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PubMed1980

Vasorelaxant action of caroverine fumarate (a quinoxaline derivative), a calcium-blocking agent.

1 Caroverine fumarate, 1-(2-diethylaminoethyl)-3-(p-methoxy-benzyl)-1,2-dihydro-2-quinoxalinone fumarate, caused a greater inhibition of the pressor response to KCl (8 x 10(-2) M) than that to noradrenaline (10(-6) M) in the rat hindquarter preparation. 2 In the isolated aorta of the rat, caroverine (up to 10(-6) M) markedly suppressed the contraction caused by KCl (4 x 10(-2) M) (high-K) but had little effect on the contractile response to noradrenaline (10(-6) M) whether added before the spasmogen or in its presence. 3 In the high-K-treated aorta, caroverine shifted the concentration-response curve for external calcium to the right, competitively. The negative logarithm of the affinity (pA2) of caroverine was calculated to be approx. 7. 4 Increased 45Ca uptake of the high-K-treated aorta measured by a modified lanthanum method was inhibited by either caroverine (3 x 10(-6) M) or verapamil (10(-6) M). 5 Concentrations of caroverine and verapamil reducing high-K-induced aortic contraction to 50% of its maximum were 2.4 x 10(-7) and 6.6 x 10(-8) M respectively. 6 Following washout the caroverine-induced inhibition of high-K-induced aortic contraction was more rapidly restored than the verapamil-induced inhibition. 7 These results suggest that caroverine fumarate is a specific and readily reversible calcium influx inhibitor in the rat vascular smooth muscle.

Animals↗
PubMed1982

Identification of membrane anchor polypeptides of Escherichia coli fumarate reductase.

Fumarate reductase of Escherichia coli has been shown to be a membrane-bound enzyme composed of a 69,000-dalton catalytic-flavin-containing subunit and a 27,000-dalton nonheme-iron-containing subunit. Using gene cloning and amplification techniques, we have observed two additional polypeptides encoded by the frd operon, with apparent molecular weights of 15,000 and 14,000, which are expressed when E. coli is grown anaerobically on glycerol plus fumarate. Expression of these two small polypeptides is necessary for the two large subunits to associate with the membrane. The four subunits remain associated in Triton X-100 extracts of the membrane, and a holoenzyme form of fumarate reductase containing one copy of each of the four polypeptides has been isolated. Unlike the well-characterized two-subunit form, the holoenzyme is not dependent on anions for activity and is not labile at alkaline pH. In these respects, it more closely resembles the membrane-bound activity.

Cell Membrane↗
PubMed1982

Molecular properties of fumarate reductase isolated from the cytoplasmic membrane of Escherichia coli.

Fumarate reductase, purified from the cytoplasmic membrane of Escherichia coli, has been cross-linked with the bifunctional reagent dimethylsuberimidate and shown to exist as an alpha beta dimer of polypeptides of molecular weights 69,000 and 25,000 in a 1:1 molar ratio. The protein has an s20,w of 7.67S and a D20,w of 6.5 X 10(-7) cm2/s. The purified enzyme contained 4-5 mol of nonheme iron and 4-5 mol of acid labile sulfur while the visible absorption spectrum showed a broad peak between 400 and 470 nm owing to the presence of an Fe-S centre and 8 alpha[N-3]histidyl FAD. Fumarate reductase activity was readily inhibited by the sulfhydryl reagents 5,5'-dithiobis-(2-nitrobenzoic acid), p-chloromercuribenzoate, and iodoacetamide. Using 5,5'-dithiobis-(2-nitrobenzoic acid) sulfhydryl group modification was followed as a function of enzyme activity. A single cysteine residue was shown to be required for activity and this essential sulfhydryl group was located in the 69,000 dalton subunit. The amino acid composition of E. coli fumarate reductase was similar to the succinate dehydrogenases from beef heart mitochondrion and Rhodospirillum rubrum.

Amino Acids↗
PubMed2004

Stability of salt double-fortified with ferrous fumarate and potassium iodate or iodide under storage and distribution conditions in Kenya.

