Arzneimittel-Forschung[JOURNAL]
Sun
200 papers
Dose-dependent pharmacokinetics of tyrosol galactoside as an anti-fatigue drug in rats.
Deng Y, Wang Q, Liu X … +2 more , Wang Y, Ding Z
Arzneimittelforschung · 2011 · PMID 21950146 · Publisher ↗
Tyrosol galactoside (TG) is a new candidate anti-fatigue agent under development. In order to have a good understanding of its pharmacokinetic characters, the paper describes the dose-dependent pharmacokinetics of TG in...
Tyrosol galactoside (TG) is a new candidate anti-fatigue agent under development. In order to have a good understanding of its pharmacokinetic characters, the paper describes the dose-dependent pharmacokinetics of TG in rats after oral and intravenous administration. TG was rapidly absorbed after oral administration and cleared with first-order rate, for the plasma half-life was independent of dose. C(max) and AUC(0-infinity) after both intravenous and oral dosing were all linearly correlated with the dose, as the regression correlation coefficient (R) was 0.998, 0.989 and 0.994 for AUC(0-infinity) (i.v., P < 0.01) AUC(0-infinity) (i.g., P < 0.01) and C(max) (i. g., P < 0.01), respectively. However, these parameters increased less than proportionally with increasing dose. In addition, the apparent volume of distribution (Vd) and the apparent clearance (Cl) seemed to be affected by the dose.
Liquid chromatographic tandem mass spectrometric assay for simultaneous quantification of compound 97/78 and its in vivo metabolite 97/63, a novel trioxane antimalarial, in human plasma and its application to a protein binding study.
Kushwaha HN, Gautam N, Singh SK
Arzneimittelforschung · 2011 · PMID 21899212 · Publisher ↗
A sensitive, selective and specific LC-MS/ MS assay for simultaneous quantification of compound 97/78 and its active in vivo metabolite 97/63, a novel 1,2,4-trioxane antimalarial, in human plasma has been developed and v...
A sensitive, selective and specific LC-MS/ MS assay for simultaneous quantification of compound 97/78 and its active in vivo metabolite 97/63, a novel 1,2,4-trioxane antimalarial, in human plasma has been developed and validated using alpha-arteether as internal standard (IS). Extraction from plasma involves a simple protein precipitation method. The analytes were chromatographed on a Columbus C18 column with guard by isocratic elution with acetonitrile:ammonium acetate buffer (10 mM, pH 4.0) (80:20 v/v) as mobile phase at a flow rate of 0.45 mL min(-1) and analyzed in multiple reaction-monitoring (MRM) positive ion mode. The chromatographic run time was 4.0 min. The weighted (1/x2) calibration curves were linear over a range of 1.56-200 ng mL(-1) with correlation coefficients > 0.998. For both analytes, the limit of detection (LOD) and lower limit of quantification (LLOQ) were 0.5 ng mL(-1) and 1.56 ng mL(-1), respectively. The recovery of 97/78, 97/63 and IS from spiked control samples were > 90% and their matrix suppression obtained were < 8 %. The accuracy (% bias) and precision (%RSD) for both analytes were < 6.78%. Both analytes were stable after three freeze-thaw cycles (% deviation < 12.80), long-term for 30 days in plasma at -60 degrees C (% deviation < 14.38), for 8 h on bench top in plasma at ambient temperature (% deviation < 1.52) and also in the auto-sampler for 12 h (% deviation < 3.9%). The validated method was successfully applied to a protein binding study of compound 97/78 and metabolite 97/63 in human plasma. Furthermore, the validated method will be applicable to pharmacokinetics, bioavailability and metabolism in various clinical phases and in drug interaction studies.
Usefulness of suplatast tosilate, a Th2 cytokine inhibitor based on the Th1/Th2 ratio for allergic disease in children: a retrospective study.
Yoshihara S, Fukuda H, Arisaka O
Arzneimittelforschung · 2011 · PMID 21899211 · Publisher ↗
BACKGROUND: Children with an atopic predisposition are presumed to have persistent Th2 dominance and thus develop allergic diseases. METHODS: A total of 45 children who fell to atopic dermatitis and/or intermittent asthm...
