Platinum agent-induced hypersensitivity reactions: data mining of the public version of the FDA adverse event reporting system, AERS

Objective: Adverse event reports (AERs) submitted to the US Food and Drug Administration (FDA) were reviewed to confirm the platinum agent-associated mild, severe, and lethal hypersensitivity reactions.Methods: Authorized pharmacovigilance tools were used for quantitative signal detection, including the proportional reporting ratio, the reporting odds ratio, the information component given by a Bayesian confidence propagation neural network, and the empirical Bayes geometric mean. Excess2, given by the multi-item gamma Poisson Shrinker algorithm, was used to evaluate the effects of dexamethasone and diphenhydramine on oxaliplatin-induced hypersensitivity reactions.Results: Based on 1,644,220 AERs from 2004 to 2009, carboplatin and oxaliplatin proved to cause mild, severe, and lethal hypersensitivity reactions, whereas cisplatin did not. Dexamethasone affected oxaliplatin-induced mild hypersensitivity reactions, but had lesser effects on severe and lethal reactions. The effects of diphenhydramine were not confirmed.Conclusion: The FDA''s adverse event reporting system, AERS, with optimized data mining tools is useful to authorize potential associations between platinum agents and hypersensitivity reactions.     

Adverse event profiles of platinum agents: data mining of the public version of the FDA adverse event reporting system, AERS, and reproducibility of clinical observations

Objective: Adverse event reports (AERs) submitted to the US Food and Drug Administration (FDA) were reviewed to confirm platinum agent-associated adverse events, and to clarify the rank-order of these drugs in terms of susceptibility.Methods: After a revision of arbitrary drug names and the deletion of duplicated submissions, AERs involving cisplatin (CDDP), carboplatin (CBDCA), or oxaliplatin (L-OHP) were analyzed. Authorized pharmacovigilance tools were used for the quantitative detection of signals, i.e., drug-associated adverse events, including the proportional reporting ratio, the reporting odds ratio, the information component given by a Bayesian confidence propagation neural network, and the empirical Bayes geometric mean.Results: Based on 1,644,220 AERs from 2004 to 2009, CDDP, CBDCA, and L-OHP all proved to cause nausea, vomiting, acute renal failure, neutropenia, thrombocytopenia, and peripheral sensory neuropathy. Higher susceptibility to nausea was found for CDDP than CBDCA and L-OHP. Acute renal failure was also more predominant for CDDP, and CBDCA did not increase the blood level of creatinine. A stronger association with thrombocytopenia was suggested for CBDCA. Susceptibility to peripheral sensory neuropathy was greatest for L-OHP, but less extensive for CDDP and CBDCA.Conclusion: The results obtained herein were consistent with clinical observations, suggesting the usefulness of the FDA''s adverse event reporting system, AERS, and the data mining method used herein.     

Down-Regulation of DUSP6 Expression in Lung Cancer —Its Mechanism and Potential Role in Carcinogenesis

