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PubMed2005

Systemic and renal pharmacokinetics of adefovir and tenofovir upon coadministration.

Adefovir and tenofovir are nucleotide analogs that undergo renal secretion by the human renal organic anion transporter. The pharmacokinetics of tenofovir and adefovir following the administration of tenofovir disoproxil fumarate and adefovir dipivoxil alone and together were determined in 24 healthy subjects in an 8-day, open-label, fixed-sequence study. Subjects received oral doses of adefovir dipivoxil on days 1 and 8 and oral doses of tenofovir disoproxil fumarate on days 2 to 8. Pharmacokinetic sampling was performed on days 1, 7, and 8. The plasma pharmacokinetics of tenofovir and adefovir were unaltered upon coadministration. Furthermore, the renal clearances (CLrenal) of tenofovir and adefovir were unaffected by their coadministration. The plasma Cmax values of tenofovir and adefovir were 33-fold and 340-fold lower than their Km values for the human renal organic anion transporter. These results demonstrate that coadministration of tenofovir disoproxil fumarate and adefovir dipivoxil does not result in substantial changes to their individual pharmacokinetic profiles.

Adenine↗
PubMed2003

The effect of ketotifen on inflammatory markers in allergic conjunctivitis: an open, uncontrolled study.

BACKGROUND: The efficacy and safety of ketotifen eye drop treatment in allergic conjunctivitis (AC) management is perfectly known by several studies, but the mechanism of action at the biochemical levels is poorly understood so we decided to perform an open, uncontrolled study in order to investigate the effect of the topical administration of ketotifen fumarate 0.05% on biochemical markers of inflammation on conjunctival cells in patients with AC. METHODS: Nineteen patients with symptoms and signs of AC (itching, discharge, burning, redness, increase in the watery discharge, swelling and follicles) and with a history of allergy were prescribed with two daily instillation of one drop of eyewash ketotifen fumarate 0,05% in both eyes during thirty days. They were studied by measuring clinical and immunologic parameters. RESULTS: Ketotifen fumarate treatment significantly reduced the total symptoms and signs score for each patient as well as each symptoms and signs at all time points compared with day 0 (p < 0.0001 and p < 0.016, respectively). Although the percentage of HLA-DR+ epithelial cells diminished only in 58% of patients, the numbers of CD29+ and eotaxin+ epithelial cells dropped significantly in 68% and 73 % of them (p < 0.0062 and <0.0082, respectively) as a consequence of the treatment. In 9 out of 19 patients a simultaneous decrease in the percentage of epithelial cells positive for CD29 and eotaxin was observed. CONCLUSION: Ketotifen besides the well-known effect in reducing signs and symptoms of AC significantly diminished production of eotaxin and expression of CD29 by epithelial cells in patients with seasonal AC.

Administration, Topical↗
PubMed1999

Electrophysiological effects of newly synthesized 1,4-pyridothiazepines on various guinea pig heart muscle preparations.

Slow channel blockers play a major role in the treatment of cardiovascular disease. The intention of this study was to investigate the electrophysiological properties of MM 4 (1-[N-[2-(3,4-dimethoxy-phenyl)ethyl]-N-methylaminoacetyl]-1,2,3,4 -tetrahydropyrido[2,3-b][1,4]thiazepine fumarate) and MM 6 (1-[N-[2-(3,4-dimethoxy-phenyl)ethyl]-N-methylaminopropionyl]-1,2, 3,4-tetrahydropyrido[2,3-b][1,4]thiazepine fumarate), two newly synthesized compounds structurally related to KT-362 (5-[3-[[2-(3,4-dimethoxy-phenyl)ethyl]-amino]-1-oxopropyl]-2,3,4,5-tetra -hydro-1,5-benzothiazepine fumarate), by means of the conventional intracellular microelectrode technique. In various guinea pig heart muscle preparations, MM 4 and MM 6 exerted very similar effects though the action of MM 6 was more pronounced. In a concentration range from 3 to 100 micromol/l the compounds did not produce any significant change in transmembrane action potential parameters of papillary muscle and left atria, whereas the action potential duration at 20% and 50% time to repolarization in spontaneously beating Purkinje fibers was significantly shortened. In sinoatrial nodes action potential amplitude, Vmax, rate of activity and slope of slow diastolic depolarization were decreased, whereas the time to 50% and 90% repolarization was significantly prolonged. A decrease in the slow calcium inward current may account for the observed effects. In contrast to KT-362, MM 4 and MM 6 do not seem to affect the fast sodium inward current. It was concluded that replacement of the 1,5-benzothiazepine nucleus by a 1,4-pyridothiazepine structure and/or methylation of the side chain may weaken or even eliminate sodium channel blocking ability while calcium antagonistic characteristics are preserved. Shortening of the side chain might result in a general loss of activity.

