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At least 631 records · Page 35Linked to original sources
PubMed2006

Anti-hepatitis B virus efficacy of tenofovir disoproxil fumarate in HIV-infected patients.

Tenofovir disoproxil fumarate (TDF) has shown in vitro activity against both HIV and hepatitis B virus (HBV). We retrospectively evaluated the efficacy of TDF (300 mg/d), administered as a part of anti-retroviral therapy, in a large cohort of HIV/HBV-coinfected patients. Sixty-five HIV/HBV-coinfected patients who received TDF for at least 6 months with serum HBV DNA levels above 2.3 log10 copies/mL at TDF initiation and who had stored serum samples before and during TDF therapy were included. Serum HBV DNA was measured on stored samples. The median follow-up period was 12 (Q1-Q3: 8-17) months. Serum hepatitis B e antigen (HBeAg) was positive in 54 patients (83.1%). Fifty-two patients (80.0%) were receiving lamivudine (LAM) (150 mg twice a day), and 68.8% had documented LAM resistance at baseline. Among HBeAg-positive patients, the median reduction from baseline (8.17; Q1-Q3 = 7.30-8.30 log10 copies/mL) of serum HBV DNA was 4.56 log10 copies/mL (Q1-Q3 = 3.33-5.55) (P < .0001). In HBeAg-negative patients, serum HBV DNA decline from baseline (4.83; Q1-Q3 = 2.69-6.40 log10 copies/mL) was 2.53 log10 copies/mL (Q1-Q3 = 0.39-4.10). At the end of the study, HBV DNA became undetectable in 29.6% and 81.6% of the HBeAg-positive and HBeAg-negative patients, respectively. Serum HBeAg became negative in 4 patients, 2 of whom acquired serum hepatitis B e antibody. In conclusion, this retrospective analysis demonstrates the efficacy of TDF against wild-type, presumed precore mutants and LAM-resistant HBV when used as a part of anti-retroviral therapy in HIV-coinfected patients.

Adenine↗
PubMed1979

Effects of dimepramine fumarate on physiological and cognitive behaviors of Parkinson patients.

Nine patients 55 to 74 years old with Parkinson's disease were tested before and after treatment with 50 to 225 mg dimepramine fumarate (CIBA G-31406) for about three weeks daily in order to determine the drug's effects on electrodermal responsiveness to a series of unpredictably occurring loud sounds. Twelve control subjects were tested and retested with the same procedure. In addition, the Parkinson patients received a number of cognitive tests before and after drug treatment. Results indicated that the drug tends to decrease autonomic arousal responses as measured by resting conductance levels, number of fluctuations in skin conduction per minute, orienting response, and habituation rate. These decreases in measures of arousal generally were accompanied by lowered performance scores on several tests of memory and temporal discrimination ability.

Aged↗
PubMed1984

The relative analgesic efficacy of propiram fumarate, codeine, aspirin, and placebo in post-impaction dental pain.

To evaluate the analgesic efficacy of orally administered 50 mg propiram fumarate, 650 mg aspirin, 60 mg codeine phosphate, and placebo in acute post-impaction dental pain, 159 patients with moderate or severe pain were randomly allocated to the four treatments in this single-dose double-blind, stratified, parallel-group study. A research nurse questioned the patients at 1/2 hour and hourly for 6 hours after medicating. A standard format was used to question subjects about their pain intensity and relief from the starting pain. Propiram, 50 mg, produced a level of analgesia approaching that of 650 mg aspirin in peak effect, total effect, and duration of action and was statistically superior to 60 mg codeine and placebo for every measure of analgesic efficacy. Several mild adverse effects were observed; however, they appeared to be evenly distributed among the active treatments.

Adolescent↗
PubMed1995

First-line therapy option with low-dose bisoprolol fumarate and low-dose hydrochlorothiazide in patients with stage I and stage II systemic hypertension.

