Effect of letrozole on the lipid profile in postmenopausal women with breast cancer.

Hormonal therapy plays a central role in the overall treatment of breast cancer. Aromatase inhibitors can inhibit the aromatase enzyme system resulting in a reduction of oestrogens. Letrozole is a non-steroidal aromatase inhibitor that effectively blocks aromatase activity without interfering with adrenal steroid biosynthesis. The drug can significantly reduce the levels of plasma oestrogens, which remain suppressed throughout the treatment. Data are scarce concerning the influence of these drugs on serum lipid levels. In the present study, we evaluated the effects of letrozole on the serum lipid profile in postmenopausal women with breast cancer. A total of 20 patients with breast cancer were treated with letrozole, 2.5 mg once daily. After an overnight fast, serum lipid parameters (total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides, apolipoproteins A1, B and E and lipoprotein (a)) were measured before treatment and at 8 and 16 weeks afterwards. A significant increase in total cholesterol (P=0.05), LDL cholesterol (P<0.01) and apolipoprotein B levels (P=0.05) in the serum, as well as in the atherogenic risk ratios total cholesterol/HDL cholesterol (P<0.005) and LDL cholesterol/HDL cholesterol (P<0.005) was noticed after letrozole treatment. We conclude that letrozole administration in postmenopausal women with breast cancer has an unfavourable effect on the serum lipid profile.

Investigation for the presence of anti-erythropoietin antibodies in patients with myelodysplastic syndromes.

OBJECTIVES: Recombinant human erythropoietin (rHuEpo) improves anemia in 25% of patients with myelodysplastic syndromes (MDS). The variable and sometimes low response rate to rHuEpo treatment raises the question whether the existence of autoantibodies against erythropoietin (epo) is partially responsible. In the present study we investigated the presence of anti-epo autoantibodies in MDS patients. METHODS: Forty-three patients with MDS were studied. Sixteen patients had refractory anemia (RA), 13 had RA with ringed sideroblasts, 3 had RA with excess of blasts (RAEB), 9 had RAEB in transformation and 2 patients had chronic myelomonocytic leukemia. They were divided in 3 groups according to rHuEpo treatment. Group A consisted of 10 patients who did not receive rHuEpo treatment. Group B included 13 patients who were on rHuEpo treatment (150 IU/kg subcutaneously, 3 times weekly) showing an increase of hemoglobin (Hb) values or reduction of transfusion requirements and Group C consisted of 20 patients who did not respond or stopped responding to rHuEpo treatment. Laboratory studies consisted of a complete blood cell count, measurement of serum epo and determination of anti-epo antibodies using ELISA. RESULTS: There were no significant differences with regard to age and sex among the three groups. No autoantibodies against epo were found in the examined sera, apart from a female patient from group A who showed a low positive titer. CONCLUSION: We suggest that anti-epo autoantibodies do not contribute to the development of MDS-related anemia and are not responsible for the modest response to rHuEpo treatment. Further investigation is needed to identify possible reasons for the low response rate to rHuEpo treatment.

Evaluation of five methods for determining low-density lipoprotein cholesterol (LDL-C) in hemodialysis patients(1).

OBJECTIVES: Current recommendations for the management of dyslipidemia are largely based on the concentration of LDL-C. Most clinical laboratories estimate the concentration of LDL-C by the recommended routine method, the equation of Friedewald, in specimens from fasting subjects and with TG concentrations < 4.52 mmol/L. Because of the limitations of the Friedewald calculation, direct methods for an accurate quantification of LDL-C are needed. DESIGN AND METHODS: In the present study we evaluated the accuracy of the following 5 different procedures for LDL-C in 98 patients on hemodialysis: the Friedewald equation, where LDL-C is calculated from HDL-C, measured either by the precipitation procedure with dextran sulfate-Mg(2+) (Method 1), or by a direct HDL-C assay (Method 2), the Direct LDL assay (Method 3), the homogeneous N-geneous LDL assay (Method 4) and the calculated LDL-C values deriving from the ApoB based equation: 0.41TC - 0.32TG + 1.70ApoB - 0.27, (Clin Chem 1997;43:808-815) (Method 5). RESULTS: All five LDL-C methods were found to be in good agreement with ultracentrifugation/dextran sulfate-Mg(2+) precipitation with the coefficients of correlation of the assays to ranging between 0.93-0.95. However, significant differences in the mean values and biases vs. the reference method were observed. The Friedewald equation and the Direct assay were less affected by high LDL-C levels, and they presented higher sensitivity and higher negative predictive value. The N-geneous assay and the ApoB derived calculation were less affected by high triglyceride levels, and they presented higher specificity and higher positive predictive value. At the diagnostic LDL-C level of 3.37 mmol/L, both Friedewald calculations correctly classified 82/92 patients; Direct assay 86/98; N-geneous assay 88/98; and ApoB derived calculation 88/98. At the diagnostic LDL-C level of 2.98 mmol/L, Friedewald calculations (Method 1 and Method 2) correctly classified 82/92 and 81/92 patients, respectively; Direct assay (LDL-3) 87/98; N-geneous assay (LDL-4) 91/98; and ApoB derived calculation (LDL-5) 91/98. CONCLUSIONS: Among hemodialysis patients, who commonly present "average" LDL-C concentrations and high TG levels, the N-geneous assay and the apoB derived calculation seem to yield more acceptable results for the estimation of LDL-C.

