Criteria revision and performance comparison of three methods of signal detection applied to the spontaneous reporting database of a pharmaceutical manufacturer.

BACKGROUND AND OBJECTIVE: Several statistical methods exist for detecting signals of potential adverse drug reactions in spontaneous reporting databases. However, these signal-detection methods were developed using regulatory databases, which contain a far larger number of adverse event reports than the databases maintained by individual pharmaceutical manufacturers. Furthermore, the composition and quality of the spontaneous reporting databases differ between regulatory agencies and pharmaceutical companies. Thus, the signal-detection criteria proposed for regulatory use are considered to be inappropriate for pharmaceutical industry use without modification. The objective of this study was to revise the criteria for signal detection to make them suitable for use by pharmaceutical manufacturers. METHODS: A model comprising 40 drugs and 1000 adverse events was constructed based on a spontaneous reporting database provided by a pharmaceutical company and used in a simulation to investigate appropriate criteria for signal detection. In total, 1000 pseudo datasets were generated with this model, and three statistical methods (proportional reporting ratio [PRR], Bayesian Confidence Propagation Neural Network [BCPNN] and multi-item gamma Poisson shrinker [MGPS]) for signal detection were applied to each dataset. The sensitivity and specificity of each method were evaluated using these pseudo datasets. The optimum critical value for signal detection (i.e. the value that achieved the highest sensitivity with 95% specificity) was identified for each method. The optimum values were also examined with the adverse events classified into two categories according to frequency. The three original detection methods and their revised versions were applied to a real pharmaceutical company database to detect 173 known adverse reactions of four drugs. RESULTS: The 1000 pseudo datasets consisted of an average of 81 862 reports and 11,407 drug-event pairs, including 1192 adverse drug reactions. The sensitivities of PRR, BCPNN and MGPS methods were 49%, 45% and 26%, respectively, whereas their specificities were 95%, 99.6% and 99.99%, respectively; these sensitivities were unacceptably low for pharmaceutical manufacturers, whereas the specificities were acceptable. The highest sensitivity for each method, obtained by changing critical values and maintaining specificity at 95%, was 44%, 62% and 62%, respectively. When adverse events were classified into two categories, sensitivities as high as 75% for regular events and 39% for rare events were achieved with the revised BCPNN method. The critical values of the information component minus two standard deviations (IC - 2SD) index of the revised BCPNN method were greater than -0.7 for regular events and greater than -0.6 for rare events. The revised BCPNN method yielded 51% sensitivity and 89% specificity for the real dataset. CONCLUSION: A lower critical value may be needed when signal-detection methodology is applied to the spontaneous reporting databases of pharmaceutical manufacturers. For example, it is recommended that pharmaceutical manufacturers use the BCPNN method with IC - 2SD criteria of greater than -0.7 for regular events and greater than -0.6 for rare events.     

Developed new agents for lung cancer

Platinum-based chemotherapy is considered to be the standard chemotherapy of non-small cell lung cancer (NSCLC) at present. New agents such as irinotecan, paclitaxel, docetaxel, vinorelbine, gemcitabine, topotecan, and amurubicin were developed in the 1990s. Combination chemotherapy using new agents improved survival rates compared with the classic regimen. Irinotecan, paclitaxel, docetaxel, vinorelbine, and gemcitabine have been confirmed to be effective against NSCLC. However, chemotherapy for NSCLC is controversial because the differences in the efficacies of combination chemotherapies including new agents have not been recognized in randomized controlled trials. The Four-Arms Cooperative Study is an ongoing postmarketing clinical trial in Japan. The a ntitumor agents irinotecan, topotecan, paclitaxel, and amurubicin have been confirmed to be effective in small cell lung cancer (SCLC). The combination of etoposide and cisplatin (PE) is the standard regimen for SCLC in Western countries. However, the combination of irinotecan and cisplatin (CP) resulted in higher response rates and better median survival times than PE for extensive-disease SCLC in a JCOG trial. At present, CP is considered to be the standard chemotherapy regimen to treat SCLC in Japan. The development of new agents, particularly molecular target-based drugs and multimodality treatment, is necessary to improve the therapeutic results in lung cancer further.     

Effective transfection of a cis element "decoy" of the nuclear factor-kappaB binding site into the experimental choroidal neovascularization

PURPOSE: To evaluate the efficacy of the gene transfer of a double-stranded phosphorothioate oligonucleotides (ODNs), called a "decoy", against the NF-kappaB binding site into cells of an experimentally-induced choroidal neovascularization. METHODS: FITC-labeled decoy was injected into the subretinal space of rat eyes by the HVJ-liposome delivery system, and 3 days later, choroidal neovascularization was induced by laser photocoagulation. The eyes were removed and the transfected cells were detected by fluorescence microscopy and also detected by immunohistochemistry. The degree of neovascularization was evaluated by fluorescein angiography. RESULTS: The decoy was transfected into the retinal pigment epithelial (RPE) cells, inner and outer segment of the photoreceptors at 3 days after the injection. When choroidal neovascularization was induced, highly effective transfection of the decoy was observed 3 to 14 days after photocoagulation, after which the level decreased. Decoys were transfected into the RPE cells and macrophages in the choroidal neovascularization. The eyes transfected with NF-kappaB decoy showed a weaker leakage in fluorescein angiograms than that of the control eyes transfected with scrambled decoy. CONCLUSIONS: A decoy can be transfected into retinal cells and cells within a choroidal neovascularization by the HVJ-liposome method. The transferred NF-kappaB decoy reduced the degree of choroidal neovascularization. Decoy targeted against NF-kappaB may be considered as a potential therapy for neovascularization.     

