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Ceyda Tunakan Dalgic,1 Asuman Camyar,1 Nihal Mete Gokmen,1 Sukriye Miray Kilincer Bozgul,2 Mehmet Zuhuri Arun,3 Zehra Tuba Karaman,2 Elif Ertuna3 1Department of Internal Medicine, Division of Allergy and Immunology, Faculty of Medicine, Ege University, Bornova, Izmir, Turkey; 2Department of Internal Medicine, Faculty of Medicine, Ege University, Bornova, Izmir, Turkey; 3Department of Clinical Pharmacy, Faculty of Pharmacy, Ege University, Bornova, Izmir, TurkeyCorrespondence: Elif Ertuna, Department of Clinical Pharmacy, Faculty of Pharmacy, Ege University, Bornova, Izmir, 35040, Turkey, Tel +90 532 672 5988, Fax +90 232 388 5258, Email elif.ertuna@ege.edu.trPurpose: Repeated exposure to platinum compounds increases the risk of immunoglobulin E-mediated immediate hypersensitivity reactions (HSR). To date, many different desensitization protocols with varying success rates have been reported. The presented study is aimed at disseminating the real-world experience of an interdisciplinary healthcare team focusing on platin desensitization.Patients and Methods: This is a cross-sectional, retrospective study of 7 female patients with carboplatin- or oxaliplatin-induced HSRs. After a discussion with the oncologist and the patient, desensitization protocols were performed by a team consisting of an allergy and immunology specialist, a clinical pharmacist, and a nurse. Clinical data were extracted from the patients’ medical records, and HSRs were reviewed and classified by an allergist according to severity and type.Results: Twenty-five desensitization protocols were carried out for patients with carboplatin- or oxaliplatin-induced HSRs (N=4 and N=3, respectively; age range: 54– 66). Two of the patients did not experience any HSR during a total of 8 desensitization cycles. The other patients had grade 1– 3 HSRs on 15 cycles, which were successfully managed by oxygen and/or pharmacological interventions and infusions were resumed at a lower rate after stabilization of the patient. Compared to baseline, serum tryptase levels were elevated during HSRs (4.77± 0.21 vs 9.50± 1.71, P=0.028).Conclusion: All the patients were able to finish the treatment protocol and receive full chemotherapeutic doses. Interdisciplinary teams may facilitate the preparation and administration of platinum-based chemotherapeutics and increase the success rates of desensitization protocols for platin-based chemotherapy, where the concentration and application of drugs differ from standard procedure.Keywords: platinum compounds, platin hypersensitivity, rapid drug desensitization, immediate reactions, chemotherapy, clinical pharmacist

Elif Ertuna,1 Mehmet Zuhuri Arun,1 Seval Ay,2 Fatma Özge Kayhan Koçak,2 Bahattin Gökdemir,2 Gül İspirli2 1Department of Clinical Pharmacy, Faculty of Pharmacy, Ege University, Izmir, Turkey; 2Department of Internal Medicine, Division of Geriatrics, Faculty of Medicine, Ege University, Izmir, Turkey Purpose: Aging increases the prevalence of diseases. The elderly population is consequently often exposed to complex medication regimens. Increased drug use is one of the main reasons for drug-related problems (DRPs). The primary objective of this study was to define and classify DRPs, pharmacist interventions, and frequently prescribed medications in relation to possible DRPs in patients admitted to the geriatric ward of a teaching hospital in Turkey.Patients and methods: Pharmacist medication review reports for 200 orders of 91 patients (mean age: 80.33±0.46) were analyzed retrospectively.Results: A total of 1,632 medications were assessed and 329 interventions were proposed for possible DRPs in 156 orders. A total of 87.5% of the patients used five or more drugs (mean: 8.17±0.23). The number of DRPs per order was higher when polypharmacy was present (1.04±0.15 vs 1.66±0.11, P