This 30-center, randomized, double-blind, placebo-controlled, parallel-group study was designed to (1) establish that 6.25 mg of hydrochlorothiazide (HCTZ) given once daily with 5 mg of bisoprolol fumarate can contribute to antihypertensive effectiveness in patients with stage I and stage II (mild to moderate) systemic hypertension; and (2) assess whether this formulation was more effective or possessed a safety advantage over standard monotherapy with bisoprolol or 25 mg of HCTZ. Results showed that HCTZ 6.25 mg contributed significantly to the antihypertensive effectiveness of bisoprolol 5 mg. Bisoprolol 5 mg/HCTZ 6.25 mg (B5/H6.25) produced significantly greater mean reductions from baseline in sitting systolic and diastolic blood pressure (-15.8 mm Hg/-12.6 mm Hg) than bisoprolol 5 mg alone (-10.0 mm Hg/-10.5 mm Hg) and HCTZ 25 mg alone (-10.2 mm Hg/-8.5 mm Hg). A 73% response rate was achieved with the low-dose formulation compared with 61% for the bisoprolol 5 mg (B5) group and 47% for the HCTZ 25 mg (H25) group. B5/H6.25 was found to be significantly more effective than B5 or H25 in all subgroups of patients, regardless of gender, race, age, or smoking history. Antihypertensive effects were maintained during the 24-hour dosing interval. The incremental effectiveness of B5/H6.25 was not accompanied by an increase in the frequency or severity of adverse experiences; the incidence of adverse experiences in the B5/H6.25 group was comparable to that in the placebo group. B5/H6.25 was shown to provide safety advantages over H25, as shown by less hypokalemia (< 1% with B5/H6.25 versus 6.5% with H25).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed2002

Modulation of marrow stromal osteoblast adhesion on biomimetic oligo[poly(ethylene glycol) fumarate] hydrogels modified with Arg-Gly-Asp peptides and a poly(ethyleneglycol) spacer.

Novel oligo[poly(ethylene glycol) fumarate] (OPF) hydrogels functionalized with cell adhesion peptides were prepared, and the effects of incorporated peptide density and macromolecular structure of hydrogels on attachment and morphology of marrow stromal cells (MSCs) were evaluated. Poly(ethylene glycol) (PEG; number average molecular weight of 930, 2860, and 6090) was used to synthesize OPF. A model peptide, Gly-Arg-Gly-Asp (GRGD), was incorporated into OPF hydrogels after being coupled to acrylated PEG of molecular weight 3400. The increase of incorporated peptide concentration enhanced MSC attachment to OPF hydrogels of PEG of molecular weight of 930 and 2860. However, the number of attached MSCs to OPF hydrogels of PEG (molecular weight 6090) remained constant regardless of the peptide density. The length of PEG in OPF also influenced cell attachment. When 1 micromole peptide/g hydrogel was incorporated into the OPF hydrogels, the degree of cell attachment at 12 h relative to the initial seeding density was 93.9 +/- 5.9%, 64.7 +/- 8.2%, and 9.3 +/- 6.6% for OPF hydrogels prepared with PEG of molecular weights of 930, 2860, and 6090, respectively. However, the crosslinking density of hydrogels did not significantly affect cell attachment. The interaction was sequence specific, in that MSC attachment to GRGD-modified hydrogels was competitively inhibited when cells were incubated in the presence of 0.5 mM soluble GRGD before cell seeding. These results suggest that we can modulate MSC attachment to OPF hydrogels by altering the peptide density and the molecular structure of OPF hydrogels.

Animals↗
PubMed2002

Effect of poly(ethylene glycol) molecular weight on tensile and swelling properties of oligo(poly(ethylene glycol) fumarate) hydrogels for cartilage tissue engineering.

This study was designed to determine the effect of changes in poly(ethylene glycol) (PEG) molecular weight on swelling and mechanical properties of hydrogels made from a novel polymer, oligo(poly(ethylene glycol) fumarate) (OPF), recently developed in our laboratory. Properties of hydrogels made from OPF with initial PEG molecular weights of 860, 3900, and 9300 were examined. The PEG 3900 formulation had a tensile modulus of 23.1 +/- 12.4 kPa and percent elongation at fracture of 53.2 +/- 13.7%; the PEG 9300 formulation had similar tensile properties (modulus: 16.5 +/- 4.6 kPa, elongation: 76.0 +/- 26.4%). However, the PEG 860 gels had a significantly higher modulus (89.5 +/- 50.7 kPa) and a significantly smaller percent elongation at fracture (30.1 +/- 6.4%), when compared with other formulations. Additionally, there were significant differences in percent swelling between each of the formulations. Molecular weight between crosslinks (M(c)) and mesh size were calculated for each OPF formulation. M(c) increased from 2010 +/- 116 g/mol with PEG 860 to 6250 +/- 280 g/mol with PEG 9300. Mesh size calculations showed a similar trend (76 +/- 2 A for PEG 860 to 160 +/- 6 A for PEG 9300). It was also found that these hydrogels could be laminated if a second layer was added before the first had completely crosslinked. Mechanical testing of these laminated gels revealed that the presence of an interfacial area did not significantly alter their tensile properties. These results suggest that the material properties of OPF-based hydrogels can be altered by changing the molecular weight of PEG used in synthesis and that multilayered OPF hydrogel constructs can be produced, with each layer having distinct mechanical properties.

