Advances and perspectives of proteolysis targeting chimeras (PROTACs) in drug discovery.

Proteolysis-targeting chimeras (PROTACs), bifunctional molecules consisting of a ligand of protein of interest (POI), an E3 ligase ligand and a linker, have been developed to hijack the ubiquitin-proteasome system (UPS) to induce different POIs degradation. Currently, the first oral PROTACs (ARV-110 and ARV-471) have shown encouraging efficacy in clinical trials of prostate and breast cancer treatment, which turns a new avenue for the development of PROTAC research. In this review, we focus on a detailed summary of the latest progress of PROTACs and elucidate the advantages of PROTACs technology. In addition, potential challenges and perspectives of PRTOACs are discussed.

The efficacy and safety of cilostazol as an alternative to aspirin in Chinese patients with aspirin intolerance after coronary stent implantation: a combined clinical study and computational system pharmacology analysis.

Dual antiplatelet therapy (DAT) with aspirin and clopidogrel is the standard regimen to achieve rapid platelet inhibition and prevent thrombotic events. Currently, little information is available regarding alternative antiplatelet therapy in patients with an allergy or intolerance to aspirin. Although cilostazol is already a common alternative to aspirin in clinical practice in China, its efficacy and safety remain to be determined. We retrospectively analyzed 613 Chinese patients who had undergone primary percutaneous coronary intervention (PCI). Among them, 405 patients received standard DAT (aspirin plus clopidogrel) and 205 patients were identified with intolerance to aspirin and received alternative DAT (cilostazol plus clopidogrel). There were no significant differences between the two groups in their baseline clinical characteristics. The main outcomes of the study included major adverse cardiac events (MACEs) and bleeding events during 12 months of follow-up. The MACEs endpoint was reached in 10 of 205 patients treated with cilostazol (4.9%) and in 34 of 408 patients treated with aspirin (8.3%). No statistically significant difference was observed in MACEs between the two groups. However, patients in the cilostazol group had less restenosis than did patients in the aspirin group (1.5% vs 4.9%, P=0.035). The occurrence of bleeding events tended to be lower in the cilostazol group (0.49% vs 2.7%, P=0.063). These clinical observations were further analyzed using network system pharmacology analysis, and the outcomes were consistent with clinical observations and preclinical data reports. We conclude that in Chinese patients with aspirin intolerance undergoing coronary stent implantation, the combination of clopidogrel with cilostazol may be an efficacious and safe alternative to the standard DAT regimen.

Drug Effects and Clinical Investigations for Contrast-Induced Nephropathy After Coronary Angiography or Percutaneous Coronary Intervention in Patients With Diabetes.

The aim of the study was to investigate the risk factors of preprocedural laboratory investigations and drug effects to the incidence of contrast-induced nephropathy (CIN) in patients with diabetes who underwent coronary angiography or percutaneous coronary intervention and to assess the short-term safety. We retrospectively studied a total of 568 patients with diabetes who underwent coronary angiography or percutaneous coronary intervention from January, 2013 to January, 2014 in our hospital and compared the baseline clinical characteristics, especially the laboratory investigations and preprocedural drugs of those 2 groups (with CIN group and without CIN group), and half year follow-up. Overall, 53 (9.33%) patients were developed into CIN according to the definition of an increase of 25% from the baseline of serum creatinine concentration, supposing that on the basis of an increase of 44.2 µmol/L, the incidence would be 0.88% (5/568). No significant differences were found between the 2 groups with respect to age, diabetes mellitus duration, operation type, contrast type and volume, left ventricular ejection fraction, and combined diseases including hypertension, myocardial infarction, Arrhythmia, etc. However, patients with CIN tended to be lighter in body weight (P = 0.027) and were more often female [odds ratio (OR) = 2.8, P < 0.01], and also had a higher prevalence with acute coronary syndrome (OR = 5.1, P < 0.01). On the contrary to most studies, the preprocedural serum creatinine in with CIN group in our study was lower than without CIN group (P < 0.001). As for the preprocedural drugs, statins seemed could decrease the incidence of CIN (OR = 0.34, P < 0.05), and the use of diuretics might increase the occurrence of CIN (OR = 2.62, P < 0.05). As regard to the follow-up results, the hospitalization days and expense of with CIN group were significantly longer and higher than the without CIN group, but no significance was found between rehospitalization rate in half year. Preprocedural preventions are essential because there is no effective treatment for CIN our findings could be considered in clinical practice. There are many risk factors for CIN; it is necessary to distinguish the high-risk patients so as to carry out corresponding protection actions.

