Research progress of Pictet-Spenglerases / 生物工程学报

Pictet-Spenglerases (P-Sases) catalyze the Pictet-Spengler (P-S) reactions and exhibit high stereoselectivity and regioselectivity under mild conditions. The typical P-S reaction refers to the condensation and recyclization of β-arylethylamine with aldehyde or ketone under acidic conditions to form tetrahydroisoquinoline and β-carboline alkaloid derivatives. The related enzymatic products of P-Sases are the backbones of various bioactive compounds, including clinical drugs: morphine, noscapine, quinine, berberine, ajmaline, morphine. Furthermore, the activity of P-Sases in stereoselective and regioselective catalysis is also valuable for chemoenzymatic synthesis. Therefore, this review summarizes the research progress in the discovery, functional identification, biological characteristics and catalytic applications of P-Sases, which provide the useful theoretical reference in future P-Sases research and development.

Major clinical research advances in gynecologic cancer in 2015 / 부인종양

In 2015, fourteen topics were selected as major research advances in gynecologic oncology. For ovarian cancer, high-level evidence for annual screening with multimodal strategy which could reduce ovarian cancer deaths was reported. The best preventive strategies with current status of evidence level were also summarized. Final report of chemotherapy or upfront surgery (CHORUS) trial of neoadjuvant chemotherapy in advanced stage ovarian cancer and individualized therapy based on gene characteristics followed. There was no sign of abating in great interest in immunotherapy as well as targeted therapies in various gynecologic cancers. The fifth Ovarian Cancer Consensus Conference which was held in November 7–9 in Tokyo was briefly introduced. For cervical cancer, update of human papillomavirus vaccines regarding two-dose regimen, 9-valent vaccine, and therapeutic vaccine was reviewed. For corpus cancer, the safety concern of power morcellation in presumed fibroids was explored again with regard to age and prevalence of corpus malignancy. Hormone therapy and endometrial cancer risk, trabectedin as an option for leiomyosarcoma, endometrial cancer and Lynch syndrome, and the radiation therapy guidelines were also discussed. In addition, adjuvant therapy in vulvar cancer and the updated of targeted therapy in gynecologic cancer were addressed. For breast cancer, palbociclib in hormone-receptor-positive advanced disease, oncotype DX Recurrence Score in low-risk patients, regional nodal irradiation to internal mammary, supraclavicular, and axillary lymph nodes, and cavity shave margins were summarized as the last topics covered in this review.

Trabectedin therapy as an emerging treatment strategy for recurrent platinum-sensitive ovarian cancer / 癌症

Epithelial ovarian cancer (OC) is a common gynecologic malignancy in women. The standard treatment for OC is maximal cytoreductive surgical debulking followed by platinum-based chemotherapy. Despite the high response rate to primary therapy, approximately 85% of patients will develop recurrent ovarian cancer (ROC). This review identifies the clinical use of trabectedin in the treatment algorithm for ROC, with specific emphasis on platinum-sensitive ROC, for which trabectedin in combination with pegylated liposomal doxorubicin has been approved as a treatment protocol. The main mechanisms of action of trabectedin at the cellular level and in the tumor microenvironment is also discussed as bases for identifying biomarkers for selecting patients who may largely benefit from trabectedin-based therapies.

A Proton Pump Inhibitor's Effect on Bone Metabolism Mediated by Osteoclast Action in Old Age: A Prospective Randomized Study

