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PubMed1969

Absorption of therapeutic preparations of iron measured with a whole body counter.

The Oxford Whole Body Counter was used to measure absorption from various therapeutic preparations of iron in five groups of subjects. Succinic acid enhanced absorption of iron when added to a solution of ferrous fumarate, but not when given with tablets of ferrous fumarate or ferrous sulphate. Ferrous fumarate plus ascorbic acid was absorbed better than ferrous fumarate alone but no better than ferrous sulphate. The addition of ascorbic acid and succinic acid to tablets of ferrous sulphate did not enhance absorption significantly.

Anemia, Hypochromic↗
PubMed1992

Effect of oxygen supply during growth on the production of cytochromes, enzymes, and acid end products by Haemophilus parasuis.

Haemophilus parasuis, grown under conditions of high aeration, was found to lack a tricarboxylic acid cycle but to possess phosphoenolpyruvate carboxylase and a reductive pathway leading to the production of succinate. Such organisms contained approximately equal quantities of b-, c-, and d-type cytochromes and excreted acetate. When the oxygen supply for growth was either reduced or eliminated, the specific activities of phosphoenolpyruvate carboxylase, malate dehydrogenase, fumarase, fumarate reductase, and NADH: fumarate oxidoreductase were increased substantially, and the acid products were succinate, acetate, and formate. Organisms grown under the latter conditions also contained increased quantities of b- and c-type cytochromes, some of which were low-potential cytochromes. These low-potential cytochromes were reduced by NADH and oxidized by fumarate, and hence, appeared to be components of NADH: furmarate oxidoreductase. Our results indicate that in H. parasuis, growing aerobically in medium containing glucose, the sole function of the reductive pathway is to provide intermediates for biosynthetic processes, and oxygen is the preferred electron acceptor. As the supply of oxygen is reduced or eliminated, the reductive pathway becomes more involved in NAD+ recycling and fumarate becomes the acceptor. In effect, irrespective of the oxygen supply, the growth of H. parasuis is absolutely dependent upon the presence of an electron transport system.

Acetates↗
PubMed2006

Absence of clinically relevant pharmacokinetic interaction between ribavirin and tenofovir in healthy subjects.

This was a 36-day, open-label, fixed-sequence, multiple-dose drug interaction study in 23 healthy subjects to evaluate the effects of multiple doses of tenofovir disoproxil fumarate on the single-dose pharmacokinetics of ribavirin. Subjects received a 600-mg once-daily oral dose of ribavirin on days 1 and 22 and 300-mg once-daily oral doses of tenofovir disoproxil fumarate on days 17 through 24. Pharmacokinetic sampling was performed on days 1 through 4 and 22 through 25. Pharmacokinetics of ribavirin was not altered by its coadministration with tenofovir disoproxil fumarate as the point estimates (day 22 [test treatment]/day 1 [reference treatment]), and the 90% confidence interval for maximum observed concentration (0.95; 88.7-101) and area under the plasma concentration-time curve up to time of last measurable concentration (1.12; 106-117) were within the equivalence bounds of 80% to 125%. Tenofovir pharmacokinetics after ribavirin coadministration was similar to that observed in previous studies. These results indicate that coadministration of tenofovir disoproxil fumarate and ribavirin does not result in substantial changes to their individual pharmacokinetic profiles.

Adenine↗
PubMed1999

Effects of novel pyridothiazepines and pyridothiazines on contractility of isolated guinea-pig heart muscle and vascular smooth muscle preparations.