Action Potentials↗
PubMed2004

Effects of novel synthesized pyridothiazines on various guinea pig heart muscle preparations.

Calcium channel blockers have become important tools in the treatment of cardiovascular disorders and other diseases. Hybridization of well established calcium antagonist subclasses was an attempt to optimize their pharmacological profile. The intension of this study was to investigate the electrophysiological properties of MM 10 and MM 11 two newly synthesized compounds structurally closely related to KT-362 (5-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-1-oxopropyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine fumarate) in various isolated guinea pig heart muscle preparations by means of the conventional intracellular microelectrode tech-nique. MM 10 (2,3-dihydro-1-[N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylaminoacetyl]-1H-pyrido[2,3-b][1,4]thiazine fumarate) and MM 11 (2,3-dihydro-1-[N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylaminopropionyl]-1H-pyrido[2,3-b][1,4]thiazine fumarate) exerted very similar effects though the action of MM 11 was more pronounced. Whereas action potential amplitude and maximum upstroke velocity (V(max)) in papillary muscle, left atria and spontaneously beating Purkinje fibers was not affected by the compounds in a concentration range from 3 to 30 micromol/l, action potential duration at 90% time to repolarization was significantly prolonged in a concentration-dependent manner. Action potential duration at 20% time to repolarization was decreased in spontaneously beating Purkinje fibers and remained unchanged in papillary muscles and left atria. In sinoatrial nodes both compounds reduced rate of activity, action potential amplitude, maximum upstroke velocity and slope of slow diastolic depolarization while time to repolarization was prolonged. In 3 out of 6 experiments with spontaneously beating Purkinje fibers, MM 11 (30 micromol/l) led to the occurrence of early afterdepolarizations with a take off potential between -50 and -60 mV. All observed effects were completely reversible during washout with drug-free physiological salt solution. From these results it was concluded that both compounds in addition to their calcium antagonistic properties might depress repolarizing potassium currents. In contrast to the mother compound KT-362 they do not seem to affect the fast sodium inward current. Replacement of the benzothiazepine nucleus by a pyridothiazine structure may weaken or even eliminate sodium channel blocking ability. Shortening of the side chain might result in a general loss in activity.

Action Potentials↗
PubMed1982

On the kinetics and mechanism of enoate reductase.