BACKGROUND/AIMS: Proton pump inhibitors (PPIs) act by irreversibly binding to the H+-K+-ATPase of the proton pump in parietal cells and may possibly affect the vacuolar H+-ATPase in osteoclasts. METHODS: We investigated the effect of 8 weeks of PPI treatment on the parameters of bone turnover and compared PPI with revaprazan, which acts by reversibly binding to H+-K+-ATPase in proton pumps. This study was a parallel randomized controlled trial. For 8 weeks, either a PPI or revaprazan was randomly assigned to patients with gastric ulcers. The parameters of bone turnover were measured at the beginning of and after the 8-week treatment period. RESULTS: Twenty-six patients (PPI, n=13; revaprazan, n=13) completed the intention-to-treat analysis. After the 8-week treatment period, serum calcium and urine deoxypyridinoline (DPD) were increased in the PPI group (serum calcium, p=0.046; urine DPD, p=0.046) but not in the revaprazan group. According to multivariate linear regression analysis, age > or =60 years was an independent predictor for the changes in serum calcium and urine DPD. CONCLUSIONS: In elderly patients, administering a PPI for 8 weeks altered bone parameters. Our study suggested that PPIs might directly alter bone metabolism via the vacuolar H+-ATPase in osteoclasts.

Design, synthesis and anti-platelet aggregation activities of ligustrazine-tetrahydroisoquinoline derivatives / 药学学报

Abstract: Fifteen novel ligustrazine-tetrahydroisoquinoline derivatives were designed and synthesized according to the association principle of pharmaceutical chemistry. The structures were identified by IR, NMR and ESI-MS. The inhibitory activities of platelet aggregation induced by ADP and AA have been measured by Bron method. Preliminary pharmacological results showed that compounds 7g, 7h and 7n had potent inhibitory activity against platelet aggregation induced by AA, and the compound 7o showed significant inhibitory activity against platelet aggregation induced by ADP.

Effect of Improvement in Lower Urinary Tract Symptoms on Sexual Function in Men: Tamsulosin Monotherapy vs. Combination Therapy of Tamsulosin and Solifenacin

PURPOSE: To evaluate how much the improvement of lower urinary tract symptoms (LUTS) affects sexual function and which storage symptoms or voiding symptoms have the greatest effect on sexual function. MATERIALS AND METHODS: A total of 187 patients were enrolled in this study. Patients were randomly assigned to receive either tamsulosin 0.2 mg (group A) or tamsulosin 0.2 mg and solifenacin 5 mg (group B). At 4 weeks and 12 weeks, the LUTS and sexual function of the patients were evaluated by use of the International Index of Erectile Function-5 (IIEF5), International Prostate Symptom Score (IPSS), Overactive Bladder Symptom Score (OABSS) questionnaire, uroflowmetry, and bladder scan. RESULTS: Both groups A and B showed statistically significant improvements in IPSS, OABSS, and quality of life (QoL). Group A showed improved maximum flow rate, mean flow rate, and residual urine volume by time. Group B did not show an improvement in flow rate or residual urine volume but total voiding volume increased with time. The IIEF5 score was not improved in either group. In group A, the IIEF5 score dropped from 13.66+/-4.97 to 11.93+/-6.14 after 12 weeks (p=0.072). Group B showed a decline in the IIEF5 score from 13.19+/-5.91 to 12.45+/-6.38 (p=0.299). Although group B showed a relatively smaller decrease in the IIEF5 score, the difference between the two groups was not significant (p=0.696). CONCLUSIONS: Tamsulosin monotherapy and combination therapy with solifenacin did not improve erectile function despite improvements in voiding symptoms and QoL. The improvement in storage symptoms did not affect erectile function.

Effect of Improvement in Lower Urinary Tract Symptoms on Sexual Function in Men: Tamsulosin Monotherapy vs. Combination Therapy of Tamsulosin and Solifenacin

