Structure Elucidation and Confirmation of Phloroglucinols from the Roots of Garcinia dauphinensis by Comparison of Experimental and Calculated ECD Spectra and Specific Rotations.

Eight phloroglucinols from Garcinia dauphinensis were recently reported to have good to moderate antiplasmodial and anticancer activities, consistent with other phloroglucinol derivatives isolated from natural sources. Chiroptical properties were previously calculated and compared to experimental data for compound 2 as a means to deduce its absolute configuration. Tentative assignments for the remaining compounds were also reported based on these data. In order to arrive at stereochemical assignments for phloroglucinols 1 and 3-8, ECD spectra and specific rotations were computed for all stereoisomers of each compound. Molecular orbital analyses were also carried out for the most energetically favorable conformers of each compound. Absolute configurations are reported for all eight phloroglucinols for the first time.

Phloroglucinols from the Roots of Garcinia dauphinensis and Their Antiproliferative and Antiplasmodial Activities.

Garcinia dauphinensis is a previously uninvestigated endemic plant species of Madagascar. The new phloroglucinols dauphinols A-F and 3'-methylhyperjovoinol B (1-7) and six known phloroglucinols (8-13) together with tocotrienol 14 and the three triterpenoids 15-17 were isolated from an ethanolic extract of G. dauphinensis roots using various chromatographic techniques. The structures of the isolated compounds were elucidated by NMR, MS, optical rotation, and ECD data. Theoretical ECD spectra and specific rotations for 2 were calculated and compared to experimental data in order to assign its absolute configuration. Among the compounds tested, 1 showed the most promising growth inhibitory activity against A2870 ovarian cancer cells, with IC50 = 4.5 ± 0.9 µM, while 2 had good antiplasmodial activity against the Dd2 drug-resistant strain of Plasmodium falciparum, with IC50 = 0.8 ± 0.1 µM.

Synthesis of rocaglamide derivatives and evaluation of their Wnt signal inhibitory activities.

Rocaglamides are bioactive natural compounds which have a cyclopenta[b]benzofuran core structure. The total synthesis of a reported natural product, 3'-hydroxymethylrocaglate (5), was achieved using [3 + 2] cycloaddition between 3-hydroxyflavone and methyl cinnamate. We also describe the synthesis of rocaglamide heterocycle derivatives and evaluate their Wnt signal inhibitory activities. Compounds 4, 5, 22a, 22b, 22c and 23c showed potent Wnt signal inhibitory activity.

Natural compounds with Wnt signal modulating activity.

Covering: up to 2015 The Wnt signalling pathway is essential in many biological processes. The Wnt signal is associated with several diseases, particularly cancer and neurodegenerative diseases. Recently, high-throughput screening systems have been developed to rapidly identify compounds, including natural compounds, that target the Wnt signal. Some studies on natural modulators of the Wnt signal have also suggested their possible target. This review highlights some important natural compounds reported to regulate Wnt activity and describes their possible mechanism of action.

Scopadulciol, Isolated from Scoparia dulcis, Induces ß-Catenin Degradation and Overcomes Tumor Necrosis Factor-Related Apoptosis Ligand Resistance in AGS Human Gastric Adenocarcinoma Cells.

Scopadulciol (1), a scopadulan-type diterpenoid, was isolated from Scoparia dulcis along with three other compounds (2-4) by an activity-guided approach using the TCF reporter (TOP) luciferase-based assay system. A fluorometric microculture cytotoxicity assay (FMCA) revealed that compound 1 was cytotoxic to AGS human gastric adenocarcinoma cells. The treatment of AGS cells with 1 decreased ß-catenin levels and also inhibited its nuclear localization. The pretreatment of AGS cells with a proteasome inhibitor, either MG132 or epoxomicin, protected against the degradation of ß-catenin induced by 1. The 1-induced degradation of ß-catenin was also abrogated in the presence of pifithrin-α, an inhibitor of p53 transcriptional activity. Compound 1 inhibited TOP activity in AGS cells and downregulated the protein levels of cyclin D1, c-myc, and survivin. Compound 1 also sensitized AGS cells to tumor necrosis factor-related apoptosis ligand (TRAIL)-induced apoptosis by increasing the levels of the death receptors, DR4 and DR5, and decreasing the level of the antiapoptotic protein Bcl-2. Collectively, our results demonstrated that 1 induced the p53- and proteasome-dependent degradation of ß-catenin, which resulted in the inhibition of TCF/ß-catenin transcription in AGS cells. Furthermore, 1 enhanced apoptosis in TRAIL-resistant AGS when combined with TRAIL.

