Metabolism of novel anti-HIV agent 3-cyanomethyl-4-methyl-DCK by human liver microsomes and recombinant CYP enzymes.

Aim: To investigate the metabolism of 3-cyanomethyl-4-methyl-DCK (CMDCK), a novel anti-HIV agent, by human liver microsomes (HLMs) and recombinant cytochrome P450 enzymes (CYPs).

Methods: CMDCK was incubated with HLMs or a panel of recombinant cytochrome P450 enzymes including CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, and 3A5. LC-ion trap mass spectrometry was used to separate and identify CMDCK metabolites.

[Research progress of enhancing quantitative sensitivity by using LC-MS(n) with derivatization method in bio-matrices].

Liquid chromatography/mass spectrometry (LC-MS(n)) has been essential to a large number of quantitative analytical applications in drug research, and especially in the drug PK/PD research, due to its high sensitivity and high specificity. But following the appearance of drugs with high activity and low dosage and the especial structural compounds, a number of limitations of LC-MS(n) have been noted. Derivatization changes the structure of drugs and therefore changes their physical and chemical properties, resulting in high ionization efficiency, low matrix effect and low disturbance by inorganic salts and endogenous compounds in LC-MS(n).

Plasma membrane as the target site of cholic acid analogs.

Although the mechanism is unknown, Calculus Bovis and its active components, cholic acid analogs (CAAs), have been used in China to treat a wide range of diseases. Based on the previous finding that the potency of CAA is strongly dependent on the intrinsic surface activity, this paper aimed to investigate the role of the plasma membrane in the pharmacological activity of CAAs. First, CAAs (0.

Injury of cell tight junctions and changes of actin level in acute lung injury caused by the perfluoroisobutylene exposure and the role of Myosin light chain kinase.

Objectives: To investigate the injury of cell tight junctions and change in actin level in the alveolus epithelial cells of the lung after perfluoroisobutylene (PFIB) exposure and the role of myosin light chain kinase (MLCK) in the injury.

Methods: Rats and mice were exposed to a sublethal dose of PFIB. The changes in tight junction zonula occludens-1 (ZO-1), actin and myosin light chain kinase (MLCK) were detected by immunofluorescence at 30 min, 1, 2, 4, 8, 16, 24, 48 and 72 h after PFIB exposure.

Pharmacokinetic properties of albiflorin and paeoniflorin after oral administration of pure compound, Radix Paeoniae alba extract and danggui-shaoyao-san extract to rats.

This study compared the pharmacokinetics of albiflorin (ALB) and paeoniflorin (PAE), respectively, after oral administration of ALB, PAE, Radix Paeoniae alba (RPA) extract, and Danggui-Shaoyao-San (DSS) extract to rats on separate occasions. Analytes were detected simultaneously with liquid chromatography-tandem mass spectrometry. Noncompartmental pharmacokinetic parameters were calculated.

Cell injuries of the blood-air barrier in acute lung injury caused by perfluoroisobutylene exposure.

Objectives: To investigate the complete process of cell injuries in the blood-air barrier after perfluoroisobutylene (PFIB) exposure.

Methods: Rats were exposed to PFIB (140 mg/m(3)) for 5 min. The pathological changes were evaluated by lung wet-to-dry weight ratio, total protein concentration of bronchoalveolar lavage fluid and HE stain.

Metabolic stability of human parathyroid hormone peptide hPTH (1-34) in rat tissue homogenates: kinetics and products of proteolytic degradation.

The present study aim to investigate the metabolic stability and degradation of cleavage sites of human parathyroid hormone peptide, hPTH (1-34), in rat tissue homogenate, and to identify the types of proteases involved in hPTH (1-34) processing degradation. The stability of hPTH (1-34) in rat kidney, lung and liver homogenates was evaluated by LC-ESI-MS, and the structures of the major degradation products were identified by MALDI-TOF MS and LC-ESI-MS/MS. The ability of protease inhibitors to inhibit hPTH (1-34) degradation was used to identify the class of proteases involved in the metabolism of hPTH (1-34).

[Determination of decapeptide LXT-101 in plasma by HPLC-MS/MS and its pharmacokinetics in Beagle dogs].

