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PubMed1987

Linogliride fumarate, representing a new class of oral hypoglycemic agent for diabetes.

This study presents the first multiday therapy trial of linogliride fumarate, a representative of a new class of oral hypoglycemic agents. Linogliride demonstrated a significant hypoglycemic activity in 26 patients with non-insulin-dependent diabetes mellitus receiving 1 week of therapy. In a dose range of 150 to 400 mg b.i.d., fasting glucose levels fell from 237 +/- 52 mg to 199 +/- 59 mg by day 7 (P less than 0.01). Eight-hour glucose AUCs fell from 2121 +/- 617 mg/dl/8 hr baseline to 1781 +/- 631 mg/dl/8 hr on day 7 of treatment (P less than 0.01). This was associated with a significant increase in insulin AUC from 380 +/- 327 to 610 +/- 417 on day 7 (P less than 0.01). Thus its initial action appears to be by an insulin secretagogue mechanism. No patient had any major adverse effect. This initial study indicates that linogliride fumarate is an effective hypoglycemic agent that significantly lowers fasting and postprandial glucose levels with short-term use. Linogliride fumarate represents a new group of hypoglycemic agents that may be shown to have therapeutic utility.

Administration, Oral↗

PubMed1994

The hemodynamic actions of the antiarrhythmic agent ipazilide fumarate in patients with congestive heart failure.

Ipazilide fumarate is an investigational antiarrhythmic agent with Vaughan Williams class I and III actions, including prolongation of both ventricular refractoriness and action potential duration. Because of the frequent use of antiarrhythmic agents in patients with heart failure, we investigated the hemodynamic effects of oral administration of 400, 200, and 100 mg of ipazilide fumarate in 15 patients with congestive heart failure. There was a marked hemodynamic response to ipazilide, with the peak effect noted 2 hours after drug administration. In patients who received 400 mg ipazilide, the mean cardiac index was decreased by 0.5 L/min/m2 at 2 hours (p < 0.05). After 200 and 100 mg ipazilide, the decreases were a more modest 0.3 and 0.1 L/min/m2, respectively. The mean arterial pressure also decreased in a dose- and time-dependent manner, although this did not reach statistical significance for any of the doses. Left ventricular filling pressure, right atrial pressure, and heart rate were not altered by ipazilide. Plasma concentrations of ipazilide peaked 90 minutes after administration of 100 or 200 of the drug, but peak concentrations were noted 3 hours after administration of 400 mg. The hemodynamic response correlated with the plasma concentration of ipazilide determined contemporaneously. We conclude that, as with most antiarrhythmic agents, single-dose administration of ipazilide fumarate can cause clinically significant hemodynamic deterioration.

Administration, Oral↗

PubMed1981

The effects of anions on fumarate reductase isolated from the cytoplasmic membrane of Escherichia coli.

A broad range of anions was shown to stimulate the maximal velocity of purified fumarate reductase isolated from the cytoplasmic membrane of Escherichia coli, while leaving the Km for fumarate unaffected. Reducing agents potentiate the effects of anions on the activity, but have no effect by themselves. Thermal stability, conformation as monitored by circular dichroism and susceptibility to the thiol reagent 5,5'-dithiobis-(2-nitrobenzoic acid) are also altered by anions. The apparent Km for succinate in the reverse reaction (succinate dehydrogenase activity) varies as a function of anion concentration, but the maximal velocity is not affected. The membrane-bound activity is not stimulated by anions and its properties closely resemble those of the purified enzyme in the presence of anions. Thus it appears that anions alter the physical and chemical properties of fumarate reductase, so that it more closely resembles the membrane-bound form.

Anions↗

PubMed2002

The membrane-bound tetrahaem c-type cytochrome CymA interacts directly with the soluble fumarate reductase in Shewanella.