BACKGROUND: Children with an atopic predisposition are presumed to have persistent Th2 dominance and thus develop allergic diseases. METHODS: A total of 45 children who fell to atopic dermatitis and/or intermittent asthma or mild persistent asthma between 2002 and 2007 were enrolled and retrospectively analyzed. Twenty-four children were administered oral treatment with the immunopharmacological drug suplatast tosilate (CAS 94055-76-2) at a dose of 3 mg/kg twice daily. Twenty-one of the control group were not administered oral suplatast tosilate but treated with other drugs. Blood was collected before and after administering suplatast tosilate or other drugs, and Th1 cells, Th2 cells, the Th1/Th2 ratio, the total IgE levels, and the eosinophil count were measured. RESULTS: In the suplatast tosilate group, Th1 cells increased to 7.9 (1.2-19.8) % from 5.5 (1.1-13.5) % (Wilcoxon P < 0.05), while the Th2 cells showed a decrease from 1.3 (0.5-6.5) % to 1.6 (0.4-2.9) %, but the differences were not significant. The Th1/Th2 ratio increased significantly from 4.1 (0.9-7.4) to 5.6 (1.3-15.5) (shifting to Th1 dominance) in the suplatast tosilate group (Wilcoxon P < 0.05), while it shifted to Th2 dominance in the control group (increased from 4.5 (2.2-12.2) to 5.7 (1.6-11.8)) but did not show significant difference. CONCLUSIONS: The Th1/Th2 ratio increased significantly after administration of suplatast tosilate, shifting to Th1 dominance. Therefore suplatast tosilate improves Th2 dominance and may inhibit subsequent progression of allergy over the long term.
Pharmacokinetics of betamethasone and betamethasone 17-monopropionate in Chinese healthy volunteers after intramuscular injection of betamethasone phosphate/betamethasone dipropionate.
He C, Fan H, Tan J … +4 more , Zou J, Zhu Y, Yang K, Hu Q
Arzneimittelforschung · 2011 · PMID 21899210 · Publisher ↗
The aim of this study was to evaluate the pharmacokinetic profiles of betamethasone (BOH, CAS 378-44-9) and betamethasone 17-monopropionate (B17P), the active metabolites of betamethasone phosphate (BSP) and betamethason...
The aim of this study was to evaluate the pharmacokinetic profiles of betamethasone (BOH, CAS 378-44-9) and betamethasone 17-monopropionate (B17P), the active metabolites of betamethasone phosphate (BSP) and betamethasone dipropionate (BDP), respectively, after administration of betamethasone i.m. (BSP 2 mg and BDP 5 mg). After ten healthy volunteers had received a single-dose intramuscular adminitration of betamethasone i.m., blood samples were collected pre-dose and for 336 h postdose. The plasma levels of B17P and BOH were measured by liquid chromatography-tandem mass spectrometry (LC-MS/ MS). When compared to BOH, B17P exhibited a longer time to maximum concentration (15.0 +/- 9.0 h vs. 2.8 +/- 1.7 h), a lower Cmax (0.6 +/- 0.2 ng/mL vs. 14.5 +/- 3.7 ng/mL), and a much longer half-life (80.8 +/- 22.7 h vs. 9.6 +/- 3.6 h). Betamethasone i.m. produced rapid onset and sustained action through an initial rapid-increased plasma concentration of BOH and a sustained plasma concentration of B17P, respectively.
A simple and sensitive liquid chromatography method for the determination of low dihydrocodeine concentrations in human plasma: its application in Chinese healthy volunteers.
Tang W, Liu X, Qiu X … +3 more , Yuan S, Wang J, Chen H
Arzneimittelforschung · 2011 · PMID 21899209 · Publisher ↗
A simple, sensitive and modified method was developed for determination of low dihydrocodeine (CAS 125-28-0) concentrations in human plasma by high performance-liquid chromatography (HPLC) with diode array detector. Meas...
A simple, sensitive and modified method was developed for determination of low dihydrocodeine (CAS 125-28-0) concentrations in human plasma by high performance-liquid chromatography (HPLC) with diode array detector. Measurement was performed on a Zorbax XDB-C18 analytical column together with a XDB-C18 precolumn at 40 degrees C after a simple one-step extraction. An isocratic mobile phase consisting of acetonitrile-0.1% trifluoroacetic acid (TFA)-water (12:40:48, v/v/v), was run at a flow rate of 1.0 mL/min. Good chromatographic separation was achieved in less than 6.2 min. This assay was linear over a concentration range of 2.50-100 ng/mL with a lower limit of quantification at 2.50 ng/mL. The intra- and inter-day precision (relative standard deviation) was less than 6.00 and 6.62%, respectively, at all concentration levels studied, while the intra- and inter-day accuracy was 1.50-3.73% and -1.35-1.92%, respectively. Recoveries were 76.10-83.81% with coefficients of variation of 1.86-6.93%. Stability of dihydrocodeine in plasma proved to be good. The validated method was successfully applied to a bioequivalence study of dihydrocodeine after a single oral administration of 20 mg dihydrocodeine tartrate in Chinese healthy male volunteers.