Absorption↗
PubMed2003

Adhesion and migration of marrow-derived osteoblasts on injectable in situ crosslinkable poly(propylene fumarate-co-ethylene glycol)-based hydrogels with a covalently linked RGDS peptide.

Marrow-derived osteoblasts were cultured on poly(propylene fumarate-co-ethylene glycol) (P(PF-co-EG)) based hydrogels modified in bulk with a covalently linked RGDS model peptide. A poly(ethylene glycol) spacer arm was utilized to covalently link the peptide to the hydrogel. Three P(PF-co-EG) block copolymers were synthesized with varying poly(ethylene glycol) block lengths relative to poly(ethylene glycol) spacer arm. A poly(ethylene glycol) block length of nominal molecular weight 2000 and spacer arm of nominal molecular weight 3400 were found to reduce nonspecific cell adhesion and show RGDS concentration dependent marrow-derived osteoblast adhesion. A concentration of 100 nmol/mL RGDS was sufficient to promote adhesion of 84 +/- 17% of the initial seeded marrow-derived osteoblasts compared with 9 +/- 1% for the unmodified hydrogel after 12 h. Cell spreading was quantified as a method for evaluating adhesivity of cells to the hydrogel. A megacolony migration assay was utilized to assess the migration characteristics of the marrow-derived osteoblasts on RGDS modified hydrogels. Marrow-stromal osteoblasts migration was greater on hydrogels modified with 100 nmol/mL linked RGDS when compared with hydrogels modified with 1000 nmol/mL linked RGDS, while proliferation was not affected. These P(PF-co-EG) hydrogels modified in the bulk with RGDS peptide are potential candidates as in situ forming scaffolds for bone tissue engineering applications.

Animals↗
PubMed2005

Osteochondral repair in the rabbit model utilizing bilayered, degradable oligo(poly(ethylene glycol) fumarate) hydrogel scaffolds.

In this study, hydrogel scaffolds, based on the polymer oligo(poly(ethylene glycol) fumarate) (OPF), were implanted into osteochondral defects in the rabbit model. Scaffolds consisted of two layers-a bottom, bone forming layer and a top, cartilage forming layer. Three scaffold formulations were implanted to assess how material composition and transforming growth factor-beta1 (TGF-beta1) loading affected osteochondral repair. Critical histological evaluation and scoring of the quantity and quality of tissue in the chondral and subchondral regions of defects was performed at 4 and 14 weeks. At both time points, no evidence of prolonged inflammation was observed, and healthy tissue was seen to infiltrate the defect area. The quality of this tissue improved over time with hyaline cartilage filling the chondral region and a mixture of trabecular and compact bone filling the subchondral region at 14 weeks. A promising degree of Safranin O staining and chondrocyte organization was observed in the newly formed surface tissue, while the underlying subchondral bone was completely integrated with the surrounding bone at 14 weeks. Material composition within the bottom, bone-forming layer did not appear to affect the rate of scaffold degradation or tissue filling. However, no bone upgrowth into the chondral region was observed with any scaffold formulation. TGF-beta1 loading in the top layer of scaffolds appeared to exert some therapeutic affect on tissue quality, but further studies are necessary for scaffold optimization. Yet, the excellent tissue filling and integration resulting from osteochondral implantation of these OPF-based scaffolds demonstrates their potential in cartilage repair strategies.

Absorbable Implants↗
PubMed2006

Evaluation of bone regeneration by DNA release from composites of oligo(poly(ethylene glycol) fumarate) and cationized gelatin microspheres in a critical-sized calvarial defect.