The stability of table salt double-fortified with iron as ferrous fumarate, and with iodine as potassium iodide or potassium iodate, has been investigated under actual field conditions of storage and distribution in the coastal and highland regions of Kenya. Seven 200-g sample packets of double-fortified salt in sealed polyethylene bags and a similar packet containing a datalogger for monitoring temperature and humidity were packaged with 21 sample bags of salt from another study into a bundle, which then entered the distribution network from a salt manufacturer's facility to the consumer. Iodine retention values of up to 90% or more were obtained during the three-month study. Double-fortified salt was prepared using ferrous fumarate microencapsulated with a combination of binders and coloring agents and coated with soy stearine, in combination with either iodated salt or salt iodized with potassium iodide microencapsulated with dextrin and coated with soy stearine. Most of the ferrous iron was retained, with less than 17% being oxidized to the ferric state. The polyethylene film overwrap of salt packs in the bundles provided significant protection from ambient humidity. Salt double-fortified with iodine and microencapsulated iron ferrous fumarate premix was generally quite stable, because both iodine and ferrous iron were protected during distribution and retail in typical tropical conditions in Kenya's highlands and humid lowlands.

Anemia, Iron-Deficiency↗
PubMed2003

Tenofovir disoproxil fumarate.

OBJECTIVE: To review the pharmacology, virology, pharmacokinetics, efficacy, safety, resistance profile, and clinical use of tenofovir disoproxil fumarate. DATA SOURCES: A MEDLINE search was performed (1966-August 2002) using the following terms: tenofovir, tenofovir disoproxil fumarate, PMPA (9-(R)-[2-(phosphonomethoxy)propyl]adenine), and Viread. Abstracts from HIV-related meetings were reviewed. DATA EXTRACTION AND STUDY SELECTION: Publications and meeting abstracts regarding tenofovir were reviewed. The most recent and pertinent items were included. DATA SYNTHESIS: Tenofovir disoproxil fumarate is a nucleotide prodrug that is diphosphorylated to its active moiety, tenofovir diphosphate. In this form, tenofovir acts as a reverse transcriptase inhibitor to inhibit HIV-1 replication. In clinical trials, tenofovir was effective at suppressing HIV-1 RNA and boosting CD4+ cell counts. Tenofovir has a long intracellular half-life, which permits once-daily dosing. Since tenofovir does not interact with the cytochrome P450 pathway, it exhibits minimal drug interactions, with the exception of didanosine. Compared with other reverse transcriptase inhibitors, tenofovir may have advantages in terms of toxicity and medication adherence profiles. Ongoing studies are also analyzing tenofovir's activity against hepatitis B virus. CONCLUSIONS: Tenofovir has been shown to be active against HIV-1 in combination with other antiretrovirals. The drug's benefit as a single-agent intensifier of highly active antiretroviral therapy in treatment-experienced patients has been established, and preliminary data for treatment-naïve patients are encouraging.

Adenine↗
PubMed2002

Potential of fumarate reductase as a novel therapeutic target in Helicobacter pylori infection.

Approximately 50% of the world's population carries Helicobacter pylori, a gastric bacterial pathogen linked to diseases including gastritis, ulcers and gastric cancer. Chemotherapies are being routinely used to treat systemic H. pylori infection. The common regimens consist of proton pump inhibitors (PPIs) or ranitidine bismuth citrate (RBC) and two antibiotics. Although these regimens efficiently eradicate H. pylori, the emergence of antibiotic-resistant H. pylori strains, their severe side effects and high costs are major drawbacks of these treatments. More efficient, economic and friendly drugs need to be developed. Fumarate reductase (FRD) catalyses the reduction of fumarate to succinate in the Krebs cycle and is also a key enzyme in anaerobic respiration with fumarate as the terminal electron acceptor for many facultative bacteria. H. pylori FRD contains three subunits, FrdA, FrdB and FrdC. Genome analysis and experimental evidence indicate that this enzyme appears to play an important role in the energy metabolism of H. pylori. In addition, FRD is essential for the colonisation of H. pylori in the acidic stomach as demonstrated in the mouse model of infection. Furthermore, three FRD inhibitors used to cure helminthic infection in animals and humans have both inhibitory and bactericidal effects on H. pylori. These lines of evidence indicate that FRD may be a promising chemotherapeutic target. Given that FrdA is strongly immunogenic in the sera from H. pylori-positive patients, this protein may also be used as a candidate for the development of an anti-H. pylori vaccine.