The effects of newly synthesized pyridothiazepines MM 4 (1-[N-[2-(3,4-dimethoxy-phenyl)ethyl]-N-methylaminoacetyl]-1,2,3,4 -tetrahydro-pyrido[2,3-b][1,4]thiazepine fumarate), MM 6 (1-[N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methylaminopropionyl]-1,2, 3,4-tetrahydro-pyrido[2,3-b][1,4]thiazepine fumarate) and the novel pyridothiazines 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-dimethoxy-phenyl)ethyl]-N-methylaminopropio nyl]-1H-pyrido[2,3-b][1,4]thiazine fumarate) on the contractility of isolated papillary muscles and aortic preparations of guinea pigs were studied using isometric contraction force measurements. The EC50 values for the negative inotropic effect were 27 micromol/l (MM 4), 19 micromol/l (MM 6), 32 micromol/l (MM 10) and 24 micromol/l (MM 11). In K+-precontracted aortic rings ([K+]o 60 mmol/l), the compounds induced relaxation with EC50 values of 27 micromol/l (MM 4), 24 micromol/l (MM 6), 84 micromol/l (MM 10) and 68 micromol/l (MM 11). Pyridothiazepines as well as pyridothiazines (100 micromol/l) were able to depress norepinephrine bitartrate (NE 10 micromol/l)-induced contraction of aortic rings in a calcium-free solution. It was concluded that the investigated compounds exert calcium antagonistic properties in both cardiac and smooth muscle. This antagonistic effect might be due to the inhibition of transmembrane calcium influx and/or intracellular calcium release.

Animals↗
PubMed2004

Molecular characterization and transcriptional regulation of nitrate reductase in a ruminal bacterium, Selenomonas ruminantium.

Nitrate reductase (NaR) of a strain of Selenomonas ruminantium was purified, and the gene encoding NaR (nar) was sequenced. The 6.4 kbp nar gene consisted of narG, H, J, and I in this order. The deduced amino acid sequences of these subunits resembled those of membrane-bound nitrate reductase-A reported for Escherichia coli. It was shown that narG, H, J, and I are transcribed as a single polycistronic message (nar operon). The level of intracellular nar-mRNA was higher when S. ruminantium was grown with nitrate than when grown without nitrate, suggesting that nar transcription is enhanced by nitrate. The level of nar-mRNA, which was in parallel to the amount of NaR per cellular nitrogen, was suggested to be enhanced in response to the deficiency of energy and electron supply. Therefore, NaR synthesis in S. ruminantium appeared to be regulated at the transcriptional level in response to the availability of energy and electrons. S. ruminantium reduced nitrate and fumarate simultaneously with no significant effect of fumarate on nar transcription. Addition of fumarate stimulated nitrate reduction, which was caused by increased cell growth because of increased acquirement of ATP via electron transport phosphorylation coupled with fumarate reduction.

Animals↗
PubMedDate not supplied

[Cytoprotective effect of antihypoxic and antioxidant preparations on cultured human cells in a model of toxic response].

An oxidative stress is considered to be one of the major mechanisms of cytotoxicity. The purpose of present work was to study effects of some drugs with antihypoxic/antioxidant activity in cultured human lung embryonic fibroblasts under conditions of cytotoxic response, provoked by cationic or anionic antiseptics. The following preparations were under study: Mafusol (Na-fumarate), superoxide dismutase from human erythrocytes (SOD), cytochrome c, alpha-tocopherol and Thioctacid T (lipoate) which were applied at concentrations comparable with those, employed in clinical application. The combinations of the used drugs were also under study. The cytotoxic response was induced by an application of antiseptics into the cell incubation medium in 2-5 fold dilutions up to minimum toxic doses for 2-24 h. The drugs under study were introduced simultaneously with antiseptics. The maximum cytoprotective effect was revealed in the case of combination fumarate-alpha-tocopherol; the combination fumarate plus SOD being the second in effectiveness. When the drugs were introduced separately, the most effective proved to be fumarate, followed by vitamin E and cytochrome c. SOD and lipoate did not reveal any cytoprotective activity in our experimental conditions. The designed model of cytotoxicity in vitro can be considered as a prospective test-system for the screening of cytoprotective drugs and their combinations.

Antioxidants↗
PubMed2000

An evaluation of EDTA compounds for iron fortification of cereal-based foods.

