M. Ilker Yilmaz

Comparative effects of nebivolol and metoprolol on oxidative stress, insulin resistance, plasma adiponectin and soluble P-selectin levels in hypertensive patients

Objectives To determine the effects of nebivolol on oxidative stress, insulin resistance, adiponectin and plasma soluble P-selectin levels in hypertensive patients in comparison with metoprolol. Material and methods Eighty newly diagnosed hypertensive patients in grade 1 hypertension according to the European Society of Hypertension and European Society of Cardiology guidelines were enrolled in this prospective, blinded, randomized study. Seventy-two patients completed the study. After baseline assessment, each patient was randomly allocated to a 5 mg daily dose of nebivolol (n = 37, 20 male) or a 100 mg daily dose of metoprolol (n = 35, 18 male) and treated for 6 months. Blood pressure, heart rate, oxidative stress (malonyldialdehyde), homeostasis model assessment: insulin resistance, adiponectin and plasma soluble P-selectin levels were measured before and after treatment. Results At the end of treatment, nebivolol and metoprolol significantly decreased blood pressure and heart rate, with a more pronounced bradycardic effect of metoprolol. Nebivolol, but not metoprolol, significantly lowered oxidative stress (P = 0.03), the insulin resistance index (P = 0.003) and plasma soluble P-selectin levels (P = 0.008), and increased adiponectin levels (P = 0.04). Conclusion Nebivolol, in contrast to metoprolol, improved oxidative stress, insulin sensitivity, decreased plasma soluble P-selectin and increased adiponectin levels in hypertensive patients. These beneficial effects of nebivolol may contribute to a reduction in cardiovascular risk in hypertensive patients.

The bisphosphonate zoledronic acid induces cytotoxicity in human myeloma cell lines with enhancing effects of dexamethasone and thalidomide.

Bisphosphonates have recently been introduced in the therapeutic armamentarium for long-term treatment of patients with multiple myeloma. These pyrophosphate analogs not only reduce the occurrence of skeletal events but also provide clinical benefit to patients and improve the survival of some of them. The existence of these capabilities raises the possibility that these compounds may have a direct antiproliferative effect on tumor cells. To investigate whether these drugs exert a direct antitumor effect, we exposed human myeloma cell lines ARH-77 and RPMI-8226 to increasing concentrations of zoledronic acid (ZOL) in vitro. A concentration- but not time-dependent cytotoxic effect was detected with drug treatment of ARH-77 and RPMI-8226 cell lines (30% and 60% at 48 hours and 38% and 62% at 72 hours, respectively, for 50µM of ZOL). Cytotoxicity was not due to ZOL-induced chelation of extracellular calcium as shown by control experiments with the calcium chelator ethylene glycol-bis(β-aminoethylether)-N,N,N’,N’-tetraacetic acid. Addition of the competitive inhibitor of the nitric oxide synthase Nω-nitro-L-arginine methyl ester did not modulate ZOL-induced cytotoxicity. However, a decrease in the number of apoptotic cells was detected when protein kinase C was inhibited by addition of staurosporine to ZOL-containing cultures. Cytotoxicity also was increased by addition of dexamethasone (Dex) and thalidomide (Thal) to ARH-77 and RPMI-8226 cultures. We demonstrated that exposing myeloma cell lines ARH-77 and RPMI-8226 to ZOL inhibits cell growth in a dose-dependent but not a time-dependent manner and that combination of Dex and Thal with ZOL induces apoptotic cell death, providing a rationale for potential applications in vivo.

Effects of Statins on Oxidative Stress

Free oxygen radicals and insufficient antioxidant enzymes have been implicated in the pathogenesis of hypercholesterolemia (HC). Trace elements function as cofactors in antioxidant enzymes. Antioxidant system and trace elements were investigated in many different studies including HC, but these subjects have not been investigated as a whole in these patients. The aim of the present study was to investigate the antioxidative system and trace elements in hypercholesterolemic patients given fluvastatin therapy.We examined malondialdehyde (MDA), copper zinc-superoxide dismutase (CuZn-SOD), and glutathione peroxidase (GSH-Px) activities together with copper (Cu), iron (Fe), and zinc (Zn) levels in erythrocytes of 35 patients with HC and 27 healthy control subjects. It was found that in patients with HC, erythrocyte MDA was significantly higher than those of controls and erythrocyte CuZn-SOD and GSH-Px activities were significantly lower in patients with HC. Erythrocyte iron levels were significantly higher than those of controls, and erythrocyte copper and zinc levels were significantly lower in patients with HC. Plasma lipid levels and the oxidative state were analyzed in statin-treatment groups given fluvastatin therapy before and after a 3-mo treatment period.In conclusion, we found that fluvastatin has significant antioxidant properties and these effects might be very important in managing dyslipidemia by improving endothelial function.