Phenolic compounds from the bark of Oroxylum indicum activate the Ngn2 promoter.

A reporter gene assay that detects neurogenin 2 (Ngn2) promoter activity was utilized to identify compounds that induce neuronal differentiation. Ngn2 is a basic helix-loop-helix transcription factor that activates transcription of pro-neural genes. Using this assay system and an activity-guided approach, seven phenolic compounds were isolated from the methanol extract of Oroxylum indicum: 1 oroxylin A, 2 chrysin, 3 hispidulin, 4 baicalein, 5 apigenin, 6 baicalin, and 7 isoverbascoside. Compounds 1 and 2 induced an estimated 2.7-fold increase in Ngn2 promoter activity, whereas 3 increased the activity by 2.5-fold. Furthermore, 1 and 2 enhanced neuronal differentiation of C17.2 cells, which are multipotent stem cells.

Spinal analgesia in terminal care: risk versus benefit.

Cancer pain treatment is well established. The World Health Organization provides clinicians an "analgesic ladder" scheme to optimize cancer pain treatment. At the beginning of the pain treatment, oral analgesic administration is preferred. The analgesic dose must be individualized. Many published papers describe the spinal administration of opioids in combination with various other drugs such as bupivacaine in selected patients with cancer pain. Although complications have been reported to be few, some recent reports debate this idea. We first describe a population of 92 cancer patients, 13 of whom received intrathecal morphine. We then present our experience with a separate group of 33 cancer patients who were also managed using intrathecal morphine. Based on this experience, the generally accepted indications for the technique appeared to be justified. Concern about spinal infection is well considered, however. Three out of those patients developed meningitis, a complication rate that is far too high.

Spinal cord stimulation: a valuable treatment for chronic failed back surgery patients.

Spinal cord stimulation (SCS) has been used in the treatment of "chronic failed back surgery syndrome" for many years. To evaluate long-term results and cost effectiveness of SCS, we interviewed 69 patients treated during a period of 13 years. Twenty-six patients stopped using SCS; there was no clear explanation for this unsatisfactory result in 10. Forty-three patients continued with the therapy and obtained good pain relief. Electrode breakage either spontaneous or due to a procedure to obtain better stimulation paresthesias was more frequent in the radiofrequency-coupled system group than in the battery group (mean +/- SEM 2.81 +/- 2.0 versus 1.42 +/- 1.51, respectively; P = 0.0018). Ten patients obtained better pain relief than during the trial procedure. Some still need opioid analgesics, but 11 of the 16 who require these drugs obtained a synergistic effect when concomitantly using the stimulator. Eleven patients have returned to work. In our center, the application of SCS costs on average $3660 per patient per year. Although this seems expensive, it may be a cost-effective treatment if other therapies fail.

Neuropathic pain in a cancer patient responding to subcutaneously administered lignocaine.

OBJECTIVE: To demonstrate difficulties encountered in alleviating neuropathic pain in a terminally ill cancer patient, with the very tentative diagnosis of postherpetic neuralgia. SETTING: A multidisciplinary pain department in a university hospital. PATIENTS: A patient with Hodgkin's lymphoma and leiomyosarcoma in the liver developed an unusual manifestation of neuropathic pain. INTERVENTION: Oral drug treatment with morphine associated with amitriptyline, valproic acid, mexilitine, flufenazine, and methylprednisolone failed to suppress pain attacks. Only the subcutaneous instillation of lidocaine (2 mg/kg/h) could partially suppress pain. A dorsal root entry zone lesion intervention could only temporary stop the pain attacks. Infiltration and nervous stimulation techniques were not helpful. OUTCOME MEASURES: In determining pain control, the visual analog scale rating scale and the number of attacks per hour were considered. RESULTS: Only the subcutaneous administration of lignocaine could partially suppress pain. Because of the patient's poor hepatic circulation, variable lidocaine plasma concentrations were responsible for intolerable side effects. CONCLUSIONS: Subcutaneous lignocaine administration remains a useful method in treating neuropathic cancer pain. The poor metabolic condition of the patient can lead to deleterious high plasma levels. A dorsal root entry zone lesion could only temporarily stop the pain.