Shewanella spp. demonstrate great variability in the use of terminal electron acceptors in anaerobic respiration; these include nitrate, fumarate, DMSO, trimethylamine oxide, sulphur compounds and metal oxides. These pathways open up possible applications in bioremediation. The wide variety of respiratory substrates for Shewanella is correlated with the evolution of several multi-haem membrane-bound, periplasmic and outer-membrane c-type cytochromes. The 21 kDa c-type cytochrome CymA of the freshwater strain Shewanella oneidensis MR-1 has an N-terminal membrane anchor and a globular tetrahaem periplasmic domain. According to sequence alignments, CymA is a member of the NapC/NirT family. This family of redox proteins is responsible for electron transfer from the quinone pool to periplasmic and outer-membrane-bound reductases. Prior investigations have shown that the absence of CymA results in loss of the ability to respire with Fe(III), fumarate and nitrate, indicating that CymA is involved in electron transfer to several terminal reductases. Here we describe the expression, purification and characterization of a soluble, truncated CymA ('CymA). Potentiometric studies suggest that there are two pairs of haems with potentials of -175 and -261 mV and that 'CymA is an efficient electron donor for the soluble fumarate reductase, flavocytochrome c(3).

Binding Sites↗

PubMed2002

Crystallographic studies of the Escherichia coli quinol-fumarate reductase with inhibitors bound to the quinol-binding site.

The quinol-fumarate reductase (QFR) respiratory complex of Escherichia coli is a four-subunit integral-membrane complex that catalyzes the final step of anaerobic respiration when fumarate is the terminal electron acceptor. The membrane-soluble redox-active molecule menaquinol (MQH(2)) transfers electrons to QFR by binding directly to the membrane-spanning region. The crystal structure of QFR contains two quinone species, presumably MQH(2), bound to the transmembrane-spanning region. The binding sites for the two quinone molecules are termed Q(P) and Q(D), indicating their positions proximal (Q(P)) or distal (Q(D)) to the site of fumarate reduction in the hydrophilic flavoprotein and iron-sulfur protein subunits. It has not been established whether both of these sites are mechanistically significant. Co-crystallization studies of the E. coli QFR with the known quinol-binding site inhibitors 2-heptyl-4-hydroxyquinoline-N-oxide and 2-[1-(p-chlorophenyl)ethyl] 4,6-dinitrophenol establish that both inhibitors block the binding of MQH(2) at the Q(P) site. In the structures with the inhibitor bound at Q(P), no density is observed at Q(D), which suggests that the occupancy of this site can vary and argues against a structurally obligatory role for quinol binding to Q(D). A comparison of the Q(P) site of the E. coli enzyme with quinone-binding sites in other respiratory enzymes shows that an acidic residue is structurally conserved. This acidic residue, Glu-C29, in the E. coli enzyme may act as a proton shuttle from the quinol during enzyme turnover.

Amino Acid Sequence↗

PubMed2006

Differences in protonation of ubiquinone and menaquinone in fumarate reductase from Escherichia coli.

Escherichia coli quinol-fumarate reductase operates with both natural quinones, ubiquinone (UQ) and menaquinone (MQ), at a single quinone binding site. We have utilized a combination of mutagenesis, kinetic, EPR, and Fourier transform infrared methods to study the role of two residues, Lys-B228 and Glu-C29, at the quinol-fumarate reductase quinone binding site in reactions with MQ and UQ. The data demonstrate that Lys-B228 provides a strong hydrogen bond to MQ and is essential for reactions with both quinone types. Substitution of Glu-C29 with Leu and Phe caused a dramatic decrease in enzymatic reactions with MQ in agreement with previous studies, however, the succinate-UQ reductase reaction remains unaffected. Elimination of a negative charge in Glu-C29 mutant enzymes resulted in significantly increased stabilization of both UQ-* and MQ-* semiquinones. The data presented here suggest similar hydrogen bonding of the C1 carbonyl of both MQ and UQ, whereas there is different hydrogen bonding for their C4 carbonyls. The differences are shown by a single point mutation of Glu-C29, which transforms the enzyme from one that is predominantly a menaquinol-fumarate reductase to one that is essentially only functional as a succinate-ubiquinone reductase. These findings represent an example of how enzymes that are designed to accommodate either UQ or MQ at a single Q binding site may nevertheless develop sufficient plasticity at the binding pocket to react differently with MQ and UQ.

Binding Sites↗

PubMed2006

A proton delivery pathway in the soluble fumarate reductase from Shewanella frigidimarina.