This paper developed a sensitive and specific liquid chromatography-electrospray ionization mass spectrometry (HPLC-MS/MS) method for the determination of decapeptide LXT-101 in Beagle dog plasma. Plasma samples spiked with internal standard (IS) were treated with acetonitrile to precipitate the protein. Selected reaction monitoring (SRM) using the precursor --> product ion combinations of m/z 472.

Determination of 4-dimethylaminophenol concentrations in dog blood using LC-ESI/MS/MS combined with precolumn derivatization.

A sensitive and reproducible LC-ESI/MS/MS method, which was combined with the precolumn dansyl chloride derivatization to enhance the signal intensity of analytes, was developed to determine blood 4-dimethylaminophenol (DMAP) concentrations. The linearity of the method was observed within the concentration range of 2-2000 ng/mL. The precision, accuracy, stability, recovery and matrix effect of the method were also investigated and found to meet the requirements for pharmacokinetic studies of the drug.

Degradation of salmon calcitonin in rat kidney and liver homogenates.

Salmon calcitonin (sCT), a 32-amino-acid peptide, is the active component in many pharmaceuticals used for the management of bone diseases. In this study, the stability of sCT in rat kidney and liver homogenates were evaluated by LC-ESI-MS, and the structures of the major degradation products were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The results show that the half life of sCT was 13.

[Effect of Danxiongfang and its components on experimental liver injury models induced by CCl4 in mice].

Objective: The study investigates the protective effect on liver of Danxionfang and its components.

Method: Mice are injected with CCl4 to establish liver injured model. ALT, AST, serum albumin, globulin in serum and SOD, MDA in liver and liver histological changes were measured to confirm the ability of protecting liver of Danxiongfang.

Simultaneous determination of harpagoside and cinnamic acid in rat plasma by liquid chromatography electrospray ionization mass spectrometry and its application to pharmacokinetic studies.

A simple and sensitive method was developed for the simultaneous quantification of harpagoside and cinnamic acid in rat plasma using high-performance liquid chromatography system coupled to a negative ion electrospray mass spectrometric analysis. The plasma sample preparation was a simple deproteinization by the addition of two volumes of acetonitrile. The analytes were separated on an Intersil C8-3 column (2.

Simultaneous quantification of chlorogenic acid and caffeic acid in rat plasma after an intravenous administration of mailuoning injection using liquid chromatography/mass spectrometry.

A simple, rapid and sensitive method was developed for the simultaneous quantification of chlorogenic acid (CGA) and caffeic acid (CA) in rat plasma using a high-performance liquid chromatography system coupled to a negative ion electrospray mass spectrometric analysis. The plasma sample preparation was a simple deproteinization by the addition of two volumes of acetonitrile followed by centrifugation. The analytes and internal standard ferulic acid were separated on an Intersil C8-3 column (5 mm; 250 x 2.

A simplified model to predict P-glycoprotein interacting drugs from 3D molecular interaction field.

A new two components partial least squares discriminant analysis (PLS) model for the prediction of P-glycoprotein-associated ATPase activity of drugs by using VolSurf compute theoretical molecular descriptors derived from 3D molecular interaction field was reported in the present study. By using 27 diverse drugs from literature, two models were constructed (R(2)=0.9003, 0.

Comparative study on pharmacological effects of DM-phencynonate hydrochloride and its optical isomers.

Aim: The 3-azabicyclo(3,3,1)nonanyl-9-alpha-yl-alpha-cyclopentyl-alpha-phenyl-alpha-glycolate (DM-phencynonate hydrochloride, DMCPG) is a demethylated metabolite of 3-methyl-3-azabicyclo(3,3,1)nonanyl-9-alpha-yl-alpha-cyclopentyl-alpha-phenyl-alpha-glycolate (phencynonate hydrochloride, CPG). (+/-)DMCPG had one chiral center and two enantiomers [R(-) and S(+)DMCPG]. Here we carried out a comparative study of the pharmacological profiles of these optical isomers.

Anticonvulsant effects of phencynonate hydrochloride and other anticholinergic drugs in soman poisoning: neurochemical mechanisms.

