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Drug-drug interactions (DDIs) can result in serious consequences, including death. Existing methods for identifying potential DDIs in post-marketing surveillance primarily rely on spontaneous reports. These methods suffer from severe underreporting, incompleteness, and various bias. The aim of this study was to more effectively screen potential DDIs using patient electronic data and temporal association mining techniques.We focus on discovery of potential DDIs by analyzing the temporal relationships between the concurrent use of two drugs of interest and the occurrences of various symptoms. We introduced innovative functional temporal association rules where the degree of temporal association between two events within a patient case was defined by a function.Preliminary test results on two drug pairs (i.e.,benazepril, losartanandbenazepril, insulin) were classified into 260 clinically meaningful categories. These categories were evaluated by physicians and the results exhibited that all the potential DDIs were confined to top 20 of the 260 outcomes.Our methodology can be used to dramatically reduce a long list of association rules to a manageable list for further analysis and investigation by drug safety professionals.

Adverse drug reactions (ADRs) represent a serious worldwide public health problem. Current post-marketing ADR detection approaches largely rely on spontaneous reports filed by various healthcare professionals such as physicians, pharmacists et.al.. Underreporting is a serious deficiency of these methods - the actually reported adverse events represent less than 10% of all cases. Studies show that two important reasons that cause the underreporting are: 1) healthcare professionals are unaware of encountered ADRs, especially for those unusual ADRs; 2) they are too busy to voluntarily report ADRs since it takes a lot of time to fill out the reporting forms. This paper addresses these two issues by developing a multi-agent ADR reporting system. The system 1) helps healthcare professionals detect the potential causal relationship between a drug and an ADR by analyzing patients’ electronic records via both case-based analysis and statistical data mining approach; 2) allows healthcare professionals to add new rules to signal potential ADRs based on their medical expertise; 3) makes the reporting much easier by automatically linking the patients’ electronic data with the reporting form. A functioning prototype of the system has been developed. The proposed data analysis approaches as well as the performance of the system have been tested. The results indicate that this system has a great potential to improve the spontaneous reporting rate of suspected adverse drug reactions.

The effects of Cobra venom cardiotoxin (CTX) on the cellular morphology, twitch amplitude and intracellular calcium ([Ca2+]i) of the ventricular myocytes were studied. [Ca2+]i and twitch amplitude were determined with a fluorometric ratio method using Fura-2/AM and Calcium Green-1 as calcium indicators, and a videomicroscopic technique, respectively. Addition of 0.001-1 microM CTX led to a time-dependent loss of rod shaped cells, beginning at 1 min, and remaining stable by 20 min. CTX 1 microM initially caused a transient augmentation in amplitude of the electrically induced-[Ca2+]i transient and twitch amplitude in the single cardiac myocyte. This was followed by a prolongation in duration of [Ca2+]i. Eventually, cells became inexcitable and abruptly underwent contracture, and [Ca2+]i remained elevated. In the absence of electrical stimulation, 1 microM CTX induced a Ca2+ spike followed by a sustained elevation of [Ca2+]i, an effect different from that of 40 mm KCl or 10 mm caffeine, which caused a transient elevation in [Ca2+]i. Digital imaging microscopy of Calcium Green-1 fluorescence revealed that the increase in [Ca2+]i was accompanied by changes in cell shape without leakage of fluorescence dye in the early stage after administration of the toxin. In the absence of [Ca2+]o, the initial [Ca2+]i spike was reduced, but the second phase of elevation of [Ca2+]i still occurred. In addition, experiments using Mn2+ quench technique suggested that Ca2+-influx was induced by CTX, and that both ryanodine and thapsigargin, known to deplete Ca2+ from its intracellular pool, abolished the second phase of the elevation of [Ca2+]i. The effects of cardiotoxin were abolished by 10 mM Ni2+ and 10 mM -Ca2+-o, but not by 5 microM verapamil. In conclusion, the observations indicate that CTX causes an initial increase followed by a second sustained elevation in [Ca2+]i, which is accompanied by changes in cell shape-from rod to round-and hypercontracture. The initial [Ca2+]i spikes were attributed to the extracellular Ca2+ influx, while the second [Ca2+]i elevation was related to internal Ca2+ release. The high [Ca2+]i may be responsible for hypercontracture and cell death. Further studies are needed to verify it.