PURPOSE: To evaluate how much the improvement of lower urinary tract symptoms (LUTS) affects sexual function and which storage symptoms or voiding symptoms have the greatest effect on sexual function. MATERIALS AND METHODS: A total of 187 patients were enrolled in this study. Patients were randomly assigned to receive either tamsulosin 0.2 mg (group A) or tamsulosin 0.2 mg and solifenacin 5 mg (group B). At 4 weeks and 12 weeks, the LUTS and sexual function of the patients were evaluated by use of the International Index of Erectile Function-5 (IIEF5), International Prostate Symptom Score (IPSS), Overactive Bladder Symptom Score (OABSS) questionnaire, uroflowmetry, and bladder scan. RESULTS: Both groups A and B showed statistically significant improvements in IPSS, OABSS, and quality of life (QoL). Group A showed improved maximum flow rate, mean flow rate, and residual urine volume by time. Group B did not show an improvement in flow rate or residual urine volume but total voiding volume increased with time. The IIEF5 score was not improved in either group. In group A, the IIEF5 score dropped from 13.66+/-4.97 to 11.93+/-6.14 after 12 weeks (p=0.072). Group B showed a decline in the IIEF5 score from 13.19+/-5.91 to 12.45+/-6.38 (p=0.299). Although group B showed a relatively smaller decrease in the IIEF5 score, the difference between the two groups was not significant (p=0.696). CONCLUSIONS: Tamsulosin monotherapy and combination therapy with solifenacin did not improve erectile function despite improvements in voiding symptoms and QoL. The improvement in storage symptoms did not affect erectile function.

Overactive bladder symptom score to evaluate efficacy of solifenacin for the treatment of overactive bladder symptoms / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Overactive bladder (OAB) is a series of symptoms with high prevalence in elderly people. This study was conducted using the overactive bladder symptom score (OABSS) to evaluate the efficacy of solifenacin succinate for the treatment of OAB.</p><p><b>METHODS</b>This was a prospective, multicenter, single-arm, 12-week study that enrolled 241 OAB patients. The patients received 5-10 mg/day solifenacin. Changes in OABSS, symptoms from voiding diary, perception of bladder condition (PPBC) score, international prostate symptom score (IPSS) and quality of life (QOL) were evaluated at weeks 0, 4, and 12. The relationship between OABSS and PPBC score or parameters of voiding diary was also evaluated.</p><p><b>RESULTS</b>At baseline, the mean OABSS for all patients was 9.41 ± 2.40, and was reduced significantly at week 12 (-3.76 points; 61.21%, P < 0.0001). The OABSS subscore, PPBC score, IPSS, and QOL were also significantly reduced during the study (P < 0.0001). The overall incidence of adverse events was 19.91% (44 cases). The gastrointestinal system was the most commonly affected (11.31%). Around 5.88% of the cases had adverse events related to the genitourinary system. There was a strong correlation between OABSS and urinary symptoms that was recorded in the 3-day voiding dairy.</p><p><b>CONCLUSIONS</b>We showed that solifenacin was clinically effective for relieving OAB symptoms, considering the balance between efficacy, patients' well-being, and tolerability. OABSS integrates four OAB symptoms into a single score and can be a useful tool for research and clinical practice.</p>

Efficacy of combination therapy of tamsulosin and solifenacin for mild and moderate benign prostatic hyperplasia with overactive bladder / 中华男科学杂志

<p><b>OBJECTIVE</b>To evaluate the efficacy and safety of the combination therapy of tamsulosin and solifenacin for mild and moderate benign prostatic hyperplasia (BPH) with overactive bladder (OAB).</p><p><b>METHODS</b>We randomly divided 166 patients with BPH and concomitant OAB into a mild obstruction symptom group (n = 88) and a moderate obstruction symptom group (n =78), 48 of the former group treated with 0. 2 mg tamsulosin + 5 mg solifenacin and the other 40 with 0. 2 mg tamsulosin; 36 of the latter group treated with 0. 2 mg tamsulosin + 5 mg solifenacin and the other 42 with 0. 2 mg tamsulosin, all administered once daily for 12 weeks. We obtained the International Prostate Symptom Score (IPSS), urine storage period symptom score (USPSS), voiding symptom score (VSS), Qmax, residual urine volume, OAB symptom score (OABSS) and adverse reactions, and compared them among different</p><p><b>RESULTS</b>Among the patients with mild obstruction symptoms, the combination of tamsulosin and solifenacin achieved remark-groups. able improvement in IPSS, USPSS, Qmax and OABSS as compared with the baseline (P < 0.05), but made no significant difference in the residual urine volume (P > 0. 05) , while tamsulosin improved IPSS only (P < 0.05). The combination therapy exhibited an obvious superiority over tamsulosin alone in improving IPSS (9.7 micro 3.0 vs 15.8 micro 3.3), USPSS (8. 1 micro 1.7 vs 12.3 micro 3.1), Qmax ([18.6 micro 2.3] ml/s vs [14.2 micro 2.3] ml/s ), and OABSS (5.3micro 1.3 vs 9.7 micro 2.7) (P < 0.05), but there were no obvious differences in residual urine, urine routine test results and adverse events between the two therapies ( P > 0. 05). In those with moderate obstruction symptoms, the combination therapy significantly improved IPSS, VSS, Qmax and OABSS (P < 0.05) but not the residual urine (P > 0. 05) in comparison with the baseline. The tamsulosin therapy achieved obvious improvement in IPSS, VSS, Qmax, OABSS and residual urine. The combination therapy showed a better effect than tamsulosin only in OABSS (4. 8 +/-1.5 vs 6.5 +/-2.5, P < 0.05), but no significant differences from the latter in IPSS, Qmax, VSS, routine urine test results, and adverse</p><p><b>CONCLUSION</b>Combination therapy of tamsulosin and solifenacin is obviously safe and efficacious in the treatment (P > 0.05). events of both mild and moderate BPH with concomitant OAB, and it is superior to tamsulosin alone.</p>