OBJECTIVE: Surgical treatment choice for coronary artery disease is coronary artery bypass grafting (CABG) surgery. Left internal mammary artery (LIMA) is frequently used as an arterial graft in CABG operations. Perioperative spasm of LIMA can result in increased morbidity and mortality. Pharmacological interventions are routinely used for prevention and treatment of LIMA spasm. In this study, we aimed to investigate the effects of carvedilol, an alpha- and beta-adrenergic receptor blocker, on responses to endogenous vasoconstrictors which play a role in graft spasm and the possible interaction between carvedilol and diltiazem/papaverine which are vasodilators commonly used in CABG surgery. PATIENTS AND METHODS: Isolated LIMA rings collected from patients undergoing CABG operation were suspended in an organ bath. Concentration-dependent responses to norepinephrine (NE), serotonin (5-HT) and diltiazem were examined before and after carvedilol incubation (10-6 M, 1 hour). Maximum relaxation response to papaverine (10-4 M) was compared in LIMA rings incubated with 0.05% dimethyl sulfoxide (DMSO, placebo) or carvedilol (10-6 M). RESULTS: Carvedilol did not affect the maximal contractile response to NE; however, it significantly reduced the sensitivity of LIMA to NE. Carvedilol increased contractile response and sensitivity to 5-HT. Promisingly, carvedilol increased the vasodilatory effects of diltiazem and papaverine. CONCLUSIONS: Our study suggests that carvedilol may be administered perioperatively in combination with diltiazem or papaverine to prevent or resolve LIMA graft spasm. [ABSTRACT FROM AUTHOR]

Exposure to mercury has detrimental effects on the cardiovascular system, particularly the vascular endothelium. The present study aimed to investigate the effects of ergothioneine (EGT) on endothelial dysfunction induced by low-dose mercury chloride (HgCl 2 ). Agonist-induced contractions and relaxations were evaluated in isolated aortic rings from 3-month-old male Wistar rats treated by intra-muscular injection to caudal hind leg muscle with HgCl 2 (first dose, 4.6 µg/kg; subsequent doses, 0.07 µg/kg/day for 15 days) and optionally with EGT (2 µg/kg for 30 days). Reactive oxygen species (ROS) in aortic rings were measured by means of lucigenin- and luminol-enhanced chemiluminescence. The protein level of endothelial nitric oxide synthase was evaluated by ELISA. Blood glutathione (GSH) and catalase levels, lipid peroxidation and total nitrite were measured spectrophotometrically. The results indicated that low-dose HgCl 2 administration impaired acetylcholine (ACh)-induced relaxation and potentiated phenylephrine- and serotonin-induced contractions in rat aortas. In addition, HgCl 2 significantly increased the levels of ROS in the aortic tissue. EGT prevented the loss of ACh-induced relaxations and the increase in contractile responses. These effects were accompanied by a significant decrease in ROS levels. EGT also improved the ratio of reduced GSH to oxidized GSH and catalase levels with a concomitant decrease in lipid peroxidation. In conclusion, to the best of our knowledge, the present study was the first to report that EGT prevents endothelial dysfunction induced by low-dose HgCl 2 administration. EGT may serve as a therapeutic tool to reduce mercury-associated cardiovascular complications via improving the antioxidant status.

The gasotransmitter nitric oxide (NO) has an important role in vascular function and a decrease in its bioavailability is accepted as a main pathological mechanism for cardiovascular diseases. However, other gasotransmitters such as hydrogen sulfide (H 2 S) are also generated by the endothelium and can also affect vascular tone and a crosstalk may exist between H 2 S and NO. We therefore investigated the consequences of deficiency, replacement or overexpression of endothelial nitric oxide synthase (eNOS) on H 2 S-induced vascular responses in murine carotid arteries. In pre-contracted carotid arteries from wild-type (WT) mice, l-cysteine elicited relaxation that was inhibited by the H 2 S synthesis inhibitor amino-oxyacetic acid (AOAA). Genetic deletion of eNOS increased l-cysteine-induced relaxation compared to WT, but the replacement of eNOS by adenoviral transfection or H 2 S synthesis inhibition by AOAA reversed it. Furthermore, eNOS deletion did not alter NaHS-induced relaxation in carotid arteries while eNOS overexpression/replacement increased NaHS-induced relaxation responses in carotid arteries from WT or eNOS -/- . We suggest that, endogenously produced H 2 S can compensate for impaired vasodilatory responses in the absence of NO to maintain vascular patency; while, eNOS abundance can limit endogenous H 2 S-induced vascular responses in mice carotid arteries. Our result suggests that endogenous vs. exogenous H 2 S-induced relaxation are reciprocally regulated by NO in mice carotid arteries., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Graft spasm is a common problem in coronary artery bypass grafting (CABG). In this study, we aimed to investigate the interaction of levosimendan, a novel inodilator, with vasodilator agents that are clinically used for the treatment of graft spasm and with endogenous vasoconstrictors that are thought to play a role in graft vasospasm, in human internal mammary artery (IMA) and saphenous vein (SV). Isolated human IMA and SV segments derived from patients undergoing CABG were suspended in an organ bath. Responses to cumulative concentrations of noradrenaline (NA), serotonin (5-HT), papaverine, nitroglycerin (NG), and diltiazem were recorded before and after 10(-5) m levosimendan incubation (30 min). In addition, cumulative levosimendan responses were taken in vessels precontracted with NA or 5-HT. 10(-5) m levosimendan reduced NA Emax and sensitivity in IMA and SV, and 5-HT Emax responses in IMA. Moreover, levosimendan caused concentration-dependent relaxation in both grafts. Papaverine Emax or sensitivity was not altered by levosimendan neither in IMA nor in SV. Levosimendan diminished NG sensitivity in IMA and Emax responses in SV and decreased diltiazem Emax responses both in IMA and SV. Our results suggest that levosimendan may be used alone for prevention or treatment of graft spasm in IMA or in combination with papaverine in IMA and SV grafts. However, as concurrent administration with diltiazem or NG causes a reduction in relaxation in vitro, we suggest caution should be exercised when using levosimendan in combination with these agents., (© 2016 Société Française de Pharmacologie et de Thérapeutique.)