The mechanism for fumarate reduction by the soluble fumarate reductase from Shewanella frigidimarina involves hydride transfer from FAD and proton transfer from the active-site acid, Arg-402. It has been proposed that Arg-402 forms part of a proton transfer pathway that also involves Glu-378 and Arg-381 but, unusually, does not involve any bound water molecules. To gain further insight into the importance of this proton pathway we have perturbed it by substituting Arg-381 by lysine and methionine and Glu-378 by aspartate. Although all the mutant enzymes retain measurable activities, there are orders-of-magnitude decreases in their k(cat) values compared with the wild-type enzyme. Solvent kinetic isotope effects show that proton transfer is rate-limiting in the wild-type and mutant enzymes. Proton inventories indicate that the proton pathway involves multiple exchangeable groups. Fast scan protein-film voltammetric studies on wild-type and R381K enzymes show that the proton transfer pathway delivers one proton per catalytic cycle and is not required for transporting the other proton, which transfers as a hydride from the reduced, protonated FAD. The crystal structures of E378D and R381M mutant enzymes have been determined to 1.7 and 2.1 A resolution, respectively. They allow an examination of the structural changes that disturb proton transport. Taken together, the results indicate that Arg-381, Glu-378, and Arg-402 form a proton pathway that is completely conserved throughout the fumarate reductase/succinate dehydrogenase family of enzymes.

Amino Acids↗

PubMed1991

Ferrous fumarate fortification of a chocolate drink powder.

An evaluation was made into the usefulness of ferrous fumarate as an iron fortificant for an experimental chocolate drink powder targetted to children and adolescents. Organoleptically ferrous furmarate was acceptable when the chocolate drink powder was reconstituted in milk or water that was heated to less than 80 degrees. Unacceptable colour changes occurred, however, when boiling milk or water were used. In human Fe absorption studies when the Fe compounds were added to the chocolate drink immediately before consumption, ferrous fumarate was 3.31% absorbed compared with 2.82% for ferrous sulphate and 2.11% for ferric pyrophosphate. When the Fe compounds were processed during the manufacture of the chocolate drink powder, the absorption of ferrous furmarate was 5.27%, ferrous sulphate 2.62% and ferric pyrophosphate 0.55%. Ascorbic acid had little or no effect on the absorption of ferrous furmarate. It is concluded that food processing can influence the relative absorption of fortification Fe and that, if not reconstituted with boiling milk or water, ferrous fumarate could be a useful compound for the fortification of chocolate drink powders.

Adolescent↗

PubMed2003

Ferrous fumarate deteriorated plasma antioxidant status in patients with Crohn disease.

BACKGROUND: Iron deficiency anaemia is a frequent complication of Crohn disease. Treatment with ferrous iron (Fe2-) compounds is often unsatisfactory and is associated with gastrointestinal side effects. Theoretically, oral iron supplementation may even be harmful, because iron may reinforce intestinal inflammation by catalysing production of reactive oxygen species. We investigated the effect of ferrous iron on disease activity and plasma antioxidant status in patients with active Crohn disease. METHODS: Ten patients with Crohn disease and iron deficiency and 10 healthy controls were given ferrous fumarate 120 mg for 7 days. The Crohn Disease Activity Index, gastrointestinal complaints and blood samples for antioxidant status, anaemia, inflammation and iron absorption were investigated on day 1 and day 8. RESULTS: During 1 week of ferrous fumarate supplementation, the Crohn Disease Activity Index tended to increase (P = 0.071). Patients experienced aggravation of diarrhoea, abdominal pain and nausea. Plasma-reduced cysteine was lower (P = 0.038) in patients than it was in controls. One week of ferrous iron supplementation further decreased reduced cysteine (P < 0.001) and significantly decreased plasma-reduced glutathione (P = 0.004) in the patients. Serum iron increased significantly in patients after an oral iron load test (from 5.8 +/- 3.2 micromol/L to 30.9 +/- 13.1 micromol/L). CONCLUSIONS: Treatment of iron deficiency with ferrous fumarate deteriorated plasma antioxidant status and increased specific clinical symptoms in patients with active Crohn disease. Plasma reduced cysteine may be a sensitive indicator for oxidative stress in the intestine.

