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PubMed2005

Microarray analysis in human hepatocytes suggests a mechanism for hepatotoxicity induced by trovafloxacin.

Idiosyncratic drug toxicity, defined as toxicity that is dose independent, host dependent, and usually cannot be predicted during preclinical or early phases of clinical trials, is a particularly confounding complication of drug development. An understanding of the mechanisms that lead to idiosyncratic liver toxicity would be extremely beneficial for the development of new compounds. We used microarray analysis on isolated human hepatocytes to understand the mechanisms underlying the idiosyncratic toxicity induced by trovafloxacin. Our results clearly distinguish trovafloxacin from other marketed quinolone agents and identify unique gene changes induced by trovafloxacin that are involved in mitochondrial damage, RNA processing, transcription, and inflammation that may suggest a mechanism for the hepatotoxicity induced by this agent. In conclusion, this work establishes the basis for future microarray analysis of new compounds to determine the presence of these expression changes and their usefulness in predicting idiosyncratic hepatotoxicity. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience. Wiley.com/jpages/0270-9139/suppmat/index.htnd).

Animals↗
PubMed1997

Phase I pilot study of the effects of trovafloxacin (CP-99,219) on the pharmacokinetics of theophylline in healthy men.

This study examined the effect of trovafloxacin (CP-99,219) on the pharmacokinetics and pharmacodynamics of a single dose of theophylline, when administered to steady-state concentrations. Twelve healthy, nonsmoking male volunteers participated. A 450-mg dose of theophylline was administered at 7:00 AM on day 1. On day 4, volunteers received 300 mg of trovafloxacin (CP-99,219) daily in the morning for 7 days. The 450-mg dose of theophylline was repeated on day 8 at 7:00 AM concomitantly with 300 mg of trovafloxacin. Theophylline concentrations in plasma and trovafloxacin in serum were determined using reverse-phase high-performance liquid chromatography. There was no significant difference between the geometric mean values for Cmax of theophylline, 6.42 micrograms/mL and 6.00 micrograms mL on days 1 and 8, respectively. A change (P = 0.032) in the geometric mean of the area under the concentration-time curve extrapolated to infinity (AUC0-infinity) for theophylline was noted for trovafloxacin was administered. Mean terminal phase elimination rate constants (Kes) were reduced (P = 0.001) by 13% after administration of trovafloxacin from day 1 to day 8. In general, changes in theophylline clearance of less than 20% are unlikely to be of clinical significance. In this study, oral administration of trovafloxacin in 300 mg doses to achieve steady-state concentration resulted in an 8.4% increase in the extent of systemic exposure (AUC0-infinity) to theophylline. Assuming that this AUC change is based on oral clearance and not absorption, one would not expect to see clinically significant changes in the pharmacokinetics of theophylline. No pharmacodynamic changes resulted from the pharmacokinetic changes of theophylline.

Administration, Oral↗
PubMed2004

In vitro and in vivo metabolism of pyronaridine characterized by low-energy collision-induced dissociation mass spectrometry with electrospray ionization.

The in vitro and in vivo metabolism of pyronaridine, an antimalarial agent, was investigated in rats and humans. In vitro incubation of pyronaridine with rat and human liver microsomes resulted in the formation of 11 metabolites, with pyronaridine quinoneimine (M3) as the major metabolite. The structures of pyronaridine metabolites were characterized on the basis of the product ion mass spectra obtained under low-energy collision-induced dissociation (CID) ion trap mass spectrometry. Both pyronaridine (m/z 518) and M3 (m/z 516) produced the same product ion (m/z 447). These results could be explained by the characteristic neutral loss of a 69 Da fragment from M3 via gamma-H rearrangement and 1,7 sigmatropic shift, whereas the neutral loss of a 71 Da fragment from the pyronaridine occurred by charge site-initiated heterolytic cleavage. These fragmentations were further supported by the tandem mass spectrum of D(3)-pyronaridine. Other metabolites generated in the microsomal incubations were carbonylated, hydroxylated and O-demethylated derivatives. Pyronaridine and its metabolites were detected in both feces and urine after intraperitoneal administration to rats. The in vivo metabolic profile in rats was different from the in vitro profile. M3, a chemically reactive quinonimine, was not detected whereas O-demethylated derivatives (M14, M15, M16, and M19) were identified in fecal and urinary extracts. The role of quinoneimine metabolites in pyronaridine-caused toxicity should be further evaluated, although these metabolites or their conjugates were not detected in urine and feces.

Animals↗
PubMed2000

Inhibitory effects of the quinolone antibiotics trovafloxacin, ciprofloxacin, and levofloxacin on osteoblastic cells in vitro.

