Polo-box domain 1 (PBD1) is a characteristic domain of polo-like kinase 1 (PLK1), which locates in C-terminal and can influence the catalytic activity and specific subcellular locations of PLK1. At present, most PLK1 inhibitors are developed to occupy the ATP pocket or its close sites. However, this kind of PLK1 inhibitors is difficult to pursue target selectivity and may encounter cross drug resistance with other kinase inhibitors due to the conserved sequence of ATP pocket. Recently, PBD1, with aberrant specificity in sequence and structure, has attracted enormous interests as the alternative target to the discovery of corresponding inhibitors for anti-tumor drugs. The structure and function of PBD1 as well as the advances of its inhibitors are reviewed in this paper.
Benzocycloheptenes ; chemistry ; pharmacology ; Benzoquinones ; chemistry ; pharmacology ; Cell Cycle Proteins ; antagonists & inhibitors ; chemistry ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Humans ; Indole Alkaloids ; chemistry ; pharmacology ; Lactams ; chemistry ; pharmacology ; Peptides, Cyclic ; chemistry ; pharmacology ; Phosphopeptides ; chemistry ; pharmacology ; Protein-Serine-Threonine Kinases ; antagonists & inhibitors ; chemistry ; Proto-Oncogene Proteins ; antagonists & inhibitors ; chemistry

This study is to investigate the effect of gamma-hydroxybutyric acid receptor (GHBR) on focal cerebral ischemia-reperfusion injury in rats and its mechanism. NCS-356 (the agonist of GHBR) and NCS-382 (the antagonist of GHBR) were adopted as the tool medicine. The ripe male Sprague-Dawley rats weighing 240 - 280 g were randomly divided into seven groups: sham operation group (sham), ischemia-reperfusion group (Isc/R), NCS-356 160 microg x kg(-1) group (N1), NCS-356 320 microg x kg(-1) group (N2), NCS-356 640 microg x kg(-1) group (N3), NCS-382 640 microg x kg(-1) + NCS-356 640 microg x kg(-1) group (NCS-382 + N3), and nimodipine (Nim) 600 microg x kg(-1) group. The middle cerebral artery occlusion (MCAO) model referring to Longa's method with modifications was adopted. The effect of GHBR on behavioral consequence of MCAO rats was studied after 2 h of ischemia-reperfusion. After 24 h of ischemia-reperfusion, part of animals were used to measure the cerebral infarction volume by TTC staining; ischemic cortex of another part of animals were used to measure the content of intracellular free calcium by flow cytometry, the tNOS, iNOS activity and the content of NO by spectrophotometric method, the content of cGMP by radioimmunoassay. The neurological function score and infarction volume rate in Isc/R group rats increased significantly than that in sham group; The content of intracellular calcium ([Ca2+]) of cortex neuron and cGMP, the activities of tNOS and iNOS, and the content of NO in Isc/R group were higher than that in sham group obviously (P < 0.01); These consequence we mentioned of N1, N2, N3 and Nim group were lower than that of Isc/R. NCS-382 + N3 group could significantly antagonize the above effect of N3. Thus, NCS-356 has protective effects against ischemia-reperfusion brain injury by activating GHBR. The neuroprotective effect of GHBR is related with decreasing the content of [Ca2+]i, NO, cGMP and tNOS, iNOS activity in MCAO rats.
Animals ; Benzocycloheptenes ; pharmacology ; Calcium ; metabolism ; Cerebral Cortex ; metabolism ; Cerebral Infarction ; pathology ; Cyclic GMP ; metabolism ; Infarction, Middle Cerebral Artery ; complications ; Male ; Neuroprotective Agents ; pharmacology ; Nitric Oxide ; metabolism ; Nitric Oxide Synthase ; metabolism ; Nitric Oxide Synthase Type II ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptors, Cell Surface ; agonists ; antagonists & inhibitors ; metabolism ; Reperfusion Injury ; etiology ; metabolism ; pathology

A new spectrophotometry was described for the simultaneous analysis of pseudoephedrine sulfate-Ioratadine combination. The derivative spectrophotometry dA/d values were read at zero-crossing point. Mean recoveries were found to be more than 98% for these compound in mixture. The procedure does not require any separation step and proven to be rapid, simple and accurate for determination of the mentioned sample or corresponding multi-component mixture
Spectrophotometry ; Ultraviolet Therapy ; Loratadine ; tablets

No abstract available.
Dizocilpine Maleate* ; Dopamine* ; Methamphetamine*

OBJECTIVE: The purpose of this study was to compare the plasma amitriptyline and nortriptyline level between before and after fluoxetine addition with patients who were currently taking amitriptyline. METHOD: From the inpatient and outpatient unit of Soon Chun Hyang University Hospital, Chunan, fourteen subjects who were taking amitriptyline 25mg more than 1 week at least were given fluoxetine 20mg. Before and 2 weeks after fluoxetine addition the plasma level of amitriptyline and nortriptyline are analyzed simultaneously by High Performance Liquid Chromatography(HPLC) At the same times, HAM-D(Hamilton Rating Scale for Depression) score and the UKU(Uldvalg for Klinske Unders phi gelser) side effect scale were checked. RESULTS: After fluoxetine addition to the patients who were taking amitriptyline, the plasma level of amitriptyline, nortriptyline and sum of amitriptyline and nortriptyline had risen. The mean plasma amitriptyline level increased from 168.9+/-89.4ng/ml to 183.0+/-102.0ng/ml after fluoxetine addition(p=0.011) but the change was not statistically significant. The mean plasma nortriptyline level increased significantly from 114.3+/-70.2ng/ml to 168.0+/-86.2ng/ml after fluoxetine addition(p=0.011) In addition, the mean plasma level of total amitriptyline and nortriptyline increased significantly from 283.1+/-125.3ng/ml to 350.9+/-78.4ng/ml after fluoxetine addition(p=0.016) After fluoxetine addition, no significant change was noted in the UKU side effect scale score. CONCLUSION: As consequence of comparson of plasma amitriptyline and nortriptyline level before and after fluoxetine addition mean amitriptyline, nortriptyline and total plasma level was increased after fluoxetine addition. This suggests that coadministration of amitriptyline and fluoxetine may induce improvement of depressive symptom in depressive patients by way of increased plasma level of amitriptyline.
Amitriptyline* ; Chungcheongnam-do ; Depression ; Fluoxetine* ; Humans ; Inpatients ; Nortriptyline ; Outpatients ; Plasma*