Effect of iloprost on biomarkers in patients with congenital heart disease-pulmonary arterial hypertension.

Some biomarkers play important roles in the endothelial dysfunction of patients with pulmonary arterial hypertension (PAH), including nitric oxide (NO), endothelin-1 (ET-1), asymmetric dimethylarginine (ADMA), galectin-3 (Gal-3), B-type natriuretic peptide (BNP), and uric acid (UA). However, studies on these biomarkers in pulmonary artery blood in congenital heart disease-PAH (CHD-PAH) and the effect of iloprost on the regulation of biomarkers are lacking. This study investigated potential CHD-PAH biomarkers and their association with the severity of disease. The effect of iloprost on the regulation of these biomarkers was also studied. A total of 31 patients with CHD-PAH were enrolled. Seven with positive effects of iloprost (the average reduction in mPAP 11.13±1.73 mm Hg) and 19 with negative effects of iloprost (the average reduction in mPAP 4.21±4.87 mm Hg; iloprost positive group [IPG] vs iloprost negative group [ING], P<.01) and five age-matched controls were studied. The pulmonary artery blood sample was collected before and after inhaling iloprost, and the plasma concentrations of Gal-3, ADMA, ET-1, and NO were measured. A significant positive linear relationship was observed between mPAP and plasma ET-1, BNP, ADMA, and UA levels in all patients with CHD-PAH. ET-1, ADMA, BNP, and UA levels had a significant linear relationship with mean pulmonary arterial pressure, which could be used to predict the severity of CHD-PAH. ET-1 might be a potential biomarker to pre-evaluate the effect of iloprost on CHD-PAH. Iloprost could affect the expression of Gal-3 and, therefore, the process of fibrosis could be influenced by iloprost.

Facile access to unnatural dipeptide-alcohols based on cis-2,5-disubstituted pyrrolidines.

Well-defined unnatural dipeptide-alcohols based on a cis-2,5-disubstitued pyrrolidine backbone were synthesized from commercially available starting materials meso-diethyl-2,5-dibromoadipate, (S)-(-)-1-phenylethylamine, and phenylalaninol. The structures of these unnatural dipeptide-alcohols are supported by HRMS, 1H- and 13C-NMR spectroscopy. These unnatural dipeptide-alcohols can act as building blocks for peptidomimetics.

Which one is the best in treating deep venous thrombosis -- percutaneous mechanical thrombectomy, catheter-directed thrombolysis or combination of them?

OBJECTIVE: To compare the treatment outcomes among percutaneous mechanical thrombectomy (PMT) with AngioJet, Catheter-directed thrombolysis (CDT), and a combination of both. METHODS: One hundred forty nine patients with acute or sub-acute iliac-femoral vein thrombosis accepting CDT and/or PMT were divided into three groups respectively: PMT group, CDT group, PMT + CDT group (PMT followed by CDT). The severity of thrombosis was evaluated by venographic scoring system. Technical success was defined as restored patent deep venous blood flow after CDT and/or PMT. Clinical follow-up were assessed by ultrasound or venography imaging. The primary endpoints were recurrence of DVT, and severity level of post-thrombotic syndrome (PTS) during the follow-up. RESULTS: Technical success and immediate clinical improvements were achieved on all patients. The proportion of sub-acute DVT and the venographic scoring in PMT + CDT group were significantly higher than that in CDT group and PMT group (proportion of sub-acute DVT: p = 0.032 and p = 0.005, respectively; venographic scoring: p < 0.001, respectively). The proportion of May-Thurner Syndrome was lower in PMT group than that in CDT and PMT + CDT group (p = 0.026 and p = 0.005, respectively). The proportion of DVT recurrence/stent thrombosis was significantly higher in CDT group than that in PMT + CDT group (p = 0.04). The severity of PTS was the highest in CDT group ( χ2 = 14.459, p = 0.006) compared to PMT group (p = 0.029) and PMT + CDT group (p = 0.006). CONCLUSION: Patients with sub-acute DVT, high SVS scoring and combined May-Thurner Syndrome were recommended to take PMT + CDT treatment and might have lower rate of DVT recurrence/stent thrombosis and severe PTS. Our study provided evidence detailing of PMT + CDT therapy.