Relevance of epidurography and epidural adhesiolysis in chronic failed back surgery patients.

OBJECTIVE: Pain treatment in the chronic failed back surgery patient remains problematic. Defining the pathogenesis of the pain could be helpful in treatment. The assumption that epidural fibrosis and adhesions might play an important role in the origin of the pain is verified. DESIGN: We investigated 34 patients in whom peridural fibrosis was suspected. An epidural catheter was inserted via the sacral hiatus. Injections of contrast dye, local anesthetic, corticosteroid, and hypertonic NaCl 10% were carried out daily for 3 days. Spread of the contrast dye in the epidural space was evaluated after 10 and 20 ml injection volume. SETTING: Subjects were patients in a pain clinic of a university hospital in Belgium. PATIENTS: Chronic pain patients with failed back surgery syndrome were examined. Nerve pathology was demonstrated and epidural fibrosis suspected or proved with magnetic resonance imaging (MRI) examination. OUTCOME MEASURES: Improvement in the contrast filling defects of the epidural space were noticed during treatment and correlated with pain improvement. RESULTS: Filling defects were noted in 30 of the 34 patients investigated. After the third day an objective improvement of contrast spread was documented in 14 patients. In seven patients improvement in pain occurred for only a very limited period (1 month). Statistical analysis (chi square analysis) could not demonstrate that improvement of contrast spread was correlated with better pain behavior. In 16 patients no improvement in contrast spread could be visualized. Pain improvement occurred in only four patients and for a limited period of 1 month. Long-term results are even worse. CONCLUSION: Epidurography might confirm epidural filling defects for contrast dye in the patients with epidural fibrosis. A better contrast dye spread, assuming scar lysis, does not guarantee a sustained pain relief. A more direct visualization of the resulting functional changes after adhesiolysis as with epiduroscopy might be useful.

Nerve root sleeve injections in patients with failed back surgery syndrome: a comparison of three solutions.

OBJECTIVE: To evaluate outcome in patients with failed back surgery syndrome treated with nerve root sleeve injections. DESIGN AND PATIENTS: An open, nonblinded, randomized study on 60 patients with documented fibrosis in fewer than three nerve roots. INTERVENTIONS: After random selection, 20 patients were injected with 1 ml bupivacaine 0.5% combined with 1500 units hyaluronidase and 1 ml saline per nerve root sleeve (group A), another 20 were treated with 1 ml bupivacaine 0.5% combined with 40 mg methylprednisolone solution (Depo Medrol) per nerve root (group B), and a third group was treated with bupivacaine 0.5% combined with 1500 units hyaluronidase and 40 mg methylprednisolone solution (group C). The volume of each injection was 2 ml. The injections were given twice at an interval of 1 week. OUTCOME MEASURES: The patients were evaluated on a verbal pain rating scale 1, 3, and 6 months after the second injection. The Kruskal-Wallis test was used to detect statistically significant differences among the three groups, and the analysis was refined with the Friedman test. RESULTS AND CONCLUSIONS: Overall, although injections induced analgesia at 1 month, these effects were reduced at 3- and 6-month follow-ups. No statistical differences were found between the three treatment groups (after 1 month, p = 0.71; after 3 months, p = 0.69; after 6 months, p = 0.66. The Friedman test showed a significant decrease in treatment score as a function of time in groups B and C (p = 0.015) but not in group A (p = 0.074). Corticosteroids seem responsible for the last phenomenon.

A psychoanalytic investigation to improve the success rate of spinal cord stimulation as a treatment for chronic failed back surgery syndrome.

OBJECTIVE: The analysis of patient data concerning psychological structure and functioning produced an instrument to determine whether a neurostimulator ought to be implanted or not. DESIGN: A questionnaire containing 24 items was developed by a psychologist and tested in 40 chronic failed back surgery patients for whom a spinal cord stimulation seemed to be the only therapeutic approach. This questionnaire was based upon some crucial psychological themes, on which the patient took a position. A predictive indication factor (I.F.; %) for implantation of the neurostimulator was obtained from the 24 items. Six months after the implantation of the neurostimulator, we correlated the evaluation factor (E.F.; %) with a six-point evaluation scale considering the pain reduction. The aim was to compare the I.F. and E.F. to verify the correlation between them. This comparison was intended to answer the question if psychological variables included in our scale improve the success rate of the therapy. SETTING: Data were collected by a psychologist at the Pain Clinic of the University Hospital of Gent, Belgium. RESULTS AND CONCLUSIONS: The correlation between the I.F. and the E.F. was calculated for the 40 patients by the Spearman correlation test. A coefficient value of 0.8083 (p = 0.000) was found, indicating the existence of a very close correlation between the predictive I.F. and the E.F. The indication scale appears to be a useful instrument for clinical psychologists to predict the success rate of a spinal cord stimulator in this group of patients.

