A Survey of the FAERS Database Concerning the Adverse Event Profiles of α1-Adrenoreceptor Blockers for Lower Urinary Tract Symptoms

Purpose: Current guidelines recommend α1-adrenoreceptor blockers (A1Bs) for treating lower urinary tract symptoms suggestive of benign prostatic hyperplasia, but their adverse effects can be problematic. In this study, reports submitted to the US Food and Drug Administration Adverse Event Reporting System (FAERS) between 1997 and 2011 were reviewed to assess the safety profiles of A1Bs.Methods: After deleting duplicated submissions and revising arbitrary drug names, reports involving A1Bs for male patients were analyzed. Data mining algorisms were used for the quantitative detection of signals, where a signal represents an association between a drug and an adverse event or a drug-associated adverse event, including the proportional reporting ratio, reporting odds ratio, information component given by a Bayesian confidence propagation neural network, and empirical Bayes geometric mean.Results: The total number of reports used was 1,260,182. Signal scores suggested the associations of alfuzosin, doxazosin, tamsulosin, and terazosin with dizziness/vertigo, orthostatic hypotension, erectile dysfunction, ejaculation dysfunction (EjD), thirst/dry mouth, and constipation; however, reports on naftopidil, silodosin, and urapidil were not enough to compare with the other 4 A1Bs. Signal scores for EjD were higher for tamsulosin, and those for dizziness/vertigo were lower for doxazosin than for the other 3 drugs.Conclusions: Tamsulosin-associated EjD, which was found in clinical studies, was reproduced in this analysis with markedly higher signal scores, and these results strongly suggest the necessity of well-organized clinical studies on A1B-associated adverse events.     

Invasive pulmonary aspergillosis associated with influenza B

Invasive pulmonary aspergillosis (IPA) usually occurs in immunocompromised patients. However, rarely, this infection can occur in normal hosts. This review of the literature identified 13 cases of IPA associated with influenza, of which 12 had influenza A and the type of influenza was not mentioned in the other case. Reported here is a case of IPA, which was associated with influenza B, in a 63-year-old immunocompetent woman. Her lungs showed gross invasion and she was treated with itraconazole and amphotericin B. She required mechanical ventilation for about 5 months but recovered completely. This is the first reported case of IPA associated with influenza B.     

High Bioavailability of α-Tocopherol Loaded into Poly (DL-Lactic-co-Glycolic Acid) Microspheres in Apolipoprotein B Knockout Mice

PURPOSE: To assess the potential clinical value of alpha-tocopherol-loaded poly (DL-lactic-co-glycolic acid) (PLGA) microspheres, we examined the disposition kinetics of alpha-tocopherol after administration of the microspheres to apolipoprotein B (apo B) knockout mice as a model of abetalipoproteinemia. METHODS: PLGA microspheres containing alpha-tocopherol were prepared by a solvent-evaporation method. The concentration of alpha-tocopherol was measured by gas chromatography-mass spectrometry. RESULTS: The mean value of particle size of alpha-tocopherol-loaded PLGA microspheres was 108 microm. The loading and the trapping efficiency of alpha-tocopherol in PLGA microspheres were 20.8% and 86.6%, respectively. When alpha-tocopherol solution (25 mg/kg) was subcutaneously administered to apob (+/+) and apob (+/-) mice, the plasma concentrations of alpha-tocopherol reached a peak at 6 h and decreased to the endogenous level within 4 days in both types of mice. However, the area under the plasma concentration-time curve (AUC) of apob (+/-) mice was significantly smaller than that in the case of apob (+/+) mice. When alpha-tocopherol-loaded PLGA microspheres (100 mg/kg) were subcutaneously administered, the plasma concentrations of alpha-tocopherol increased slowly and remained about 2-fold higher than the endogenous level at 5 to 10 days after administration in both types of mice, and there was no significant difference between the AUC values. CONCLUSIONS: The PLGA microsphere preparation of alpha-tocopherol is expected to be a very useful drug delivery system in vitamin E supplementation therapy for abetalipoproteinemia.     

Intratumoral ethanol injection for malignant tracheobronchial lesions: a new bronchofiberscopic procedure

We performed intratumoral ethanol injection via a flexible bronchofiberscope in 13 patients with malignant tracheobronchial lesions in order to evaluate its effects on airway dilatation and hemostasis. The results obtained are described below. Immediately after intratumoral injection of ethanol, bronchofiberscopic findings revealed that the tumor turned faintly white, there was a little regression of tumor, and a promising effect was demonstrated on patients with bleeding from tumors. The injected tumor turned necrotic within several days, and histological examination revealed no viable tumor cells in necrotic tissues. The histological anti-tumor effect of ethanol was also demonstrated in experiments with nude mice. This endoscopic treatment was very effective in polypoid tumor protruding into the tracheobronchial lumen, but ineffective in the case of compressed stenosis or obstruction. In conclusion, intratumoral injection of ethanol is considered to be a promising endoscopic treatment for malignant tracheobronchial lesions.     