No abstract available.
Animals ; Dizocilpine Maleate* ; Rats* ; Spinal Cord*

Tardive dyskinesia(TD) is a serious side effect of long-term treatment with neuroleptic medications. To investigate if glutamatergic hyperfunction is associated with TD, effect of MK-801 on the prevention and treatment of TD was studied using a rat model, i.e., vacuous chewing movements(VCM). When comparing VCM scores of Group I(haldol decanoate+MK-801) with that of Group II(hadol decanoate+phosphate buffer saline), late measured VCM scores of former were significantly lower than that of latter, meaning that MK-801 is effective in the prevention of VCM. Furthermore, when MK-801 is also effective in the treatment of VCM. From the above results, it is suggested that glutamatergic hyperfunction might be involved in the development of TD and MK801 could be effective in the prevention and treatment of it.
Dizocilpine Maleate* ; Mastication ; Models, Animal ; Movement Disorders*

BACKGROUND: Optimal use of tricyclic antidepressants (TCAs) requires serum monitoring to determine if the appropriate therapeutic range has been attained and to assess possible side effects. This study was to evaluate the resolution capacity of the following four mobile phases which were previously reported; mobile phase I (methanol, acetonitrile and 5 mmol/L Na2HPO4: 41/15/44 by volume), II (methanol, acetonitrile and 5 mmol/L Na2HPO4,: 15/60/25 by volume), III (acetonitrile and 2-propanol: 95/5 by volume) and IV (methanol and n-butylamine: 99.5/0.5 by volume). METHODS: Amitriptyline (AT), nortriptyline (NT), imipramine (IMI) and doxepin (DOX) were used for the selection of appropriate mobile phase in high performance liquid chromatographic (HPLC) determination. TCAs were extracted from serum with hexane, isoamyl alcohol (99:1). The drug was re-extracted into 0.1 N HCl and an aliquot was injected into the HPLC. The analytical column was C-18 reversed phase column (3.9 mm x 30 cm; Waters, USA) with the flow rate of 1.5 mL/min. The UV detector signal was monitored at 254 nm. RESULTS: Mobile phase I disclosed 9.8-15.8 retention time (min), 5.1-8.8 capacity ratio and 1.0-2.2 resolution factors for the above four TCAs. Precision studies using this mobile phase demonstrated a coefficient variation of 2.4-4.7% in the concentration range of 500-125 ng/mL. Analytical recovery of AT and IMI was 85-90% at a concentration of 125 ng/mL and 250 ng/mL. CONCLUSIONS: Mobile phase I provided a reliable and excellent resolution of TCAs in the use of HPLC with the C-18 reversed phase column and UV absorbance detector.
2-Propanol ; Amitriptyline ; Antidepressive Agents, Tricyclic* ; Chromatography, High Pressure Liquid ; Doxepin ; Imipramine ; Nortriptyline

No abstract available.
6-Cyano-7-nitroquinoxaline-2,3-dione* ; Cycloheximide* ; Dizocilpine Maleate*

PURPOSE: To compare the inhibitory effects of various tricyclic antidepressants (TCAs) on contractile response of the rat vas deferens to electrical stimulation of hypogastric nerve. MATERIALS AND METHODS: A total of forty Spraque Dawley rats (weight 300-350gm) were divided into 8 groups (n=5 in each): doxepine, amitriptyline, trimipramine, desipramine, imipramine, clomipramine, protriptyline, and prazosin treated groups. Before (baseline pressure) and 20 minutes after intravenous injection of each agent (0.1-, 1-, 10-, and 20-fold of therapeutic doses for human in each agent), the hypogastric nerves, iden tified under operative microscope, were electrically stimulated with rectangular pulses of 0.5 mseconds duration, 10 Hz, and 10 V for 10 seconds. Dose of drug administered was gradually increased in order of 0.1- to 20-fold dose. RESULTS: All drugs tested in this study caused dose-dependent inhibition of the rat intravasal pressure induced by the electrical stimulation of hypogastric nerve. Inhibitory potency of each drug was doxepine (88.5% and 96.5% at 10- and 20-fold dose)> OR = amitriptyline (76.8% and 91.8%)>clomipramine (66.7% and 74.4%)> OR =imipramine (48.2% and 67.0%)=prazosin (45.6% and 63.5%)=trimipramine (52.7% and 65.4%)> OR =desi pramine (45.3% and 49.0%)> protriptyline (18.9% and 19.9%). CONCLUSIONS: Inhibitory effects of TCAs on contractile response of the rat vas deferens to electrical stimulation of hypogastric nerve would increase in proportion to their potency of alpha1-adrenoceptor blocking actions.
Amitriptyline ; Animals ; Antidepressive Agents, Tricyclic* ; Clomipramine ; Desipramine ; Doxepin ; Electric Stimulation* ; Humans ; Imipramine ; Injections, Intravenous ; Prazosin ; Protriptyline ; Rats* ; Trimipramine ; Vas Deferens*