Differential modulation by baclofen on antinociception induced by morphine and beta-endorphin administered intracerebroventricularly in the formalin test

Our previous studies have demonstrated that supraspinal GABAergic receptors are differentially involved in the antinociception induced by morphine and beta-endorphin given intracerebroventricularly (i.c.v.) in the tail-flick and hot-plate tests. These two models employed a phasic, thermal nociceptive stimulus. The present study was designed to examine the possible involvement of supraspinal GABAergic receptors in opioid-induced antinociception in the formalin test. Morphine (1 microg) and beta-endorphin (1 microg) given i.c.v. displayed the almost complete inhibitory effects against the hyperalgesic response in both phases. Muscimol (75-100 ng) and baclofen (5-10 ng) injected i.c.v. produced the hypoalgesic response in the both phases. The hypoalgesic response induced by muscimol and baclofen observed during the second phase was more pronounced than that observed during the second phase. Baclofen (2.5 ng), at the dose which did not affect the hyperalgesic response, resulted in a significant reversal of the i.c.v. administered beta-endorphin-induced hypoalgesic response observed during the second, but not the first, phase. However, the hypoalgesic response induced by i.c.v. administered morphine was not changed by the same dose of muscimol or baclofen injected i.c.v. Our results indicate that, at the supraspinal level, GABA(B)receptors appear to be involved in the modulation of antinociception induced by supraspinally administered beta-endorphin, but not morphine, in the formalin test model.     

Synthesis of 4-hydroxy-1-thiocoumarin derivatives-1: An efficient synthesis of thioflocoumafen

An efficient procedure for the preparation of 4-hydroxy-3-{1,2,3,4-tetra-hydro-3-[4-(4-triflu-oromethylbenzyl oxy)phenyl]-1-naphthyl}thiocoumarin (thioflocoumafen, 1a and 1b) is described. The key step in the synthesis involves the condensation reaction of 3-(4-methoxyphenyl)-1-tetralol (2) with 4-hydroxy-1-thiocoumarin (3).     

Central core disease--a case report.

Central core disease is a rare congenital myopathy characterized by the formation of "cores" that consist of abnormal arrangement of myofibrils inside the myofibers. We report a 5-year-old Korean girl who showed a fairly typical clinical course of non-progressive muscle weakness. Electrodiagnostic studies showed low-amplitude polyphasic electromyograph and normal nerve conduction velocity. Gastrocnemius muscle biopsy showed central cores in over 80% of the fibers on H&E section. Histochemistry revealed deficient or absent mitochondrial enzyme in the cores and type I predominance. Ultrastructurally both structured and non-structured cores were found separately or simultaneously in one fiber. This case is the first report in the Korean literature.     

Studies on constituents of Korean basidiomycetes (L)

To find antitumor metabolites in Korean basidiomycetes, the shake-cultured mycelia of eight of the higher fungi were extracted with hot water and the extracts, after being partially purified, were subjected toin vivo antitumor test. When administeredi.p. at the dose of 30mg/kg/day for ten consecutive days into the female ICR mice, which had been implanted with 1×10⁵ cells of sarcoma 180 twenty-four hours before the first injection, the extracts ofAgaricus campestris, Lyophyllum decastes, Lyophyllum ulmarium, Armillaria tabescence andCalvatia exipulitormis respectively showed inhibition ratios of 64.1%, 65.4%, 60.0%, 53.0% and 49.3%. These five species were selected for further study, whereas the extracts ofPhallus impudicus, Coprinus comatus andPholiota squarrosa which showed the inhibition ratios of 31.2%, 33.5% and 19.0% were discontinued.     