Adult↗

PubMed2005

Effect of ketotifen fumarate, olopatadine, and levocabastine on ocular active anaphylaxis in the guinea pig and ocular immediate hypersensitivity in the albino rat.

PURPOSE: To study the effects of ketotifen fumarate, olopatadine, and levocabastine on ocular active anaphylaxis in guinea pigs and on ocular immediate hypersensitivity in albino rats. METHODS: Clinical grading scores and Evans blue dye leakage to eyelids and to eyeballs were assessed in five treatment groups (n = 10): ketotifen fumarate 0.025%, olopatadine 0.1%, levocabastine 0.05%, negative control, and positive control. RESULTS: At 20 minutes after challenge, edema scores for ketotifen-treated guinea pigs were statistically significantly lower than those for levocabastine or olopatadine. Active treatment significantly reduced vascular leakage in both models. Ketotifen significantly reduced vascular leakage in eyelids compared with the other drugs. In guinea pigs, vascular leakage in eyeballs was significantly reduced with ketotifen fumarate compared with olopatadine and levocabastine. CONCLUSIONS: In the guinea pig model, ketotifen was more effective than olopatadine and levocabastine at reducing conjunctival edema and vascular permeability in eyelids and eyeballs. In the rat model, ketotifen was more effective at reducing vascular permeability in eyelids than olopatadine and levocabastine.

Anaphylaxis↗

PubMed1989

Iron fortification of infant cereals: a proposal for the use of ferrous fumarate or ferrous succinate.

Hemoglobin-repletion tests in rats, organoleptic studies, and iron-absorption studies in humans were used to search for Fe sources with high bioavailability that could be added to infant cereals as alternatives to the Fe compounds currently used for fortification. From rat and organoleptic studies on 11 alternative Fe sources, ferrous fumarate, ferrous succinate, and ferric saccharate were selected as the most suitable for infant-cereal fortification and, by use of radioactive labels, absorption of those compounds from fortified cereal was measured in adult human volunteers. There was no difference in absorption between ferrous fumarate and ferrous sulfate whereas the values for ferrous succinate, ferrous saccharate (10% Fe), and ferric pyrophosphate were 92%, 74%, and 39% of the ferrous sulfate values, respectively. We conclude that ferrous fumarate and ferrous succinate are highly available Fe sources in man that can be used to fortify infant cereals without causing fat oxidation or discoloration.

Absorption↗

PubMed2002

Ketotifen fumarate treatment of superior limbic keratoconjunctivitis.

PURPOSE: To report the effect of topically applied ketotifen fumarate in the treatment of superior limbic keratoconjunctivitis (SLK). METHODS: Five patients with clinical findings of bilateral SLK with no relief of symptoms with standard reported modalities of treatment were treated with topical ketotifen fumarate twice daily in both eyes. All patients were evaluated 2 to 4 weeks after initiation of treatment of symptomatic and clinical improvement and at regular intervals thereafter. RESULTS: Topical ketotifen provided immediate relief of ocular symptoms in all patients. In one patient, the response was long lasting, whereas in the other four, it was temporary, lasting 1 to 3 months. The objective signs, however, did not necessarily correlate with the subjective improvement. CONCLUSIONS: Ketotifen fumarate can be effective at least in the short to medium term in the management of SLK. Although the mechanism of action of ketotifen remains unclear, this preliminary experience further supports the use of agents with mast cell-stabilizing activity in the treatment of SLK.

Administration, Topical↗

PubMed2003

A novel cobalt(II) coordination polymer containing the fumarate anion and o-phenanthroline.

The self-assembly of three crystallographically distinct fumarate ions, two unique cobalt(II) ions and two unique o-phenanthroline molecules results in a two-dimensional polymeric structure with the formula [Co(2)(C(4)H(2)O(4))(2)(C(12)H(8)N(2))(2)](n), namely di-mu-fumatato-bis(o-phenanthroline)dicobalt(II). The Co atoms are at the nodes of a two-dimensional array linked by coordinated fumarate ligands. Each Co atom is coordinated in a distorted octahedral manner to four fumarate O atoms and two N atoms from the chelating phenanthroline ligands.

Journal Article↗

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↗