Our preliminary studies revealed that oncogenic KRAS (KRAS/V12) dramatically suppressed the growth of immortalized airway epithelial cells (NHBE-T, with viral antigen-inactivated p53 and RB proteins). This process appeared to be a novel event, different from the so-called premature senescence that is induced by either p53 or RB, suggesting the existence of a novel tumor suppressor that functions downstream of oncogenic KRAS. After a comprehensive search for genes whose expression levels were modulated by KRAS/V12, we focused on DUSP6, a pivotal negative feedback regulator of the RAS-ERK pathway. A dominant-negative DUSP6 mutant, however, failed to rescue KRAS/V12-induced growth suppression, but conferred a stronger anchorage-independent growth activity to the surviving subpopulation of cells generated from KRAS/V12-transduced NHBE-T. DUSP6 expression levels were found to be weaker in most lung cancer cell lines than in NHBE-T, and DUSP6 restoration suppressed cellular growth. In primary lung cancers, DUSP6 expression levels decreased as both growth activity and histological grade of the tumor increased. Loss of heterozygosity of the DUSP6 locus was found in 17.7% of cases and was associated with reduced expression levels. These results suggest that DUSP6 is a growth suppressor whose inactivation could promote the progression of lung cancer. We have here identified an important factor involved in carcinogenesis through a comprehensive search for downstream targets of oncogenic KRAS.Oncogenic mutations of KRAS occur very early in carcinogenesis of the lung and affect even premalignant lesions.^1,2 It is therefore likely that additional genetic and/or epigenetic alterations are necessary for lung neoplasms to develop into advanced form of cancers. The inactivation of putative tumor suppressors, p53 and p16INK4A/RB protein, and activation of telomerase, are generally accepted as crucial to the promotion carcinogenesis.^1,3 A recent study, however, reported that these alterations are not enough to provide primary bronchial epithelial cells with a fully malignant phenotype in vitro, ⁴ and suggested further alterations would be necessary for the progression of lung cancer.DUSP6, dual-specificity phosphatase 6, is a putative negative feedback regulator for the RAS-ERK pathway, playing physiologically important role(s) in the maintenance of cellular homeostasis in response to growth factors.^{5,6,7,8,9,10,11} Disruption of this feedback loop could therefore result in neoplastic, and even malignant, transformation by providing cells with enhanced growth activity. Actually, a series of previous studies reported the involvement of DUSP6 down-regulation caused by the hypermethylation of its promoter in the progression of pancreatic cancers.^{12,13,14,15,16} To our knowledge, however, there have been only a few reports investigating the significance of DUSP6 in other types of cancers including lung cancers.^4,17Our preliminary study revealed that oncogenic KRAS (KRAS/V12) dramatically suppressed growth of immortalized airway epithelial cells whose p53 and RB proteins were inactivated by viral antigens. This seemed a novel event different from so-called premature senescence that is induced by p53 or RB pathway,³ and suggested there might exist novel tumor suppressors downstream of oncogenic KRAS. Thus, we have been interested in identifying such suppressors. Also, our recent study demonstrated that insulin-like growth factor-binding proteins 2 and 4, downstream targets of oncogenic KRAS, suppress the growth of cancer cells in a negative-feedback manner and that disruption of this feedback loop, through their promoter’s hypermethylation, is possibly involved in the progression of lung cancers.¹⁸ It is worth noting that growth suppressors lie hidden downstream of the signal transduction pathway of an oncogene. Thus, we were prompted to search for downstream targets of oncogenic KRAS comprehensively, to further identify potential growth suppressors. Among genes whose expression was modulated by oncogenic KRAS, this study has focused on DUSP6, and elucidated its role in the KRAS-induced growth suppression and in carcinogenesis of the lung.     

Association between the pharmacokinetics of capecitabine and the plasma dihydrouracil to uracil ratio in rat: A surrogate biomarker for dihydropyrimidine dehydrogenase activity

Capecitabine is a 5‐fluorouracil (5‐FU) derivative that is used widely in the treatment of colorectal cancer. The plasma ratio of dihydrouracil (UH₂) to uracil (Ura) is expected to gain relevance as an indirect‐response biomarker to estimate the activity of dihydropyrimidine dehydrogenase (DPD). The latter is a rate‐limiting enzyme in the catabolism of 5‐FU in the capecitabine‐based regimen. However, the relationship between the pharmacokinetics of capecitabine and the plasma UH₂/Ura ratio is still unknown. This study evaluated the time‐course alterations of the plasma UH₂/Ura ratio in rats treated with 180 mg/kg capecitabine. The molar ratio tended to increase within 1.5 h (1.85 ± 0.76 at 1.5 h after administration of capecitabine) and gradually recovered to its initial level (1.00 ± 0.46). The results of the current study suggest that the plasma UH₂/Ura ratio temporarily increases following administration of capecitabine, possibly related to the DPD activity levels. The plasma UH₂/Ura ratio might assist in monitoring the alteration of DPD activity levels in capecitabine treatments.     

Effects of 12 Ca2+ antagonists on multidrug resistance, MDR1-mediated transport and MDR1 mRNA expression.