Spinal cord stimulation in chronic pain: evaluation of results, complications, and technical considerations in sixty-nine patients.

Sixty-nine patients undergoing spinal cord stimulation (SCS) were studied for a period of up to 8 years. Indications, implantation techniques, and stimulation systems are presented in this article. Pain-suppressor effects of SCS are reviewed, assessing the clinical efficacy over time as well as complications with the stimulation device. Immediately following implantation, inadequate pain relief was noted in 20% of the patients. Decrease of the efficacy of pain alleviation occurs during the first 3 years after implantation. Most failures are noted in patients presenting with failed back surgery. This study also demonstrates that SCS systems should offer the capability of both monopolar and bipolar stimulation modes by the use of multipolar electrodes.

Spinal cord stimulation in chronic pain therapy.

Spinal cord stimulation was undertaken in 45 patients referred to the University Hospital in Ghent. Failed back surgery was the major indication for implantation. Raynaud's phenomenon, causalgia, polyneuropathy, phantom limb pain, and diverse causes were the other indications. Before neurosurgical implantation of the system, a percutaneous epidural trial procedure was performed. The efficacy of the implanted stimulation system was estimated by considering the use of medication and the patients' personal appreciation of the obtained pain relief. Thirty-five patients experienced very good pain relief. Only two patients needed further narcotic analgesics. Eight patients stopped using the stimulation system. To ensure good results, strict selection criteria and many surgical reinterventions seemed to be necessary. Although spinal cord stimulation is a nonablative technique, many complications may occur.

Elective induction of labor conducted under lumbar epidural block. II. Labor induction by amniotomy and intravenous prostaglandin.

Labor was electively induced at term in 117 clinically normal nulliparae and parous women by combining low amniotomy with intravenous administration of prostaglandin F2 alpha (n = 64) or prostaglandin E2 (n = 53). Analgesia was obtained by continuous lumbar epidural block with bupivacaine. The procedure was very effective in producing vaginal delivery within 24 h after prostaglandin infusion (n = 115), but it was accompanied by an extremely high incidence of uterine hypertonus. Tentative explanations for the transient uterine hyperstimulation are a direct stimulatory effect of the local anesthetic on the contractility of the myometrial fiber and/or a temporarily higher amount of circulating oxytocic compound reaching the myometrium due to local vasodilatation as a result of sympathetic nerve blockade. In some cases uterine hypertonus was associated with slowing of the basal fetal heart rate and, when severe, with the appearance of late deceleration patterns and fetal acidosis. In other cases the fetal heart rate deceleration is explained by the toxic effect of bupivacaine on the myocard. Since both the myometrial hyperactivity and the FHR alterations were temporary, fetal biochemical parameters were unaffected at completion of the first stage of labor. Because with intravenous prostaglandin uterine hyperstimulation is more difficult to avoid and regional analgesia further increases the hazard of both hypertonus and fetal heart rate deceleration, the combined application of an intravenous prostaglandin and continuous epidural analgesia should not be introduced into obstetrical practice.

Elective induction of labor conducted under lumbar epidural block. I. Labor induction by amniotomy and intravenous oxytocin.

Epidural analgesia (bupivacaine) was administered during labor after amniotomy, in some cases supplemented by intravenous oxytocin. A higher incidence of transient uterine hypertonus was seen after blocking. Fetal heart rate changes mainly took the form of bradycardia (in association with uterine hypertonus). At birth, the maternal biochemical condition was characterized by a lower degree of metabolic acidosis, compared to normal unanesthetized controls. The fetuses displayed a slight degree of hypoxia and hypercapnia. The mechanisms underlying these modifications are discussed. Epidural blockade in combination with elective induction of labor, whether or not supplemented by intravenous oxytocin, may carry a risk. Its magnitude is considered acceptable for both mother and fetus provided they are constantly under close surveillance, limited amounts of bupivacaine are administered and the second stage of labor is kept short. However, some warnings against epidural analgesia apply to patients with placental insufficiency and very active labor.

