Photosensitivity with Angiotensin II Receptor Blockers: A Retrospective Study Using Data from VigiBase(®).

BACKGROUND: Angiotensin II receptor blockers (ARBs) are widely used to treat hypertension and heart failure. Photosensitivity reactions are cutaneous adverse events due to exposure to a drug and either ultraviolet or visible radiation. Among the ARB class, this type of adverse drug reaction is labeled only for losartan. OBJECTIVE: The aim of this study was to provide a descriptive evaluation of photosensitivity reports with ARBs in the World Health Organization Global Individual Case Safety Report database, VigiBase(®). METHODS: All reports of photosensitivity reported with ARBs were identified from VigiBase(®). All variables contained in the reports were analyzed. Information component (IC) and its lower limit of a 95% credibility interval (IC025) values were considered as measures of disproportionality for the assessment of photosensitivity cases reported with ARBs. VigiGrade completeness score (C) was used as a measure of quality of each report. Well-documented reports (C > 0.8) were fully described and analyzed. RESULTS: Up to December 2014, a total of 203 reports on photosensitivity reported with ARBs and submitted by 25 different countries had been recorded in VigiBase(®). Among them, 25.1% involved losartan, 23.1% involved irbesartan, and 21.7% involved valsartan. In 126 cases, the ARB was the only suspected drug and in 10% of them the reaction was serious. IC and IC025 values indicated a possible positive correlation between photosensitivity and both irbersartan and losartan. A focus on well-documented reports, after excluding those with a co-prescription of other drugs known to cause photosensitivity, showed that out of 18 cases, six were related to losartan, four to olmesartan, three to irbesartan, two to valsartan and to candesartan, and one to telmisartan. Causality assessment was 'probable' in ten cases and 'possible' in eight cases. Moreover, positive dechallenge was reported in ten cases and positive rechallenge in one case. CONCLUSIONS: Photosensitivity reactions have been reported with almost all ARBs in VigiBase(®) with a positive disproportionality for irbesartan and losartan. Considering that ARBs share the same chemical structure, which may have the same response to sunlight, it is plausible to consider photosensitivity as a possible class effect. Physicians and patients should be aware of potentially serious photosensitivity reactions related to treatment with ARBs.

Oxidative stress with altered element content and decreased ATP level of erythrocytes in hepatocellular carcinoma and colorectal liver metastases.

Our aim was to study the possible alterations of redox status (enzymatic and nonenzymatic parameters and metal elements) in erythrocytes of patients with hepatocellular carcinoma (HCC), colorectal liver metastases (CRLM) and benign liver neoplasms. The function of redox homeostasis is closely connected to the energy level of erythrocytes, therefore, the ATP level was also determined. Antioxidant parameters, enzyme activities of superoxide dismutase and glutathione peroxidase were estimated in the erythrocytes of 11 patients with benign tumour, 23 patients with primary malignant and 37 metastatic liver tumour patients and 30 age-matched and sex-matched healthy controls. Element content with inductively coupled plasma optical emission spectrometer and ATP level by the chemiluminometric method were also determined from the samples. Free radical intensity was significantly increased, whereas erythrocyte glutathione peroxidase and superoxide dismutase activities were significantly decreased in the HCC and CRLM groups versus benign groups and controls. Se, Mn and Zn levels were lowered in HCC and CRLM groups versus benign and control groups. The content of Cu, Mg, Se and Zn changed significantly between HCC and CRLM groups. Similarly, ATP concentration decreased in HCC and CRLM versus controls and benign groups. The lowest levels of ATP and antioxidant enzyme activities were found in the case of CRLM patients. These results reveal an alteration in the ATP level of erythrocytes with concomitant changes in the antioxidant defence system in hepatic cancer patients. Altered redox homeostasis (oxidative damage) may lead to decreased ATP level and consequently may play an important role in primary carcinogenesis and generation of metastases, as well.

Alterations in the content of metal elements and fatty acids in hepatic ischaemia-reperfusion: induction of apoptotic and necrotic cell death.

Ischaemia and reperfusion are related to oxidative stress, which alters with the redox-homeostasis of the liver cells. Our aim was to reveal the correlations between changes of metal element and fatty acid concentration (two main components of redox-balance) and apoptotic and necrotic processes of hepatic ischaemia-reperfusion. Wistar rats were divided into three groups: control, sham-operated and reperfusion. Hepatic ischaemia was induced for 45 min in the left lateral, left medial and right medial lobes followed by 24 h of reperfusion. Global redox parameters and glutathione peroxidase and superoxide dismutase activity were detected by luminometry and spectrophotometry. Routine laboratory measurements, fatty acid composition (with gas chromatography) as well as metal ion concentration of liver (with ICP-OES) were determined. Metallothionein activity was measured by atomic absorption spectrometry. Immunohistochemical and histological examinations were carried out to investigate apoptotic and necrotic changes in the liver. During reperfusion, global antioxidant parameters decreased and superoxide dismutase level of the liver was significantly lower than in the sham-operated group. Changes in the metal element concentration are essential for cellular biochemical pathways, and significant correlations were found between decrease in Cu and Zn content and decreased superoxide dismutase activity. Necrotic lesions along with increased number of apoptotic cells were found in the liver after 24 h of reperfusion. Alterations in the metal element and fatty acid content was found in the liver tissue during 24 h of ischaemia-reperfusion along with increase in the number of apoptotic cells and significant disturbance of the antioxidant balance. Study of the metal element content of the liver during hepatic ischaemia-reperfusion may provide new supportive strategies for liver surgery and transplantation.