Fe absorption was measured in adult human subjects consuming different cereal foods fortified with radiolabelled FeSO4, ferrous fumarate or NaFeEDTA, or with radiolabelled FeSO4 or ferric pyrophosphate in combination with different concentrations of Na2EDTA. Mean Fe absorption from wheat, wheat-soyabean and quinoa (Chenopodium quinoa) infant cereals fortified with FeSO4 or ferrous fumarate ranged from 0.6 to 2.2%. For each infant cereal, mean Fe absorption from ferrous fumarate was similar to that from FeSO4 (absorption ratio 0.91-1.28). Mean Fe absorption from FeSO4-fortified bread rolls was 1.0% when made from high-extraction wheat flour and 5.7% when made from low-extraction wheat flour. Fe absorption from infant cereals and bread rolls fortified with NaFeEDTA was 1.9-3.9 times greater than when the same product was fortified with FeSO4. Both high phytate content and consumption of tea decreased Fe absorption from the NaFeEDTA-fortified rolls. When Na2EDTA up to a 1:1 molar ratio (EDTA:Fe) was added to FeSO4-fortified wheat cereal and wheat-soyabean cereal mean Fe absorption from the wheat cereal increased from 1.0% to a maximum of 5.7% at a molar ratio of 0.67:1, and from the wheat-soyabean cereal from 0.7% to a maximum of 2.9% at a molar ratio of 1:1. Adding Na2EDTA to ferric pyrophosphate-fortified wheat cereal did not significantly increase absorption (P > 0.05). We conclude that Fe absorption is higher from cereal foods fortified with NaFeEDTA than when fortified with FeSO4 or ferrous fumarate, and that Na2EDTA can be added to cereal foods to enhance absorption of soluble Fe-fortification compounds such as FeSO4.

Absorption↗
PubMed1990

Rat renal cortical slices demonstrate p-aminohippurate/glutarate exchange and sodium/glutarate coupled p-aminohippurate transport.

In isolated basolateral membrane vesicles p-aminohippurate (PAH) transport may be coupled indirectly to the sodium gradient through PAH/glutarate [or alpha-ketoglutarate (alpha-KG)] exchange and Na/glutarate cotransport. In this study, rat renal cortical slices were used to examine indirect coupling of PAH transport to sodium in intact renal tissue. Like basolateral membrane vesicles, slices demonstrated avid uptake of 50 microM [14C]glutarate. Steady-state tissue/medium ratios of 30 were achieved by 90 to 120 min. Uptake was inhibited markedly by lithium and fumarate. PAH also inhibited glutarate accumulation, but through acceleration of glutarate efflux i.e., PAH/glutarate exchange, rather than direct inhibition of uptake. PAH-driven efflux of glutarate from slices was blocked by probenecid, which inhibits PAH/glutarate exchange in vesicles. Inasmuch as slices showed both Na/glutarate uptake and PAH/glutarate exchange, externally added glutarate should stimulate PAH uptake in slices. Indeed, in the presence of sodium, 50 microM external glutarate approximately doubled PAH accumulation by the slices. Stimulation by glutarate was abolished by either lithium or fumarate, or by elimination of sodium from the external buffer. The stimulatory effect was specific for glutarate or alpha-KG. Acetate, fumarate and succinate stimulated PAH uptake poorly, if at all. Neither fumarate nor lithium was able to eliminate concentrative PAH uptake completely, suggesting that a portion of PAH transport may occur without Na-dependent glutarate or alpha-KG recycling, i.e., that it may run directly off metabolic alpha-KG production or via a completely glutarate/alpha-KG independent mechanism.

Animals↗
PubMed1994

Kinetics of enzymes with iso-mechanisms: dead-end inhibition of fumarase and carbonic anhydrase II.