Enoate reductases from Clostridium spec. La 1 and Clostridium kluyveri show a rather broad substrate specificity i.e. many alpha,beta-unsaturated carboxylates are reduced in a NADH-dependent reaction. The relative rates for different substrates are different for both reductases. The Km value of NADH for the reductase from C. spec. La 1 is about 12 muM. The transhydrogenase activity (reduction of N-acetylpyridine adenine dinucleotide) with NADH shows a maximum at pH 8 which is about 2 units higher than that for the reduction of enoates. Results of initial rate studies can be best explained by a Bi Bi ping pong mechanism. No back reaction and no proton exchange from 2(-3)H-labelled acylates could be demonstrated. NAD+ is a mixed-type inhibitor. The product inhibition constant Ki = 0.84mM and the dissociation constant for the dead-end inhibition complex 4.8mM. Aliphatic acylates show no measurable inhibition when they are applied in concentrations at the 100-fold Km values of the corresponding enoates. Measurable inhibitions can be observed with phenyl group-containing acylates. 3-Phenylpropionate (38mM) shows about 86% inhibition. Fumarate which is not a substrate inhibits the reduction of enoates by NADH as well as by reduced methylviologen. However, the reduction of NAD+ by reduced methylviologen as well that of acetylpyridine adenine dinucleotide by NADH is not inhibited by fumarate. On the other hand inhibitors such as morin or dicoumarol which probably bind to the flavin domain do not impair the reduction of enoates by reduced methylviologen however, all reductions with NADH are inhibited. These results are indicative for three binding domains: one for NADH which can be blocked by dicoumarol or morin, another for enoates which can be occupied by fumarate and a third one for reduced methylviologen. Enoate reductase splits off exclusively the (4S)-hydrogen atom from NADH. There is no direct hydrogen transfer from NADH to the products. Depending on the substrate concentration the isotope effect of the reduction of (E)-2-methyl-2-butenoate with (4S)-[4(-3)H]NADH varies from 6.8 to 1.3. The presence of NAD+ decreases the isotope effect.

Aerobiosis↗
PubMed2006

Growth of Campylobacter in media supplemented with organic acids.

The growth of Campylobacter spp. in media supplemented with organic acids was examined. A Bioscreen C Microbiology Reader was used to measure growth of cultures incubated at 37 degrees C for 48 h in a tryptose-yeast extract basal broth medium and in basal broth supplemented with 10, 20, 30, 40, or 50 mM citric, fumaric, lactic, malic, or succinic acid. Growth of three of six isolates was significantly greater (P < or = 0.05) in media supplemented with 20 to 50 mM citric acid than in nonsupplemented media, growth of five of six isolates was significantly greater in media supplemented with 10 to 50 mM succinic acid than in nonsupplemented media, and growth of six of six isolates was significantly greater in media supplemented with 10 to 50 mM fumaric or malic acid or with 20 to 50 mM lactic acid than in nonsupplemented media. Isolates were also cultured in basal media supplemented with a mixture of 10, 20, 30, 40, or 50 mM fumaric, malic, lactic, and succinic acids. Results indicated that the growth of all Campylobacter isolates was significantly greater in media supplemented with mixtures containing each of these organic acids at 10 to 40 mM than in nonsupplemented media. These findings indicate that in vitro growth of Campylobacter spp. may be significantly enhancedin media supplemented with organic acids that support the growth of these bacteria.

Acids↗
PubMedDate not supplied

Effect of dose and formulation on iron tolerance in pregnancy.

BACKGROUND: The National Nutritional Anaemia Prophylaxis Programme (NNAPP) in India was launched in 1971. However, anaemia continues to be a major public health problem. Partial coverage of the population, inadequate dose of the iron supplement, defective absorption due to intestinal infestations and problems with formulation have been recognized as factors responsible for its failure. Therefore, the bioavailability of iron from different formulations containing 60 mg of elemental iron and of tablets with varying doses of elemental iron was undertaken. METHODS: One hundred and fifteen women were randomly allotted to receive different formulations and doses of iron and then undergo iron tolerance tests. They received ferrous sulphate tablets containing 60 mg, 120 mg and 180 mg of elemental iron; formulations containing 60 mg of elemental iron as pure ferrous sulphate salt, ferrous fumarate tablets, ferrous fumarate syrup, excipients added to pure ferrous sulphate salts, powdered ferrous sulphate tablets, iron tablets distributed by the NNAPP and pure ferrous salt in gelatin capsules. RESULTS: The data obtained from 32 subjects were excluded because of non-compliance, intolerance of the medication and lack of results of blood tests. Data from the remaining 83 subjects indicated that increasing the dose of elemental iron from 60 mg to 180 mg improved the bioavailability of iron, but was associated with unacceptable side-effects. Also, liquid formulations of iron had a better bioavailability, with ferrous fumarate syrup and gelatin capsules being the most superior. CONCLUSION: Providing the iron formulation with a high bioavailability should enable the NNAPP to be more successful in decreasing the prevalence of anaemia.

