Expert panel consensus recommendations for the pharmacological treatment of acute pain in the Middle East region.

The findings of an expert panel convened to review critically how best to apply evidence-based guidelines for the treatment of acute pain in the Middle East region are presented. The panel recommended a three-step treatment protocol. Patients with mild-to-moderate levels of acute pain should be treated with paracetamol (step 1). If analgesia is insufficient after 1-2 days, a selective cyclo-oxygenase-2 inhibitor or, if gastrointestinal safety and bleeding risk are not an issue, a non-specific nonsteroidal anti-inflammatory drug, should be used (step 2). If analgesia remains inadequate, treatment with tramadol, or paracetamol plus codeine/tramadol is recommended (step 3). Patients reporting severe pain should be referred to a pain clinic or specialist for opioid analgesic treatment. Measures of pain and functioning that have been validated in Arabic, with culturally appropriate and easy to understand descriptors, should be used. Early and aggressive acute pain management is important to reduce the risk of pain becoming chronic, especially in the presence of neuropathic features.

Echinocystic acid 3,16-O-bisglycosides from Albizia procera.

Three triterpene glycosides and two known ones were isolated from the bark of Albizia procera by using chromatographic techniques. The structures of the compounds were determined to be 3-O-beta-D-xylopyranosyl-(1-->2)-beta-D-galactopyranosyl-(1-->6)-2-acetamido-2-deoxy-beta-D-glucopyranosyl echinocystic acid 16-O-beta-D-glucopyranoside, 3-O-beta-D-xylopyranosyl-(1-->2)-alpha-L-arabinopyranosyl-(1-->6)-2-acetamido-2-deoxy-beta-D-glucopyranosyl echinocystic acid 16-O-beta-D-glucopyranoside and 3-O-alpha-L-arabinopyranosyl-(1-->2)-alpha-L-arabinopyranosyl-(1-->6)-2-acetamido-2-deoxy-beta-D-glucopyranosyl echinocystic acid 16-O-beta-D-glucopyranoside. Their structures were determined by NMR techniques including HOHAHA, (1)H-(1)H COSY, ROE, HMQC and HMBC experiments together with FABMS as well as acid hydrolysis. To the best of our knowledge, the new compounds are considered the first examples of echinocystic acid 3,16-O-bisglycosides. In contrast to other cytotoxic echinocystic acid glycosides with N-acetyl glucosamine unit, the new glycosides were found inactive when assayed by MTT method for their cytotoxicities against the human tumor cell lines HEPG2, A549, HT29 and MCF7. The results showed the importance of the free hydroxyl group at the aglycone C-16 for exhibiting cytotoxic properties.

Molluscicidal and schistosomicidal activities of a steroidal saponin containing fraction from Dracaena fragrans (L.).

The steroidal saponin-containing fraction from methanolic extract of Dracaena fragrans (Family: Agavaceae) was tested for molluscicidal and ovicidal activities against Biomphalaria alexandrina and Bulinus truncatus, the snail vectors of Schistosoma mansoni and S. haematobium in Egypt, respectively. It was also tested for schistosemicidal activity in vitro on adult S. mansoni and against the free-living miracidia and cercariae of the parasite. The homogenated soft body of B. alexandrina was used to determine the effect of the saponin fraction on total protein, albumen, aminotransferase enzymes and acetylcholin esterase. The results showed that the saponin fraction had considerable molluscicidal activity; LC50 & LC90 were 2.7 ppm & 3.7 ppm for B. alexandrina and 2 ppm & 2.5 ppm for B. truncatus, respectively. Snail eggs did not hatch in concentration as low as half molluscicidal LC50 (1.35 ppm). The LC50 killed all miracidia and cercariae in 30 seconds and after 22 & 40 minutes at a very low concentration (0.165 ppm) respectively, and had in vitro lethal effect on adults with LC50 18.4 microg/ml 4 days post-exposure. The snail tissue homogenate showed significant increase in total protein content & albumen, in aminotransferases and acetylcholinesterase activities.

Triterpenoid saponins with N-acetyl sugar from the bark of Albizia procera.