A novel machine learning model to predict high on-treatment platelet reactivity on clopidogrel in Asian patients after percutaneous coronary intervention.

BACKGROUND: Various genetic and nongenetic variables influence the high on-treatment platelet reactivity (HTPR) in patients taking clopidogrel. AIM: This study aimed to develop a novel machine learning (ML) model to predict HTPR in Chinese patients after percutaneous coronary intervention (PCI). METHOD: This cohort study collected information on 507 patients taking clopidogrel. Data were randomly divided into a training set (90%) and a testing set (10%). Nine candidate Machine learning (ML) models and multiple logistic regression (LR) analysis were developed on the training set. Their performance was assessed according to the area under the receiver operating characteristic curve, precision, recall, F1 score, and accuracy on the test set. Model interpretations were generated using importance scores by transforming model variables into scaled features and representing in radar plots. Finally, we established a prediction platform for the prediction of HTPR. RESULTS: A total of 461 patients (HTPR rate: 19.52%) were enrolled in building the prediction model for HTPR. The XGBoost model had an optimized performance, with an AUC of 0.82, a precision of 0.80, a recall of 0.44, an F1 score of 0.57, and an accuracy of 0.87, which was superior to those of LR. Furthermore, the XGBoost method identified 7 main predictive variables. To facilitate the application of the model, we established an XGBoost prediction platform consisting of 7 variables and all variables for the HTPR prediction. CONCLUSION: A ML-based approach, such as XGBoost, showed optimum performance and might help predict HTPR on clopidogrel after PCI and guide clinical decision-making. Further validated studies will strengthen this finding.

The effect of different frames filters on the prevention of pulmonary embolism in fracture patients subsequent with deep venous thrombosis on a multicenter prospective observational study.

BACKGROUND: A retrievable inferior vena cava filter (RIVCF) is used for the prevention of a pulmonary embolism, especially originated from deep venous thrombosis (DVT). However, which frame of RIVCF has an better effect on the specific thrombus has not been reported. METHODS: All patients enrolled underwent RIVCF placement in the study, and the placement and retrieval followed the respective instructions of different brands of RIVCFs. During the study period, the frame of the filter, the combined fracture site and operation, and the filter trapped embolus (TE) were collected. The primary observation indicators of this study were the occurrence of TE in two frames of filters and different fracture sites. Secondary observation indicators were the occurrence of TE with two different frames filters in different fracture site and surgical site subgroups. RESULTS: In all 2892 patients enrolled, RIVCF TE was detected in 308 cases (10.7%) according to our definition. Among them, there were 1968 cases of fusiform RIVCF and 924 cases of umbrella RIVCF. There were 663 patients combined with fractures before DVT. The incidence of TE was significantly higher in patients with fusiform RIVCF (230 [74.68%]) than in those with umbrella RIVCF (78 [25.32%]) (P < .05). In patients with below-the-knee fracture surgery, there was significant difference in the incidence of TE between the two frames of RIVCF (P < .05). CONCLUSIONS: This conclusion suggests that, in patients with DVT secondary to below-the-knee fracture, the detached thrombus may be more suitable for prophylaxis with fusiform frame RIVCF.

[Acupuncture improves cognitive function of vascular dementia rats by regulating PI3K/Akt/mTOR pathway].

