which agreed with previous literature reports of different techniques. Although the diffusion through a synthetic membrane was more rapid, introduction of a nonionic surfactant enhanced the biological perfusion rate while having no significant effect on the synthetic barrier. The enhancement of the diffusion rate effected by 0.1 and 0.01% (w/v) surfactant was about twofold, rapid in onset, and not progressive, giving clearance values per square centimeter of 0.606 and 0.537 ml/hr/cm2, respectively.

Animals↗
PubMed1987

Flocculation of suspensions containing nonionic surfactants by sorbitol.

Aqueous suspensions of sulfamerazine, salicylamide, and butamben, containing either polysorbate 20 or polysorbate 80 as a wetting agent, were deflocculated. The presence of relatively high concentrations of sorbitol in the suspensions resulted in flocculation due to dehydration of surfactant polyoxyethylene groups (reflected by the cloud point). The critical flocculation concentration of sorbitol was reduced by raising the storage temperature, lowering the surfactant concentration, switching from polysorbate 80 to polysorbate 20, or adding sodium sulfate to the suspension formulation. Both the cloud point and the sorbitol critical flocculation concentration depended on the particular drug that was suspended. Methylparaben lowered the cloud point, suggesting that the choice of preservative could influence the suspension characteristics in certain cases. The various dehydrating influences were additive. By assuming that interparticle repulsion becomes negligible at the cloud point, it was possible to use cloud point curves to estimate the critical flocculation concentration of sorbitol.

Benzocaine↗
PubMed1993

Purification and characterization of salicylhydroxamic acid reductase from rat liver.

Salicylhydroxamic acid reductase, which catalyzes the reduction of salicylhydroxamic acid to salicylamide, was purified from rat liver cytosol. The purification procedure consisted of fractionation with ammonium sulfate, chromatography with Phenyl-Toyopearl 650, DEAE-cellulose, hydroxyapatite, and Sephadex G-200, and chromatofocusing with PBE94. The molecular weight of the enzyme was estimated to be about 140,000 by Sephadex G-200 gel filtration and 152,000 by polyacrylamide gel electrophoresis. The enzyme was dissociated into two different subunits with estimated molecular weights of 41,000 and 32,000, respectively, by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. These facts suggested that the enzyme is a heterotetramer consisting of two pairs of two nonidentical polypeptide chains. The Km value of the enzyme for salicylhydroxamic acid was estimated to be 91.5 or 88.7 microM in the presence of NADH or NADPH, respectively. The isoelectric point of the enzyme is pH 5.4. The enzyme was highly specific for salicylhydroxamic acid, but it also showed some activity with other hydroxamic acids such as nicotinohydroxamic acid and N-hydroxy-2-acetylaminofluorene. The enzyme activity was inhibited by allopurinol, oxipurinol, dicumarol, menadione, p-chloromercuribenzoic acid, sodium arsenite, potassium cyanide, cupric sulfate, and disulfiram, but little inhibition was observed with oxygen.

Animals↗
PubMed1984

Modulation of genotoxic and cytotoxic effects of aromatic amines in monolayers of rat hepatocytes.

Cultured rat hepatocytes exposed to 2-acetylaminofluorene (AAF), 2-aminofluorene (AF) or N-hydroxy-2-acetylaminofluorene (N-OH-AFF) for 3 hrs resulted in an increase in DNA repair measured as unscheduled DNA synthesis, with N-OH-AAF greater than AAF greater than AF. Cytotoxic effects were only seen with N-OH-AAF above 10(-6) M. alpha-Naphthoflavone increased the unscheduled DNA synthesis and cytotoxic effects of N-OH-AAF, whereas it decreased DNA repair and the covalent binding of AAF to cellular proteins. In contrast, very little effects of paraoxon were seen on the repair synthesis elicited by AAF, AF or N-OH-AAF. The addition of ascorbate reduced the covalent binding of AAF, the DNA repair synthesis caused by AAF and N-OH-AAF, and the cytotoxic effects of N-OH-AAF. The addition of pentachlorophenol or salicylamide all resulted in similar effects as ascorbate, through reduction of sulfation. Galactosamine, an inhibitor of glucuronidation, and the nucleophile GSH caused no or only minor effects of the activation of AAF, AF or N-OH-AAF as judged from the endpoints tested. These results are consistent with an arylnitrenium ion, a sulfate ester or a free radical as the arylamine metabolite causing cellular DNA damage, whereas the sulfate ester or a radical intermediate may be responsible for the cytotoxic effects of N-OH-AAF.