Rationale for the Use of Anticholinergic Agents in Overactive Bladder With Regard to Central Nervous System and Cardiovascular System Side Effects

PURPOSE: Central nervous system (CNS) and cardiovascular system (CVS) side effects of anticholinergic agents used to treat overactive bladder (OAB) are underreported. Hence, this review aimed to focus on the mechanisms of CNS and CVS side effects of anticholinergic drugs used in OAB treatment, which may help urologists in planning the rationale for OAB treatment. MATERIALS AND METHODS: PubMed/MEDLINE was searched for the key words "OAB," "anticholinergics," "muscarinic receptor selectivity," "blood-brain barrier," "CNS," and "CVS side effects." Additional relevant literature was determined by examining the reference lists of articles identified through the search. RESULTS: CNS and CVS side effects, pharmacodynamic and pharmacokinetic properties, the metabolism of these drugs, and the clinical implications for their use in OAB are presented and discussed in this review. CONCLUSIONS: Trospium, 5-hydroxymethyl tolterodine, darifenacin, and solifenacin seem to have favorable pharmacodynamic and pharmacokinetic properties with regard to CNS side effects, whereas the pharmacodynamic features of darifenacin, solifenacin, and oxybutynin appear to have an advantage over the other anticholinergic agents (tolterodine, fesoterodine, propiverine, and trospium) with regard to CVS side effects. To determine the real-life situation, head-to-head studies focusing especially on CNS and CVS side effects of OAB anticholinergic agents are urgently needed.

Dauricine can inhibit the activity of proliferation of urinary tract tumor cells

OBJECTIVE@#To explore the anti-tumor effects of asiatic moonseed rhizome extraction-dauricine on bladder cancer EJ cell strain, prostate cancer PC-3Mcell strain and primary cell culture system.@*METHODS@#The main effective component-phenolic alkaloids ofMenispermum dauricum was extracted and separated from asiatic moonseed rhizome by chemical method. MTT method was used to detect dauricine anti-tumor effect.@*RESULTS@#Dauricine had an obvious proliferation inhibition effect on the main tumor cells in urinary system. The minimum drug sensitivity concentration was between 3.81-5.15 μg/mL, and the inhibition ratio increased with the increase of concentration.@*CONCLUSIONS@#Dauricine, the main effective component extracted from asiatic moonseed rhizome, had a good inhibition effect on tumor cells in urinary system. At the same time, Dauricine has certain inhibition effects on the primary cultured tumor cell.