Assessment of the extent of oxidative stress induced by intravenous ferumoxytol, ferric carboxymaltose, iron sucrose and iron dextran in a nonclinical model.
Toblli JE, Cao G, Oliveri L … +1 more , Angerosa M
Arzneimittelforschung · 2011 · PMID 21899208 · Publisher ↗
Intravenous (i.v.) iron is associated with a risk of oxidative stress. The effects of ferumoxytol, a recently approved i.v. iron preparation, were compared with those of ferric carboxymaltose, low molecular weight iron d...
Intravenous (i.v.) iron is associated with a risk of oxidative stress. The effects of ferumoxytol, a recently approved i.v. iron preparation, were compared with those of ferric carboxymaltose, low molecular weight iron dextran and iron sucrose in the liver, kidneys and heart of normal rats. In contrast to iron sucrose and ferric carboxymaltose, low molecular weight iron dextran and ferumoxytol caused renal and hepatic damage as demonstrated by proteinuria and increased liver enzyme levels. Higher levels of oxidative stress in these tissues were also indicated, by significantly higher levels of malondialdehyde, significantly increased antioxidant enzyme activities, and a significant reduction in the reduced to oxidized glutathione ratio. Inflammatory markers were also significantly higher with ferumoxytol and low molecular weight iron dextran rats than iron sucrose and ferric carboxymaltose. Polarographic analysis suggested that ferumoxytol contains a component with a more positive reduction potential, which may facilitate iron-catalyzed formation of reactive oxygen species and thus be responsible for the observed effects. Only low molecular weight iron dextran induced oxidative stress and inflammation in the heart.
Relative bioavailability and pharmacokinetic study of two trimetazidine modified release formulations in healthy Bangladeshi male volunteers.
Chowdhury MM, Ullah MA, Iqbal N … +7 more , Al Maruf A, Shohag MH, Harun S, Akter KA, Begum B, Latif AH, Hasnat A
Arzneimittelforschung · 2011 · PMID 21899207 · Publisher ↗
Trimetazidine (CAS 5011-34-7) is an effective and well-tolerated antianginal drug that possesses protective properties against ischemia-induced heart injury. The relative bioavailability and pharmacokinetic characteristi...
Trimetazidine (CAS 5011-34-7) is an effective and well-tolerated antianginal drug that possesses protective properties against ischemia-induced heart injury. The relative bioavailability and pharmacokinetic characteristics of two modified release formulations of 35 mg trimetazidine, one as the test product (Metacard MR) and one as the reference product, were compared in healthy Bangladeshi male volunteers. The randomized, two-way crossover study was conducted in 24 healthy male volunteers after administration of a single 35 mg dose of each modified release formulation after 12-h overnight fasting, with a washout period of two weeks. Blood samples were collected at various time intervals following oral administration and analyzed for trimetazidine concentrations using a validated HPLC method. The pharmacokinetic parameters were determined by a non-compartmental method. After administering a single dose of 35 mg of each trimetazidine formulation, the obtained mean (SD) values for the test and reference products were 104.78 (29.3) and 98.57 (28.7) ng/ml for Cmax; 4.00 (1.1) and 3.54 (1.32) h for t(max); 423.81 (173.9) and 410.01 (195.87) ng x h/ml for AUC0-12; and 472.51 (195.2) and 462.78 (225.13) ng x h/ml for AUC0-infinity respectively. The mean t1/2 was found 3.69 (1.1) h and 3.45 (0.72) h for test and reference products respectively. From paired t-test, no significant differences were observed (p > 0.05) for any pharmacokinetic parameters. The 90% confidence intervals of the test/reference mean ratios of the In-transformed AUC0-12, AUC0-infinity, and Cmax mean values were 106.19% (97.16%-116.06%), 104.74% (95.04%-115.42%) and 106.30% (95.23%-118.66%), respectively. The two formulations demonstrated similar bioavailability with respect to both the rate and extent of trimetazidine absorption.
Effects of calcium antagonists and agonists on isolated human v. saphena magna used for coronary artery bypass grafting and guinea pig's papillary muscle.