Anemia↗
PubMed2003

Comparison of intestinal absorption of selected calcium organic salts through the rat jejunum in vitro.

The calcium penetration rates through the rat's ileum were determined for calcium fumarate, calcium gluconate and calcium chloride in solution by means of a set for determination of drug penetration through membranes. The highest penetration rate of calcium was observed for the calcium fumarate solutions, a lower one for calcium gluconate solutions and the lowest--for calcium chloride solutions. The calcium penetration rate was independent from the calcium doses in the studied concentration range. The obtained results suggest that calcium fumarate, till now not used in therapy might find an application in the corrective therapy of calcium deficiency.

Animals↗
PubMedDate not supplied

Gateways to clinical trials.

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs:(R)-Flurbiprofen, 90Yttrium-DOTA-huJ591; ABT-510, ACP-103, Ad5-FGF4, adalimumab, ademetionine, AG-7352, alemtuzumab, Amb a 1 ISS-DNA, anakinra, apaziquone, aprepitant, aripiprazole, atazanavir sulfate; BAL-8557, bevacizumab, BMS-188797, bortezomib, bosentan, brivudine; Calcipotriol/betamethasone dipropionate, cannabidiol, caspofungin acetate, catumaxomab, CERE-120, cetuximab, ciclesonide, cilomilast, cizolirtine citrate, Cypher, cystemustine; Dalbavancin, darifenacin hydrobromide, dasatinib, deferasirox, denosumab, desmoteplase, dihydrexidine, dimethyl fumarate, dutasteride, DW-166HC; Eculizumab, enfuvirtide, entecavir, epratuzumab, erlotinib hydrochloride, escitalopram oxalate, eszopiclone, etoricoxib, everolimus; Fallypride, febuxostat, fenretinide, fesoterodine, fingolimod hydrochloride; Gabapentin enacarbil, gefitinib; hMaxi-K, human papillomavirus vaccine, HYAL-CT1101; Imatinib mesylate, indiplon, inolimomab, ISAtx-247; J591; Lacosamide, landiolol, lasofoxifene tartrate, lestaurtinib, lidocaine/prilocaine, linezolid, lixivaptan, lonafarnib, lopinavir, lopinavir/ritonavir, lumiracoxib; Natalizumab, nesiritide; OC-108, omalizumab, onercept, OSC; Palifermin, palonosetron hydrochloride, parathyroid hormone (human recombinant), parecoxib sodium, PD-MAGE-3 vaccine, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, pegsunercept, pelitinib, pitavastatin calcium, plerixafor hydrochloride, posaconazole, prasterone sulfate, pregabalin; Ramelteon, ranelic acid distrontium salt, rasburicase, rosuvastatin calcium, rotigotine, RSD-1235, rufinamide, rupatadine fumarate; Sarizotan hydrochloride, SHL-749, sirolimus-eluting stent, solifenacin succinate, sunitinib malate; Tadalafil, talampanel, tasidotin hydrochloride, Taxus, tegaserod maleate, telavancin hydrochloride, tenofovir disoproxil fumarate, tiotropium bromide, tocilizumab, tositumomab, treprostinil sodium, tridolgosir hydrochloride, TTS-CD3; Ularitide; Valdecoxib, Val-Tyr sardine peptidase, vardenafil hydrochloride hydrate, voriconazole; Yttrium (90Y) edotreotide, Yttrium 90 (90Y) ibritumomab tiuxetan; Zileuton, zucapsaicin.

Clinical Trials as Topic↗
PubMed1990

Pharmacology of the new H1-receptor antagonist setastine hydrochloride.