2-Acetylaminofluorene↗
PubMed1980

Metabolic activation of 2-acetylaminofluorene by isolated rat liver cells. Involvement of different metabolites causing DNA-repair and bacterial mutagenesis.

Isolated rat liver cells are able to metabolize 2-acetylaminofluorene (2-AAF) to reactive species, capable of producing mutagenic effects in Salmonella typhimurium TA 1518 and evoking unscheduled DNA synthesis within the hepatocytes. Indications are presented, that these genotoxic effects are caused by different reactive metabolites. Mutagenesis could be blocked almost completely by paraoxon, an inhibitor of the de-acetylation reaction, whereas induction of DNA excision repair was prevented by antagonizing the sulfation reaction by means of salicylamide.

2-Acetylaminofluorene↗
PubMed1985

Drug-induced toxic epidermal necrolysis (Lyell's syndrome) in a 4-year-old girl.

Toxic epidermal necrolysis (Lyell's syndrome) with erythematous skin lesions and bulla formation developed in a 4-year-old girl. An accurate diagnosis using the cryostat technique on the top of a bulla was available within 1 h of hospital admission. The course was unusually mild, probably because of early treatment with corticosteroids. Skin prick tests revealed salicylamide as the agent responsible for inducing the disease. The patient was advised to avoid this substance for the rest of her life.

Child, Preschool↗
PubMed1993

Nonlinear protein binding and enzyme heterogeneity: effects on hepatic drug removal.

The kinetics of substrate removal by the liver and the resulting nonlinear changes in unbound fraction along the flow path at varying input drug concentrations were examined by a model simulation study. Specifically, we varied the binding association constant, KA, and the Michaelis-Menten constants (Km and Vmax) to examine the steady state drug removal (expressed as hepatic extraction ratio E) and changes in drug binding for (i) unienzyme systems and (ii) simple, parallel metabolic pathways; zonal metabolic heterogeneity was also added as a variable. At low KA, E declined with increasing input drug concentration, due primarily to saturation of enzymes; only small differences in binding were present across the liver. At high KA, a parabolic profile for E with concentration was observed; changes in unbound fraction between the inlet and the outlet of the liver followed in parallel fashion. Protein binding was the rate-determining step at low input drug concentrations, whereas enzyme saturation was the rate-controlling factor at high input drug concentration. Heterogeneous enzymic distribution modulated changes in unbound fraction within the liver and at the outlet. Despite marked changes in unbound fraction occurring within the liver for different enzymic distributions, the overall transhepatic differences were relatively small. We then investigated the logarithmic average unbound concentration and the length averaged concentration as estimates of substrate concentration in liver in the presence of nonlinear drug binding. Fitting of simulated data, with and without assigned random error (10%), to the Michaelis-Menten equation was performed; fitting was repeated for simulated data obtained with presence of a specific inhibitor of the high-affinity, anteriorly distributed pathway. Results were similar for both concentration terms: accurate estimates were obtained for anterior, high affinity pathways; an overestimation of parameters was observed for the lower affinity posteriorly distributed pathways. Improved estimations were found for posteriorly distributed pathways upon inhibition with specific inhibitors; with added random error, however, the improvement was much decreased. We applied the method for fitting of several sets of metabolic data obtained from rat liver perfusion studies performed with salicylamide (SAM) (i) without and (ii) with the presence of 2,6-dichloro-4-nitrophenol (DCNP), a SAM sulfation inhibitor. The fitted results showed that SAM sulfation was a high-affinity high-capacity pathway; SAM glucuronidation was of lower affinity but comparable capacity as the sulfation pathway, whereas SAM hydroxylation was of lower affinity and lower capacity.

Animals↗
PubMed1991

Biotransformation and disposition of hexachlorocyclopentadiene in fish.