This research examines the bone formation response to release of plasmid DNA encoding human Bone Morphogenetic Protein-2 from hydrogel composites consisting of cationized gelatin microspheres (CGMS) embedded within a crosslinked oligo(poly(ethylene glycol) fumarate) (OPF) hydrogel network in a critical-sized rat cranial defect model after 30 days. Four composite groups were investigated: (1) composites with 10 microg DNA loaded into the CGMS phase, (2) composites with 10 microg DNA loaded into the OPF phase, (3) composites with 100 microg DNA loaded into the OPF phase, and (4) composites without DNA (material control). Light microscopy revealed no enhancement in bone formation for groups releasing plasmid DNA, relative to the material control group. Limited formation of new bone was observed from the defect margins and within the defect for some samples. The hydrogels swelled appreciably and fragmentation of the implants was noted to varying degrees among samples within groups, with a presence of inflammatory cells related to the degree of fragmentation. The lack of enhancement in bone formation indicates that the release of plasmid DNA from the composites was not sufficient to elicit a bone regeneration response.

Animals↗
PubMed2006

Characterization of DNA release from composites of oligo(poly(ethylene glycol) fumarate) and cationized gelatin microspheres in vitro.

This research investigates the release of plasmid DNA from novel hydrogel composites of oligo(poly(ethylene glycol) fumarate) (OPF) and cationized gelatin microspheres (CGMS), as well as the swelling and degradation of these materials in vitro. The release of total DNA and of double-stranded DNA was measured fluorescently, and the swelling properties and polymer mass loss of the hydrogels were assessed. Further, the structural integrity of the released DNA was determined through electrophoresis. It was found that plasmid DNA can be released in a sustained fashion over the course of up to 49-140 days in vitro from hydrogels of OPF synthesized from poly(ethylene glycol) of nominal molecular weights of 10 kDa and 3 kDa, respectively, with the release kinetics depending upon the material composition and the method of DNA loading. Released DNA was predominately double-stranded DNA (dsDNA) in structure and of the open-circular conformation. The results suggest that DNA release from hydrogel composites of OPF and CGMS is dominated by the degradation of the OPF component of the gels. Electrophoresis results indicate that the released DNA retains suitable conformation for potential bioactivity over the course of at least 63 days of release. Thus, these studies demonstrate the potential of composites of OPF and CGMS in controlled gene delivery applications.

DNA↗
PubMed2003

Mechanical evaluation of a porous bone graft substitute based on poly(propylene glycol-co-fumaric acid).

A porous, resorbable polymer composite based on poly(propylene glycol-co-fumaric acid) (PPF) was mechanically evaluated in vitro for use as a bone graft substitute and fracture fixative. The test material created a dynamic system capable of initially providing mechanical integrity to bony voids and a degradative mechanism for ingrowth by native bone. The unsaturated polymer, PPF, was crosslinked in the presence of effervescent agents to yield a porous microstructure upon curing. An in vitro degradation study first assessed the temporal mechanical properties of the test material. This research was followed by an ex vivo study using a long-bone osteotomy model to characterize the mechanics of fixation. Results showed the initial compressive strength of the cross-linked PPF system was comparable to cancellous bone. The rate of strength loss was commensurate with the predicted mechanical recovery of healing bone with analogous results in a composite that comprised also 25% (by weight) autograft. Mechanical testing in the long-bone model demonstrated that PPF-based bone-graft substitute increased the flexural strength of K-wire stabilized osteotomies. These results suggest that this type of bone graft substitute may have clinical utility in the stabilization of complex tubular bone fractures.

Animals↗
PubMed1981

Bioavailability of orally administered propiram fumarate in humans.

Propiram bioavailability was determined in 10 healthy volunteers after a single role administration of 50 mg (base equivalent) of propiram fumarate in tablet or solution dosage from in a randomized crossover design. The plasma drug concentration-time curve revealed a one-compartment open model with first-order absorption kinetics. There were no statistically significant differences (P greater than 0.05) between all of the measured pharmacokinetic parameters obtained from the tablet and the solution with the exception of the absorption lag time (tlag), where the tablet had a significantly longer tlag. The drug given as a tablet or solution was absorbed rapidly after oral administration with an apparent absorption rate constant of 3.7 hr-1 for both dosage forms. The Cmax value (308 ng/ml for the tablet and 342 ng/ml for the solution) was attained at approximately 1 hr after oral administration. The elimination half-life was 5.2 hr for the tablet and 4.4 hr for the solution, and the apparent distribution volume was 2.31 liters/kg for the tablet and 1.94 liters/kg for the solution. Total body clearance was much greater than renal clearance, indicating extensive metabolic clearance for both dosage forms. The study showed that propiram administered as the tablet was bioequivalent to the solution.

