Arzneimittel-Forschung-Drug Research最新文献

The study aimed to compare and evaluate the bioequivalence of a new generic preparation of trospium chloride (CAS NO:10405-02-4) capsule (20 mg, test) and the available import tablet (20 mg , reference) for the requirement of state regulatory criteria in China. A randomized- sequence, 2-period crossover study was conducted in 20 healthy Chinese male volunteers in the fasted state. Blood samples were collected before and 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60 h after administration of a single oral dose of 40 mg trospium chloride capsules or tablets, followed by a 7-day washout period. The concentration of trospium chloride was determined by a LC-MS/MS method. Drug And Statistical-Version 2.0 was used to calculate the pharmacokinetics parameters and assess bioequivalence of the two preparations. It was considered bioequivalent if the 90% CIs of the mean ratios (test: reference) for Cmax, AUC0-t and AUC0-∞ were within the range from 80% to 125%, respectively. The main pharmacokinetics parameters of test and reference were as follows: t1/2 was (15.11 ± 3.24) h and (16.00 ± 3.96) h; Tmax was (4.0 ± 1.2) h and (4.1 ± 0.9) h; Cmax was (3.76 ± 1.87) ng·mL - 1 and (3.70 ± 1.89) ng·mL - 1; AUC0-t was (33.51 ± 14.39) ng·mL - 1·h and (33.33 ± 14.88) ng·mL - 1·h, and the AUC0-∞ was (35.20 ± 14.88) ng·mL - 1·h and (35.16±15.17) ng·mL - 1·h. The ratios (test: reference) for Cmax, AUC0-t, and AUC0-∞ were 94.0%~111.7%, 96.4%~106.8%, and 96.1%~105.3%, respectively. No significant differences in pharmacokinetic parameters were found between preparations and periods (p>0.05). No obvious adverse events were monitored throughout the study based on clinical parameters and patient reports.

A simple, rapid, selective and sensitive HPLC-UV method was developed and validated for the determination of swainsonine (SWSN) in rat plasma. The analyte was extracted from rat plasma with methanol as the extraction solvent. The LC separation was performed on a Diamonsil® C18 (250×4.6 mm, 5 µm) analytical column with a mobile phase consisting of acetonitrile-potassium dihydrogen phosphate (25 mmol/l, pH=7.5) at a flow rate of 1.0 ml/min. There was a good linearity over the range of 10-500 ng/ml (r=0.9995) with a weighted (1/C2) least square method. The lower limit of quantification was proved to be 10 ng/ml. The accuracy was within 4.8% in terms of relative error and the intra- and inter-day precisions were less than 9.0% in terms of relative standard deviation. After validation, the method was successfully applied to characterize the pharmacokinetics of SWSN in rats.

Schizophrenia (SCZ) is a debilitating disorder afflicting around 1% of the world population. Recent literature reveals oxidative injuries contribute enormously to the pathophysiology of SCZ alongside other psychopathological disturbances. Histamine H3R-antagonists have shown dual mechanism of action in experimental models of SCZ. Firstly it prevents oxidative stress and secondly alleviates schizophrenic symptoms, particularly the negative symptoms and cognitive deficits. In the present study, histamine H3R-antagonists used were ciproxifan (3.0 mg/kg, ip) and clobenpropit (15 mg/kg, ip) markedly controlled the elevated levels of various oxidative stress markers, for example, thiobarbituric acid reactive substance (TBARS), glutathione (GSH), superoxide dismutase, catalase, etc., as a result of augmented oxidative stress in the experimental models of SCZ such as amphetamine (0.5 mg/kg, sc) and dizocilpine (MK-801) (0.2 mg/kg, ip) induced locomotor hyperactivity, apomorphine (1.5 mg/kg, sc) induced climbing behavior and haloperidol (2.0 mg/kg, po) induced catalepsy. The results of the present study revealed that H3R-antagonists possess antioxidant activity and could serve with dual mechanism by supplementing antioxidant needs of SCZ and at the same time controlling symptoms of SCZ.

A sensitive and selective high performance liquid chromatographic (HPLC) method was developed and validated for quantification of lacosamide in rat plasma. A liquid-liquid extraction procedure was optimized to extract lacosamide from rat plasma. Chromatographic separation was accomplished using a reversed phase C18 Hichrom (250×4.6 mm, 5 µm) column with the mobile phase consisting of acetonitrile-phosphate buffer (pH 3.2±0.1; 20 mM) (21:79, v/v) at a flow rate of 1 mL/min. Both intra- and inter day assay precision and accuracy were lower than 15% CV. The lower limit of quantitation was 25 ng/mL for lacosamide and the response was linear in a concentration range from 25 to 10 000 ng/mL. The developed method was successfully used for the preclinical pharmacokinetic study of lacosamide in rats.