Garaliene V, Barsys V, Jakuska P … +2 more , Krauze A, Duburs G
Arzneimittelforschung · 2011 · PMID 21899206 · Publisher ↗
BACKGROUND: The goal of this study was to investigate the movement of contraction-relaxation effects on isolated human blood vessel samples by the actions of amlodipine (CAS 88150-42-9), cerebrocrast (CAS 118790-71-9), d...
BACKGROUND: The goal of this study was to investigate the movement of contraction-relaxation effects on isolated human blood vessel samples by the actions of amlodipine (CAS 88150-42-9), cerebrocrast (CAS 118790-71-9), diltiazem (CAS 42399-41-7), and a benzimidazole derivative. Additionally, their effects on isometric contraction force and the duration of the action potential (AP) were measured. METHODS: The experiments were carried out on isolated human v. saphena magna samples and papillary muscles of adult guinea pigs. Isometric contraction and the AP were recorded using a force transducer and standard microelectrode technique. RESULTS: Phenylephrine (10(-4) M) caused contractions of vein rings to 928 +/- 76.5 mg. All the tested agents at a concentration of 10(-7)-10(-4) M significantly relaxed the smooth muscle in a dose-dependent manner. The weakest response was shown by amlodipine. Pre-treatment with 50 microM of amlodipine, diltiazem and benzimidazole for 30 min significantly increased the magnitude of the contraction induced by phenylephrine in concentration-dependent (10(-6)-10(-4) M) fashion but only in the benzimidazole group versus other tested agents and the control. The benzimidazole derivative caused augmentation of isometric contraction of the papillary muscles and negligible lengthening of AP duration; the other agents tested showed opposite effects. CONCLUSION: These results show that agents possessing positive or negative inotropic action significantly relaxed the isolated vein samples precontracted with phenylephrine. These responses point to a different mechanism of action underlying both calcium antagonist and agonist effects even though their action ultimately resulted in vasodilatation.
Effect of mangiferin, a naturally occurring glucoxylxanthone, on fear memory in rats.
Andreu GL, Maurmann N, Reolon GK … +3 more , de Farias CB, Delgado R, Roesler R
Arzneimittelforschung · 2011 · PMID 21899205 · Publisher ↗
Mangiferin (1,3,6,7-tetrahydroxy-2-[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] -xanthen-9-one, CAS 4773-96-0), a naturally occurring glucosylxanthone, is widely distributed in higher plants and a constituent of folk me...
Mangiferin (1,3,6,7-tetrahydroxy-2-[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] -xanthen-9-one, CAS 4773-96-0), a naturally occurring glucosylxanthone, is widely distributed in higher plants and a constituent of folk medicine. In the present study the effect of systemic administration of mangiferin on behavioural outcomes of neurological function in normal rats was investigated. A single intraperitoneal injection of mangiferin (10, 50 and 100 mg/kg body weight) immediately post-training produced an impairment of long-term memory for aversive training and a reduced freezing in a dose independent manner, when given immediately post-training. The administration of mangiferin 6 h post-training did not affect fear memory. The results indicate that mangiferin might induce deficits of emotionally motivated memory.
Synthesis and biological evaluation of some novel quinoxaline derivatives as anticonvulsant agents.
Elhelby AA, Ayyad RR, Zayed MF
Arzneimittelforschung · 2011 · PMID 21899204 · Publisher ↗
In view of their expected anticonvulsant activity, some new derivatives of quinonxaline (V1-7) were designed and synthesized by condensation of different aromatic aldehydes with 2-(2-oxo-3-phenylquinoxalin-1(2H)-yl)aceto...
In view of their expected anticonvulsant activity, some new derivatives of quinonxaline (V1-7) were designed and synthesized by condensation of different aromatic aldehydes with 2-(2-oxo-3-phenylquinoxalin-1(2H)-yl)acetohydrazide (IV). All synthesized compounds were isolated and confirmed by IR, 1H-NMR, MS, elemental analysis and then tested as anticonvulsant agents. Compound V3 and V1 showed the highest anticonvulsant effect with anticonvulsant potency relative to phenobarbital sodium of 0.8 and 0.75 whereas compound V5 exhibited the lowest relative potency of 0.09. The other compounds showed variable activity between these values as follows: V2 = 0.19, V4 = 0.41, V6 = 0.1 and V7 = 0.15. All compounds showed less activity than the reference compound phenobarbital. But the compounds provided a basis for further optimization.
Synthesis and pharmacological evaluation of some quinoline derivatives as potential cognition enhancers.