The effects of 12 Ca(2+) antagonists on MDR1 were examined by two independent models: the inhibitory effect on MDR1-mediated transport of [(3)H]digoxin using MDR1-overexpressing LLC-GA5-COL150 cell monolayers and the reversal effect on cytotoxicity of vinblastine or paclitaxel using MDR1-overexpressing Hvr100-6 cells. The inhibitory effects on [(3)H]digoxin transport were assessed as the 50% inhibitory concentration during 4 h exposure, and the values were the lowest for nicardipine (4.54 microM), manidipine (4.65 microM) and benidipine (4.96 microM), followed by bepridil (10.6 microM), barnidipine (12.6 microM), efonidipine (13.0 microM), verapamil (13.2 microM) and nilvadipine (18.0 microM). The reversal effect on cytotoxicity was assessed by the 50% growth inhibitory concentration after 3 days exposure, and the resistance to vinblastine or paclitaxel in Hvr100-6 cells was reversed by manidipine, verapamil, benidipine, barnidipine, and nicardipine, in that order. Bepridil, barnidipine, efonidipine, verapamil and nilvadipine showed similar inhibitory effects on [(3)H]digoxin transport, but barnidipine and verapamil showed a stronger effect in reversal of cytotoxicity. Real-time quantitative RT-PCR assay indicated a decrease in MDR1 mRNA expression by barnidipine and verapamil. It is concluded that Ca(2+) antagonists cannot only be direct inhibitors of MDR1 but that some may at the same time act as inhibitors of expression of MDR1 via down-regulation of MDR1 mRNA.     

Antipsychotics-Associated Serious Adverse Events in Children: An Analysis of the FAERS Database

Objective: The reports submitted to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from 1997 to 2011 were reviewed to assess serious adverse events induced by the administration of antipsychotics to children.Methods: Following pre-processing of FAERS data by elimination of duplicated records as well as adjustments to standardize drug names, reports involving haloperidol, olanzapine, quetiapine, clozapine, ziprasidone, risperidone, and aripiprazole were analyzed in children (age 0-12). Signals in the data that signified a drug-associated adverse event were detected via quantitative data mining algorithms. The algorithms applied to this study include the empirical Bayes geometric mean, the reporting odds ratio, the proportional reporting ratio, and the information component of a Bayesian confidence propagation neural network. Neuroleptic malignant syndrome (NMS), QT prolongation, leukopenia, and suicide attempt were focused on as serious adverse events.Results: In regard to NMS, the signal scores for haloperidol and aripiprazole were greater than for other antipsychotics. Significant signals of the QT prolongation adverse event were detected only for ziprasidone and risperidone. With respect to leukopenia, the association with clozapine was noteworthy. In the case of suicide attempt, signals for haloperidol, olanzapine, quetiapine, risperidone, and aripiprazole were detected.Conclusions: It was suggested that there is a level of diversity in the strength of the association between various first- and second-generation antipsychotics with associated serious adverse events, which possibly lead to fatal outcomes. We recommend that research be continued in order to gather a large variety and quantity of related information, and that both available and newly reported data be placed in the context of multiple medical viewpoints in order to lead to improved levels of care.     

Prediction of systemic exposure to cyclosporine in Japanese pediatric patients

The monitoring of the blood concentration at 2 h (C₂) after the oral administration of a cyclosporine (CsA) microemulsion was reconfirmed to be useful for the prediction of systemic exposure, the area under the blood concentration–time curve from 0 to 4 h (AUC_0–4), in a group of Japanese patients, consisting of 33 children aged 5–15 years and 19 young adults aged 16–27 years, with a greater correlation for C₂ (r = 0.927) than the trough concentration (r = 0.488). The dose-normalized AUC_0–4 was independent of gender or indications for CsA, while it depended on body size, i.e., the age (P = 0.065) and total body weight (P = 0.026). MDR1 C3435T had a weak, but insignificant effect (P = 0.072); it was about 22–31% lower in the patients with TT³⁴³⁵. Co-administration of a steroid and further treatment with nifedipine had a more intensive effect (P = 0.018); co-administration resulted in a 51% increase in the dose-normalized AUC_0–4. A strong effect was also observed for the serum total cholesterol level (P = 0.001). Collectively, the discrepancies in the results on MDR1 C3435T among investigators might be due to variability in the age/total body weight, co-administration drugs or serum lipid level.