Estimation of LDL cholesterol based on the Friedewald formula and on apo B levels.

OBJECTIVES: The plasma apolipoprotein B (apo B) concentrations have been considered to be a more accurate representation of atherogenic particles and it has been proposed that the formula LDL-C (mmol/L) = 0.41TC - 0.32TG + 1.70apo B - 0.27 is reliable for the estimation of LDL-C (Clin Chem 1997; 43: 808-15). We undertook the present study to investigate the reliability of this formula in a large number of hyperlipidemic patients. DESIGN AND METHODS: 1) The Friedewald formula (LDL-F) and the apo B-based formula (LDL-B) were compared with the beta-quantification reference procedure in 130 individuals with a wide range of total cholesterol (TC) and triglyceride (TG) levels, and 2) the LDL-C levels obtained by the Friedewald formula were compared with those calculated by the apo B-based formula in 1010 individuals attending our outpatient lipid clinic. RESULTS: The LDL-F and the LDL-B formulae for LDL-C estimation were found to be in good agreement with the beta-quantification (r = 0.96 and 0.97, respectively). The bias of each method plotted as a function of TG (up to 4.52 mmol/L) was found positive for the LDL-F, whereas the LDL-B was independent of the concentrations of TG. When a large number of individuals were examined, a good correlation between the two equations was found (n = 1010, r = 0.98). The difference between the two methods was not correlated with serum TG levels. However, it was correlated to serum TC, and apo B levels. CONCLUSIONS: The LDL-B formula is a more reliable and accurate method than the LDL-F formula, especially at TG levels >2.26 mmol/L, although it underestimates LDL-C concentrations. Furthermore, this equation can be used in hypertriglyceridemic patients (TG >4.52 mmol/L) in whom the Friedewald equation is inaccurate.

The effect of moxonidine on plasma lipid profile and on LDL subclass distribution.

Moxonidine is a new antihypertensive agent whose mechanism of action appears to involve specific stimulation of imidazoline receptors resulting in an inhibition of the activity of the central and peripheral sympathetic nervous system. The drug seems to behave neutrally with respect to plasma lipid parameters. However, there are no data on the effects of moxonidine on the low-density lipoprotein (LDL) subclass pattern or on the LDL oxidation susceptibility, both of which are known to play a prominent role in the pathogenesis of atherosclerosis. Thus, we undertook the present study to examine the influence of moxonidine on the LDL subspecies profile and their susceptibility to copper-induced oxidative modification in 20 hypertensive patients (11 men, 9 women) aged 38-61 years. Moxonidine administered at a dose of 0.4 mg daily for 8 weeks produced a significant decrease in both systolic and diastolic blood pressure (from 147 +/- 10 to 131 +/- 11 mm Hg, P < 0.001, and from 98 +/- 4.5 to 86 +/- 5 mm Hg, P < 0.001, respectively). No significant change in plasma lipid profile was observed after moxonidine administration. Additionally, no change in the susceptibility of LDL subclasses to copper-induced oxidative modification was noticed. Finally, drug therapy was not followed by any change in either LDL phenotype or in mass and composition of the three LDL subfractions. We conclude, that unlike other antihypertensive drugs, such as beta-blockers which may predispose to expression of a relatively atherogenic lipoprotein subclass pattern, moxonidine does not affect either plasma lipid parameters or lipoprotein composition.

Comparison of the efficacy of atorvastatin and micronized fenofibrate in the treatment of mixed hyperlipidemia.

OBJECTIVE: To evaluate and compare the influences of micronized fenofibrate and atorvastatin on serum lipid profile, including lipoprotein(a) levels, and on fibrinogen levels in a large group of patients with primary mixed hyperlipidemia (serum total and low-density lipoprotein cholesterol levels > 240 and 160 mg/dl, respectively, and serum triglyceride level > 200 mg/dl). METHODS: This was a 16-week, open-label, parallel-design study conducted in our lipid clinic. After a 6-week dietary baseline phase, we implemented a treatment phase, during which patients received 10 mg/day atorvastatin (n = 45) or 200 mg/day micronized fenofibrate (n = 46) for 16 weeks. Patients were assigned to one of the drugs in sequential orders. Serum lipid profiles, including levels of lipoprotein(a) and fibrinogen, as well as muscle and liver enzymes, were measured during screening, and during weeks -4, -2, 0, 8, and 16 of the treatment period. RESULTS: Atorvastatin was more effective than was micronized fenofibrate at lowering levels of total and low-density lipoprotein cholesterol, whereas fenofibrate was more effective at lowering levels of triglycerides, and raising levels of high-density lipoprotein cholesterol and apolipoprotein A1. However, micronized fenofibrate could significantly decrease plasma fibrinogen levels, whereas atorvastatin evoked a small increase. CONCLUSION: Both atorvastatin in small doses and micronized fenofibrate are effective for improving serum lipid profiles of patients with mixed hyperlipidemia. However, there are considerable differences between the two drugs concerning their influences on plasma fibrinogen levels.