Adult↗
PubMed1999

Free-living nematodes Caenorhabditis elegans possess in their mitochondria an additional rhodoquinone, an essential component of the eukaryotic fumarate reductase system.

The respiratory chain of Caenorhabditis elegans was characterized in mitochondria isolated from aerobically grown nematodes. Nematode mitochondria contain ubiquinone-9 as a major component and rhodoquinone-9 as a minor component. The ratio of ubiquinone-9/rhodoquinone-9 is higher in C. elegans mitochondria than in mitochondria from second-stage larvae of Ascaris suum, the free-living stage of porcine gut-dwelling nematode. The individual oxidoreductase activities comprising succinate oxidase and the amount of substrate-reducible cytochromes are comparable to those of mitochondria from second-stage larvae of A. suum. The specific activity of fumarate reductase is lower in C. elegans mitochondria than in mitochondria from second-stage larvae of A. suum, but still higher than in mammalian mitochondria. These results indicate that the free-living nematode C. elegans is capable of synthesizing rhodoquinone, as distinguished from aerobic mammalian species, although its mitochondria appear more aerobic than A. suum larval mitochondria.

Aerobiosis↗
PubMed1993

Chronic (1-year) safety evaluation of ipazilide fumarate, an antiarrhythmic agent, administered orally to rats.

Ipazilide fumarate (WIN 54177-4) is a chemically novel antiarrhythmic agent that prolongs ventricular refractoriness and possesses antiectopic activity. The compound is being developed as oral and iv therapy for ventricular and supraventricular arrhythmias. Since ipazilide therapy may require long-term use, a 1-year oral gavage study (daily dosages of 20, 80, or 160 mg/kg) was conducted in rats. Controls received the purified water vehicle. Treatment-related clinical signs were limited to post-dosing salivation. Increased relative liver weight (females, at 80 and 160 mg/kg) was correlated with centrilobular hypertrophy, but was not associated with significant increased serum liver enzymes activities. These liver weight changes were interpreted as an adaptive metabolic response and were not considered toxicologically significant. An increased incidence of centrilobular hepatocellular vacuolation representing lipid accumulation over that observed for male controls occurred for males in all ipazilide-treated groups. This observation, however, was not correlated with elevated hepatic enzyme activities. Hepatocellular basophilic foci were observed for females only (80 and 160 mg/kg groups); however, the significance of this lesion is unclear. Transient dosage-related duodenal villous atrophy/sloughing was observed for males from the 80 and 160 mg/kg groups. Mild increases in hemoglobin, hematocrit, urea, and creatinine (160 mg/kg), attributed to treatment, were considered of minor toxicologic importance. Likewise, no clinical or anatomical pathologic observations that may indicate cardiac toxicity were determined. It is concluded that a dosage of 20 mg/kg (two to three times the clinical efficacious dosage) was considered a no-effect dosage level since it did not produce any effects of toxicological significance.

Administration, Oral↗
PubMed1999

Crystallization and preliminary X-ray analysis of flavocytochrome c(3), the fumarate reductase from Shewanella frigidimarina.

The fumarate reductase (flavocytochrome c(3)) from Shewanella frigidimarina (formerly S. putrefaciens) NCIMB400 has been crystallized in the space group P2(1), with cell dimensions of a = 45.447 A, b = 92.107 A, c = 78.311 A, and beta = 91.038 degrees and one molecule per asymmetric unit. A native data set has been collected to 1.8 A. The gene encoding Fcc(3) from the S. frigidimarina type strain ACAM591 has been cloned and sequenced and the protein crystallized in space group P2(1) with cell dimensions of a = 45.359 A, b = 88.051 A, c = 77.473 A, and beta = 104.499 degrees. Anomalous data have also been collected from the NCIMB400 crystal allowing the heme iron positions to be identified.

Base Sequence↗
PubMed2000

Overexpression, purification, and crystallization of the membrane-bound fumarate reductase from Escherichia coli.