Effects of tumor necrosis factor, alone or in combination with topoisomerase-II-targeted drugs, on human lung cancer cell lines

Tumor necrosis factor alpha (TNF) exhibits cytotoxic activity on some solid tumors and has been reported to be synergistic with topoisomerase-II-targeted antineoplastic agents. A wide range of TNF concentrations (from 10 to 10,000 U/ml) was tested in 9 human lung cancer cell lines (5 small-cell and 4 non-small-cell carcinomas) using a semi-automated MTT assay. TNF was not cytotoxic in 8 cell lines, while an adenocarcinoma cell line was marginally sensitive to the cytokine. Using 125I-TNF we were able to show the presence of specific binding sites for TNF in 4/9 human lung cancer cell lines. Scatchard analysis of the marginally sensitive cell line showed high-affinity, saturable binding. With 5 cell lines we also tested whether TNF affected the cytotoxicity of doxorubicin and etoposide, 2 topoisomerase II-targeted drugs which are widely used in the therapy of lung cancer. No significant increase in cytotoxicity was seen when TNF was added to the 2 anti-neoplastic agents. In contrast to certain other human and mouse lines, human lung cancer cell lines appear to be resistant to TNF, despite the presence of the receptor in some of them; moreover, no synergistic effect of TNF and 2 topoisomerase-II-targeted drugs was evident in these human cell lines.     

Detection of donor specific cytotoxic T lymphocyte activity in lung grafted mongrel dogs

Cytotoxic activity against donor skin fibroblasts in peripheral blood mononuclear cells was evaluated by using 10 mongrel dogs with left lung allografts and the results obtained herein were as follows. 1) Culture of skin fibroblasts primarily separated with collagenase and disperse was feasible to grow monolayers within several days to 1 weeks. Four hour responding time of mononuclear cells to targets was superior to 18 hour responding time, with the reproducibility of this assay under the 4 hour cocultivation between effectors and targets. 2) The effectors in this assay established in our laboratory were the cells nonadherent on plastics and nylon wool, suggesting T lymphocytes and donor specificity was confirmed by cold competition. 3) This donor specific cytotoxic activity derived from T lymphocytes was steeply elevated 4 to 8 days postoperatively with the average of 6 days in rejecting lung allografts and histologic examination revealed edema and fibrin-like substance in alveolar space. Cyclosporin A, however, could remarkably suppress its activity and grafted lung maintained function. In conclusion, the effectors in cytotoxic activity against donor skin fibroblasts in lung allografted mongrel dogs developed in our laboratory revealed as donor specific cytotoxic T lymphocytes and this assay is very useful to demonstrate rejection, the effect of immunosuppressive drugs and the differentiation between rejection and infection.     

A new sterilization technique with balloon-tube thoracostomy for thoracic empyema

Objective: Failure or prolongation of treatment for refractory thoracic empyema by the current chesttube drainage technique is often due to sterilization difficulties. Insufficient sterilization prolongs hospitalization, and is often associated with life-threatening complications and/or additional invasive surgical procedures. A new chest-tube sterilization technique aimed at making it less invasive and shortening the therapy is proposed.Methods: Following pretreatment for complications including loculation, bronchopleural fistula, or corticated lung, a double-lumen trocar catheter was introduced at the bottom of the empyemic cavity through the lateral chest wall. Then, a Foley balloon urethra-catheter was inserted and attached just inside the anterior chest wall at the top of the cavity for the evacuation of intrathoracic air. After irrigation of the cavity with distilled water once or twice, the cavity was completely filled with a bactericidal solution which was left in place for 30–60 minutes, followed by an antibiotic solution for more than 20 hours.Results: Among the five treated post-lobectomy or pneumonectomy cases, sterilization was obtained after only one treatment in four cases and after two courses in the other. Catheterization duration from the initial treatment was 2–13 days. Neither recurrence nor treatment-related major complications were observed.Conclusions: This balloon-tube thoracostomy technique is simple, minimally invasive and cost-effective, due to shortening of the treatment time with minimal manpower and equipment requirements. It is thus a promising therapeutic approach to thoracic empyema and has the potential for application to other intrathoracic disorders.     

Omeprazole- and esomeprazole-associated hypomagnesaemia: data mining of the public version of the FDA Adverse Event Reporting System

Objective: Case reports showing that proton-pump inhibitors (PPIs), omeprazole and esomeprazole, can cause hypomagnesaemia have been accumulating since 2006. In this study, the reports submitted to the Adverse Event Reporting System (AERS) of the US Food and Drug Administration (FDA) were evaluated to assess omeprazole and esomeprazole in terms of susceptibility to hypomagnesaemia.Methods: After a revision of arbitrary drug names and the deletion of duplicated submissions, the reports involving omeprazole and esomeprazole were analyzed. Standardized official pharmacovigilance tools were used for the quantitative detection of a signal, i.e., an association between a drug and an adverse drug event, 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: A total of 22,017,956 co-occurrences were found in 1,644,220 reports from 2004 to 2009, where a co-occurrence was a pair of a drug and an adverse drug event. In total, 818 and 743 adverse drug events were listed as omeprazole- and esomeprazole-associated, with hypomagnesaemia ranking 85^th and 135^th, respectively. Although both PPIs were associated with hypomagnesaemia, the statistical metrics suggested that the association was more noteworthy for omeprazole.Conclusion: The data obtained in this study do not provide sufficient evidence to recommend systematic monitoring of magnesium levels in plasma, but chronic exposure to a PPI can lead to severe hypomagnesaemia.