Three (1,2,4) and one known (3) triterpenoid saponins were isolated from the bark of Albizia procera. The saponins were characterized as 3-O-[beta-D-xylopyranosyl-(1-->2)-alpha-L-arabinopyranosyl-(1-->6)-2-acetamido-2-deoxy-beta-D-glucopyranosyl] echinocystic acid (1), 3-O-[alpha-L-arabinopyranosyl-(1-->2)-beta-D-fucopyranosyl-(1-->6)-2-acetamido-2-deoxy-beta-D-glucopyranosyl] echinocystic acid (2) and 3-O-[beta-D-xylopyranosyl-(1-->2)-alpha-L-arabinopyranosyl-(1-->6)-2-acetamido-2-deoxy-beta-D-glucopyranosyl] acacic acid lactone (4). Their structures were elucidated by 1D and 2D NMR experiments, FABMS as well as chemical means. Saponins 1 and 3 exhibited cytotoxicity against HEPG2 cell line with IC50 9.13 microg/ml and 10 microg/ml, respectively.

Peroxynitrite mediates VEGF's angiogenic signal and function via a nitration-independent mechanism in endothelial cells.

The modulation of angiogenic signaling by reactive oxygen species (ROS) is an emerging area of interest in cellular and vascular biology research. We provide evidence here that peroxynitrite, the powerful oxidizing and nitrating free radical, is critically involved in transduction of the VEGF signal. We tested the hypothesis that VEGF induces peroxynitrite formation, which causes tyrosine phosphorylation and mediates endothelial cell migration and tube formation, by studies of vascular endothelial cells in vitro and in a model of hypoxia-induced neovascularization in vivo. The specific peroxynitrite decomposition catalyst FeTPPs blocked VEGF-induced phosphorylation of VEGFR2 and c-Src and inhibited endothelial cell migration and tube formation. Furthermore, exogenous peroxynitrite mimicked VEGF activity in causing phosphorylation of VEGFR2 and stimulating endothelial cell growth and tube formation in vitro and new blood vessel growth in vivo. The selective nitration inhibitor epicatechin enhanced VEGF's angiogenic function in activating VEGFR2, c-Src, and promoting endothelial cell growth, migration, and tube formation in vitro and retinal neovascularization in vivo. Decomposing peroxynitrite with FeTPPs or blocking oxidation using the thiol donor NAC blocked VEGF's angiogenic functions in vitro and in vivo. In conclusion, peroxynitrite is critically involved in transducing VEGF's angiogenic signal via nitration-independent and oxidation-mediated tyrosine phosphorylation.

Role of mast cells and T-lymphocytes in pemphigus vulgaris: significance of CD44 and the c-kit gene product (CD117).

Molecular mechanisms underlying the pathophysiology of pemphigus vulgaris are still not clear. We aimed to determine the significance of detecting expression of some antigens that might be pivotal to the process, namely CD44 and CD117, in patients with active pemphigus vulgaris. Seventeen patients with active pemphigus vulgaris and 19 normal healthy controls were included in the study. The immunohistochemical results showed prominent expression of CD44 in 13 of the patients and CD117 in 9 of the patients with new blister formation. CD44 percentage values in peripheral T-lymphocytes were significantly higher in patients than controls, as detected by flow cytometry. In addition, there was a significant increase in a soluble form of c-kit in sera of patients with active pemphigus vulgaris compared to controls.

Role of mast cells and T-lymphocytes in pemphigus vulgaris: significance of CD44 and the c-kit gene product [CD117]

Molecular mechanisms underlying the pathophysiology of pemphigus vulgaris are still not clear. We aimed to determine the significance of detecting expression of some antigens that might be pivotal to the process, namely CD44 and CD117, in patients with active pemphigus vulgaris. Seventeen patients with active pemphigus vulgaris and 19 normal healthy controls were included in the study. The immunohistochemical results showed prominent expression of CD44 in 13 of the patients and CD117 in 9 of the patients with new blister formation. CD44 percentage values in peripheral T-lymphocytes were significantly higher in patients than controls, as detected by flow cytometry. In addition, there was a significant increase in a soluble form of c-kit in sera of patients with active pemphigus vulgaris compared to controls

Further saponins from Meryta lanceolata.