We studied the inhibitory effects of the fluoroquinolones levofloxacin, ciprofloxacin, and trovafloxacin on growth and extracellular matrix mineralization in MC3T3-E1 osteoblast-like cell cultures. Levofloxacin had the least inhibitory effect on cell growth, with a 50% inhibitory concentration of approximately 80 microg/ml at 48 and 72 hours. Ciprofloxacin had an intermediate degree of inhibition, with a 50% inhibitory concentration of 40 microg/ml at 48 and 72 hours. Trovafloxacin exerted a profound inhibitory effect on cell growth, with a 50% inhibitory concentration of 0.5 microg/ml, lower than clinically achievable serum levels. The decreased cell counts with up to 2.5 microg/ml of trovafloxacin and with up to 40 microg/ml of ciprofloxacin were not associated with decreased rates of 5-bromo-2'-deoxyuridine incorporation per cell. Alatrovafloxacin, the L-alanyl-l-alanine prodrug of trovafloxacin, exerted effects on proliferation and 5-bromo-2'-deoxyuridine incorporation similar to those of the parent compound. The quinolones evaluated also inhibited extracellular matrix mineralization by MC3T3-E1 cells. Treatment of confluent cultures with trovafloxacin, ciprofloxacin, or levofloxacin resulted in strong inhibition of calcium deposition, as determined on day 14 by alizarin red staining and biochemical analysis. The effect was apparent with 2.5-5 microg/ml of each of the three antibiotics tested and progressively increased to more than a 90% decline in the calcium/protein ratio with 20-40 microg/ml antibiotic concentration. Further in vivo studies are advocated to evaluate the relevance of the in vitro cytotoxicity reported here to bone healing in orthopaedic patients.

Animals↗
PubMed2006

Orexin-A is composed of a highly conserved C-terminal and a specific, hydrophilic N-terminal region, revealing the structural basis of specific recognition by the orexin-1 receptor.

Orexins-A and B, also called hypocretins-1 and 2, respectively, are neuropeptides that regulate feeding and sleep-wakefulness by binding to two orphan G protein-coupled receptors named orexin-1 (OX(1)R) and orexin-2 (OX(2)R). The sequences and functions of orexins-A and B are similar to each other, but the high sequence homology (68%) is limited in their C-terminal half regions (residues 15-33). The sequence of the N-terminal half region of orexin-A (residues 1-14), containing two disulfide bonds, is very different from that of orexin-B. The structure of orexin-A was determined using two-dimensional homonuclear and (15)N and (13)C natural abundance heteronuclear NMR experiments. Orexin-A had a compact conformation in the N-terminal half region, which contained a short helix (III:Cys6-Gln9) and was fixed by the two disulfide bonds, and a helix-turn-helix conformation (I:Leu16-Ala23 and II:Asn25-Thr32) in the remaining C-terminal half region. The C-terminal half region had both hydrophobic and hydrophilic residues, which existed on separate surfaces to provide an amphipathic character in helices I and II. The nine residues on the hydrophobic surface are also well conserved in orexin-B, and it was reported that the substitution of each of them with alanine resulted in a significant drop in the functional potency at the receptors. Therefore, we suggest that they form the surface responsible for the main hydrophobic interaction with the receptors. On the other hand, the residues on the hydrophilic surface, together with the hydrophilic residues in the N-terminal half region that form a cluster, are known to make only small contributions to the binding to the receptors through similar alanine-scan experiments. However, since our structure of orexin-A showed that large conformational and electrostatical differences between orexins-A and B were rather concentrated in the N-terminal half regions, we suggest that the region of orexin-A is important for the preference for orexin-A of OX(1)R.

Amino Acid Sequence↗
PubMed2003

Antifungal compounds from Zanthoxylum chiloperone var. angustifolium.

An alkaloidal extract of the stem barks of Zanthoxylum chiloperone var. angustifolium exhibited antifungal activity against Candida albicans, Aspergillus fumigatus and Trichophyton mentagrophytes var. interdigitale using a TLC bioautographic method. Bioassay-guided fractionation of this extract resulted in the isolation of two active compounds identi fi ed as canthin-6-one and 5-methoxycanthin-6-one. Canthin-6-one exhibited a broad spectrum of activities against Aspergillus fumigatus, A. niger, A. terreus, Candida albicans, C. tropicalis, C. glabrata, Cryptococcus neoformans, Geotrichum candidum, Saccharomyces cerevisiae, Trichosporon beigelii, Trichosporon cutaneum and Trichophyton mentagrophytes var. interdigitale with MICs values between 5.3 and 46 micro mol/L. 5-methoxy-canthin-6-one was active against only Trichophyton mentagrophytes var. interdigitale with a MIC value of 12.3 micro mol/L.