Quinol-fumarate reductase (QFR) from Escherichia coli is a membrane-bound four-subunit respiratory protein that shares many physical and catalytic properties with succinate-quinone oxidoreductase (EC 1.3.99.1) commonly referred to as Complex II. The E. coli QFR has been overexpressed using plasmid vectors so that more than 50% of the cytoplasmic membrane fraction is composed of the four-subunit enzyme complex. The growth characteristics required for optimal levels of expression with minimal degradation by host cell proteases and oxidation factors were determined for the strains harboring the recombinant plasmid. The enzyme is extracted from the enriched membrane fraction using the nonionic detergent Thesit (polyoxyethylene(9)dodecyl ether) in a monodisperse form and then purified by a combination of anion-exchange, perfusion, and gel filtration chromatography. The purified enzyme is highly active and contains all types of redox cofactors expected to be associated with the enzyme. Crystallization screening of the purified QFR by vapor diffusion resulted in the formation of crystals within 24 h using a sodium citrate buffer and polyethylene glycol precipitant. The crystals contain the complete four-subunit QFR complex, diffract to 3.3 A resolution, and were found to be in space group P2(1)2(1)2(1) with unit cell dimensions a = 96.6 A, b = 138.1 A, and c = 275.3 A. The purification and crystallization procedures are highly reproducible and the general procedure may prove useful for Complex IIs from other sources.

Bacterial Proteins↗
PubMed1980

Genetic and physical characterization of lambda transducing phages (lambda frdA) containing the fumarate reductase gene of Escherichia coli K12.

Two types of fumarate reductase transducing phages, lambda frdA, carrying the wild-type frdA gene but differing in the orientation of a R.HindIII fragment of bacterial DNA were isolated from populations of recombinant transducing phages by their ability to complement the lesions of frdA mutants of E. coli. In lysogens, the cloned frdA gene was controlled by its own promoter and was fully responsive to normal regulatory stimuli. The lambda frdA phages would not complement the defects of succinate dehydrogenase (sdh) mutants. Genetic studies showed that the R.HindIII fragment contains ampA, the cis-acting regulatory locus for the chromosomal beta-lactamase gene ampC. No evidence for the presence of other markers was detected but the bacterial segment could be extended to produce plaque-forming phage derivatives containing the amp operon and a gene concerned with bacteriophage morphogenesis, groE(mop). A physical map of the 4.9 kb R.HindIII fragment was constructed by restriction analysis and flanking fragments were identified by DNA:DNA hybridization analysis. The frdA region contained a single asymmetric R.EcoRI target 3.33 kb from one end and the orientation of the physical map with respect to the E.coli linkage map was established.

Bacteriophage lambda↗
PubMed1981

Effects of a new antiarrhythmic compound [2-benzal-1-(2' diisopropyl-amino-ethoxy-imino)-cycloheptane hydrogen fumarate] on the electrophysiological properties of mammalian cardiac cells.

Intracellular microelectrodes were used to study the effects of Th 494 [2-benzal-1-(2' diisopropyl-amino-ethoxy-imino)-cycloheptane hydrogen fumarate; 1-100 mumol/1) on transmembrane electrical activity of sinus node and Purkinje fibres of the rabbit as well as on atrial trabeculae and papillary muscles of the guinea pig. In the atrial and in the ventricular myocardium (32 degrees C; driving rate 0.3-0.5 Hz) Th 494 exerted the following electrophysiological actions: no change of the resting potential nor of the amplitude of the action potential; concentration- dependent reduction of the maximum rate of rise (dV/dt)max of the action potential; slight increase of the action potential duration at lower concentrations (1-20 mumol/l), loss of the plateau at higher concentrations (above 20 mumol/l). The isometric force of contraction was moderately reduced by Th 494 (about 20% reduction by 2 mumol/l). The h infinity-curve relating (dV/dt)max of the action potential to the membrane potential was depressed by Th 494 without being shifted along the voltage axis. The reduction of (dV/dt)max was considerably more pronounced at higher driving frequencies. After interruption of stimulation for various periods, (dV/dt) max of the first action potential attained a steady-state value in a two-exponential fashion, suggesting use-dependence as well as a change in the recovery kinetics of the fast Na+ channel by Th 494. In Purkinje fibres (37 degrees C) Th 494 reduced (dV/dt) max in a similar manner. The duration of the action potential was considerably decreased at the level of the plateau. In the primary pacemaker region of the sinus node (37 degrees C) Th 494 moderately reduced the rate of diastolic depolarization and diminished at higher concentrations the amplitude of the action potential. All effects of Th 494 were only slowly reversible by drug-free perfusion. In view of its effect on (dV/dt) max, Th 494 resembles quinidine in its potential-dependence, whereas its time-dependence bears greater similarity with lidocaine.

Action Potentials↗