Meta-analysis comparing denosumab and zoledronic acid for treatment of bone metastases in patients with advanced solid tumours.

The purpose of this meta-analysis was to evaluate the efficacy of denosumab, compared with zoledronic acid (ZA), in delaying skeletal-related events (SREs) and enhancing overall survival in patients with advanced solid tumours and bone metastases. A systematic literature search of several electronic databases, including PubMed, Medline, Embase, the Cochrane Library, CKNI and Web of Science with Conference Proceedings, was performed. Only randomised controlled trials assessing denosumab in comparison with ZA, in patients with advanced solid tumours and metastatic-stage disease, were included. The primary outcome was the time to first SRE. The risk of developing subsequent on-study SREs and overall survival were also evaluated. Three randomised controlled trials with a total of 5,544 patients with advanced solid tumours and bone metastases were included in the meta-analysis. There were 2,776 patients treated with denosumab and 2,768 treated with ZA. The pooled analysis showed that denosumab was superior to ZA in delaying time to first on-study SRE (odds ratio [OR]: 0.82; 95% CI: 0.75-0.89, p < 0.0001) and multiple SREs (risk ratio: 0.81; 95% CI: 0.74-0.88, p < 0.0001). However, no significant difference was found in overall survival improvement between denosumab and ZA (OR: 1.02; 95% CI: 0.91-1.15, p = 0.71). This meta-analysis indicates that denosumab is superior to ZA in delaying SREs for patients with bone metastases. No significant difference was observed between denosumab and ZA, regarding overall survival. We support denosumab as a potential novel treatment option for the management of bone metastases in advanced solid tumours.

Blockade of mGluR1 receptor results in analgesia and disruption of motor and cognitive performances: effects of A-841720, a novel non-competitive mGluR1 receptor antagonist.

BACKGROUND AND PURPOSE: To further assess the clinical potential of the blockade of metabotropic glutamate receptors (mGluR1) for the treatment of pain. EXPERIMENTAL APPROACH: We characterized the effects of A-841720, a novel, potent and non-competitive mGluR1 antagonist in models of pain and of motor and cognitive function. KEY RESULTS: At recombinant human and native rat mGluR1 receptors, A-841720 inhibited agonist-induced calcium mobilization, with IC50 values of 10.7+/-3.9 and 1.0 +/- 0.2 nM, respectively, while showing selectivity over other mGluR receptors, in addition to other neurotransmitter receptors, ion channels, and transporters. Intraperitoneal injection of A-841720 potently reduced complete Freund's adjuvant-induced inflammatory pain (ED50 = 23 micromol kg(-1)) and monoiodoacetate-induced joint pain (ED50 = 43 micromol kg(-1)). A-841720 also decreased mechanical allodynia observed in both the sciatic nerve chronic constriction injury and L5-L6 spinal nerve ligation (SNL) models of neuropathic pain (ED50 = 28 and 27 micromol kg(-1), respectively). Electrophysiological studies demonstrated that systemic administration of A-841720 in SNL animals significantly reduced evoked firing in spinal wide dynamic range neurons. Significant motor side effects were observed at analgesic doses and A-841720 also impaired cognitive function in the Y-maze and the Water Maze tests. CONCLUSIONS AND IMPLICATIONS: The analgesic effects of a selective mGluR1 receptor antagonist are associated with motor and cognitive side effects. The lack of separation between efficacy and side effects in pre-clinical models indicates that mGluR1 antagonism may not provide an adequate therapeutic window for the development of such antagonists as novel analgesic agents in humans.

[Separation and identification of main medicinal saponin components from mass cell cultures of Panax notoginseng (Burk) F. H. Chen].

Five main saponins were separated from the cell cultures of Panax notoginseng (Burk) F. H. Chen. They were sanchinoside Rb1, Re, R1, Rg1 and Rh1 identified by TLC, HPLC, IR, M. P., 13CNMR and EI-MS. Saponin components of the cell cultures were almost the same as those of the cultivated plants. But the content of saponins was different between the cell cultures and the cultivated plants. Saponin extraction and separation procedure suitable for the cell cultures has to be different from that for the cultivated plants.

[Evaluation of synovectomy in hemophilic arthropathy follow-up of 26 cases].