Antifungal Agents↗
PubMed2002

Chemical constituents and biological activities of Zanthoxylum usambarense.

Bioassay-guided fractionation of the dichloromethane extracts of the roots and the bark of Zanthoxylum usambarense led to the isolation of two physiologically active compounds, i.e. canthin-6-one 1 (fungicide) and pellitorine 4 (insecticide). Together with oxychelerythrine 2, norchelerythrine 3, (+)-sesamin 5 and (+)-piperitol-3,3-dimethylallyl ether 6, they were isolated for the first time from this plant.

Animals↗
PubMed2003

A direct injection high-throughput liquid chromatography tandem mass spectrometry method for the determination of a new orally active alphavbeta3 antagonist in human urine and dialysate.

A generic high-throughput liquid chromatography (HTLC) tandem mass spectrometry (MS/MS) assay for the determination of compound I in human urine and dialysate (hemodialysis) was developed and validated. By using the HTLC on-line extraction technique, sample pretreatment was not necessary. The sample was directly injected onto a narrow bore large particle size extraction column (50 x 1.0 mm, 60 microm) where the sample matrix was rapidly washed away using a high flow rate (5 mL/min) aqueous mobile phase while analytes were retained. The analytes were subsequently eluted from the extraction column onto an analytical column using an organic-enriched mobile phase prior to mass spectrometric detection. The analytes were then eluted from the analytical column to the mass spectrometer for the determination. The linear dynamic range was 2.0-6000 ng/mL for the urine assay and 0.1-300 ng/mL for the dialysate assay. Intraday accuracy and precision were evaluated by analyzing five replicates of calibration standards at all concentrations used to construct the standard curve. For the urine assay, the precision (RSD%, n=5) ranged from 1.9 to 8.0% and the accuracy ranged from 87.8 to 105.2% of nominal value. For the dialysate assay, the precision (RSD%, n=5) ranged from 1.1 to 10.0% and the accuracy from 94.5 to 105.2% of nominal value. In-source fragmentation of the acyl glucuronide metabolite (compound III) did not interfere with the determination of parent compound I. The developed HTLC/MS/MS methodology was specific for compound I in the presence of compound III. Column life-time is increased and sample analysis time is decreased over traditional reversed-phase methods when direct injection assays for urine and dialysate are coupled with the technology of HTLC.

Chromatography, High Pressure Liquid↗
PubMed1992

Differential effects of amfonelic acid on the haloperidol- and clozapine-induced increase in extracellular DOPAC in the nucleus accumbens and the striatum.

This study compares the effects of the nonamphetamine stimulant amfonelic acid on the increase in extracellular 3,4-dihydroxyphenylacetic acid (DOPAC) induced by haloperidol and clozapine in the nucleus accumbens and the striatum of anaesthetized rats. DOPAC was simultaneously recorded in both regions using differential pulse voltammetry with electrically pretreated carbon fibre electrodes. Amfonelic acid (2.5 mg/kg s.c.) did not alter basal striatal DOPAC but produced a significant reduction in extracellular DOPAC in the nucleus accumbens. Haloperidol (1 mg/kg s.c.) increased extracellular DOPAC in both regions. When amfonelic acid was injected 5 min before haloperidol, the increase in DOPAC was potentiated in both the nucleus accumbens and the striatum but with a greater effect in the striatum. Clozapine (30 mg/kg i.p.) increased extracellular DOPAC in both regions, an effect partially attenuated by amfonelic acid in both regions but to a greater extent in the striatum. When ritanserin (5 mg/kg i.p.), a serotonergic antagonist (5-HT-2), was co-administered with haloperidol, the potentiation by amfonelic acid of the increase in extracellular DOPAC induced by haloperidol was attenuated in both the nucleus accumbens and the striatum. The present results confirm that amfonelic acid can be used to discriminate neurochemically between haloperidol and clozapine in vivo. The effects of amfonelic acid on the neuroleptic-induced changes in extracellular DOPAC were greater in the striatum than the nucleus accumbens. These results further demonstrate that both neuroleptics increase dopamine metabolism in the two brain regions but by different mechanisms, supporting the view that the regulation of dopamine metabolism differs in the two regions.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Interaction of amfonelic acid with antipsychotic drugs on dopaminergic neurons.