Fate of hexachlorocyclopentadiene (Hex) was studied in fresh-water fish using in vivo and in vitro systems. Hex injected intraperitoneally into goldfish is readily distributed, stored and metabolized (greater than 11 organosoluble and hydrophilic metabolites). The body radioactivity in tissues declines, but levels in bile remain high, indicating biliary excretion as a major route of elimination for Hex and its metabolites. Total radioactivity eliminated in water indicated three phases with a calculated half-life (t1/2) of 7 days and predicted 90 and 95% clearance of 162 and 211 days, respectively. A 3-segment straight line model gave the best fit of the elimination data. A compartmental model indicated two elimination and one reabsorption phase. For a static system, two phases of elimination were detected with a calculated t1/2 of 9 days and predicted 90 and 95% clearance of 77 and 107 days, respectively. A compartmental model indicated that one elimination and one reabsorption phase were involved. Goldfish produced a number of organosoluble and watersoluble metabolites in vivo. Several of the organosolubles may be volatile, and at least 11 were characterized by thin-layer chromatography. The primary metabolites may react with endogenous molecules which render them more hydrophilic. Hepatic microsomal P-450 oxygenases and cytosolic GSH-transferases from bluegills may be involved in Hex metabolism. GSH can also alter HEX nonenzymically. The two hexane-extractable (in vitro) metabolites of Hex were more polar than Hex. The inhibitors of the microsomal P-450 oxygenases (piperonyl butoxide) and UDPGA-transferase (salicylamide) do not affect the toxicity of HEX to goldfish fingerlings, indicating that its toxicity may not be related to these pathways.

Animals↗
PubMed2000

Metabolism and cytotoxicity of bisphenol A and other bisphenols in isolated rat hepatocytes.

The relation between the metabolism and the cytotoxic effects of bisphenol A (BPA, 2,2-bis(4-hydroxyphenyl)propane) has been studied in freshly isolated rat hepatocytes and isolated hepatic mitochondria. The incubation of hepatocytes with BPA (0.25-1.0 mM) elicited a concentration- and time-dependent cell death, accompanied by losses of intracellular ATP and total adenine nucleotide pools. BPA at a low-toxic level (0.25 mM) in the hepatocyte suspensions was rapidly converted to its major conjugate, BPA-glucuronide, and other minor products without marked loss of cell viability, although at a toxic level (0.5 mM), more than 65% of the compound presented in an unaltered form 2 h after the incubation. Addition of salicylamide (2 mM), non-toxic to hepatocytes during the incubation period, enhanced BPA-induced cytotoxicity and reduced the loss of BPA and the formation of BPA-glucuronide. The addition of BPA to isolated hepatic mitochondria caused a concentration (0-0.5 mM)-dependent increase in the rate of state 4 oxygen consumption in the presence of an FAD-linked substrate (succinate), indicating an uncoupling effect, whereas the rate of state 3 oxygen consumption was inhibited by BPA. Further, the addition of BPA (0.25 mM) reduced state 3 respiration with NAD+-linked substrates (pyruvate plus malate) and/or with the FAD-linked substrate, whereas state 3 respiration with ascorbate plus tetramethyl-p-phenylenediamine (cytochrome oxidase-linked respiration) was not significantly affected by BPA. A comparative study of the toxic effects of BPA and some bisphenols on cell viability (at 1.0 mM) and mitochondrial respiration (at 0.25 mM) revealed that 4,4'-(1,2-diethyl-1,2-ethenediyl)bisphenol (diethylstilbestrol) was more toxic than BPA, followed by 4,4'-methylenediphenol and 4,4'-biphenol. These results indicate that the onset of cytotoxicity caused by BPA may depend on the intracellular energy status and that mitochondria are important targets of the compound. The toxicity caused by the inhibition of ATP synthesis may be related to the concentration of unmetabolised free BPA remaining in the cell suspensions. In addition, the toxic potency of bisphenols to hepatocytes and mitochondria depends on the relative elongation and/or molecular size of the hydrocarbon bridge between the phenolic groups.

Adenosine Triphosphate↗
PubMed1984

A new photometric assay for blood alcohol.

The proposed method for ethanol determination is based on the simultaneous oxidation of ethanol and reduction of nitrosodimethylaniline to a quinonediimine derivative in the presence of NAD and horse liver alcohol dehydrogenase. Quinonediimine formed in this reaction is coupled with salicylamide and the absorbance of the resulting blue indaniline dye is measured. The new method yields identical results when compared with the currently used methods for the determination of blood alcohol (i.e., with the conventional enzymatic method, Widmark's method, and gas chromatography). Its main advantage is high sensitivity, little consumption of both enzyme and coenzyme, and the measurement in the visible range of the spectrum.

Alcohol Oxidoreductases↗