Piplani P, Rani A, Saihgal R … +1 more , Sharma M
Arzneimittelforschung · 2011 · PMID 21899203 · Publisher ↗
The present paper describes the synthesis of a series of substituted 6-amino (1a-c) and 8-aminoquinoline derivatives (2b-c) and the evaluation of their ability to prevent the memory decline using a behavioural model, i.e...
The present paper describes the synthesis of a series of substituted 6-amino (1a-c) and 8-aminoquinoline derivatives (2b-c) and the evaluation of their ability to prevent the memory decline using a behavioural model, i.e. the elevated plus maze test. The effect of the candidate drugs on the activity of acetylcholinesterase was studied using the enzyme source from the mouse brain. The structures of the synthesized compounds were confirmed by UV, IR, 1H-NMR and elemental analysis. The 6-aminoquinoline derivative [6-(4-pyridyl)methylaminoquinoline] (1c) oxalate showed maximum % retention (50% at 5 mg/kg and 75% at 10 mg/kg) in the elevated plus maze test and maximum % inhibition (71% at 25 microM) of AChE on biochemical evaluation.
Synthesis of some Mannich bases with dimethylamine and their hydrazones and evaluation of their cytotoxicity against Jurkat cells.
Kucukoglu K, Gul M, Atalay M … +4 more , Mete E, Kazaz C, Hanninen O, Gul HI
Arzneimittelforschung · 2011 · PMID 21827048 · Publisher ↗
1-Aryl-3-dimethylamino-1-propanone hydrochlorides type mono Mannich bases, D series, and corresponding hydrazone derivatives, K series, were synthesized and their cytotoxicity was tested against Jurkat cells (transformed...
1-Aryl-3-dimethylamino-1-propanone hydrochlorides type mono Mannich bases, D series, and corresponding hydrazone derivatives, K series, were synthesized and their cytotoxicity was tested against Jurkat cells (transformed human T-lymphocytes). The aryl part was changed as phenyl in D1 and K1, 4-methylphenyl in D2 and K2, 4-methoxyphenyl in D3 and K3, 4-hydroxyphenyl in D4 and K4, 4-chlorophenyl in D5 and K5, 3-methoxyphenyl in D6 and K6, 4-fluorophenyl in D7 and K7, 4-bromophenyl in D8 and K8, 3-hydroxyphenyl in D9 and K9, and 2-acetylthiophene in D10 and K10. Of the compounds synthesized, K2, K3, K5, K6, K7, K8, K9, and K10 are reported for the first time. Cytotoxic activities of the D and K series were compared with each other to see alterations in bioactivity depending on the chemical structures in Jurkat cells. Cytotoxicities of the compounds synthesized were also compared with the reference compound, 5-fluorouracil (CAS 148-82-3). Mono Mannich bases, D1 (3.60 times), D2 (4.45 times), D3 (2.46 times), D4 (3.52 times), D5 (5.18 times), D6 (3.20 times), D7 (3.23 times), D8 (3.95 times), D9 (3.36 times) and D10 (3.99 times) had 2.46-5.18 times higher cytotoxic potency than the reference compound 5-fluorouracil against Jurkat cells, while hydrazones K1 (4.92 times), K2 (4.65 times), K3 (6.04 times), K4 (6.34 times), K5 (4.67 times), K6 (5.12 times), K7 (5.39 times), K8 (8.31 times), K9 (4.65 times) and K10 (8.65 times) had 4.65-8.65 times higher cytotoxic potency than the reference compound 5-fluorouracil against the same cell line. On the other hand, hydrazone compounds K1 (1.37 times), K3 (2.46 times), K4 (1.80 times), K6 (1.60 times), K7 (1.67 times), K8 (2.11 times), K9 (1.38 times), and K10 (2.17 times) had 1.37-2.46 times higher cytotoxic potency than their corresponding mono Mannich bases. The results of this study suggest that hydrazones were better compounds compared with the corresponding mono Mannich bases in terms of cytotoxicity, and they may serve as model compounds to develop new cytotoxic agents for further studies.
Synthesis and in vitro antiplasmodial activity of quinoline-ferrocene esters.
N'Da DD, Breytenbach JC, Smith PJ … +1 more , Lategan C
Arzneimittelforschung · 2011 · PMID 21827047 · Publisher ↗
New 4-aminoquinoline-derived esters containing the redox-active ferrocene group brought in by either ferrocenyformic or 4-ferrocenylbutanoic acids were synthesized and tested in vitro for their antiplasmodial activity. T...