Characterization of Bladder Selectivity of Antimuscarinic Agents on the Basis of In Vivo Drug-Receptor Binding / 대한배뇨장애요실금학회지

The in vivo muscarinic receptor binding of antimuscarinic agents (oxybutynin, solifenacin, tolterodine, and imidafenacin) used to treat urinary dysfunction in patients with overactive bladder is reviewed. Transdermal administration of oxybutynin in rats leads to significant binding of muscarinic receptors in the bladder without long-term binding in the submaxillary gland and the abolishment of salivation evoked by oral oxybutynin. Oral solifenacin shows significant and long-lasting binding to muscarinic receptors in mouse tissues expressing the M3 subtype. Oral tolterodine binds more selectively to muscarinic receptors in the bladder than in the submaxillary gland in mice. The muscarinic receptor binding of oral imidafenacin in rats is more selective and longer-lasting in the bladder than in other tissues such as the submaxillary gland, heart, colon, lung, and brain, suggesting preferential muscarinic receptor binding in the bladder. In vivo quantitative autoradiography with (+)N-[11C]methyl-3-piperidyl benzilate in rats shows significant occupancy of brain muscarinic receptors with the intravenous injection of oxybutynin, solifenacin, and tolterodine. The estimated in vivo selectivity in brain is significantly greater for solifenacin and tolterodine than for oxybutynin. Imidafenacin occupies few brain muscarinic receptors. Similar findings for oral oxybutynin were observed with positron emission tomography in conscious rhesus monkeys with a significant disturbance of short-term memory. The newer generation of antimuscarinic agents may be advantageous in terms of bladder selectivity after systemic administration.

Are Solifenacin and Ramosetron Really Ideal to Treat Irritable Bowel Syndrome?

No abstract available.

Are Solifenacin and Ramosetron Really Ideal to Treat Irritable Bowel Syndrome?: Author's Reply

No abstract available.

Efficacy and Safety of Solifenacin Succinate for Urinary Difficulty in Brain Lesion: Multicenter Prospective Study

OBJECTIVE: We studied the efficacy and safety of solifenacin for urinary difficulty in brain lesion from multicenter prospective study. METHOD: Eighty patients with brain lesion who visited from 5 multicenter department of rehabilitation medicine from May 2009 to June 2010 were included. Patients were treated with solifenacin 5 mg to 10 mg for 12 weeks. The outcome measure was mean change in daily micturation frequency, daily frequency of incontinence, urgency episodes, and nocturia episodes from baseline to week 12. Patient's attitude to drug was assessed using the BSW Questionnaire (Benefit, Satisfaction and Willingness to Continue Questions). RESULTS: Sixty-one of 80 were evaluated for effect. All voiding parameters showed significant improvement after 12 weeks of treatment (p<0.05). There was no significant difference in efficacy of solifenacin between ischemic and hemorrhagic stroke. A twenty-two patients experienced 27 adverse events (AE). The most frequent AE were dry mouth (12.5%) and constipation (6.3%). Treatment related adverse events with solifenacin were mainly mild in severity, and only led to discontinuation in 6.3% of patients. CONCLUSION: Solifenacin succinate improve urinary difficulty symptoms with acceptable efficacy and safety in patient with brain lesion.

The Efficacy of Short-term Administration of Revaprazan on Gastroesophageal Reflux Symptoms: Comparison with Half Dose Esomeprazole, a Pilot Study

BACKGROUND/AIMS: Revaprazan, an acid pump antagonist, is a kind of gastric acid suppressant and is prescribed for the treatment of peptic ulcers and gastritis. However, the efficacy of revaprazan on gastroesophageal reflux symptoms has not been established. The aim of this study was to evaluate the short-term efficacy of revaprazan on gastroesophageal reflux symptoms. MATERIALS AND METHODS: Patients who complained of gastroesophageal reflux symptoms without any specific diseases except gastritis on esophagogastroduodenoscopy were included in this study. Patients were randomized to receive revaprazan 200 mg or esomeprazole 20 mg for 2 weeks. Symptoms were assessed by using the frequency score questionnaire before and after treatment. RESULTS: Fifteen patients received revaprazan and 19 patients received esomeprazole. The changes of the symptom frequency score before and after treatment were 7.0 in revaprazan group and 8.6 in esomeprazole group (P=0.778). CONCLUSIONS: Revaprazan is not inferior to esomeprazole in therapeutic efficacy for gastroesophageal reflux symptoms and is a safe and useful therapeutic agent to reduce the frequency of gastroesophageal reflux symptoms.