Effect of melatonin on the regulation of proenkephalin and prodynorphin mRNA levels induced by kainic acid in the rat hippocampus

The in vivo short-term effect of melatonin on kainic acid (KA)-induced proenkephalin (proENK) or prodynorphin (proDYN) mRNA, and on AP-1 protein levels in the rat hippocampus, were studied. Melatonin (5 mg/kg) or saline was administered intraperitoneally (i.p.) to rats 30 min prior to and immediately after i.p. injection of KA (10 mg/kg). Rats were sacrificed 1 and 3 h after KA injection. The proENK and proDYN mRNA levels were significantly increased 3 h after KA administration. The elevations of both proENK and proDYN mRNA levels induced by KA were significantly inhibited by the preadministration with melatonin. The increases of proENK and proDYN mRNA levels induced by KA were well-correlated with the increases of c-Fos, Fra-2, FosB, c-Jun, and JunB protein levels, which were significantly increased 3 h after KA administration and effectively inhibited by administration with melatonin. In an electrophoretic mobility shift assay, both AP-1 and ENKCRE-2 DNA binding activities were increased by KA, which were also attenuated by the administration of melatonin. In addition, cross-competition studies revealed that AP-1 or ENKCRE-2 DNA binding activity was effectively reduced by the 50x unlabeled cross-competitor. Therefore, these data suggest that melatonin has an inhibitory role in KA-induced gene expression, such as proENK and proDYN mRNA expression, and this may be due to a reduction of KA-induced AP-1 or ENKCRE-2 DNA binding activity.     

Classification of metaphyseal change with magnetic resonance imaging in Legg-Calvé-Perthes disease

Seventy-eight patients (85 affected hips and 71 unaffected hips) with Legg-Calvé-Perthes disease were included in this study to evaluate the metaphyseal change in radiographs and magnetic resonance imaging (MRI) and to define the type of the metaphyseal cyst according to presence or absence of the epiphyseal involvement. The content of the metaphyseal cyst was evaluated by using T1,T2, proton, and gadolinium-enhanced T1-weighted MRI scans. Among 85 hips, there were no changes in 32 hips, marrow edema in 13 hips, false cyst with epiphyseal involvement in 28 hips, and true cyst without epiphyseal involvement in 12 hips. Granulation tissue was found in the false cysts and water-rich fibrotic tissue was found in the true cysts based on the MRI scans. The metaphyseal change in MRI scans was shown in 71% of groups 3 and 4 and in 35% of groups 1 and 2 according to the Catterall classification, and 52% of group A, 56% of group B, and 86% of group C according to the Herring classification. Of the 30 hips at the avascular stage, 33% showed metaphyseal cyst in MRI scans. Of the 53 hips at the fragmentation stage, 60% showed the metaphyseal cyst.     

Synchronous coexpression of epidermal growth factor receptor and cyclooxygenase-2 in carcinomas of the uterine cervix: a potential predictor of poor survival.

PURPOSE: To evaluate the potential of the new prognostic information gained by analyzing the coexpression of epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) in cervical cancer patients. EXPERIMENTAL DESIGN: Sixty-eight patients with International Federation of Gynecology and Obstetrics stage IIB squamous cell carcinoma of the uterine cervix, who underwent concurrent chemoradiotherapy between 1993 and 1996, were divided into the following four groups according to their immunoreactivities for EGFR and COX-2 in paraffin-embedded sections: (a). the EGFR-negative/COX-2-negative group (n = 11); (b). the EGFR-negative/COX-2-positive group (n = 8); (c). the EGFR-positive/COX-2-negative group (n = 27); and (d). the EGFR-positive/COX-2-positive group (n = 22). The clinical features, patterns of treatment failure, and survival data in the four groups were compared. RESULTS: Positive immunoreactivity for EGFR and COX-2 was observed in 49 of 68 (72%) and 19 of 68 (28%), respectively. However, no strong correlation was found between the levels of EGFR and COX-2 immunopositivity (R(2) = 0.05, P = 0.07). Patients in the EGFR-positive/COX-2-positive group had a higher likelihood of locoregional recurrence than those in the other three groups (P = 0.02). Of the patients in the four groups, patients positive for both oncoproteins were found to have the worst prognosis with an overall 5-year disease-free survival rate of 55% compared with 91% for the EGFR-negative/COX-2-negative patients, 88% for the EGFR-negative/COX-2-positive patients, and 69% for the EGFR-positive/COX-2-negative patients (P = 0.05, log-rank test). In addition, the synchronous coexpression of the EGFR and COX-2 oncoproteins was found to be an independent prognostic factor by univariate and multivariate analyses (relative risk = 4.0, P = 0.03). CONCLUSIONS: Given these observations, we conclude that the coexpression of EGFR and COX-2 immunoreactivity may be used as a potent molecular risk factor for predicting the poor survival of patients with the International Federation of Gynecology and Obstetrics stage IIB squamous cell carcinoma of the uterine cervix.     