PIP: The maternal and neonatal influences of continuous lumbar epidural analgesia (CLEA; bupivacaine) administered during labor after amniotomy were studied. Intravenous oxytocin supplementation was employed in some cases. Analgesic blockade increased the incidence of transient uterine hypertonus. Fetal heart rate changes, primarily bradycardia, were associated with uterine hypertonus. At birth, a lower degree of maternal metabolic acidosis was observed in comparison with normal unanesthetized controls. A slight degree of hypoxia and hypercapnia was observed in the fetuses. Possible explanations for these changes are discussed. The application of CLEA in the elective induction of labor, whether accompanied by intravenous oxytocin or not, may have risks, though these are probably acceptable for the mother and fetus if they are closely observed, the amounts of bupivacaine administered are limited, and if the duration of the 2nd stage of labor is kept to a minimum. However, epidural analgesia poses greater risks to patients with placental insufficiency and very active labor.

Dual channel electrostimulation in pain.

Spinal cord stimulation is an accepted treatment for neuropathic pain. Technical advances in electrode design and better patient selection have led to better and sustained pain control by these devices. Multilead electrical stimulation is the latest innovation in implantable electrostimulation (Mattrix, Medtronic Minneapolis, USA). Two combined multipolar leads connected to a radiofrequency--coupled system can deliver electrical pulses of various amplitudes and pulse widths at different dermatome levels. Single stimulation is applied with different electrode configurations using both electrodes with identical stimulation parameters. In dual stimulation, the amplitude and the pulse width can vary between the electrode configurations. Dual channel stimulation helps steering stimulation paresthesias. Three patients illustrate the technical advantages of dual channel electrostimulation in the pain relief at multiple sites. Two patients with failed back surgery syndrome obtained more easily stimulation-induced paresthesias in the back and the legs. Dual channel stimulation is cost saving in patients implanted with two electrodes. This is presented in a third patient with an electrode in the thalamus--as pain treatment for cervicobrachialgia and a second in the epidural space--as treatment for the failed back surgery syndrome. These electrodes were connected to the Mattrix stimulator.

Epidural spinal cord stimulation does not improve microvascular blood flow in neuropathic pain.

For many years, spinal cord stimulation (SCS) has been used successfully in various pain syndromes. SCS is also used to treat vascularly-impaired patients since it apparently improves the microcirculation. The exact physiological mechanisms involved are still unclear. There are even some anecdotal reports of a cooling of the legs during SCS. This study investigated the vascular effects of SCS in 15 patients with failed back surgery syndrome, using infrared thermography of the affected foot and capillaroscopy in the nailfold of the big toe. There were no statistically significant differences (Student's t test) in temperature (P = 0.923) or red blood cell velocity (P = 0.819 first day and P = 0.218 second day) in the affected foot with or without stimulation. A physiological difference in relation to neuropathic pain might explain the lack of improvement in skin microcirculation with SCS.

Physiopathologic changes during anesthesia administration for gynecologic laparoscopy.

The physiopathologic effects of CO2 pneumoperitoneum on the respiratory and cardiovascular systems were studied in seven patients during gynecologic laparoscopy and volume-controlled ventilation. The CO2 pneumoperitoneum and Trendelenburg position induced a statistically significant decrease in CTL and a significant increase in CVP, PaCO2 and PACO2.

A combination of buprenorphine and naloxone compared with buprenorphine administered intramuscularly in postoperative patients.

Sixty patients suffering from moderate to severe pain following either orthopaedic or gynaecological surgery were treated with intramuscular buprenorphine (0.3 mg) or an intramuscular combination of buprenorphine (0.3 mg)/naloxone (0.2 mg) and the analgesic efficacy and safety of the two treatments was compared. The evaluation of efficacy showed that both treatments provided good analgesia which was apparent at the first assessment time (10 minutes) and continued for approximately 10 hours. Only seven patients suffered from unwanted side-effects with only drowsiness/sleepiness and nausea being reported by more than one patient. Over-all analysis of the results showed that there were no significant differences between the two treatments with regard to efficacy and safety.