Five new oleanane-type saponins along with 11 known ones were isolated from the leaves and stems of Meryta lanceolata. The new saponins were characterised by spectroscopic analysis including FAMS, 1 and 2D NMR experiments and the results of hydrolysis as 3-O-[beta-d-glucopyranosyl-(1-->2)-beta-d-glucuronopyranosyl] hederagenin 28-O-[alpha-l-rhamnopyranosyl-(1-->4)-beta-d-glucopyranosyl-(1-->6)-beta-d-glucopyranosyl] ester, 3-O-[beta-d-glucopyranosyl-(1-->2)-beta-d-glucuronopyranosyl] oleanolic acid 28-O-[alpha-l-rhamnopyranosyl-(1-->4)-beta-d-glucopyranosyl-(1-->6)-beta-d-glucopyranosyl]ester, 3-O-[beta-d-glucopyranosyl-(1-->2)-beta-d-glucuronopyranosyl] oleanolic acid 28-O-[alpha-l-rhamnopyranosyl-(1-->4)-beta-d-6-O-acetyl glucopyranosyl-(1-->6)-beta-d-glucopyranosyl]ester, 3-O-[beta-d-glucopyranosyl-(1-->3)-beta-d-glucopyranosyl-(1-->3)-alpha-l-arabinopyranosyl] oleanolic acid 28-O-[alpha-l-rhamnopyranosyl-(1-->4)-beta-d-glucopyranosyl-(1-->6)-beta-d-glucopyranosyl] ester and 3-O-[beta-d-glucopyranosyl-(1-->2)-beta-d-glucuronopyranosyl] hederagenin, respectively.

Triterpenoid saponins from Meryta lanceolata.

Four new oleanane-type saponins and a known one were isolated from the leaves and stems of Meryta lanceolata. The new saponins were characterised by spectroscopic means and chemical hydrolysis as 3-O-[beta-D-glucopyranosyl-(1-->3)-beta-D-glucopyranosyl-(1-->3)-[beta-D-glucopyranosyl-(1-->2)]-alpha-L-arabinopyranosyl]oleanolic acid 28-O-[alpha-L-rhamnopyranosyl-(1-->4)-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl] ester, 3-O-[beta-D- glucopyranosyl-(1-->3)-beta-D-glucopyranosyl-(1-->3)-[beta-D-glucopyranosyl-(1-->2)]-alpha-L-arabinopyranosyl]oleanolic acid 28-O-[alpha-L-rhamnopyranosyl-(1-->4)-beta-D-6-O-acetyl glucopyranosyl-(1-->6)-beta-D-glucopyranosyl] ester, 3-O-[beta-D-glucopyranosyl-(1-->2)-beta-D-glucopyranosyl-(1-->3)-beta-D-glucopyranosyl-(1-->3)-alpha-L-arabinopyranosyl]oleanolic acid 28-O-[alpha-L-rhamnopyranosyl-(1-->4)-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl] ester and 3-O-[beta-D-glucopyranosyl-(1-->2)-beta-D-glucopyranosyl-(1-->3)-beta-D-glucopyranosyl-(1-->3)-alpha-L-arabinopyranosyl]echinocystic acid 28-O-[alpha-L-rhamnopyranosyl-(1-->4)-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl] ester. The NMR assignments were made by means of HOHAHA, 1H-1H COSY, HMQC, HMBC and NOE difference studies.

TGF-beta increases retinal endothelial cell permeability by increasing MMP-9: possible role of glial cells in endothelial barrier function.