Animals↗
PubMed2000

Succinate oxidase and fumarate reductase systems of filarial parasite Setaria digitata.

Activities of succinate oxidase, fumarate reductase (FR) and succinate dehydrogenase (SDH) under a set of defined conditions were determined in the mitochondrial isolate from Setaria digitata, the filarial parasite from the cattle Bos indicus. Presence of only two activities namely SDH and succinate--UQ reductase of the succinate oxidase system could be detected in S. digitata. In the absence of cytochromes, the 3rd enzyme of the complex namely cytochrome oxidase is absent and it is proposed that an alternative oxidase is responsible for completing the succinate oxidation expressed as succinate oxidase activity. Though SDH and FR catalyse reverse reactions, they responded differently to modulators such as oxaloacetate, aspartate, alanine, pyruvate and fumarate. The degree of response of the two activities against inhibitors of electron transport was also different. Interestingly fumarate caused only 50% inhibition of succinate oxidation, while the effect against FR was more convincing.

Animals↗
PubMedDate not supplied

Permeation kinetics of ketotifen fumarate alone and in combination with hydrophobic permeation enhancers through human cadaver epidermis.

Permeation kinetics for ketotifen fumarate from transdermal system through hairless mice skin and hog skin have been reported. However, permeation of ketotifen fumarate through human skin is not available till date. In view of the above, permeation profile and related kinetic parameters of ketotifen fumarate alone and in presence of three compatible enhancers namely Myristic acid isopropyl ester, Palmitic acid propyl ester and Lauric acid propyl ester through normal and delipidized human cadaver have been reported in the present study. The observed permeability flux, permeation coefficient and epidermal partition coefficient through 50% dried human cadaver epidermis were found to increase in presence of the three enhancers, amongst which the effect was found to be maximum with Myristic acid isopropyl ester. The more pronounced enhancing effect of Myristic acid isopropyl ester regarding permeability flux, permeation coefficient, epidermal partition coefficient and diffusion coefficient was attributed with solubility parameter being nearer to the skin lipid solubility parameter and probably due to its passage across the skin barrier through the lipid pathway.

Administration, Topical↗
PubMed2003

Use of microencapsulated iron(II) fumarate sprinkles to prevent recurrence of anaemia in infants and young children at high risk.

OBJECTIVE: To compare the effectiveness of microencapsulated iron(II) fumarate sprinkles (with and without vitamin A), iron(II) sulfate drops, and placebo sprinkles in preventing recurrence of anaemia and to determine the long-term haematological outcomes in children at high risk of recurrence of anaemia 12 months after the end of supplementation. METHODS: A prospective, randomized, placebo-controlled design was used to study 437 Ghanaian children aged 8-20 months who were not anaemic (haemoglobin > or = 100 g/l). Four groups were given microencapsulated iron(II) fumarate sprinkles, microencapsulated iron(II) fumarate sprinkles with vitamin A, iron(II) sulfate drops or placebo sprinkles daily for six months. Primary outcome measures were change in haemoglobin and anaemic status at baseline and study end. Non-anaemic children at the end of the supplementation period were reassessed 12 months after supplementation ended. FINDINGS: Overall, 324 children completed the supplementation period. Among the four groups, no significant changes were seen in mean haemoglobin, ferritin or serum retinol values from baseline to the end of the supplementation period. During the trial, 82.4% (267/324) of children maintained their non-anaemic status. Sprinkles were well accepted without complications. At 12 months post-supplementation, 77.1% (162/210) of children with no intervention remained non-anaemic. This proportion was similar for children among the four groups. CONCLUSION: In most children previously treated for anaemia, further supplementation was not needed to maintain their non-anaemic status. These results may have important implications for community intervention programmes in which initial high-dose treatment is needed because of a high prevalence of anaemia.

Administration, Oral↗
PubMed2004

[Ketotifen fumarate (Zaditen) eye drops in the treatment of seasonal allergic conjunctivitis].