Setastine HCl (N-(1-phenyl-1-[4-chlorophenyl])-etoxy-ethylene-perhydroazepine hydrochloride, Loderix; CAS 64294-95-7) is a potent antagonist of histamine H1-receptor mediated responses. The antihistamine activity of the compound is similar to that of clemastine fumarate in the following assays: histamine-induced lethality and bronchospasm in guinea-pigs, plasma extravasation in rats, and contractile action in isolated guinea-pig ileum. Setastine HCl inhibits anaphylactic shock in guinea-pigs sensitized by horse serum. No antiserotonin, anticholinergic and antiadrenergic effect of the compound can be detected. Setastine HCl has a long lasting (up to 16 h) antihistamine effect with a good oral effectiveness. It shows no cardiovascular effects in cats. Setastine HCl shows a much weaker CNS depressant activity than clemestine fumarate measuring inhibition of amphetamine-induced hypermotility, rotarod performance, potentiation of ethanol-narcosis in mice, and prolongation of hexobarbital sleeping time in rats. In displacement studies (3H-mepyramine) setastine HCl had significantly weaker affinity for the central nervous system (CNS) H1-receptors than clemastine fumarate. It is concluded that setastine HCl is a non-sedative highly active H1-antagonist.

Animals↗
PubMed1995

Thermodesulforhabdus norvegicus gen. nov., sp. nov., a novel thermophilic sulfate-reducing bacterium from oil field water.

A novel gram-negative, thermophilic, acetate-oxidizing, sulfate-reducing bacterium, strain A8444, isolated from hot North Sea oil field water, is described. The rod-shaped cells averaged 1 micron in width and 2.5 microns in length. They were motile by means of a single polar flagellum. Growth was observed between 44 and 74 degrees C, with an optimum at 60 degrees C. Spores were not produced. Sulfate and sulfite were used as electron acceptors. Sulfur, thiosulfate, nitrate, fumarate, and pyruvate were not reduced. In the presence of sulfate, growth was observed with acetate, lactate, pyruvate, butyrate, succinate, malate, fumarate, valerate, caproate, heptanoate, octanoate, nonadecanoate, decanoate, tridecanoate, pentadecanoate, palmitate, heptadecanoate, stearate, and ethanol. Pyruvate, lactate, and fumarate did not support fermentative growth. Cytochromes of the c-type were present. Desulfoviridin, desulforubidin, P582, and desulfofuscidin were not present. The G+C content of the DNA was 51 mol%. Sequence analysis of 16S rDNA showed that phylogenetically strain A8444 belongs to the delta subdivision of the Proteobacteria. The closest relatives are Desulfacinum infernum and Syntrophobacter wolinii: Strain A8444 is described as the type strain of the new taxon Thermodesulforhabdus norvegicus gen. nov., sp. nov.

Base Composition↗
PubMed1977

[The effect of fludilat on carbohydrate metabolism].

Fludilat (bencyclane-hydrogen-fumarate) increases the O2 consumption and CO2 production of a 10% bovine lens homogenate. An increase of the glucose substrate supply of the homogenate from 25 mM to 37 mM enlarges the above mentioned effects. Investigations on the content of ATP, ADP and AMP show that bencyclane is able to stabilize the physiologic distribution pattern of the three free adenine nucleotides. Changes of the distribution pattern pointing to disturbances of the energy metabolism could in part be normalized by incubation with the addition of bencyclane. This is not only true for lens homogenates but also for whole bovine lenses. Investigations with the enzymes fumarase and malatedehydrogenase indicate that the fumaric acid rest of bencyclane may serve as a substrate for these enzymes in the same way as fumarate. The Km-values found are identical.

Adenosine Diphosphate↗
PubMed1994

Allergenic components in modified and unmodified rosin. Chemical characterization and studies of allergenic activity.