Isomerization of free enzyme can be detected in kinetic patterns of dead-end inhibition because competitive substrate analogs yield noncompetitive inhibition versus product in reverse reaction kinetics. The ratio of slope and intercept inhibition constants allows a quantitative estimation of the relative kinetic significance of the isomerization to a catalytic turnover. Applying this kinetic analysis theoretically to inhibition data for bovine carbonic anhydrase II by anions [Y. Pocker and T. L. Deits (1982) J. Am. Chem. Soc. 104, 2424] provides an estimate of 43 +/- 13% for how rate-limiting the isomerization segment is at pH 6.6. Applying the analysis experimentally to porcine heart fumarase provides a competitive pattern of inhibition by trans-aconitate versus fumarate with Ki(s) = 2.0 +/- 0.5 mM, together with a non-competitive pattern versus malate, with Ki(s) = 0.8 +/- 0.1 mM and Kii = 2.3 +/- 0.4 mM. Assuming that the isomerization segment of fumarase is the reprotonation of an active site carboxyl and imidazole with pK1 = 5.53 and pK2 = 7.78 [Blanchard and Cleland (1980) Biochemistry 19, 4506], an apparent rate constant for the isomerization segment of fumarate hydration is estimated as 95 +/- 22 s-1, compared to 42 +/- 13 s-1 for the chemical segment and 29 +/- 0.7 s-1 for a complete turnover. In contrast, the values are 17000 +/- 5200, 82 +/- 25, and 82 +/- 3 s-1, respectively, for malate dehydration. Hence, the isomerization segment is 30 +/- 7% rate-limiting during fumarate hydration but less than 1% during malate dehydration.

Aconitic Acid↗
PubMed1975

[Regulation and physiological significance of aspartate-ammonium lyase (aspartase) of Pseudomonas fluorescens type R (author's transl)].

The biosynthesis of aspartate-ammonium lyase, the enzyme which is induced by aspartic acid, is specifically repressed by fumaric acid. In the presence of aspartate, the enzyme permits the deamination of this compound by the cell. Aspartic acid is converted into fumaric acid which is an intermediate in the Krebs'cycle. The reaction may be considered as an anaplerotic sequence. In the absence of aspartic acid in the culture medium, its role is anabolic; the enzyme catalyses the biosynthesis of this amino acid. Therefore it appears that the reversible reaction fumarate + NH3 = aspartate catalysed by aspartase is included in amphibolic processes.

Ammonia-Lyases↗
PubMed1998

Production of L-malic acid via biocatalysis employing wild-type and respiratory-deficient yeasts.

The yeast Saccharomyces cerevisiae has been used to efficiently produce L-malic acid from fumaric acid. Fumarase is responsible for the reversible conversion of fumaric and L-malic acids in the TCA cycle. To investigate the function of mitochondrial and cytoplasmic fumarase isoenzymes in L-malic acid bioconversion, a wild-type strain and a cytoplasmic respiratory-deficient mutant devoid of functional mitochondria were employed. The mutant strain, which only contained the cytoplasmic fumarase, was still functional in fumaric acid to L-malic acid bioconversion However, its specific conversion rate was much lower (0.20 g/g.h) than that of the wild-type strain (0.55 g/g.h).

Catalysis↗
PubMed1975

Chicken fumarase. II. Kinetic studies.

The catalysis of the hydration of fumarate and deshydration of L - malate by chicken fumarase was measured spectrophotometrically over a range of substrate concentrations from 4 times 10(-3) M to 8 times 10(-5) M for fumarate and from 8 times 10(-2) M to 10(-3) M for L - malate. For the forward and reverse reactions, linear Lineweaver and Burk plots were obtained. The Michaelis constants and the maximum initial velocities for both substrates were determined and the Haldane relation was found to be obeyed. The effect of pH on activity was investigated over a pH range from 5.5 to 9.0 and the data indicate the presence, in the active site, of two ionizable groups, one in the acidic form and one in the basic form. The values of the ionization constants, determined for the enzyme - substrate complexes, agree closely with the ones obtained for the porcine enzyme. The mode of action of twenty-four structural analogs on the initial velocity of the dehydration of L-malate, by chicken fumarase was examined. From these studies, two regions positively charged appear necessary for the effective binding of the carboxylates of the substrates and competitive inhibitors to the active center. Moreover, the data suggest the presence of an additional group, in the catalytic site of chicken fumarase, that stabilizes the carbon-carbon double bond common to fumarate and its structural analogs. Finally, from the comparison of the kinetic properties of the chicken and pig fumarases, it may be concluded that the catalytic mechanism of the homologous enzymes are very similar, if not identical.