OBJECTIVE: To explore the mechanism of acupuncture in improving cognitive ability by regulating hippocampal phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway in vascular dementia (VD) rats. METHODS: A total of 80 male SD rats were randomized into sham operation, model, non-acupoint and acupoint groups (n=18 per group). The VD model was established by ligation of the bilateral common carotid arteries. For rats of the acupoint group, "Baihui" (GV20) and bilateral "Zusanli "(ST36) were needled and stimulated by twirling the needles with reinforcing method, and for rats of the non-acupoint group, the bilateral subcostal spots (about 10 mm superior to the iliac cresta) were needled and stimulated by twirling the needles with uniform reinforcing and reducing method. The treatment was conducted once daily, 6 times a week for two weeks, beginning 3 days after successful modeling. Rats of the sham operation group and model group received grasps as those in the acupoint groups. Morris water maze test was used to detect the abilities of learning and spatial memory. The contents of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) and the activities of acetylcholinesterase (AChE) and acetylcholine transferase (ChAT) in the hippocampus tissue were detected by using ELISA, changes of hippocampal mitochondrial membrane potential (MMP) detected using JC-1 fluorescence probe, and the expression levels of hippocampal phosphorylated (p)-PI3K, p-Akt and mTOR proteins measured using Western blot. RESULTS: Compared with the sham operation group, the escape latency, contents of ROS and MDA, and AChE activity were significantly increased (P<0.05), and the spatial memory ability, SOD activity, ChAT activity, MMP, p-PI3K, p-Akt and mTOR expression levels were significantly decreased in the model group (P<0.05). Compared with the model group, carotid artery ligature-induced increase of the escape latency, contents of ROS and MDA, and AChE activity, and decrease of the spatial memory ability, SOD activity, ChAT activity, MMP, p-PI3K, p-Akt and mTOR expression levels were significantly reversed in the acupuncture group (P< 0.05), but not in the non-acupoint group (P>0.05). The therapeutic effects of acupoint needling were obviously superior to those of non-acupoint needling in decreasing the escape latency, contents of ROS and MDA, and AChE activity (P<0.05), and in increasing the spatial memory ability, SOD activity, ChAT activity, MMP, p-PI3K, p-Akt and mTOR expre-ssion levels (P<0.05). CONCLUSION: Acupuncture can improve cognitive function of VD rats, which may be related with its functions in easing oxidative stress and MMP reduction by activating PI3K/Akt/mTOR signaling pathway in the hippocampus.

Quantitative HPLC method and pharmacokinetic studies of ergosta-4,6,8(14),22-tetraen-3-one, a natural product with diuretic activity from Polyporus umbellatus.

A simple and specific HPLC method with dual wavelength UV detection for the determination of ergosta-4,6,8(14),22-tetraen-3-one (ergone) in rat plasma was developed and proved to be efficient. The method used ergosterol as internal standard (IS). Following a single-step protein precipitation, the analyte and IS were separated on an Inertsil ODS-3 column with a mobile phase containing methanol-water (99:1, v/v) at a flow rate of 1 mL/min. The analytes were detected by using UV detection at wavelength of 350 (ergone) and 283 (IS) nm, respectively. The calibration curve was linear over the range of 0.1-2.0 µg/mL and the lower limit of quantification was 0.1 µg/mL. The intra-day and inter-day precision studies showed good reproducibility with RSD less than 8.5%. The intra-day and inter-day accuracy ranged from 95.6 to 104%. Mean extraction recovery was above 95% at the low, medium and high concentrations. The present HPLC-UV method was simple and reliable. The method described herein had been successfully applied for the pharmacokinetic studies in male SD rats after administration of 20 mg/kg dose of solution of ergone.

[Role of JAK2/STAT3 signaling pathway in microglia activation after hypoxic-ischemic brain damage].

Hypoxic-ischemic encephalopathy (HIE) is the leading cause of neonatal death and neurodevelopmental disorders in infants. Part of patients have different degrees of neurological sequelae, such as cerebral palsy, cognitive and motor function development disorders. Hypoxia-ischemia may activate JAK2/STAT3 signaling pathway, which leads to the microglia activation and neuroinflammation. Down-Regulating JAK2/STAT3 signaling pathway can inhibit microglia activation and regulate the inflammatory injury of nervous system. At present, the treatment of hypoxic ischemic encephalopathy is limited, so the study of regulatory mechanism about microglia activation has important value for the treatment of hypoxic-ischemic encephalopathy. This paper summarizes the role of JAK2/STAT3 signaling pathway in microglia activation and analyzes the relationship between them, in order to provide new ideas and strategies for treatment on hypoxic-ischemic encephalopathy.

[Clinical observation of selective posterior rhizotomy for improving spasticity and gross movement in patients with cerebral palsy].