To investigate the pharmacokinetics of KW-7158 (CAS 214763-95-8), a new drug candidate for urinary incontinence and bladder hyperactivity, in male and female rats, we developed and validated a simultaneous quantification method for KW-7158 and its 2 metabolites, M1 and M2, in plasma using high performance liquid chromatography-tandem mass spectrometry with positive/negative ion-switching scan mode. The method was selective and sensitive to KW-7158, M1 and M2 with overall precision expressed as coefficient of variance less than 11.8% and accuracy (relative error) within ± 13.7% in intra- and inter-assay variability. This method was used to determine the plasma concentration of KW-7158, M1 and M2 after intravenous and oral administration of KW-7158 in male and female rats. KW-7158 was detected as a primary constituent in plasma in both administration routes. M1 was a major metabolite with the concentration ratio of 10-20% of KW-7158, and M2 was a minor metabolite. Pharmacokinetics of KW-7158 after oral administration was considered to be linear at doses from 0.01 to 1 mg/kg. Bioavailability was relatively high with the values of 69.4 ± 17.1% and 82.6 ± 20.0% at a dose of 0.1 mg/kg in male and female rats, respectively. There was a little gender difference in pharmacokinetics of KW-7158 and its metabolites in rats.

Serotonin and dopamine play an important role in the aetiology of schizophrenia. Combination of the structural scaffolds of both neurotransmitters in a single molecule lead to aromatic [d,g]-bisannelated azecine derivatives, which have been shown to be nanomolar to subnanomolar dopamine D1-D5 receptor antagonists with a preference for the D1 family. In this work the potential antipsychotic activity of some azecine derivatives was predicted by their dopamine receptor affinities obtained in vitro from radioligand binding experiments and conclusively confirmed in vivo (rats) by applying a conditioned avoidance model. Furthermore, the compounds were tested in vivo for the development of catalepsy, which is a predictive parameter for extra-pyramidal side-effects caused by many antipsychotics. The investigated azecines displayed low cytotoxicity, and the affinities for human dopamine D1-D5 and serotonin 5-HT2 A receptors were in a nanomolar range. In vivo, their antipsychotic activities in the rat model were comparable with those of haloperidol and risperidone, but revealed a 2-5 times better therapeutic range with regard to catalepsy. Preliminary tests for oral bioavailability also revealed promising results for this new class of potential antipsychotic compounds. In conclusion, our in vivo experiments show that aromatic [d,g]-annelated azecines represent a novel and advantageous class of potential atypical neuroleptics.

Naringin (CAS 10236-47-2), a flavanone glucoside widely present in fruits of citrus plants, has received extensive studies on its potential effects on health benefits and was recently demonstrated to be a putative antitussive. In this study, we determined the tissue distributions of naringin and its metabolites (naringenin and naringenin's conjugates) in rats to examine whether they undergo selective uptake by specific organs. Naringin was administered orally to rats at the dose of 42 mg/kg and the concentrations of naringin and its metabolites in tissue compartments were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The areas under curve values in the individual tissues decreased as follows: stomach, small intestine, liver, trachea, muscle, kidney, lung, fat, heart, spleen, ovary, testis, brain for naringin; and liver, stomach, small intestine, kidney, trachea, lung, testis, heart, ovary, fat, spleen, muscle, brain for total naringenin (including free and its conjugates). Naringin and total naringenin were rapidly and widely distributed to all the tissues except brain in rats. They had difficulties in crossing the blood-brain barrier. There are no accumulations in rats. This study identifying naringin in several organs including lung and trachea may explain its effects as antitussive.

Paclitaxel(PTX)-loaded microspheres composed of poly(D,L-lactide-co-glycolide) (PLGA) were prepared by an O/W emulsion solvent evaporation method. This study was designed to investigate the preparation, in vitro release, in vivo pharmacokinetics and tissue distribution of a PTX-loaded microspheres system. Microspheres are characterized according to drug loading, size and shape. With a dynamic light scattering sizer and a transmission electron microscopy, it is shown that the PTX-loaded microspheres had a mean size of approximately 10.24 µm with narrow size distribution and a spherical shape. The in vitro release profiles indicate that the release of PTX from the microspheres exhibit a sustained release behavior. A similar phenomenon is observed in a pharmacokinetic study in rats, in which AUC of the microspheres formulation were 3.7-fold higher than that of PTX injection. The biodistribution study in mice showed that the PTX-loaded microspheres not only decreased drug uptake by liver, but also increased distribution of drug in lung. These results suggest that PTX-loaded microspheres may efficiently load, protect and retain PTX in both in vitro and in vivo environments, and could be a useful drug carrier for i. v. administration of PTX.

Literature data on the clinical pharmacokinetics of various VEGFR-2 inhibitors along with in vitro potency data were correlated and a linear relationship was established in spite of limited data set. In this work, a model set comprised of axitinib, recentin, sunitinib, pazopanib, and sorafenib were used. The in vitro potencies of the model set compounds were correlated with the published unbound plasma concentrations (Cmax, Cavg, Ctrough). The established linear regression (r2>0.90) equation was used to predict Cmax, Cavg, Ctrough of the 'prediction set' (motesanib, telatinib, CP547632, vatalanib, vandetanib) using in vitro potency and unbound protein free fraction. Cavg and Ctrough of prediction set were closely matched (0.2-1.8 fold of reported), demonstrating the usefulness of such predictions for tracking the target related modulation and/or efficacy signals within the clinically optimized population average. In case of Cmax where correlation was least anticipated, the predicted values were within 0.1-1.1 fold of those reported. Such predictions of appropriate parameters would provide rough estimates of whether or not therapeutically relevant dose(s) have been administered when clinical investigations of novel agents of this class are being performed. Therefore, it may aid in increasing clinical doses to a desired level if safety of the compound does not compromise such dose increases. In conclusion, the proposed model may prospectively guide the dosing strategies and would greatly aid the development of novel compounds in this class.