A group of 25 patients with signs of seasonal allergic conjunctivitis treated during the period of 2 to 6 month with ketotifen fumarate 0.05% eye drops 2-3 times daily (Zaditen eye drops, Novartis Ophthalmic, AG, Switzerland) is described here. As subjective symptoms of itching, stinging, tearing, and mucous discharge were observed and evaluated, as well as objective signs of hyperemia of the conjunctiva and hypertrophy of the tarsal papillae. Similarly the onset of action, duration time, and toleration of the drug were assessed. Subjective symptoms disappeared after 10 days of treatment duration in 60% to 80% patients, after two months of treatment were present in the range 0% to 20%. Objective signs diminished after 10 days of treatment in 60%-72% patients, and after 2 months in 72% to 96% of patients. Hypertrophy of papillae of the tarsal conjunctiva did not totally disappear even after 6 month of treatment with ketotifen fumarate eye drops. Onset of action in all patients was 20 minutes or less, the duration of action was in the range of 8-13 hours. The drug was found as a good tolerable by all patients. Sixteen per cent of patients felt some burning following the instillation. The study states that ketotifen fumarate 0.05% eye drops are effective in a monotherapy of seasonal allergic conjunctivitis. Due to its multiple action, the drug prevents the allergic reaction as well. Subjective symptoms are influenced faster and more effective than the objective signs. The treatment of objective signs needs prolonged use of these drops.

Adult↗
PubMedDate not supplied

[Effectiveness and mechanism of action of isoprenaline sulfate and clemastine hydrogen fumarate on histamine wheal-induced pruritus. A placebo-controlled proband study].

In order to investigate the effect of a gel containing isoprenaline and a gel containing clemastine hydrogen fumarate on histamine-induced skin reactions compared with placebo, a histamine solution was injected intradermally in four given fields on the backs of 12 healthy volunteers 15 min and 60 min after application of the gel preparations. The study was controlled by a non-treated field on the volunteers' backs. The main points of interest in this study included the size of the erythema reaction, the capillary blood flow and onset and intensity of itching. With respect to the size of the erythema reaction, both clemastine hydrogen fumarate and isoprenaline proved more effective than placebo in most cases. This superiority was, in some cases, statistically significant. There were no statistically significant differences between the gel preparations for the other parameters investigated. Clemastine hydrogen fumarate is regarded as a classical antihistamine, whereas a possible effect on the superficial circulation of the skin is being discussed for isoprenaline.

Adolescent↗
PubMed1988

Subunit location of the iron-sulfur clusters in fumarate reductase from Escherichia coli.

The subunit location of the [2Fe-2S], [3Fe-4S], and [4Fe-4S] clusters in Escherichia coli fumarate reductase has been investigated by EPR studies of whole cells or whole cells extracts of a fumarate reductase deletion mutant with plasmid amplified expression of discrete fumarate reductase subunits or groups of subunits. The results indicate that both the [2Fe-2S] and [3Fe-4S] clusters are located entirely in the iron-sulfur protein subunit. Information concerning the specific cysteine residues that ligate these clusters has been obtained by investigating the EPR characteristics of cells of the deletion mutant amplified with a plasmid coding for the flavoprotein subunit and a truncated iron-sulfur protein subunit. While the results are not definitive with respect to the location of the [4Fe-4S] cluster, they are most readily interpreted in terms of this cluster being entirely in the flavoprotein subunit or bridging between the two catalytic domain subunits. These new results are discussed in light of the amino acid sequences of the two subunits and the sequences of structurally well characterized iron-sulfur proteins containing [2Fe-2S], [3Fe-4S], and [4Fe-4S] centers.

Amino Acid Sequence↗
PubMed1986

Reconstitution of quinone reduction and characterization of Escherichia coli fumarate reductase activity.