The influence of refractory ceramic fibres on pulmonary morphology, redox and immune system in rats.

Refractory ceramic fibres (RCF) were studied in male SPRD rats by both in vivo long term sequential and in vitro methods. RCF was administered by single intratracheal instillation and the lungs were examined at the end of months 1, 3 and 6 after exposure. In addition, the direct toxicity of the fibres was examined in a primary culture of alveolar macrophages (AM) and in pneumocytes type II (T2). Pulmonary morphological changes, a number of parameters of the redox system, such as activity of extracellular Cu,Zn/superoxide dismutase (EC-SOD), total glutathione content of the lungs (GSH) and immunoglobulins in bronchoalveolar lavage (IgA, IgG, IgM) and in the blood were measured. The composition of the original RCF and the elemental content of the lung tissue were compared by energy dispersive x-ray analysis (EDXA) before and after exposure. Macrophage alveolitis became confluent and moderate fibrosis developed by the end of month 3, and after 6 months of exposure the intensity decreased to the level of the first month. The RCF did not significantly influence the activity of EC-SOD or the total glutathione content of the lungs. Although aluminium and silicon could be demonstrated by EDXA in the lung tissue at the end of month 3, these elements were no longer detectable by the end of month 6. The RCF decreased IgA significantly in bronchoalveolar lavage (BAL). The main components of RCF induced pulmonary alterations, whereas no significant change could be detected in EC-SOD and GSH. Injuries caused by direct toxicity could be observed in the cell membranes only at the highest concentration. On the basis of these results RCF can be determined as moderately toxic fibres.

The effect of stone-wool on rat lungs and on the primary culture of rat alveolar macrophages and type II pneumocytes.

The effect of stone-wool has been studied in both in vivo long term sequential and in vitro methods in male Sprague-Dawley rats. Stone-wool was administered by single intratracheal instillation and the lungs were examined after 1, 3 and 6 months of exposure by morphological methods. UICC crocidolite was applied as a positive control. In addition, the effects of both fibres were examined in primary cultures of alveolar macrophages (AM) and type II pneumocytes (T2) by morphological, biochemical and immunological methods. By the end of 6 months stone-wool induced moderate pulmonary interstitial inflammation and fibrosis without progression, whereas crocidolite induced progressive interstitial inflammation and fibrosis as a function of time. Although stone-wool inhibited phagocytosis, it did not induce serious membrane damage to the cells examined and did not destroy their ultrastructure. It significantly reduced the activity of Cu,Zn/superoxide dismutase (SOD) and alkaline phosphatase (AP) in alveolar macrophages and significantly decreased the activity of AP and gamma-glutamyl transpeptidase (GGT) in type II pneumocytes. Crocidolite, on the other hand, decreased the activity of all enzymes (glutathione peroxidase, GSH-Px; glutathione reductase, GSH-Rd) of glutathione metabolism as well as alkaline phosphatase in alveolar macrophages. It decreased the activity of all enzymes in type II pneumocytes, except for Cu,Zn/SOD. On exposure to stone-wool, the production of inflammatory proteins, macrophage chemoattractant protein-1 (MCP-1) and macrophage inhibitory protein-1alpha (MIP-1alpha) increased in both cultured cells but did not reach the level induced by crocidolite. Our results suggested that stone-wool is less toxic than crocidolite. Whether it is carcinogenic or not, is still an open question.

[Radiosensitizing effect of hyperfractionated radiation]. / A frakcionált besugárzás sugárérzékenyítô hatása.

To determine whether hyperfractionated treatment has benefits in the radiation therapy, two melanoma cell lines were irradiated with eight 0.5 Gy fractions as well as one single 4 Gy in vitro. The radiation was performed in air and in hypoxia as well. Cells were also irradiated in the presence of dibromodulcitol, a bifunctional alkylating agent with a weak radiosensitizer effect. The aim of the study was to examine whether hyperfractionation can influence the radiosensitizing effect of the bioreductive agent. Survival of the cells was determined immediately and 24 hours after various treatments by cell counting in hemocytometer and clonogenic assay. The number of the apoptotic cells was determined by the TUNEL assay and was followed up to 72 hours after treatment. Hypoxic cells had higher sensitivity than normoxic cells after 0.5 Gy irradiation. Radiosensitizing enhancement of DBD was higher with fractionated irradiation. The number of the apoptotic cells was significantly higher after hyperfractionated treatments than after single dose treatment combinations. Our results showed the significance of the hyperfractionated irradiation with 0.5 Gy per fraction in vitro.