New 4-aminoquinoline-derived esters containing the redox-active ferrocene group brought in by either ferrocenyformic or 4-ferrocenylbutanoic acids were synthesized and tested in vitro for their antiplasmodial activity. The results revealed that only esters derived from ferrocenylformic acid were active against both chloroquine (CQ)-resistant Dd2 and CQ-sensitive D10 strains of Plasmodium falciparum. However, none of these showed higher actvity than CQ against the sensitive strain. Ester 16, which possesses a butyl branch in the structure, was the most active of all. With an IC50 of 0.13 mM on the resistant strain, this ester possessed 2.5-fold higher activity than CQ (IC50 = 0.34 mM). All tested esters showed good selectivity towards P. falciparum with indexes higher than 60.
Study on bioavailability difference between clopidogrel bisulfate form I and form II using liquid chromatography/tandem mass spectrometry.
Zou QG, Tan XH, Che WJ … +3 more , Zhang ZJ, Wei P, Ou-Yang PK
Arzneimittelforschung · 2011 · PMID 21827046 · Publisher ↗
The bioavailability of clopidogrel bisulfate (CAS 135046-48-9) form I was compared with that of clopidogrel bisulfate form II in 12 male Sprague-Dawley rats. The rats, randomly divided into two groups, received a single...
The bioavailability of clopidogrel bisulfate (CAS 135046-48-9) form I was compared with that of clopidogrel bisulfate form II in 12 male Sprague-Dawley rats. The rats, randomly divided into two groups, received a single oral dose of 8 mg/kg clopidogrel (CP) bisulfate form I and form II, respectively, under fasting condition. The plasma concentrations of CP and its inactive carboxylic acid metabolite (CAS 144457-28-3, IM) were simultaneously determined by a sensitive, specific LC-MS/MS method. The pharmacokinetic parameters included C(max), T(max), t1/2, AUC(0-t), AUC(0-infinity). The AUC(0-infinity) of CP was 13.78 +/- 0.67 and 11.46 +/- 1.98 ng/ mL x h for CP form I and form II, respectively. The AUC(0-infinity) of IM was 33.08 +/- 5.76 and 21.67 +/- 8.95 microg/mL x h for CP form I and form II, respectively. The maximum plasma concentration (C(max)) of CP was 3.81 +/- 0.54 ng/mL for CP form I and 3.18 +/- 0.31 ng/mL for CP form II, the C(max) of IM was 3.42 +/- 0.41 and 2.08 +/- 0.68 microg/ mL for the CP form I and form II, respectively. There was an obvious difference between form I and form II for C(max) and the area under the plasma concentration time curve for both CP and IM after a t-test. This study shows that CP form I has better bioavailability in rats than CP form II.
Simultaneous determination of liensinine, isoliensinine and neferine from seed embryo of Nelumbo nucifera Gaertn. in rat plasma by a rapid HPLC method and its application to a pharmacokinetic study.
Huang Y, Zhao L, Bai Y … +3 more , Liu P, Wang J, Xiang J
Arzneimittelforschung · 2011 · PMID 21827045 · Publisher ↗
A rapid and specific HPLC method has been developed and validated for the simultaneous determination of liensinine (CAS 2586-96-1), isoliensinine (CAS 6817-41-0) and neferine (CAS 2292-16-2) in rat plasma. The sample was...
A rapid and specific HPLC method has been developed and validated for the simultaneous determination of liensinine (CAS 2586-96-1), isoliensinine (CAS 6817-41-0) and neferine (CAS 2292-16-2) in rat plasma. The sample was prepared by a liquid-liquid extraction with diethyl ether and the recovery was above 80% from the plasma for the three compounds. Chromatographic separation was achieved with a Hypersil BDS C18 column (4.0 mm x 250 mm, particle size 5 microm). A mobile phase consisting of methanol: 0.2 M KH2PO4:0.2 M NaOH:triethylamine (71:17:12:0.002, v/v/v/v, pH 9.2-9.3) was slowly delivered at 0.8 ml/min in isocratic mode with a detection wavelength of 282 nm. The linearity of calibration curves were good (r > 0.999) in the concentration range of 0.031-2.00 microg/ ml. The lower limit of quantification can reach 0.03 microg/ml for the three compounds. The intra-day and inter-day variations estimated with QC samples were less than 8% for the three tested concentration levels. This developed method was applied in the plasma pharmacokinetic study of total bisbenzylisoquinoline alkaloids (TAL) of the lotus flower (Lian Zi Xin) following a single oral and intravenous administration of TAL in rats.