Previous studies have paid little attention to the anticonvulsant effect of anticholinergic drugs that act on both muscarinic (M) and nicotinic (N) receptors during soman-induced seizures. Therefore, with the establishment of a soman-induced seizures model in rats, this study evaluated the efficacy in preventing soman-induced convulsions of two antagonists of both the M and N receptors, phencynonate hydrochloride (PCH) and penehyclidine hydrochloride (8018), which were synthesized by our institute, and of other anticholinergic drugs, and investigated the mechanisms of their antiseizures responses. Male rats, previously prepared with electrodes to record electroencephalographic (EEG) activity, were pretreated with the oxime HI-6 (125 mg kg-1, i.

[Anticonvulsant effect of phencynonate hydrochloride on maximal electroshock seizure and the metrazol seizure threshold test in mice].

Aim: To test the antiepileptic effect of phencynonate hydrochloride and investigate its antiepileptic mechanism.

Methods: Through establishment of different epilepsy models, antiepileptic effects of phencynonate hydrochloride and other drugs were examined. Besides, the effect of phencynonate hydrochloride and other compounds against NMDA-induced lethality in mice, NMDA-induced injury in rat primary hippocampal neuronal cultures and NMDA-induced current were also observed.

Pharmacological profiles of an anticholinergic agent, phencynonate hydrochloride, and its optical isomers.

Aim: To comparatively study the pharmacological profiles of 3-methyl-3-azabicyclo(3,3,1)nonanyl-9-alpha-yl-alpha-cyclopentyl-alpha-phenyl-alpha-glycolate (phencynonate hydrochloride, CPG), an anticholinergic agent, and its enantiomers [R(-)-and S(+)-CPG].

Methods: The affinity and relative efficacy were tested using radioligand-binding assay with muscarinic acetylcholine receptors from rat cerebral cortex. The pharmacological activities were assessed in three individual experiments: (1) potentiating the effect of subthreshold hypnotic dose of sodium pentobarbital; (2) inhibiting oxotremorine-induced salivation; and (3) inhibiting the contractile response to carbachol.

Screening of traditional Chinese remedies for SARS treatment.

The SARS epidemic is breaking out worldwide. To select suitable herbal drugs for clinical uses is important and urgent amongst the controversial treatment proposals. Nine pharmacological experimental models were used to evaluate the comprehensive efficacy of traditional Chinese remedies by cross validation in different institutes.

[RP-HPLC determination of loganin in mouse plasma and its pharmacokinetics].

Aim: To develop a method for determination of loganin in mouse plasma by using high-performance liquid chromatography. The method was employed to study pharmacokinetics of loganin.

Methods: An RP-C18 was used as the stationary phase.

Effects of pretreatment with 8018 on the toxicokinetics of soman in rabbits and distribution in mice.

The effects of 8018 [3-(2'-phenyl-2'-cyclopentyl-2'-hydroxyl-ethoxy)quinuclidine] on the elimination of soman in rabbits blood and distribution in mice brain and diaphragm were investigated using the chirasil capillary gas chromatographic analysis method. In all experiments, the concentration of P(+)soman was below the detection limit (<0.1 ng x mL(-1)).

[Identification of the metabolites of penehyclidine hydrochloride raceme in rats by LC-MS/MS and ion cluster].

Aim: To study the metabolites of penehyclidine hydrochloride (PH) raceme, a new anticholinerigic drug invented by the Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences.

Methods: Three healthy rat urine samples were collected within 24 h after a single i.m.

Effects of pretreatment with verapamil on the toxicokinetics of soman in rabbits and distribution in mouse brain and diaphragm.

The effects of verapamil on the elimination of soman in rabbit blood and distribution in mouse brain and diaphragm by determining the concentration of P(-)soman using the chirasil capillary gas chromatographic analysis method were studied in order to study the effects of verapamil on the metabolic detoxification of soman. Verapamil (10 mg kg(-1), im, 30 min before soman administration) could significantly reduce the concentration of P(-)soman in rabbit blood at 15, 60, 90, 120, 180 and 240 s after soman injection (43.2 microg kg(-1), iv) as compared to soman-treated control animal respectively.