OBJECTIVE: To explore the effect of selective lumbosacral posterior rhizotomy(SPR) on lower limb spasticity and gross motor function in patients with cerebral palsy. METHODS: From January 2018 to October 2018, 47 patients with cerebral palsy were treated with rehabilitation alone and SPR combined with rehabilitation. According to whether SPR was performed, the patients were divided into group A and group B. Group A was treated with rehabilitation combined with SPR at lumbosacral level, and group B was treated with rehabilitation alone. There were 23 cases in group A, including 15 males and 8 females, with an average age of (7.30±3.25) years old; 24 cases in group B, 13 males and 11 females, with an average age of (7.00±3.09) years old. Forty-seven patients were assessed with modified Ashworth(MAS) and Gross Motor Function Scale(GMFM-88 items) before and after treatment. The changes of MAS and GMFM-88 scores before and after treatment were compared to evaluate the degree of spasm and the improvement of gross motor function in the two groups. RESULTS: All 47 patients were followed up. At 6 months after treatment, the MAS classification of the two groups was significantly improved(P<0.05), and the improvement of group A was more obvious than that of group B(P<0.05). Six months after treatment, the D, E and total scores of GMFM-88 between two groups were significantly improved compared with those before operation(P<0.05). The improvement of D and total scores in group A was more obvious than that in group B. There was no significant difference in the improvement of area E between two groups. CONCLUSIONS: Selective posterior rhizotomy combined with rehabilitation can significantly improve the spastic state and gross motor function of lower limbs in children with cerebral palsy, and can effectively promote the reconstruction and recovery of motor function of lower limbs in children with cerebral palsy.

Determination of venlafaxine in human plasma by high-performance liquid chromatography using cloud-point extraction and spectrofluorimetric detection.

A new straightforward method based on cloud-point extraction (CPE) has been developed, optimized and validated for the determination of venlafaxine in human plasma by reversed-phase high-performance liquid chromatography with fluorescence detection. The non-ionic surfactant Triton X-114 (polyethylene glycol tert-octylphenyl ether) was chosen as the extract solvent. Separation was obtained using a reversed-phase Diamonsil column (C(18), 250 mm x 4.6 mm I.D., 5 microm) and a mobile phase composed of acetonitrile-phosphate buffer solution (pH 3.0)-triethylamine (33.5:66.5:0.4). Fluorescence detection was used (lambda(ex) 276 nm, lambda(em) 598 nm). Maprotiline was used as the internal standard. Under the optimum conditions, the linear range of venlafaxine in human plasma was 10-800 ng mL(-1) (r(2)=0.9995). The limit of detection (LOD) was less than 2 ng mL(-1) (S/N=3) and the limit of quantification (LOQ) was less than 10 ng mL(-1) (S/N=10). The method was successfully applied for the evaluation of pharmacokinetic profiles of venlafaxine capsules in nine healthy volunteers.

Pharmacokinetic of rhein in healthy male volunteers following oral and retention enema administration of rhubarb extract: a single dose study.

Rhubarb is a common herb used in traditional Chinese medicine. However, few publications exist about its pharmacokinetic profiles in animals or healthy volunteers. Whether retention enema administration of rhubarb extract affects its pharmacokinetics as well as its tolerability is unknown. Therefore, we set out to compare the pharmacokinetic parameters of rhein administered by retention enemas with those of conventional oral dosing of rhubarb extract. Eight healthy male volunteers were enrolled in a prospective crossover study. All subjects received a single dose of rhubarb extract (50 mg.kg(-1)) on two separate occasions, once orally, once by a retention enema. Rhein plasma concentration was measured by HPLC. The C(max), AUC(0-infinity), AUMC were significantly higher in oral administration than those in retention enema administration (p < 0.05), while V(d) of rhein after oral administration of rhubarb extract was significantly lower (p < 0.05) than that after retention enema administration. However, no statistically significant differences between the two treatments were observed for any of the other pharmacokinetic parameters (T(max), t(1/2), MRT(0-infinity), CL). Dosage adjustment is advisable for retention enema administration of rhubarb extract in patients.

[The pharmacokinetics of rhein in 12 healthy volunteers after oral administration of rhubarb extract].