Antioxidant effects of 1,5-anhydro-D-fructose, a new natural sugar, in vitro

The antioxidant effects of 1,5-anhydro-D-fructose (1,5-AF), a unique anhydrohexulose, were studied in 1,1-diphenyl-2-picrylhydrazyl (DPPH) solution, in human cells along with lipid peroxidation of low-density lipoprotein (LDL). We have confirmed that 1,5-AF scavenges DPPH radicals directly in solution and inhibits the formation of hydrogen peroxide and superoxide anion, typical reactive oxygen species (ROS), induced by phorbol myristate acetate (PMA) in a dose-dependent manner in THP-1 cells. We also observed the dose-dependent antioxidant effects of 1,5-AF on copper-mediated LDL oxidation. These findings suggest that 1,5-AF might play a role in reducing the risk of atherosclerosis and may help prevent coronary heart disease.     

A possible role of neurotensin in NANC relaxation of longitudinal muscle of the jejunum and ileum of Wistar rats

The mediators of nonadrenergic, noncholinergic (NANC) relaxation in longitudinal muscle of the jejunum and ileum of Wistar rats were examined in vitro. Treatment of the jejunal and ileal segments with alpha-chymotrypsin resulted in decreases in the NANC relaxations induced by electrical field stimulation (EFS) by about one half. The NANC relaxations were also decreased by about one half after the segments had been desensitized to neurotensin. A neurotensin receptor antagonist, SR48692 (10 microM) inhibited the NANC relaxation by 56 and 34% in the jejunal and ileal segments, respectively. An inhibitor of small conductance Ca2+ -activated K+ channel (SK channel), apamin (100 nM) also inhibited the NANC relaxation by 83 and 63%, respectively. Exogenous neurotensin-induced relaxations of the two segments were abolished by apamin. In the ileal segments, N(G)-nitro-L-arginine (L-NOARG, 100 micro M), inhibited the NANC relaxation by 43%. L-NOARG, but not apamin, further inhibited the relaxation which persisted after the desensitization to neurotensin. Apamin with SR48692 inhibited the relaxation only to the same extent as apamin alone. EFS induced inhibitory junction potentials (i.j.ps) in the longitudinal muscle cells of the ileum. I.j.ps consisted of a rapid and a delayed phase. L-NOARG significantly inhibited only the delayed phase. EFS induced only a rapid i.j.ps in the jejunum. SR48692 and apamin inhibited the i.j.ps. These findings suggest that neurotensin and unknown substance(s) mediate NANC relaxation via SK channels in the jejunum of Wistar rats, and that neurotensin via SK channels and nitric oxide not via SK channels separately mediate the relaxation in the ileum.     

Anesthetic factors that influence pH of neonatal umbilical artery from mothers in severe gestosis during cesarean section under sevoflurane anesthesia

Twenty-two patients complicated with severe gestosis underwent cesarean section. General anesthesia was induced with intravenous thiopental and suxamethonium and maintained with sevoflurane below 1.5% with 40-50% oxygen and 50-60% nitrous oxide. Mean artery pressure at and after the induction as well as at the delivery, expired maternal sevoflurane concentrations at the delivery and neonate birth weight were measured for statistical analyses in relation with neonates pH of umbilical artery. Mean artery pressure at the delivery and neonates birth weight influence neonates pH of umbilical artery.     

Bispectral index monitoring is useful to reduce total amount of propofol and to obtain immediate recovery after propofol anesthesia

Bispectral index (BIS) is a processed EEG parameter for assessment of hypnotic effects of anesthetics. We studied whether BIS monitoring can improve recovery from propofol anesthesia and decrease the total amount of propofol needed. Forty-six patients without hypertension and obesity were studied. In the BIS group (n = 20), propofol infusion rate was adjusted to achieve a target BIS value between 40-60, increasing to 65 during the final 10 min of the surgical procedure. In the control group (n = 19), propofol infusion rate was adjusted based only on standard clinical signs. Compared with the control group, patients in the BIS group required lower propofol infusion rates(4.3 +/- 1.1 vs 4.9 +/- 0.8 mg.kg-1.h-1; P < 0.05), and the total amount of propofol decreased significantly (709 +/- 210 vs 914 +/- 326 mg; P < 0.05). BIS monitoring led to immediate recovery after propofol anesthesia. There were no significant differences in the incidence of intraoperative responses between the two groups. BIS monitoring decreased the total amount of propofol and led to immediate recovery after propofol anesthesia. These findings indicate that the use of BIS monitoring may be useful in controlling the infusion rate of propofol during surgery.     

Mosaic development of the olfactory cortex with Pax6-dependent and -independent components

The olfactory cortex is the target area of olfactory bulb axons and is suggested to be derived from neuroepithelial progenitors of various ventricular domains during development. In the present study, we examined the development of the olfactory cortex, using the newly developed monoclonal antibody (mAb) 9-4c, which recognizes reticulon 1-A and -B. The mAb labeled neuroepithelial progenitors at the pallio-subpallial boundary (PSB) and their putative descendants in the deep layers of the olfactory cortex. In the Pax6 mutant embryo, labeling at the PSB was specifically lacking, and the number of immunopositive cells in the olfactory cortex was markedly reduced. In contrast, the guidepost neurons of olfactory bulb axons, lot cells, developed relatively normally in the superficial layer of the olfactory cortex in the mutant embryo. These guidepost neurons have been recently shown to originate in the pallium and eventually guide the initial projection of olfactory bulb axons. The olfactory bulb projection in the Pax6 mutant embryo also suggested the dualistic nature of the olfactory cortex development; the initial projection of olfactory bulb axons developed relatively normally, whereas the final projection of their collateral branches was severely defective.