Animals↗
PubMed1980

Use of isotope effects to deduce the chemical mechanism of fumarase.

The pH variation of primary 18O and primary and secondary deuterium isotope effects has been determined by the use of the equilibrium perturbation method for the reaction catalyzed by fumarase. The primary 18O effect is 1.073 from the malate side at pH 5 (with an equilibrium 18O effect of 1.033) but decreases rapidly to near unity above pH 7. The primary deuterium isotope effect is near unity at pH 5 and 9 but is strongly inverse at neutral pH (0.915 from the malate said at pH 7, compared to the equilibrium isotope effect of 0.98). Secondary isotope effects with dideuterated substrates from (Brant malate side were 1.31 at pH 5-6 but decreased to a value of 1.08 at pH 9.6 (the equilibrium isotope effect is 1.45). These data are interpreted to mean that the 3R proton of malate is transferred to a group (probably carboxyl) on the enzyme with a fractionation factor relative to water of at least 1.2, to give a carbanion intermediate with an acicarboxylate structure which is tetrahedral at C-2 and trigonal at C-3. Carbon-oxygen bond cleavage accompanied by proton transfer from a group (probably imidazole) on the enzyme then gives water and fumarate. By quantities analysis of the isotope effects, partition ratios for forward and reverse reaction of the E-malate, EH-carbanion, and EH-H2O-fumarate intermediates are calculated as a function of pH. The commitments to catalysis of malate, fumarate, water, and the proton on the enzyme are small at pH 5, and carbon-oxygen bond breaking is totally rate limiting. At neutral and high pH, however, the commitment factors (except that for water) are large, so that no 18O isotope effect is seen, and the other isotope effects are equilibrium ones, with the exact value seen depending on the ratio of forward and reverse commitments.

Deuterium↗
PubMed1984

Membrane enzymes associated with the dissimilation of some citric acid cycle substrates and production of extracellular oxidation products in chemostat cultures of Pseudomonas fluorescens.

Enzyme activities forming extracellular products from succinate, fumarate, and malate were examined using washed cell suspensions of Pseudomonas fluorescens from chemostat cultures. Membrane-associated enzyme activities (glucose, gluconate, and malate dehydrogenases), producing large accumulations of extracellular oxidation products in carbon-excess environments, have previously been found in P. fluorescens. Investigations carried out here have demonstrated the presence in this microorganism of a malic enzyme activity which produces extracellular pyruvate from malate in carbon-excess environments. Although the three membrane dehydrogenase enzymes decrease significantly in carbon-limited chemostat cultures, malic enzyme activity was found to increase fourfold under these conditions. The regulation of malate dehydrogenase and malic enzyme by malate or succinate was similar. Malate dehydrogenase increased and malic enzyme decreased in carbon-excess cultures. The opposite effect was observed in carbon-limited cultures. When pyruvate or glucose was used as the carbon source, malate dehydrogenase was regulated similarly by the available carbon concentration, but malic enzyme activity producing extracellular pyruvate was not detected. While large accumulations of extracellular oxalacetate and pyruvate were produced in malate-excess cultures, no extracellular oxidation products were detected in succinate-excess cultures. This may be explained by the lack of detectable activity for the conversion of added external succinate to extracellular fumarate and malate in cells from carbon-excess cultures. In cells from carbon-limited (malate or succinate) cultures, very active enzymes for the conversion of succinate to extracellular fumarate and malate were detected. Washed cell suspensions from these carbon-limited cultures rapidly oxidized added succinate to extracellular pyruvate through the sequential action of succinate dehydrogenase, fumarase, and malic enzyme. Succinate dehydrogenase and fumarase activities producing extracellular products were not detected in cells from chemostat cultures using pyruvate or glucose as the carbon source. Uptake activities for succinate, malate, and pyruvate also were found to increase in carbon-limited (malate or succinate) and decrease in carbon-excess cultures. The role of the membrane-associated enzymes forming different pathways for carbon dissimilation in both carbon-limited and carbon-excess environments is discussed.