OBJECTIVE: To study the pharmacokinetics of rhein in 12 healthy volunteers after oral administration of rhubarb extract. METHOD: The blood sample were obtained at 0,0.083,0.5,1,1.5,2,3,4,5,7,10 h after a single dose oral administration of rhubarb (50 mg x kg(-1)). The plasma rhein concentration was determined by HPLC. The pharmacokinetics of rhein were analysed by 3P97 program. RESULT: The absorption of rhein was very fastafter oral administration of rhubarb extract in the healthy volunteers. The main pharmacokinetic parameters of rhein were C(max) (3.20 +/- 1.08) microg x mL(-1); t(max) (1.03 +/- 0.41) h; t(1/2alpha) (0.21 +/- 0.02) h; t(1/2beta) (2.68 +/- 1.09) h; MRT(5.31 +/- 1.78) h; AUC(0-infinity) (1 573.08 +/- 366.48) microg x mL(-1) min(-1), respectively. CONCLUSION: Rhein could be absorbed rapidly and its pharmacokinetics was consistent with two-compartment model.

[Studies on ultrasonic wave extracting method determining konjac glucomannanin konjac refined powder].

OBJECTIVE: To investigate the effect of ultrasonic wave on extracting Konjac Glucomannan(KGM) in Konjac refined powder. METHOD: Free reduced sugar in Konjac refined powder was removed and Konjac refined powder in the aqueous solution was processed by ultrasonic wave and KGM content was measured by spectrophotometry. RESULT: KGM content in the Konjac refined powder aqueous solution by ultrasonic process at fixed 40 kHz, 100 W, 30-45 min was equal to that by routine method at 4 h; whereas, by 1 h of ultrasonic process, KGM content was significantly enhanced than that by 4 h of routine method(P < 0.01), enhancement rate was 6.5%. Linearity of standard glucose was good (r = 0.9996) in range of 0.2-1.6 mg. The average recovery was 97.8%, RSD of repeatability was 1.27%. CONCLUSION: Ultrasonic extraction in aqueous solution is a reliable and rapid method that can enhance extraction efficiency of KGM in Konjac refined powder.

[The determination of konjac glucomannan in konjac refined powder and monosaccharide compositions by HPLC].

OBJECTIVE: To establish a quantitative method for the content determination and monosaccharide composition analysis of Konjac glucomannan (KGM) in Konjac refined powder by pre-column derivatization high performance liquid chromatographic method (HPLC). METHOD: The two derivatives combined reducing monosaccharides with 1-phenyl-3-methyl-5-pyrazolone (PMP) were separated by reverse-phase HPLC using a developed fragment gradient elution process, and monitored by ultraviolet detector at 250 nm. The broad reagent peak of PMP was separated very well from all the PMP-sugars, and good separation was achieved for derivatives of mannose and glucose. The quantitative methods of two reducing monosaccharides were studied by the method combined internal and external standard; while the KGM content in Konjac refined powder was determined. RESULT: Linearity of glucose was good (r = 0.9990) in range of 1.002-8.016 nmol; while mannose (r = 0.9994) in range of 1.001-8.008 nmol. The average recovery of this method was 98.1%, RSD of repeatability was 1.72%. KGM content in Konjac refined powder was 79.5%, ratio of glucose to mannose in KGM was 1:1.51. CONCLUSION: This method is a sample, convenient and rapid method that can determine KGM content and analyze monosaccharide compositions in KGM, which will be helpful to quality assessment of Konjac refined powder.

[Rehabilitation by hollow obturator prosthesis immediately after total maxillectomy for malignant tumor].