Thirty-five joint synovectomies performed between 1973 and 1986 in 26 patients with hemophilic arthropathy at the Department of orthopaedics, University of Colorado Health Sciences Center (UCHSC), USA, were reviewed. There were 15 knees, 15 elbows, 3 ankles and 2 shoulders. Arthroscopic synovectomy was performed on 8 knees. The remaining 27 synovectomies were performed by open surgical synovectomy. Twenty-one (60%) of the 35 joints have had no recurrent hemarthrosis reported, in 14 (40%) there were occasional episodes of bleeding. Among 9 (60%) of the 15 knees and 9 (60%) of the 15 elbows, no further hemarthrosis was observed; 6 (40%) of the knees and 6 (40%) of the elbows reported occasional bleeding episodes. After synovectomy the range of motion improved in 6 (17.2%), 11 (31.4%) remained unchanged and 18 (51.4%) demonstrated decrease. Five joints lost 5 to 10 degrees, 4 joints lost 10 to 20 degrees and 9 joints lost more than 20 degrees. In the group of arthroscopic knee synovectomy the average of motion loss was 20 degrees while in the open surgical knee synovectomy the average motion loss was 38 degrees. After synovectomy the possibility of recurrent hemarthrosis would be 50% and three years later it would be decreased to 31.6%. This review demonstrated that synovectomy was an effective treatment and the decreased degree of the motion after arthroscopy was less than that of open surgery.

A study on mass culture of Panax quinquefolium cells.

By omitting the component NH4NO3 and doubling the amount of KNO3 in MS medium, the Panax quinque folium cells cultured in such medium grew more rapidly and their saponin content was much higher than that cultured in regular MS medium. The growth rate and saponin content of the cells cultured in such medium (KNO33300 mg/l) increased 65.1% and 166.2% respectively as compared with that cultured in the regular medium. The application of oligosaccharins from Panax ginseng and Dendrobium candidum also increased their saponin content and growth rate. Especially, the content of Rg group saponins was apparently raised. It took more than 25 days for the cell suspension cultures to produce saponins in large amounts. The curve of saponin formation lagged slightly behind the growth curve in cell suspension culture and fermentation culture. The cell fermentation culture with a stabilized pH value was better than the culture with the pH value changing spontaneously on saponin content, growth rate and biomass. Finally, the culture patterns of P. quinque folium cells were compared and discussed.

Establishment of Panax notoginseng tissue culture.

Calli were induced from Panax notoginseng roots, tubers, stems, petioles, leaves, and flower buds, and preliminary identification of medicinal compounds in the callus was carried out by TLC, using subcultured sixth-generation calli. The results demonstrated that callus was capable of synthesizing saponins, including ginsenosides Rb1, Rg1, and Rh1. The saponin content (5.33%, D.W.) in the callus was higher than that in intact plants (4.25%, D.W.). Callus also produced a larger amount of sapogenins than intact plants. Callus growth rate was 54.0 mg D.W./liter/day. Callus induced from stems was superior in terms of growth, saponin and sapogenin contents, and saponin composition. MS medium proved optimal for growth of callus induced from stems. The optimum pH was about 5.8 and the optimum temperature about 26 degrees C. Light had little stimulatory effect on callus growth.

Microscopic and submicroscopic studies on the peripheral nerve and the skeletal muscle of the female. cadaver found in the Han Tomb No.1.

The present paper deals with the microscopic and submicroscopic structures of the peripheral nerve of the lumbar plexus and the skeletal muscle of the m. psoas major of the ancient female cadaver buried about 2100 years ago, which was excavated from the Han Tomb No. 1 at Mawangdui (Mawangtui) near Changsha, Hunan Province. The connective tissues in the peripheral nerve and the skeletal muscle of the ancient cadaver were found well preserved. Under the electron microscope were observed the characteristic periodic bands of the collagenous fibrils as well as some axons and degenerated myelin sheath in the lumbar plexus. And in some of the better preserved nerve fibers, their axons and myelin sheaths are readily discernible. In the m. psoas major, cross striations are clearly visible in some muscle fibers. The remains of a blood vessel with only their connective tissues left were observed in the nerve of the lumbar plexus. Bacterial spores appeared in the two tissues.

Pyridopyrimidine analogues as novel adenosine kinase inhibitors.

A novel series of pyridopyrimidine analogues 9 was identified as potent adenosine kinase inhibitors based on the SAR and computational studies. Substitution of the C7 position of the pyridopyrimidino core with C2' substituted pyridino moiety increased the in vivo potency and enhanced oral bioavailability of these adenosine kinase inhibitors.