Efficacy of Solifenacin on Irritable Bowel Syndrome With Diarrhea: Open-label Prospective Pilot Trial

BACKGROUND/AIMS: Solifenacin, a muscarinic type 3 receptor antagonist, is used to treat overactive bladder in adults. The aim of this study is to examine the efficacy of solifenacin on the symptomatic relief of diarrhea predominant irritable bowel syndrome (IBS-D). METHODS: A total of 20 patients with IBS-D were enrolled. After a 2-week observation period, all participants received solifenacin for 6 weeks. Subsequently, the administration of solifenacin was discontinued and ramosetron, a serotonin 3 receptor antagonist, was administered for 4 weeks. Overall improvement, the IBS-symptom severity scale (IBS-SSS), and frequency of defecation were assessed. RESULTS: Six weeks after initiation of solifenacin treatment and 4 weeks after initiation of ramosetron treatment, overall improvement was observed in 19 out of 20 (95%) and 17 out of 20 (85%) participants, respectively. At 2 weeks after initiation of solifenacin, overall improvement was observed in 16 out of 20 participants (80%). Total IBS-SSS scores at 2 and 6 weeks after the administration of solifenacin, and at 4 weeks after administration of ramosetron, were significantly lower than those at week 0. Compared to before administration, the participants' quality of life and frequency of defecation were significantly lower in all participants at 2 and 6 weeks after the administration of solifenacin and at 4 weeks after administration of ramosetron. CONCLUSIONS: The efficacy of solifenacin in the treatment of IBS with diarrhea was not inferior to that of ramosetron. Further placebo-controlled parallel studies are needed.

Establishment of BCRP expressed pig kidney cell line LLC-PK1/BCRP and its biological profile / 药学学报

To establish a pig kidney cell line LLC-PK1/BCRP in which human breast cancer resistance protein was highly expressed, the expression vector pcDNA3.1(+)-BCRP which contained BCRP gene was constructed and transfected into LLC-PKI cells via liposomes. After selecting with G418, population doubling time, flow cytometry and Western blotting analysis were used to evaluate the cell line. MTT assays were employed to determine the drug resistance index of mitoxantrone and doxorubicin. Invert fluorescent microscope was used to observe the efflux of fluorescence dye Hoechst 33342 by BCRP, furthermore, the BCRP's inhibitor GF120918 was applied to reverse the efflux of Hoechst 33342. The experiment results showed that the expression of BCRP protein increased in LLC-PK1/BCRP cell. The population doubling time of LLC-PK1/BCRP cell was a little longer than that of the parental cell LLC-PK1. The resistance indexes to mitoxantrone and doxorubicin were 51.95 and 6.09 times, respectively, higher than LLC-PK1 cell. The efflux of Hoechst 33342 was significantly enhanced and could be reversed by GF120918. So a LLC-PK1/BCRP cell line was established, which highly expressed BCRP protein successfully. This cell line could be a valuable model to further investigate the biological profile of BCRP and select the substrate and inhibitor of BCRP.

Design, synthesis, and PPARalpha/gamma agonistic activity of novel tetrahydroisoquinoline derivatives / 药学学报

A series of tetrahydroisoquinoline derivatives were prepared and their peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonistic activities were evaluated to obtain more potent PPAR agonist. All of them were new compounds, and their structures were confirmed by 1H NMR and HR-MS. Three compounds exhibited higher agonistic activities of PPARgamma than that of the comparison, six compounds exhibited higher agonistic activities of PPARalpha than that of the comparison, and compound 8a was discovered as a highly potent PPARalpha/gamma agonist that is much more active than that of WY14643 and rosiglitazone. The development of potent PPAR agonists may offer a new choice for the treatment of diabetes.