The effects of two inhibitors of dopamine (DA) reuptake, amfonelic acid and GBR 12909, on the clozapine- and haloperidol-induced increases in DA synthesis, release, and metabolism were investigated in the rat. In the striatum, as well as in the nucleus accumbens, the haloperidol-induced increase in tissue concentrations of dihydroxyphenylacetic acid (DOPAC) or the accumulation of dihydroxyphenylalanine (DOPA) was potentiated or unaltered, respectively, in rats treated with amfonelic acid. In contrast, amfonelic acid attenuated the stimulatory effects of clozapine on DOPAC concentrations and DOPA accumulation in both brain regions. GBR 12909 also differentially affected the haloperidol- and clozapine-induced increases in DOPAC concentrations. However, the clozapine-induced increase in DOPA accumulation in the median eminence was not significantly altered by treatment with amfonelic acid. The haloperidol-induced increase in the extracellular concentrations of DA and DOPAC in the striatum also was potentiated by amfonelic acid, whereas the increase elicited by clozapine was suppressed. The increase in extracellular DA produced by the administration of morphine or the coadministration of ritanserin, a 5-HT2 antagonist, and haloperidol also was potentiated by amfonelic acid. The ability of amfonelic acid to distinguish between the actions of clozapine and haloperidol on nigrostriatal and mesocorticolimbic DA neurons does not appear to be related to differences in the effects of the drugs on DA autoreceptors or 5-HT2 receptors. Moreover, the mechanism through which clozapine activates tuberoinfundibular DA neurons may differ from that which is involved in the activation of nigrostriatal or mesocorticolimbic DA neurons.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Changes in dopamine, serotonin and their metabolites in discrete brain areas of rat offspring after in utero exposure to cocaine or related drugs.

The concentrations of dopamine (DA), serotonin (5HT) and their metabolites were quantified in 5 brain areas of rats exposed to saline, cocaine (15 mg/kg b.i.d.), amitriptyline (10 mg/kg), or amfonelic acid (AFA, 1.5 mg/kg) throughout gestation. Male pups from 3 similarly treated dams were fostered to 2 surrogate dams. The process of breeding and rearing was repeated 4 times with new dams to build the groups to 4-12, since only one pup per litter was used for any one measurement. AFA was used to mimic the dopamine (DA) uptake blockade and stimulant properties of cocaine and amitriptyline was used to mimic the other pharmacological effects of cocaine. At postnatal days (PND) 30, 60, and 180, one pup per litter was removed for HPLC analysis of monoamines. A second pup received 0.3 mg/kg haloperidol, catalepsy assessed after 1 hr, and the brain used for analysis. The cataleptic response to haloperidol was unaffected by any prenatal treatment. The striatum from PND 30 cocaine rats had decreased levels of DA without a decrease in DA metabolites. At PND 60 in cocaine exposed rats, DA and DOPAC concentrations were increased, and 5HT levels were decreased in the striatum. The amitriptyline-exposed group exhibited decreased 5HT and 5-HIAA levels in the striatum. The hypothalamus of the cocaine group had lower levels of 5-HIAA, and other brain areas had a trend for lower levels of 5HT and 5-HIAA. At PND 180, DOPAC was increased in the striatum and prefrontal cortex of the cocaine group. Haloperidol-induced altered monoamine metabolism was unaffected by any prenatal treatment at any age. These data suggest that age-related changes in the DA and 5HT neurotransmission systems occur in rats exposed prenatally to cocaine. However, the ability of the dopaminergic system to respond to a challenge by a DA receptor blocker is unaltered by these in utero treatments.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2000

Plasmodium yoelii nigeriensis (MDR)-efficacy of oral pyronaridine against multidrug-resistant malaria in Swiss mice.

A multidrug-resistant strain of Plasmodium yoelii nigeriensis (MDR) showing a wide spectrum of resistance to chloroquine, amodiaquine, mepacrine, mefloquine, halofantrine, quinine, and quinidine was used in this study for in vivo evaluation of the blood schizontocidal activity of pyronaridine, a topoisomerase II inhibitor, in Swiss mice. The parasite produces 100% lethal infection in mice. The drug was administered orally once a day from day 0 onward. The initial studies showed that low doses of pyronaridine (0.625 to 5.0 mg base/kg x9 days) did not completely control blood-induced P. yoelii nigeriensis infection. Finally a series of doses of pyronaridine ranging from 1.25 to 30.0 mg/kg administered orally for 7 consecutive days were evaluated and in spite of high level of resistance to standard antimalarials, the parasite P. yoelii nigeriensis has shown complete susceptibility to pyronaridine (15 mg/kg dose x7 days). The present paper also compares the merits of a single MDR strain vs a battery of different resistant lines for quick antimalarials screening.

