Enhanced Salivary and General Oxidative Stress in Hashimoto's Thyroiditis Women in Euthyreosis.

Hashimoto's thyroiditis (HT) is one of the most common autoimmune diseases. Although HT is inextricably linked to oxidative stress, there have been no studies assessing salivary redox homeostasis or salivary gland function in patients with HT. This study is the first to compare antioxidant defense and oxidative stress biomarkers in non-stimulated (NWS) and stimulated (SWS) whole saliva and plasma/erythrocytes of HT patients compared to controls. The study included 45 women with HT in the euthyreosis period as well as an age- and gender-matched control group. We showed that NWS secretion was significantly lower in HT patients compared to healthy controls, similar to salivary amylase activity in NWS and SWS. Catalase and peroxidase activities were considerably higher in NWS and SWS of HT patients, while the concentrations of reduced glutathione and uric acid were significantly lower in comparison with healthy subjects. Total antioxidant potential was significantly lower, while total oxidant status and the level of oxidation products of proteins (advanced glycation end products, advanced oxidation protein products) and lipids (malondialdehyde, lipid hydroperoxides) were significantly higher in NWS, SWS and plasma of HT patients. In conclusion, in both salivary glands of women with HT in euthyreosis, the ability to maintain redox homeostasis was hindered. In HT patients we observed oxidative damage to salivary proteins and lipids; thus, some biomarkers of oxidative stress may present a potential diagnostic value.

Therapeutic drug monitoring as a tool to optimize 5-FU-based chemotherapy in gastrointestinal cancer patients older than 75 years.

AIMS: Most clinical trials exclude elderly people, leading to a limited understanding of the benefit-to-risk ratio in this population. Despite existing data regarding the oncological management of elderly receiving fluorouracil (5-FU)-based regimen, our objective was to investigate 5-FU exposure/toxicity relationship in patients ≥75 years and compare the effectiveness of 5-FU therapeutic drug monitoring between elderly and younger patients. METHODS: Hundred fifty-four patients (31 of whom are older than 75 years) with gastrointestinal cancers, who were to receive 5-FU-based regimens, were included in our study. At cycle 1 (C1), the 5-FU dose was calculated using patient's body surface area, then a blood sample was drawn to measure 5-FU concentration and 5-FU dose was adjusted at the subsequent cycles based on C1 concentration. Assessments of toxicity were performed at the beginning of every cycle. RESULTS: Seventy-one percent of elderly patients required dose adjustments after C1, compared with 50% for younger patients. Percentages of patients within 5-FU area under the curve range at cycle 2 were 64% and 68%, respectively, for elderly and younger patients. The proportion of elderly patients experiencing severe toxicities fell from 15% at C1 to only 5% at cycle 3. CONCLUSION: Pharmacokinetic-guided 5-FU-dosing algorithm, leading to an improved tolerability while remaining within therapeutic concentration range, is even more valuable for patients older than 75 years than in younger patients.

Glutathione Metabolism, Mitochondria Activity, and Nitrosative Stress in Patients Treated for Mandible Fractures.

The aim of the study was to evaluate the effect of titanium bone fixations on mitochondrial activity, reactive oxygen species (ROS) production, glutathione metabolism, and selected markers of oxidative/nitrosative stress in the periosteum-like tissue of patients treated with mandible fractures. The study group consisted of 30 patients with bilateral fractures of the mandible body eligible for surgical treatment. Our study is the first one that indicates disturbances of mitochondrial activity as well as a higher production of ROS in the periosteum-like tissue covering titanium fixations of the mandible. We also found significantly higher levels of reduced glutathione and enhanced activity of glutathione reductase in the periosteum homogenates of patients in the study group compared to the control group. Levels of nitrosative (S-nitrosothiols, peroxynitrite, nitrotyrosine) and oxidative stress biomarkers (malondialdehyde, protein carbonyls, dityrosine, kynurenine, and N-formylkynurenine) were statistically elevated in periosteum-like tissue covering titanium fixations. Although exposure to titanium fixations induces local antioxidant mechanisms, patients suffer oxidative damage, and in the periosteum-like tissue the phenomenon of metallosis was observed. Titanium implants cause oxidative/nitrosative stress as well as disturbances in mitochondrial activity.

5-FU therapeutic drug monitoring as a valuable option to reduce toxicity in patients with gastrointestinal cancer.

AIMS: 5-FU is used as the main backbone of chemotherapy regimens for patients with colorectal and other gastrointestinal cancers. Despite development of new strategies that allowed enhancing clinical effectiveness and tolerability of 5-FU, 10-30% of patients treated with 5-FU-based regimens experience severe treatment-related toxicity. In our study, we evaluated the 5-FU exposure-toxicity relationship and investigated the efficacy of PK-guided dosing in increasing tolerability of 5-FU-based chemotherapy. RESULTS: 50.7% of patients required dose adjustments after cycle 1. Percentage of patients within 5-FU AUC range was 49.3%, 66.9%, 61.0% at cycle 1, 2 and 3 respectively (p = 0.002 cycle 1 vs cycle 2). At all 3 cycles, lower incidences of grade I/II toxicities were observed for patients below or within range compared with those above range (19.4% vs 41.3%, p < 0.001 respectively). CONCLUSIONS: Our analysis confirms that the use of BSA-guided dosing results in highly variable 5-FU exposure and strongly suggests that PK-guided dosing can improve tolerability of 5-FU based chemotherapy in patients with gastrointestinal cancers, thus supporting 5-FU therapeutic drug monitoring. METHODS: 155 patients with gastrointestinal cancers, who were to receive 5-FU-based regimens were included in our study. At cycle 1, the 5-FU dose was calculated using patient's Body Surface Area (BSA) method. A blood sample was drawn on Day 2 to measure 5-FU concentration. At cycle 2, the 5-FU dose was adjusted using a PK-guided dosing strategy targeting a plasma AUC range of 18-28 mg·h/L, based on cycle 1 concentration. Assessments of toxicity was performed at the beginning of every cycle.