RSR13 plus cranial radiation therapy in patients with brain metastases: comparison with the Radiation Therapy Oncology Group Recursive Partitioning Analysis Brain Metastases Database.

PURPOSE: This phase II, open-label, multicenter study assessed the efficacy and safety of the potential radiation enhancer RSR13 plus cranial radiation therapy (RT) in patients with brain metastases. The primary end point was patient survival in comparison with the Radiation Therapy Oncology Group Recursive Partitioning Analysis Brain Metastases Database (RTOG RPA BMD). PATIENTS AND METHODS: Eligibility criteria were age > or = 18 years, Karnofsky performance score > or = 70, and brain metastases with solid tumor histology. Patients received cranial RT, 30 Gy in 10 fractions of 3 Gy each, preceded by RSR13, 50 to 100 mg/kg intravenously over 30 minutes. Univariate and multivariate comparisons of survival and cause of death were made between class II study patients and RTOG BMD patients. RESULTS: Fifty-seven RPA class II patients were enrolled. With a minimum follow-up of 24 months, the median survival time and 1- and 2-year survival rates were 6.4 months, 23%, and 11% for the RSR13-treated patients compared with 4.1 months, 15%, and 3% for the RTOG BMD patients (P =.0174). In an exact-matched case analysis (n = 38), median survival time for RSR13 patients was 7.3 months versus 3.4 months for the RTOG BMD patients (P =.006). There was a 54% reduction in the risk of death for RSR13 patients (P =.0267). RSR13-related adverse events of greater than or equal to grade 3 toxicity that occurred in more than one patient included hypoxia, headache, anemia, fatigue, hypertension, and intracranial hypertension. CONCLUSION: RSR13 plus cranial RT resulted in a significant improvement in survival, as well as a reduction in death due to brain metastases, compared with class II patients in the RTOG BMD.     

Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases.

PURPOSE: This phase III randomized trial evaluated survival as well as neurologic and neurocognitive function in patients with brain metastases from solid tumors receiving whole-brain radiation therapy (WBRT) with or without motexafin gadolinium (MGd). PATIENTS AND METHODS: Patients were randomly assigned to 30 Gy of WBRT +/- 5 mg/kg/d MGd. Survival and time to neurologic progression determined by a blinded events review committee (ERC) were coprimary end points. Standardized investigator neurologic assessment and neurocognitive testing were evaluated. RESULTS: Four hundred one (251 non-small-cell lung cancer) patients were enrolled. There was no significant difference by treatment arm in survival (median, 5.2 months for MGd v 4.9 months for WBRT; P =.48) or time to neurologic progression (median, 9.5 months for MGd v 8.3 months for WBRT; P =.95). Treatment with MGd improved time to neurologic progression in patients with lung cancer (median, not reached for MGd v 7.4 months for WBRT; P =.048, unadjusted). By investigator, MGd improved time to neurologic progression in all patients (median, 4.3 months for MGd v 3.8 months for WBRT; P =.018) and in lung cancer patients (median, 5.5 months for MGd v 3.7 months for WBRT; P =.025). MGd improved neurocognitive function in lung cancer patients. CONCLUSION: The overall results did not demonstrate significant differences by treatment arm for survival and ERC time to neurologic progression. Investigator neurologic assessments demonstrated an MGd treatment benefit in all patients. In lung cancer patients, ERC- and investigator-determined time to neurologic progression demonstrated an MGd treatment benefit. MGd may improve time to neurologic and neurocognitive progression in lung cancer.