PURPOSE: To determine transforming growth factor (TGF) beta effects on matrix metalloproteinases (MMPs) as a potential cause of the blood-retinal barrier breakdown at the onset of angiogenesis. Previously, glial cells were shown to play a role in the angiogenesis process and to express the angiogenic regulating factor TGF-beta, which becomes active under hypoxia conditions. Here, the authors demonstrate that retinal endothelial cells express MMP-9 when treated with TGF-beta or cocultured with glial cells and that both TGF-beta and MMP-9 increase endothelial cell permeability. METHODS: Primary cultures of bovine retinal endothelial (BRE) cells grown on porous membranes were treated with TGF-beta or purified MMP-9, and permeability changes were assayed. The amount and distribution of the tight junction protein occludin also was analyzed by immunocytochemistry and Western blotting. Cell extracts or conditioned media from TGF-beta-treated BRE cells and from glial cell-BRE cocultures were analyzed for MMP-9 content by substrate gel electrophoresis (zymography) or Western blotting. RESULTS: Both TGF-beta and MMP-9 increased the permeability of BRE monolayers and reduced the levels of the junction protein occludin. The effect of MMP-9 on permeability was rapid, but the TGF-beta-induced permeability required longer incubation and was blocked by anti-TGF-beta and anti-MMP-9 antibodies as well as by TGF-beta latency-associated peptide. Zymography showed that MMP-9 activity, which was very low or absent in untreated BRE cultures, was dramatically increased by TGF-beta as well as by coculturing with either astrocytes or Müller glial cells. Anti-TGF-beta antibody blocked the TGF-beta effect, but not the coculture effect on MMP-9 production. CONCLUSIONS: These data indicate a direct correlation between TGF-beta-induced MMP-9 activity and increased endothelial cell permeability. Moreover, endothelial cell production of MMP-9 is regulated by glial cells through expression of TGF-beta or by direct cell-to-cell contact. During retinal disease, glial cell production of active TGF-beta may contribute to breakdown of the blood-retinal barrier by stimulating endothelial cell MMP-9 production.

Saponins from Fagonia glutinosa.

Twelve triterpenoid saponins, including six new, were isolated and identified from the aerial parts of Fagonia glutinosa. The new saponins were characterised as 3-O-[beta-D-glucopyranosyl(1-->2)][beta-D-glucopyranosyl(1-->3)]-alpha-L - arabinopyranosyl-27-hydroxy oleanolic acid 28-O-beta-D-glucopyranosyl ester, 3-O-[beta-D-glucopyranosyl(1-->3)]-alpha-L-arabinopyranosyl ursolic acid, 3-O-alpha-L-arabinopyranosyl ursolic acid 28-O-beta-D-glucopyranosyl ester, 3-O-[beta-D-xylopyranosyl(1-->2)][beta- D-glucopyranosyl(1-->3)]-alpha-L-arabinopyranosyl ursolic acid, 3-O-[beta-D-glucopyranosyl(1-->2)][beta-D- glucopyranosyl(1-->3)]-alpha-L-arabinopyranosyl ursolic acid 28-O-beta-D-glucopyranosyl ester and 3-O-[beta-D-glucopyranosyl(1-->2)][beta-D-glucopyranosyl(1-->3)]-alpha-L - arabinopyranosyl-27-hydroxy ursolic acid 28-O-beta-D-glucopyranosyl ester. The structures of the saponins were established by spectral and chemical evidences. The assignments of the NMR signals were performed by means of HOHAHA, 1H-1H COSY, ROE, HMQC and HMBC experiments.

U.S. experience with the AddVent VDD(R) pacing system. AddVent Phase I Investigators.

The AddVent pacemaker generator and model 1328C AV single-pass lead is a new pacemaker system capable of VDD or VDDR modes. The purpose of this study was to present the initial experience with AddVent in the United States and Canada. Between May 10, 1995 and May 3, 1996, 53 devices were implanted in 52 patients and followed for a mean of 217 (+/- 39) days. At the predischarge, 1-, 3-, and 6-month follow-up evaluations, atrial sensing thresholds and ventricular sensing and capture thresholds were measured in the supine, sitting, and standing positions to evaluate stability of atrial sensing with respect to body posture at rest. At the 1-month follow-up, a treadmill exercise test was performed to evaluate atrial sensing during exercise and to evaluate two new features of the AddVent called "sensor-mediated rate smoothing" and "preferential P wave sensing." Atrial sensing thresholds were not significantly different (P > 0.05) among body postures for any follow-up period or among follow-up periods for each posture. At rest, the percentage of appropriately tracked P waves observed was > 99% at each follow-up period. During treadmill exercise, the percentage of appropriately tracked P waves was > 98.7%. Appropriate preferential P wave sensing and sensor-mediated rate smoothing (VDDR mode) was observed. The AddVent pacing system provides safe and effective pacing therapy. Several features of VDDR pacing offer advantages over standard VDD pacing.