Gäfvert, E. 1994. Allergenic components in modified and unmodified rosin. Chemical characterization and studies of allergenic activity. Acta Dermato-Venereologica. Suppl. 184. 36pp. Uppsala. Unmodified rosin (colophony) is a well-known cause of contact allergy (delayed type hypersensitivity). Rosin is obtained from coniferous trees and consists mainly of diterpenoid resin acids. Most rosin used in technical products is chemically modified. In the common modification of rosin with maleic anhydride, the major product formed is maleopimaric acid (MPA). MPA was identified in experimental sensitization studies as a potent contact allergen. MPA is also formed when rosin is modified with fumaric acid at high temperature and with prolonged heating. The amounts of MPA in technical quality rosins modified with maleic anhydride or fumaric acid might be enough to sensitize individuals handling these rosins. The major product of the modification of rosin with fumaric acid, fumaropimaric acid (FPA), did not elicit any reactions in the animals tested. In another common rosin modification, glycerol esterification, the major product formed was identified as glyceryl triabietate (GTA). In an experimental sensitization study none of the animals reacted to GTA. However, a minor product formed, glyceryl 1-monoabietate (GMA) showed sensitizing capacity. The presence of new contact allergens due to the modification, together with remaining unmodified material, contributes to the risk of developing allergy from contact with these types of rosin. A new main contact allergen in unmodified rosin was identified; 13,14(beta)-epoxyabietic acid. The allergenicity of this epoxide was comparable to that of an earlier identified rosin allergen, 15-hydroperoxyabietic acid (15-HPA). The allergens were detected as their methyl esters. Experimental sensitization and cross-reactivity of oxidation products of resin acids were studied. A pattern of cross-reactivity was observed which indicates that the hydroperoxide of abietic acid (15-HPA) may react to form a complete antigen via two different routes. One route seems to be via the formation of epoxides which then react with skin protein to form the complete antigen, and the other, via radical formation due to cleavage of the peroxide bond. The radical formed may then react with skin protein, so producing the complete antigen. Few other studies have shown results indicating the formation of several antigens from one hapten.

Abietanes↗
PubMed1975

Oxalate accumulation from citrate by Aspergillus niger. II. Involvement of the tricarboxylic acid cyclase.

Carbon-14 was incorporated into oxalate and CO2 from either citrate-1,5-14C, succinate-1,4-14C, or fumarate-1,4-14C by cultures of Aspergillus niger pregrown on a medium which contained glucose as the sole carbon source and which did not allow citrate accumulation. In cell-free extracts of mycelium forming oxalate and CO2 from added citrate the following enzymes of the tricarboxylic acid (TCA) cycle were identified: citrate synthase CE 4.1.3.7), aconitate hydratase (EC4.2.1.3), NAD and NADP-dependent isocitrate dehydrogenase (EC 1.1.1.41, 1.1.1.42), (alpha-oxoglutarate dehydrogenase (EC 1.2.4.2), succinate dehydrogenase (EC 1.3.99.1), fumarate hydratase (EC 4.2.1.2), and malate dehydrogenase (EC 1.1.1.37). The in vitro activity of aconitate hydratase and of NADP-dependent isocitrate dehydrogenase was shown to be almost identical to the rate of in vivo degradation of citrate or to exceed this rate. The degradation of citrate to oxalate was inhibited completely by 9 mM fluoroacetate. It is concluded that the TCA cycle is involved in the formation of oxalate from citrate.

Aconitate Hydratase↗
PubMed1996

Purification and characterization of fumarase from the syntrophic propionate-oxidizing bacterium strain MPOB.