Simultaneous determination of L-arginine, asymmetric dimethylarginine, and symmetric dimethylarginine in the plasma of rodents with LC-MS/MS.
Chae JW, Baek IH, Kang W … +1 more , Kwon KI
Arzneimittelforschung · 2011 · PMID 21827044 · Publisher ↗
Nitric oxide (NO) is synthesized from L-arginine (Arg) by NO synthase (NOS), and asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are endogenous inhibitors of NO formation. Normal distribution val...
Nitric oxide (NO) is synthesized from L-arginine (Arg) by NO synthase (NOS), and asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are endogenous inhibitors of NO formation. Normal distribution values of Arg, ADMA, and SDMA are required to evaluate the effects of cardiovascular drugs on blood vessels, but insufficient normal reference values from rat and mouse plasma exist for new drug development and screening. To determine the means and variations in the basal endogenous materials concentration, Arg, ADMA, and SDMA in blank rat (n = 24) and mouse (n = 37) plasma samples were quantified using LC-MS/MS equipped with an electrospray ionization interface to generate positive mode ions. Accuracy and precision were within 90.42-110.91%, and 0.88-13.84%, respectively, for analyses of Arg, ADMA, and SDMA. The average plasma concentrations of Arg, ADMA, and SDMA were 175.38 +/- 13.87 microM, 0.79 +/- 0.20 microM, and 0.84 +/- 0.20 microM, respectively, in rats and 70.81 +/- 19.38 microM, 0.66 +/- 0.21 microM, and 0.42 +/- 0.10 microM, respectively, in mice. These results will provide a basis on which to evaluate cardiovascular drug effects on ARG, ADMA, and SDMA levels in new drug development.
Plasma levels of clozapine and norclozapine in Mexican schizophrenia patients.
González-Esquivel DF, Castro N, Ramírez-Bermúdez J … +4 more , Custodio V, Rojas-Tomé S, Castro-Román R, Jung-Cook H
Arzneimittelforschung · 2011 · PMID 21827043 · Publisher ↗
The aim of the present study was to determine the prescribing practice for clozapine (CAS 5786-21-0) as well as the plasma levels of clozapine and its main metabolite norclozapine (CAS 6104-71-8) in Mexican patients. A p...
The aim of the present study was to determine the prescribing practice for clozapine (CAS 5786-21-0) as well as the plasma levels of clozapine and its main metabolite norclozapine (CAS 6104-71-8) in Mexican patients. A prospective study was performed in 69 in and out psychotic patients taking clozapine. Blood samples were taken at steady state. Plasma concentrations of clozapine and norclozapine were determined by HPLC. The results showed that the mean daily dose administered was 250 mg/d. Plasma levels showed a large interindividual variability. Mean plasma levels were 411.3 +/- 328.12 ng/mL, for clozapine and 172.0 +/- 129.9 ng/mL for norclozapine. When data were compared with those reported in other populations, it was found that although the dose was lower than that reported in Caucasians, the plasma levels were similar. As a result, the predictive models for the estimation of clozapine concentration in Caucasians were not appropriate for application in Mexican patients. The findings suggest ethnic differences in the ratio dose/plasma levels of clozapine in Mexican patients. Further studies are required to expand the observations.
Synthesis and anticonvulsant evaluation of some novel (thio)semicarbazone derivatives of arylalkylimidazole.
Caliş U, Septioğlu E, Aytemir MD
Arzneimittelforschung · 2011 · PMID 21827042
A number of novel 2-(1H-imidazole-1-yl)-1-aryl-substituted ethane-1-one N-substituted phenyl(thio)semicarbazones (1-14) were synthesized to test for their anticonvulsant activity against the two seizure models, maximal e...