Ammonia↗
PubMed2001

[Study on the optimal conditions in simultaneous reaction and separation for L-malic acid production].

Based on the principle of coupling reaction and separation process, free cells containing fumarase were used for producing L-malic acid. The calcium fumarate was used as substrate to produce calcium malate directly. This new method was more advantageous than the traditional immobilized cells conversion system in aspects such as simple equipment and operation, high conversion efficiency and the yield of product. The results showed that at reaction temperature 40 degrees C, pH7.0-7.5, reaction time 20-28 h, the conversion efficiency was up to 99.9% and about 3.2 kg calcium fumarate was converted to calcium malate per liter enzyme suspension. Also, L-malic acid produced in free fumarase system satisfied USP criterion, the residual fumaric acid was less than 0.1% and the cost was approximately to that of DL-malic acid produced by chemical synthesis.

Biotransformation↗
PubMed1976

Demonstration and possible function of NADH:NAD+ transhydrogenase from ascaris muscle mitochondria.

Mitochondria from the muscle of Ascaris lumbricoides var. suis function anaerobically. NADH is generated in the intermembrane space as a consequence of the "malic" enzyme reaction. It has been suggested that this reducing equivalent in the form of hydride ion, would be translocated across the inner membrane in order to mediate ATP generation via the fumarate reductase reaction. In accord with this suggestion, intact Ascaris mitochondria showed appreciable NADH oxidase activity. Sonication resulted in an approximately 2-fold increase in NADH oxidase activity, whereas "malic" enzyme, fumarase, and NADH:NAD+ transhydrogenase activities increased approximately 7- to 14-fold, respectively. Phosphorylation capabilities and permeability toward pyridine nucleotides also indicated the intactness of the mitochondria. Ascaris mitochondria incubated anaerobically in the presence of fumarate, and [14C]NADH catalyzed a rapid reduction of the fumarate to succinate with the concomitant formation of equivalent quantities of extramitochondrial NAD+. However, very little isotope was recovered from the washed mitochondria, indicating the possibility of hydride ion translocation in the absence of nucleotide translocation. NADH:NAD+ transhydrogenase has been isolated from the muscle mitochondria of the intestinal nematode, Ascaris lumbricoides var. suis. The enzyme seems to have been solubilized from the mitochondrial membrane fraction by treatment with sodium deoxycholate followed by dialysis and subsequent adsorption by and elution from alumina C gamma. No NADPH:NAD+ transhydrogenase activity was detectable, making the Ascaris system unique over others reported. Activity was protected by L-cysteine, reduced glutathione and dithioerythritol, but strongly inhibited by low concentrations of p-chloromercuribenzoate or silver nitrate. The thionicotinamide derivative of NAD+ (thioNAD+) was employed to accept hydride ions from NADH in order to assay spectrophotometrically at 398 nm. Apparent Km values for thioNAD+ and NADH were 1 X 10(-4) M and 8 X 10(-6) M, respectively. That the physiological nucleotide, could act as hydride ion acceptor from NADH was indicated by the findings that NAD+ competitively inhibited the reduction of thioNAD+ when assayed at 398 nm. The additional finding of a noncompetitive inhibition between NAD+ and NADH suggested at least two binding sites on the enzyme, one for NADH and another common site for NAD+ and thioNAD+. More conclusive evidence indicating the participation of NAD+ as acceptor was obtained by incubation of the enzyme with NADH and [14C]NAD+ and demonstrating a rapid formation of [14C]NADH. These findings, in conjunction with those discussed above, suggest a physiological function of this enzyme in hydride ion translocation.