Resolution of the fumarate reductase complex (ABCD) of Escherichia coli into reconstitutively active enzyme (AB) and a detergent preparation containing peptides C and D resulted in loss of quinone reductase activity, but the phenazine methosulfate or fumarate reductase activity of the enzyme was unaffected. An essential role for peptides C and D in quinone reduction was confirmed by restoration of this activity on recombination of the respective preparations. Neither peptide C nor peptide D by itself proved capable of permitting quinone reduction and membrane binding by the enzyme when E. coli cells were transformed with plasmids coding for the enzyme and the particular peptides. Transformation of a plasmid coding for all subunits resulted in a 30-fold increase in membrane-bound complex, which exhibited, however, turnover numbers for succinate oxidation and fumarate reduction that were intermediate between the high values characteristic of chromosomally produced complex and the relatively low values found for the isolated complex. It is also shown that preparations of the isolated complex and membrane-bound form of the enzyme, as obtained from anaerobically grown cells, are in the deactivated state owing to the presence of tightly bound oxalacetate and thus must be activated prior to assay.

Aerobiosis↗
PubMed1984

Structural features required for the reactivity and intracellular transport of bis(3,5-dibromosalicyl)fumarate and related anti-sickling compounds that modify hemoglobin S at the 2,3-diphosphoglycerate binding site.

Bis(3,5-dibromosalicyl)fumarate (I) reacts preferentially with oxyhemoglobin to cross-link the two beta 82 lysine residues within the 2,3-diphosphoglycerate (DPG) binding site and as a result markedly increases the solubility of deoxyhemoglobin S. The cross-link acts by perturbing the acceptor site for Val 6 within the sickle cell fiber (Chatterjee, R., Walder, R. Y., Arnone, A., and Walder, J. A. (1982) Biochemistry 21, 5901-5909). In the present studies we have compared a large number of analogs of I to determine the structural features of the reagent required for specificity and for transport into the red cell. Both electrostatic and hydrophobic interactions contribute to the binding of these compounds at the DPG site. The optimal position for the negatively charged groups on the cross-linking agent for productive binding is adjacent to the ester as in the original salicylic acid derivatives. There is a direct correlation between the reactivity toward hemoglobin and the hydrophobicity of the substituent attached at the para position. Phenyl and substituted phenyl derivatives as in the analgesic, antiinflammatory drug diflunisal are particularly effective. These groups probably interact with hydrophobic residues of the amino-terminal tripeptide and the EF corner of the beta chains adjacent to the DPG binding site. Although bis(3,5-dibromosalicyl)fumarate is very reactive toward hemoglobin in solution, it is much less effective in modifying hemoglobin within the red cell. The reaction with intracellular hemoglobin was shown to be limited by competing hydrolysis of the reagent catalyzed at the outer surface of the erythrocyte membrane. Inactivation of the red cell membrane acetylcholinesterase with phenylmethylsulfonyl fluoride did not inhibit this reaction. Introduction of a single methyl group onto the carbon-carbon double bond of the fumaryl moiety decreases the lability of the ester 10-fold, due to steric effects, and allows the reagent to be taken up by the red cell and modify intracellular hemoglobin. The kinetics of transport of the methylfumarate derivative, bis(3,5-dibromosalicyl)mesaconate, are first-order, consistent with passive diffusion. The attachment of larger alkyl groups onto the cross-link bridge further enhances the transport of the reagent into the red cell. The solubility of deoxyhemoglobin S cross-linked with the butylfumarate derivative was found to be increased by almost 10% compared to the original fumarate diester.(ABSTRACT TRUNCATED AT 400 WORDS)

2,3-Diphosphoglycerate↗
PubMed1985

Thermodynamics of the conversion of fumarate to L-(-)-malate.

The thermodynamics of the conversion of aqueous fumarate to L-(-)-malate has been investigated using both heat conduction microcalorimetry and a gas chromatographic method for determining equilibrium constants. The reaction was carried out in aqueous Tris-HCl buffer over the pH range 6.3-8.0, the temperature range 25-47 degrees C, and at ionic strengths varying from 0.0005 to 0.62 mol kg-1. Measured enthalpies and equilibrium ratios have been adjusted to zero ionic strength and corrected for ionization effects to obtain the following standard state values for the conversion of aqueous fumarate 2- to malate 2- at 25 degrees C: K = 4.20 +/- 0.05, delta G degrees = -3557 +/- 30 J mol-1, delta H degrees = -15670 +/- 150 J mol-1, and delta C degrees p = -36 +/- J mol-1 K-1. Equations are given which allow one to calculate the combined effects of pH and temperature on equilibrium constants and enthalpies of this reaction.