Fluvastatin improves insulin resistance in nondiabetic dyslpidemic patients

Statins have multiple actions, independent of their classical effects on lipoproteins. The data about the effects of statins on insulin resistance is controversial. This study was designed to search the statin effects on nondiabetic dyslipidemic patients. Thirty-five (17 male, 18 female) consecutive dyslipidemic patients 54.25±8.81 yr were enrolled in the study. After a standard follow-up period of lifestyle modification, the patients were given fluvastatin 40 mg/d for 8 wk. Serum analyses were done both before and after treatment. Insulin resistance was assessed by homeostasis assessment model (HOMA). Fasting plasma triglyceride, total and LDL cholesterol, fasting insulin, and HOMA index were significantly reduced and HDL cholesterol was improved after fluvastatin treatment. HOMA-IR was not correlated with triglycerides, LDL, HDL, or total cholesterol levels. The same situation was present for both fasting plasma insulin and fasting plasma glucose levels. Also age was not associated with HOMA-IR and fasting plasma insulin levels. As a conclusion, the present study indicates that fluvastatin treatment improves insulin resistance in dyslipidemic patients who do not have diabetes or impaired fasting glucose. Also, the effect of fluvastatin on insulin resistance is not associated with the lowering of triglycerides. The latter finding indicates that the effect of statins on insulin sensitivity may not be related with the lowering of triglycerides in dyslipidemic patients.

Effects of postmenopausal hormone replacement therapy on insulin resistance

Postmenopausal hormone replacement therapy (HRT) protects women from the risk of cardiovascular system disease, osteoporosis, and dementia. There are conflicting reports about the effects of HRT on insulin resistance. The purpose of this study was to investigate the effects of HRT on insulin resistance with the hyperinsulinemic euglycemic clamp technique, the most sensitive technique measuring insulin resistance. Conjugated estrogen (0.625 mg/d) and medroxyprogesterone acetate (5 mg/d) were given to 15 postmenopausal women with insulin resistance. After 3 mo of HRT, the M value (total glucose consumption) increased 28% (p<0.001), low-density lipoprotein (LDL) cholesterol decreased 12.9% (p<0.044), high-density lipoprotein (HDL) cholesterol increased 17% (p<0.009), total cholesterol decreased 9.1% (p<0.016), and serum insulin decreased 33% (p<0.022) compared to baseline values before HRT was started. No significant changes in glucose, C-peptide, and triglyceride levels were observed. Whereas there were no differences regarding glucose, total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels between the insulin-resistant (n=15) and non-insulin-resistant women (n=24) (p>0.05), there were significant differences in M value, insulin, and C-peptide levels between these groups (p<0.05). We believe that HRT with this combination may protect postmenopausal women from coronary artery disease (CAD) through its beneficial effects on insulin resistance, hyperinsulinemia, and lipid levels, which are considered to be important factors in CAD pathogenesis.

Association of plasma adiponectin concentrations with chronic lymphocytic leukemia and myeloproliferative diseases.

Adiponectin, an adipocyte-secreted hormone, is an important negative regulator in the immune system and hematopoiesis. In this study, we investigated the association of adiponectin levels with chronic lymphocytic leukemia (CLL) and myeloproliferative diseases (MPDs). We measured adiponectin levels in 19 patients with CLL and 30 patients with MPD (chronic myelogenous leukemia, 15; polycythemia vera, 9; myelofibrosis, 4; essential thrombocythemia, 2). The data were compared with results from a control group of healthy volunteers who were matched according to age, sex, and body mass index. The adiponectin levels in patients with CLL were lower than in the controls (4.71 ± 1.33 μg/mL versus 16.61 ± 3.91 μg/mL; P < .001). They were also significantly lower in patients with MPD than in the controls (8.95 ± 2.64 μg/mL versus 17.16 ± 4.77 μg/mL; P < .001). In addition, we compared the adiponectin levels of MPD patients who were treated with interferon (IFN) to the levels of patients who were not treated with IFN. Adiponectin levels were significantly higher in IFN-treated patients (11.03 ± 1.39 μg/mL versus 6.87 ± 1.79 μg/mL; P < .001). These results suggest that lymphopoiesis and myelopoiesis negatively influence adiponectin levels. Adiponectin may be related to inflammatory cytokine release. IFN therapy appears to have a positive influence on adiponectin secretion by suppressing inflammatory cytokines. Future studies are needed to prove causality and to provide insight about this hormone’s mechanism of action and its potential role regarding the etiology and progression of CLL and MPD.