Tumor cells from NPC patients are regularly and latently infected with EBV. To examine whether the virus serves as target for immune intervention of the cancer, we determined levels of EBV-specific CTLp in peripheral blood from NPC patients, long-term survivors of the cancer and healthy subjects. CTLp levels of test subjects varied between 3-3,000/10(6) PBMCs. The plasma EBV burden increased when the CTLp level fell below 150, whereas the EBV burden of PBMCs was not correlated with CTLp level. Compared with healthy carriers, CTLp levels of patients were lower and varied over a wider range, between 3-1,500/10(6) PBMCs. The quantitative immune deficit was probably attributed to the tumor because, first, CTLp in survivors was restored to levels similar to those in healthy carriers after the tumor had been successfully treated. Second, the CTLp level changed as disease progressed, being lower in local disease, increased in locoregional disease and decreased again when the tumor metastasized. Based on these findings, 4 patients with advanced disease were infused with 5 x 10(7)-3 x 10(8) autologous EBV CTLs. The treatment was safe and unaccompanied by inflammatory or other complications, but whether it improved tumor control could not be discerned from the large tumor bulk. Nevertheless, the treatment regularly increased CTLp levels of patients, maintained it at higher levels for protracted periods and, in 3 patients, restored host surveillance of EBV replication, reducing the plasma EBV burden. Taken together, these results provided a rationale to further explore EBV as a target of immune intervention of NPC. (C) 2001 Wiley-Liss, Inc.

FA stem cells and progenitor cells are apoptotic in the ground state and hypersensitive to a variety of extracellular apoptotic cues. The relative lifetime risk of AML or MDS in FA is high and clonal cytogenetic defects are universally found in evolved clones, but the mechanisms involved in leukemogenesis are unknown. The combined influences of genetic instability and high level stem cell apoptosis represents a de-facto selective pressure that in our view favors the emergence of more resistant stem cell clones. Predictions of this model are: (1) Non clonal FA progenitor cells (FAwt) are hypersensitive to apoptotic cues but FA progenitors derived from cytogenetically abnormal clones (FAclon) will be resistant, (2) anti-apoptotic events that attend cytogenetic clonal evolution should interdict precisely those apoptotic pathways activated by FA gene mutations, and (3) Key transcripts differentially expressed in the normal (N) vs. FAwt comparison should normalize (ie. should register as "no change") in the N vs. FAclon comparison. Preliminary studies support the first 2 predictions (Lensch et al, Leukemia, 1999 and Haneline et al, Blood, 2003). To further test the adaptive model, we compared transcriptomes of 41 low density bone marrow cell samples: (11 normal volunteers [N], 9 FAclon [marrow replaced [>75%] by cells bearing clonal cytogenetic defects] and 21 FAwt [no cytogenetic abnormalities]). RNA was prepared in the participating institutions and shipped to Portland on dry ice. Complementary DNA and cRNA was prepared, cRNA fragments labeled for use as targets of the probes in the human U133A Affymetrix chip. MAS 5.0 was utilized to process images, quantify signals, adjust background, and to scale the data. A linear mixed model was used for inter-chip normalization. Unsupervised hierarchical clustering and multidimensional scaling (MDS) distinguished N from FAwt samples but FAclon fell within the mathematical space defined by the N RNA. Of 17,044 genes tested, 1,430 were expressed differentially (FDR adjusted p

The mechanism by which kappa-opioid receptor (kappaor) modulated apoptosis was investigated in CNE2 human epithelial tumor cells. Induction of these cells to undergo apoptosis with staurosporine was associated with a massive increase in intracellular cAMP level. The inhibition of the increase in cAMP partially inhibited apoptosis as evidenced by a reduction of PARP and caspase-3 cleavage. Accordingly, a low but significant level of apoptosis is induced in these cells by the elevation of cAMP through the addition of forskolin and isobutylmethylxanthine. The existence of a cAMP-dependent and a cAMP-independent apoptotic pathway is therefore suggested. Receptor binding studies, RT-PCR experiments and Western blot analysis demonstrated the presence of type 1 kappaor in the CNE2 cells. Stimulation of kappaor in these cells resulted in the production of inositol (1,4,5)-trisphosphate, reduction of cAMP level and a marked enhancement of staurosporine-induced apoptosis. The potentiation of apoptosis by kappaor was prevented by inhibition of phospholipase C but was slightly enhanced by the presence of the active cAMP analogues, 8-CPT-cAMP and dibutyryl-cAMP. These data demonstrate for the first time that the phospholipase C pathway activated by type 1 kappaor expressed by cancer cells is involved in the potentiation of apoptosis.