Animals↗
PubMed1992

Variability of clinical presentation in fumarate hydratase deficiency.

A 5-year-old girl with a previous diagnosis of cerebral palsy, nonprogressive psychomotor retardation, and hypotonia was found to excrete excessive fumaric acid in urine. Fumarate hydratase activity in skin fibroblasts was 10% of the control value. This case underscores the clinical heterogeneity of neurometabolic disorders and the importance of organic acid analysis in the diagnosis of static encephalopathy.

Cerebral Palsy↗
PubMedDate not supplied

Conversion of fumaric acid to L-malic by sol-gel immobilized Saccharomyces cerevisiae in a supported liquid membrane bioreactor.

Conversion of fumaric acid (FA) to L-malic acid (LMA) was carried out in a bioreactor divided by two supported liquid membranes (SLMs) into three compartments: Feed, Reaction, and Product. The Feed/Reaction SLM, made of tri-n-octylphosphine oxide (vol 10%) in ethyl acetate, was selective toward the substrate, fumaric acid (S(FA/LMA) = 10). The Reaction/Product SLM, made of di(2-ethylhexyl) phosphate (vol 10%) in dichloromethane, was selective toward the product, L-malic acid (S(LMA/FA) = 680). Immobilized yeast engineered to overproduce the enzyme fumarase [E.C. 4.2.1.2] was placed in the Reaction compartment and served as the catalyst. The yeast was immobilized in small glasslike beads of alginate-silicate sol-gel matrix. The construction of the bioreactor ensured unidirectional flow of the substrate from the Feed to the Reaction and of the product from the Reaction to the Product compartments, with the inorganic counterion traveling in the opposite direction. The conversion of almost 100%, above the equilibrium value of ca. 84% and higher than that for the industrial process, 70%, was achieved. In contrast to the existing industrial biocatalytic process resulting in L-malic acid salts, direct production of the free acid is described.

Bioreactors↗
PubMed2005

Improvement of herpetic stromal keratitis with fumaric acid derivate is associated with systemic induction of T helper 2 cytokines.

Fumaric acid derivates have been shown to stimulate T helper-2-cytokines (interleukin (IL)-4, -5) without affecting the T-helper-1-cytokine (IL-2, interferon (IFN)-gamma)-response. Herein, the influence of systemic treatment with the fumaric acid derivate dimethylfumarate (DMF) on the secretion of T helper-cytokines and the development of HSV-1 stromal keratitis (HSK) was studied in mice. The corneas from BALB/c mice were infected with 10(5) PFU of HSV-1 (KOS strain). While one group of mice was treated intraperitoneally with PBS, another group of mice received DMF at 15 mg/kg of body weight. Expression of IL-2, -4, -10 and IFN-gamma was analysed in HSV-1 activated lymphocytes by ELISA. The severity of epithelial and stromal herpetic keratitis was investigated clinically. Corneas were studied for the inflammatory cell infiltration, and the CD3-, CD4- and CD8-positive cells were analysed by immunohistochemistry. The IL-2, -4, 10 and IFN-gamma content was measured in the corneas. Virus replication in the eyes was analysed by a plaque-assay. The DTH-response, the HSV-specific T cell proliferation and the serum neutralizing antibody-titres were investigated. DMF increased IL-4 and IL-10, but not IL-2 and IFN-gamma, secretion in activated lymphocytes from the spleen. Incidence and severity of stromal HSV-1 keratitis was reduced in the DMF group (P < 0.01). In the corneas from DMF-treated mice, the numbers of CD3+ and CD4+ cells were decreased and IL-4 was increased. Severity of epithelial disease and the virus-clearance from the eyes did not differ between the PBS and DMF group of mice. DTH, HSV-specific T cell proliferation and the neutralizing antibody-titres were not impaired. DMF increased the T helper-2-cytokine secretion in activated lymphocytes. After corneal HSV-1 infection, corneas from DMF treated mice had increased IL-4 content. This is associated with an improvement of herpetic stromal keratitis and reduced corneal T cell infiltration. DMF did not impair the systemic antiviral response.

Animals↗