OBJECTIVE: The feasibility and clinical effects of hollow obturator prosthesis for the repair of maxillofacial defect immediately after maxillectomy for cancer were assessed. METHODS: Thirteen patients with T3-4aN0M0 maxillary neoplasm were treated by the prostheses immediately after maxillectomy. According to the 3D-CT reconstruction of nasal sinus, the 3D stereoscopic prototype was constructed before the surgery. Simulating surgery with Surgicare 5.0 software and then the prosthesis 3D stereoscopic model was shaped. The prosthesis was made quickly and precisely with methacrylate resins according to the model and the print mold before surgery, with supplementary tooth at the bottom of prosthesis. In the surgery, the prosthesis was installed instantly after maxillectomy. The patients were followed up at 1, 3 and 6 month after the surgery, respectively. The facial features and the pronunciation clarity were examined and the questionnaires were carried out in the patients, with comparation by paired t-test. The hollow obturator prosthesis would be replaced by permanent prosthesis made of methacrylate resins at 6 month after the surgery. RESULTS: The hollow obturator prostheses were installed accurately and maxillofacial defects were repaired immediately after maxillectomy in the 13 patients. Postoperative follow-up showed there were significant differences in eyeball sagging (t = 4.67, P < 0.05), mid-facial region collapse (t = 5.67, P < 0.05), and pronunciation clarity (t = 16.38, P < 0.05) between patients with and without prostheses. Questionnaires showed that all the patients were satisfied with the retention of prostheses, the improvement of appearance, the improvement of the symptom of water choking and speech definition. Six months after the surgery, the hollow obturator prostheses were replaced smoothly by permanent prostheses in 11 of the 13 patients. CONCLUSION: The precise and instant repair of maxillofacial defect by prosthesis after maxillectomy can improve survival quality of patient.

Rapid resolution liquid chromatography-mass spectrometry and high-performance liquid chromatography-fluorescence detection for metabolism and pharmacokinetic studies of ergosta-4,6,8(14),22-tetraen-3-one.

Ergosta-4,6,8(14),22-tetraen-3-one (ergone) from many medicinal plants has been demonstrated to possess a variety of pharmacological activities in vivo and in vitro, including cytotoxic, diuretic and immunosuppressive activity. Metabolism and pharmacokinetic studies on rat were conducted for ergone. Rapid resolution liquid chromatography with atmospheric pressure chemical ionization tandem multi-stage mass spectrometry (RRLC-APCI-MS(n)) and high-performance liquid chromatography with fluorescence detection (HPLC-FLD) methods were applied for the identification and quantification of ergone and its metabolite from rat plasma, faeces and urine. A metabolite was identified by RRLC-DAD-APCI-MS(n): 22,23-epoxy-ergosta-4,6,8(14)-triaen-3-one (epoxyergone). The concentrations of the analyte with its metabolites were determined by HPLC-FLD at excitation wavelength of 370 nm and emission wavelength of 485 nm. The samples were deproteinized with methanol after addition of camptothecin as internal standard (IS). The analysis was performed on a Diamonsil C18 column (150 mm x 4.6 mm x 5 microm) with a mobile phase gradient consisting of methanol and water at a flow rate of 1 mL min(-1). The assay was linear over the concentration range of 42-1500, 36-7500 and 42-1500 ng mL(-1) for plasma, faecal homogenate and urine respectively. The absolute recoveries were found to be 97.0+/-1.2%, 98.1+/-0.7% and 96.6+/-1.8% for plasma, faecal homogenate and urine respectively. The intra-day and inter-day relative standard deviations (RSD) were less than 10%. The previous HPLC-MS/MS method is not affordable for most laboratories because of the specialty requirement and high equipment cost. However, the HPLC-FLD method is economic and operating simply for quantitative determination of ergone and its metabolite in rat plasma, faeces and urine. In addition, liquid chromatography coupled with ion trap multi-stage mass spectrometry is becoming a useful technique for ergone metabolite identification.

Synthesis of chiral vicinal diols and analysis of them by capillary zone electrophoresis.

This paper describes an improved access to 1,4-bis (9-O-quininyl) phthalazine [(QN)(2)PHAL], a very useful chiral ligand for catalytic asymmetric dihydroxylation (AD), by using CaH(2) as acid-binding reagent in a high yield under mild conditions. The application of (QN)(2)PHAL to the AD reactions of eight olefins exhibited excellent enantioselectivity and activity with corresponding chiral vicinal diols. Furthermore, a capillary zone electrophoresis method was developed to separate the aforementioned chiral vicinal diols by using of neutral beta-cyclodextrin (beta-CD) as chiral selector and borate as running buffer. High resolution was achieved under the optimal conditions of beta-CD 2.2% (w/v), pH 10, 200 mM borate buffer at 15 kV, and 20 degrees C within 15 min. The relative standard deviations of the corrected peak areas and migration time were less than 3.9% and 1.3%, respectively. In addition, the developed method was successfully applied to the determination of the purity and the enantiomeric excesses value (%ee) of the AD reaction products.