Fumarase from the syntrophic propionate-oxidizing bacterium strain MPOB was purified 130-fold under anoxic conditions. The native enzyme had an apparent molecular mass of 114 kDa and was composed of two subunits of 60 kDa. The enzyme exhibited maximum activity at pH 8.5 and approximately 54 degrees C. The Km values for fumarate and L-malate were 0.25 mM and 2.38 mM, respectively. Fumarase was inactivated by oxygen, but the activity could be restored by addition of Fe2+ and &beta;-mercaptoethanol under anoxic conditions. EPR spectroscopy of the purified enzyme revealed the presence of a [3Fe-4S] cluster. Under reducing conditions, only a trace amount of a [4Fe-4S] cluster was detected. Addition of fumarate resulted in a significant increase of this [4Fe-4S] signal. The N-terminal amino acid sequence showed similarity to the sequences of fumarase A and B of Escherichia coli (56%) and fumarase A of Salmonella typhimurium (63%).

Amino Acid Sequence↗
PubMed2004

Influence of dimethylfumarate on experimental HSV-1 necrotizing keratitis.

BACKGROUND: This study was performed to investigate the influence of fumaric acid esters on the course of herpes stromal keratitis (HSK). METHODS: The corneas of BALB/c mice were inoculated with 105 plaque-forming units of herpes simplex virus 1 (HSV-1, KOS strain). Groups of mice were treated intraperitoneally with phosphate buffered saline (PBS) (control mice), or with dimethylfumarate (DMF) at 15 mg/kg of body weight dissolved in PBS daily for 28 days pre-infection and for 14 days post-infection. The course of HSV-1 keratitis was studied clinically. Corneal sections were examined for inflammatory cell infiltration. The numbers of CD3, GR-1, CD11b and F4/80-expressing cells infiltrating the corneas were analyzed by immunohistochemistry. RESULTS: On day 14 after HSV infection, 72% of the mice in the control group had severe HSK. The development of HSK was reduced by DMF treatment in the DMF group (22%) (P=0.004). The total number of inflammatory cells and infiltration of polymorphonuclear-neutrophils (PMNs) were reduced in the corneas of DMF-treated mice. Compared to the PBS-treated mice, numbers of CD3, CD11b, GR-1 and F4/80-positive cells were reduced in the DMF group of mice. CONCLUSIONS: The course of experimental herpes stromal keratitis can be improved with systemic fumaric acid ester treatment. The improvement of keratitis correlates with a reduced corneal infiltration of T cells and mononuclear cells.

Animals↗
PubMed1979

Active enzyme sedimentation of pig heart fumarase.

Active band sedimentation studies of pig heart fumarase indicate that the enzyme is predominantly tetrameric at enzyme concentrations between 0.0125 and 0.25 mg/ml and at a fumarate concentration of 2.5 mM. At enzyme concentrations of 0.25--1.0 mg/ml and fumarate concentrations known to activate and inhibit the enzyme, the sedimentation band of fumarase becomes disperse and indicates the presence of polymers greater than tetramers.

Animals↗
PubMed2006

Molecular and biochemical investigations in fumarase deficiency.

Fumarase (FH) deficiency is a rare autosomal recessive disease of the Krebs cycle causing severe neurological impairment in early childhood, characterized by encephalopathy with seizures and muscular hypotonia. Only a handful of patients with various recessive mutations in the FH gene have been described so far. Interestingly, autosomal dominant mutations in the same gene are associated with hereditary leiomyomatosis and renal cell cancer (HLRCC). We investigated a boy with developmental and growth delay, microcephaly, and muscular hypotonia recognized at the age of 3 months. No leiomyomatosis or renal cancer is known in the parents. Investigation of the patient's urine revealed massive fumarate excretion. FH activity was severely reduced in muscle and fibroblasts. Respirometric investigation of fibroblasts showed only modest changes indicating that fumarate mediated inhibition of enzymatic pathways other than oxidative phosphorylation might be more relevant in pathophysiology of FH deficiency. Molecular analysis revealed a known 435insK mutation on the paternal allele and a novel H275L mutation due to an A to T transversion of nucleotide 824 on the maternal allele. This mutation affects the same codon as a C to T transition of nucleotide 823, resulting in a H275Y mutation that was found in two families with HLRCC.

Amino Acid Substitution↗