A number of novel 2-(1H-imidazole-1-yl)-1-aryl-substituted ethane-1-one N-substituted phenyl(thio)semicarbazones (1-14) were synthesized to test for their anticonvulsant activity against the two seizure models, maximal electroshock (MES) and subcutaneous pentylenetetrazol (scPTZ). Title compounds were prepared by the reaction of appropriate (thio)semicarbazides with ketones. Neurotoxicity was screened by the rotarod test. The structure of compounds was confirmed by elemental analysis results and the spectroscopic techniques such as IR, 1H-NMR, 13C-NMR, ESI-MS and HRMS. As a result of activity studies, when the thiosemicarbazone compounds were compared at different doses, 2-(1H-imidazole-1-yl)-1-(2-naphthyl)ethane-1-one N-(3-chlorophenyl)thiosemicarbazone (3) and 2-(1H-imidazole-1-yl)-1-(2-biphenyl)ethane-1-one N-(4-fluorophenyl) thiosemicarbazone (12) were found selective and highly active compounds against MES-induced seizures after 0.5 h and 4 h, respectively. Beside this, 2-(1H-imidazole-1-yl)-1-(1-biphenyl)ethane-1-one N-(4-methylphenyl)thiosemicarbazone (14) was the most active compound in the scPTZ-induced seizure test after 4 h. The 2,4-dichlorophenyl (9) and 2-fluorophenyl (10) substituted biphenyl derivatives of thiosemicarbazone compounds showed neurotoxicity at higher doses.
Mono-, di- and trisubstituted derivatives of eflornithine: synthesis for in vivo delivery of DL-alpha-difluoromethylornithine in plasma.
Cloete TT, Johansson CC, N'Da DD … +4 more , Vodnala SK, Rottenberg ME, Breytenbach JC, Ashton M
Arzneimittelforschung · 2011 · PMID 21755816 · Publisher ↗
The aim of this study was to synthesize a series of mono-, di- and trisubstituted derivatives of the human African trypanosomiasis drug eflornithine (alpha-difluoromethylornithine, DMFO, CAS 70052-12-9) to determine thei...
The aim of this study was to synthesize a series of mono-, di- and trisubstituted derivatives of the human African trypanosomiasis drug eflornithine (alpha-difluoromethylornithine, DMFO, CAS 70052-12-9) to determine their partition coefficients, and to assess whether they deliver the parent drug in the plasma. If increased plasma concentrations of eflornithine could be achieved in this way, an oral dosage form would be possible. The derivatives, nine in total, were successfully synthesized by multi-step derivatisation of eflornithine on either its alpha-carboxylic or/and alpha-amino or/and delta-amino groups by either esterification or/and amidation or/and carbamylation, and their structures confirmed by NMR and MS spectroscopy. The majority of derivatives were more lipophilic than eflornithine with log D values in phosphate buffer solution (pH 7.4) ranging from -1.34 to 1.59 (vs. -0.98 for eflornithine). The in vivo absorption after oral administration to Sprague-Dawley rats showed that no derivative delivered eflornithine in the plasma, indicating that the derivatives were either not absorbed from the gastrointestinal tract or not metabolized to the parent drug. Two of the monosubstituted activities were toxic for T. brucei blood stream forms.
Risk of hepatotoxicity with add-on leflunomide in rheumatoid arthritis patients.
Gupta R, Bhatia J, Gupta SK
Arzneimittelforschung · 2011 · PMID 21755815 · Publisher ↗
Combination of disease-modifying antirheumatic drugs (DMARDs) is increasingly used in the treatment of rheumatoid arthritis (RA) patients. Hepatotoxicity has been an important safety concern with DMARDs therapy. Though l...
Combination of disease-modifying antirheumatic drugs (DMARDs) is increasingly used in the treatment of rheumatoid arthritis (RA) patients. Hepatotoxicity has been an important safety concern with DMARDs therapy. Though leflunomide (CAS 75706-12-6) has emerged as an effective oral DMARD, its use is associated with hepatotoxicity. Limited data is available regarding hepatotoxic risk when leflunomide is used in combination therapy in RA patients. An open-label, prospective study was conducted to evaluate the hepatotoxic risk after addition of leflunomide with other DMARDs in RA patients, who did not respond to their ongoing DMARD therapy. A total of 46 patients were enrolled and leflunomide was given as add-on therapy with earlier DMARDs. Biochemical parameters of serum aminotransferase levels (AST and ALT) were estimated at the baseline and then every month after addition of leflunomide. Study results showed that 13.0% patients developed > 1.5 to < 2 times upper limit of normal (ULN) elevation; 6.5% patients developed > 2 to < 3 times the ULN elevation and 2.2% patients developed > 3 times the ULN elevation. In 20% of the patients with hepatic enzyme elevations, enzyme levels returned to normal within 4-6 weeks after discontinuation of leflunomide therapy, whereas in 50% of patients the dose of leflunomide was reduced from 20 mg/day to 10 mg/day for normalization of enzymes levels. 30% of patients were continued with leflunomide without dose reduction. None of the patients showed clinical signs and symptoms of hepatotoxicity. Leflunomide therapy with other DMARDs requires strict monitoring of serum aminotransferases.
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