Animals↗
PubMed2002

Plasmodium falciparum: in vitro interactions of artemisinin with amodiaquine, pyronaridine, and chloroquine.

In the scenario of drug-resistant Plasmodium falciparum malaria combination therapy represents an effective approach. Artemisinin and its derivatives are of special interest because they represent the most effective group of compounds against multidrug-resistant malaria with a rapid onset of action and a short half-life. Interactions of artemisinin with amodiaquine, pyronaridine, and chloroquine were therefore investigated against three strains of P. falciparum using a 48-h in vitro culture assay. Two of the strains were chloroquine sensitive and one was partially chloroquine resistant. Observed effective concentrations (O) of the combined compounds at different concentration ratios were calculated for different degrees of inhibition (EC50, EC90, EC99) and compared to expected calculated effective concentrations (E) using a probit method. Synergism with mean O/E EC90 values of 0.25 and 0.8 were found with the combination of artemisinin and the two Mannich bases, amodiaquine and pyronaridine, respectively, whereas chloroquine showed addition with a mean value of 1.2. Although both amodiaquine and chloroquine are 4-aminoquinolines, their interaction with artemisinin appears to be different. The combination of artemisinin with amodiaquine represents an important option for the treatment of falciparum malaria.

Amodiaquine↗
PubMed2000

The inhaled administration of KF19514, a phosphodiesterase 4 and 1 inhibitor, prevents antigen-induced lung inflammation in guinea pigs.

We examined in this study the effect of KF19514, a phosphodiesterase 4 and 1 inhibitor, on antigen-induced lung inflammation by inhaled administration in guinea-pigs. It was previously reported that inhaled KF19514 prevented antigen-induced bronchoconstriction and platelet-activating factor (PAF)-induced lung inflammation. In fact, a variety of factors other than PAF are related to lung inflammation in real subjects with asthma. Guinea-pigs were actively sensitized by exposure to ovalbumin (OA). Fifteen to 20 days later, the guinea pigs were challenged by exposure to aerosols of five successively increasing concentrations of OA (0.01, 0.1, 0.5, 1 and 5 mg/ml). Bronchoalveolar lavages (BALs) were performed 24 h after the antigen challenge, and airway hyperresponsiveness to acetylcholine (ACh) was studied 24 h after the challenge by measuring lung resistance and dynamic compliance. Ovalbumin antigen challenge produced a marked and significant eosinophil accumulation in the BAL fluids and airway hyperresponsiveness to ACh 24 h after the challenge. Inhaled KF19514 (0.01-0.1%) inhibited the eosinophil accumulation significantly and dose-dependently but inhaled rolipram (0.01-0.1%) and aminophylline (0.1-1%) did not. In addition, the development of airway hyperresponsiveness was prevented by inhaled KF19514 (0.01%) but not by inhaled rolipram (0.01%) and aminophylline (0.1%). Based on these data, KF19514 was suggested to be a promising drug in the treatment of asthma by local administration to the lung.

Acetylcholine↗
PubMed1987

Quinolones.

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Animals↗
PubMed1989

Kinetic properties of the accumulation of 3H-raclopride in the mouse brain in vivo.

The kinetic properties of the accumulation of 3H-raclopride, a selective dopamine (DA) D-2 receptor antagonist, in mouse striatum in vivo was examined under various experimental conditions. The accumulation in striatum was saturable in contrast to that in cerebellum, which linearily increased with the dose. The specific binding of 3H-raclopride in the striatum, defined as the difference in the accumulation in striatum and cerebellum 30 min after the injection was completely inhibited by the D-2 receptor antagonists spiperone and (+)-butaclamol [but not (-)-butaclamol] and the DA receptor agonist N-n-propylnorapomorphine. The mean Bmax value of the specific binding was 40.7 +/- 2.8 pmol/g tissue and the mean apparent KD value, based on the dose injected, was 87.8 +/- 11.5 nmol/kg i.v. (18 different experiments). Pretreatment of the mice with a single injection of reserpine 4 h or 3 days beforehand reduced the apparent KD value which in part seemed to be due to the decreased concentration of synaptic DA. Similarly, gamma-butyrolactone injected immediately before raclopride reduced the apparent KD value, whereas amfonelic acid and (-)-amphetamine increased the observed KD values. These findings indicate competition between endogenous DA and raclopride for the D-2 receptors. Both reserpine and gamma-butyrolactone increased the apparent Bmax value by about 50% which indicates a receptor pool of DA for which raclopride does not compete.

4-Butyrolactone↗