Aerobiosis↗
PubMed1977

[Determination of the KM-value of the fumarase (E.C. 4.2.1.2) with bencyclan-hydrogenfumarate as the substrate (author's transl)].

The Michaelis-Menten constant for fumarase (E.C. 4.2.1.2) has been determined by measuring the enzyme activity by the spectrophotometric method of Racker, which depends on the formation or disappearance of the double bond of fumaric acid. When using Na2-fumarate or bencyclan hydrogenfumarate (Fludilat), respectively, as a substrate, a KM-value of 1.3 X 10(-3) M was found for both substances. In a linked assay where the formation of NADH in the reaction of fumarate leads to malate leads to oxaloacetate was used as a parameter for the reaction rate, a KM-value of 1.35 X 10(-3) M was found.

Animals↗
PubMed1997

Quetiapine in patients with schizophrenia. A high- and low-dose double-blind comparison with placebo. Seroquel Study Group.

BACKGROUND: Quetiapine fumarate (Seroquel [ICI 204,636]) is an atypical dibenzothiazepine antipsychotic with a greater affinity for 5-hydroxytryptamine2 (5-HT2) receptors than for D2 dopamine receptors; its efficacy in patients with schizophrenia was shown in early phase 2 trials (maximum dose, 750 mg/d). METHODS: In this multicenter, double-blind, placebo-controlled trial, 286 patients hospitalized with chronic or subchronic schizophrenia (DSM-III-R) were randomized to 6 weeks of treatment with high-dose quetiapine fumarate (< or = 750 mg/d), n = 96; low-dose quetiapine fumarate (< or = 250 mg/d), n = 94; or placebo, n = 96. The Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression Severity of Illness item scores were the primary efficacy variables. Secondary efficacy variables included the BPRS positive-symptom cluster score, the Modified Scale for the Assessment of Negative Symptoms summary score (United States only), and the total score from the negative scale of the Positive and Negative Syndrome Scale (Europe only). Scores were analyzed using an analysis of covariance for change from baseline at end point with last observations carried forward. The model included baseline score (covariate), center, and treatment. Extrapyramidal symptoms were assessed using the Simpson-Angus Scale and the Barnes Akathisia Scale; abnormal involuntary movements were assessed using the Abnormal Involuntary Movement Scale. Frequency distributions of grouped change-from-baseline scores were analyzed using chi 2 tests. RESULTS: Of 280 patients in whom the efficacy of quetiapine was evaluated, 159 (42% of those receiving high-dose treatment; 57%, low-dose treatment; and 59%, placebo) withdrew before trial completion, primarily because of treatment failure. Significant (P < .001, BPRS; P = .003, Clinical Global Impression Severity of Illness item; and P = .003, BPRS positive-symptom cluster) differences were identified between patients receiving high-dose quetiapine and placebo for both primary efficacy variables, with end point differences in the BPRS positive-symptom cluster score showing quetiapine's consistency in reducing positive symptoms. The reduction of negative symptoms was less consistent; high-dose quetiapine was superior on the Modified Scale for the Assessment of Negative Symptoms but not on the negative scale of the Positive and Negative Syndrome Scale. Quetiapine was well tolerated and did not induce extrapyramidal symptoms, sustained elevations of prolactin, or clinically significant changes in hematologic parameters. CONCLUSIONS: Quetiapine is an effective antipsychotic with a favorable safety profile. The optimum dose is probably greater than 250 mg/d.

Adult↗