Endocan, a novel marker of endothelial dysfunction in patients with essential hypertension: comparative effects of amlodipine and valsartan

Abstract Vascular inflammation plays an important role in the pathophysiology of hypertension and high levels of endocan may reflect ongoing vascular inflammation in hypertensive patients. In the present hypothesis-generating study, we aimed at investigating the comparative effects of amlodipine and valsartan on endocan levels in newly diagnosed hypertensive patients. The study population consisted of 37 untreated hypertensive patients who were randomized to the two treatment arms. After baseline assessment, each patient was randomly allocated to either 10 mg daily of amlodipine (n = 18, 7 males) or 160 mg daily of valsartan (n = 19, 3 males) and treated for a 3-month period. Sphygmomanometric blood pressure (BP) and serum endocan were measured before and every 2 weeks during drug treatment. There was no statistically significant difference between the two treatment arms as far as baseline socio-demographic and clinical characteristics are concerned. After a 3-month treatment period, systolic and diastolic BP values significantly reduced by antihypertensive treatment (p < 0.001). Furthermore, endocan levels were significantly decreased in both treatment arms (p < 0.05). However, amlodipine caused a greater percent decrease in circulating endocan levels compared with valsartan at the end of the treatment period. Both drugs reduced high sensitivity C-reactive protein values. However, the statistical significant difference vs baseline was achieved only in the group treated with amlodipine. No correlation was found between endocan plasma levels and BP reduction. The results of this hypothesis-generating study suggest that amlodipine and valsartan decrease endocan levels in newly diagnosed hypertensive patients. The effects, which are more evident with amlodipine, may contribute to the anti-inflammatory effects exerted by the two drugs on the vascular target.

The effect of fluvastatin on plasma adiponectin levels in dyslipidaemia.

Objective  There is controversy about the effects of statins on insulin resistance and plasma adiponectin. The aim of this study was to investigate the effects of fluvastatin treatment on these parameters in a group of dyslipidaemic patients who had no confounding factors for insulin resistance or alterations in plasma adiponectin.

The relationship between red blood cell Na/K-ATPase activities and diabetic complications in patients with type 2 diabetes mellitus

The development of complications does not depend entirely on diabetes duration and control. Red-blood-cell Na/K-ATPase plays a central role in the regulation of intra- and extracellular cation homeostasis. Alteration of this transport enzyme is thought to be linked to several complications of diabetes mellitus. The aim of this study was to find out any association between diabetic complications and red-blood-cell Na/K-ATPase activities in type 2 diabetes mellitus. Sixty-seven patients and 25 controls were enrolled in the study. Patients were evaluated for retinopathy, neuropathy, and nephropathy. The membrane Na/K-ATPase activities were measured. The studies were done twice with and without ouabain. The results of the calculations are written as micromol Pi/mg protein/h.The duration of diabetes and enzyme levels were negatively correlated (r=−0.38, p=0.001). Na/K-ATPase enzyme activity was significantly lower in the diabetic patients than the control group (p<0.0001). In neuropathic patients the activity was also significantly lower (p<0.0001). The enzyme activities of the people with retinopathy were significantly lower than the ones without retinopathy (p<0.001). The enzymatic activities did not differ among the degrees of nephropathy. The results indicate that erythrocyte Na/K-ATPase enzyme activities are decreased in type 2 diabetes and the decrement of the enzyme is correlated with the diabetes duration.

Antibody response following hepatitis B vaccination in dialysis patients: does depression and life quality matter?

Previously, it was demonstrated that antibody production against hepatitis B virus (HBV) surface antigen (anti-HBs) achieved in hemodialysis patients is suboptimal. Decreased health-related quality of life (HRQOL) and depression is common among hemodialysis patients. This study evaluated whether HRQOL and depressive behavior are associated with antibody response against HBV surface antigen in hemodialysis patients. Depressive symptoms and HRQOL were assessed by Beck Depression Inventory (BDI) and Medical Outcomes Study Short Form (SF-36), respectively. Patients were separated into non-seroconversion (anti-HBs antibody titers <10 IU/L) and seroconversion (anti-HBs antibody titers > or =10 IU/L) groups. Among 188 patients, 37 (19.7%) were diagnosed as nonresponsive to vaccination (anti-HBs antibody titers <10 IU/L). Anti-HBs response is positively associated with Physical Component Summary Score of SF-36 (odds ratio: 1.44; P: 0.009) and albumin (odds ratio: 10.615, P: 0.007), and negatively with BDI score (odds ratio: 0.903, P: 0.007). We concluded that HRQOL and depression is closely related with antibody response following HBV vaccine in hemodialysis patients.