Background: Methylglyoxal is a major precursor in the formation of advanced glycation end products and is associated with the pathogenesis of diabetes-related vascular complications. The aim of this study was to evaluate whether methylglyoxal induces endothelial dysfunction and to determine the contributors involved in this process., Methods: Rat thoracic aortic rings were treated for 24 h with 100 μM methylglyoxal by using an organ culture method. A cumulative dose-response curve to acetylcholine was obtained to determine endothelium-dependent relaxation. The protein levels of endothelial nitric oxide synthase (eNOS) and its phosphorylated form at the serine 1177 site [p-eNOS (Ser1177)], heat shock protein 90 (Hsp90), AMP-activated protein kinase α (AMPKα) and its phosphorylated form at the threonine 172 site [p-AMPKα (Thr172)] were evaluated. Superoxide production was determined by lucigenin-chemiluminescence., Results: Treatment with 100 μM methylglyoxal for 24 h decreased acetylcholine-induced vascular relaxation. The levels of eNOS and p-eNOS (Ser1177) were reduced while no effect on Hsp90 was observed. Levels of p-AMPKα (Thr172) were significantly decreased without any change in total AMPKα protein levels. Superoxide level was not affected by methylglyoxal treatment., Conclusions: In rat aortic rings, methylglyoxal determines a reduction in endothelium-dependent relaxation. This effect seems to be mediated via a reduction in p-eNOS (Ser1177) and p-AMPKα (Thr172).

AMP-activated protein kinase (AMPK) is a regulator of cellular metabolism and is involved in the pathogenesis of several diseases, including type 2 diabetes and cardiovascular diseases. Data showing the effects of AMPK on vasculature are controversial. Therefore, the aim of this study was to determine the impact of prolonged AMPK activation on vascular functions. For this purpose we have examined the role of AMPK in endothelium-dependent and -independent relaxation and vascular contractions. For this, we incubated thoracic aortic rings, from rats, with AMPK activator 5-aminoimidazole-4-carboxamide-1-4-ribofuranoside (AICAR, 500 μmol/L or 2 mmol/L) in the presence or absence of AMPK inhibitor compound C (10 μmol/L). Next, cumulative dose-response curves to acetylcholine (ACh) (10(-9)-10(-4) mol/L), nitroglycerine (NG) (10(-9)-3 × 10(-5) mol/L), and noradrenaline (NA) (10(-9)-10(-4) mol/L) were obtained. Endothelial nitric oxide synthase (eNOS) protein expression was determined. Our results show that endothelium-dependent relaxation was inhibited after AICAR treatment, and that this effect was reversed by AMPK inhibition. Moreover, AICAR enhanced the contractile response to NA and caused a decrease in eNOS protein expression. In conclusion, prolonged AMPK induction causes endothelial impairment, possibly via increased degradation and (or) reduced expression of eNOS.