The incidence of thyroid function abnormalities in patients attending an outpatient lipid clinic.

Thyroid disorders are known to influence lipoprotein metabolism. In the current study we examined the incidence of thyroid function abnormalities in patients attending our outpatient lipid clinic. During the last 2 years, 248 patients were admitted to our lipid clinic for the diagnosis and management of dyslipidemia. In all cases, a detailed medical history was obtained and a thorough physical examination was performed with emphasis on the presence of symptoms/signs indicative of underlying thyroid diseases. In addition to lipid parameters, thyrotropin (TSH) and free thyroxine (FT4) levels were measured in a fasting blood sample. Seven female asymptomatic patients (2.8%) had frank biochemical hypothyroidism, and 11 patients (9 female, 2 male) (4.4%) had subclinical hypothyroidism with TSH levels between 5.8-19 mU/L. After restoration of a euthyroid state with levothyroxine therapy, no significant changes in serum lipid parameters were observed in the whole group of patients with subclinical hypothyroidism. However, in 4 patients with TSH levels >12 mU/L relatively small doses of levothyroxine (75 microg/day) were followed by a significant improvement of serum lipid profile. Interestingly, 3 patients exhibited clinical or subclinical hyperthyroidism that influenced serum lipid parameters as well as the effectiveness of hypolipidemic treatment. It is concluded that thyroid function abnormalities are relatively common in dyslipidemic patients attending a lipid clinic and could significantly affect the patients' lipid profile as well as the patients' management.

Effect of L-carnitine supplementation on lipid parameters in hemodialysis patients.

It has been reported that cumulative carnitine losses through dialysis membranes may worsen hyperlipidemia during long-term hemodialysis. However, carnitine supplementation has not shown a consistent beneficial response. We undertook the present study to determine if there is any hypolipidemic effect of L-carnitine on Greek dialysis patients in concert with the dialysate buffer composition (acetate or bicarbonate). A total of 28 patients (16 male, 12 female), mean age 43 years (range 21-61), with end-stage renal disease on maintenance hemodialysis for a mean period of 25 months (range 7-84) were studied. The dialysis schedule was 4 h, 3 times/week using cuprophane hollow-fiber dialyzers and acetate (n = 14) or bicarbonate (n = 14) dialysate. In all patients L-carnitine (5 mg/kg body weight) was infused intravenously 3 times/week at the end of each hemodialysis session. Blood samples for carnitine and lipid determinations were obtained before treatment, and 3 and 6 months following treatment. Even though L-carnitine did not modify most of the serum lipid levels, a significant decrease in serum triglycerides was evident in the whole group of patients (from 225 +/- 76 to 201 +/- 75 mg/dl, p = 0.03). Furthermore, L-carnitine could decrease serum triglycerides only in hypertriglyceridemic patients (from 260 +/- 64 to 226 +/- 82 mg/dl, p < 0.05). L-Carnitine resulted in a reduction of serum triglycerides in both patients on bicarbonate and on acetate dialysis, while there were no significant differences in the changes of lipid parameters after L-carnitine between the two groups of hemodialysis patients. We conclude that relatively low doses of L-carnitine supplementation could contribute to the management of some hypertriglyceridemic hemodialysis patients.

Lipoprotein (a) concentrations in patients with various dyslipidaemias.

Although the genetic background is the most important determinant of lipoprotein (a) (Lp(a)) concentration other factors, such as coexistent dyslipidaemia, could modify its levels. We undertook the present study to examine the serum Lp(a) concentration in various dyslipidaemias and to reveal any correlation of serum Lp(a) concentration with the other lipid parameters in a large group of dyslipidaemic Greek patients. A total of 242 patients followed as outpatients in our lipid clinic were studied. The patients were stratified into four main groups. Patients with cholesterol levels greater than 5.17 mmol/L but normal triglycerides were regarded as hypercholesterolaemic (n=85), patients with triglycerides greater than 2.25 mmol/L but normal cholesterol levels as hypertriglyceridaemic (n=51), patients with both increased cholesterol and triglyceride levels as having mixed hyperlipidaemia (n=62), and finally patients with decreased (<0.90 mmol/L) high-density lipoprotein (HDL) cholesterol but normal cholesterol and triglyceride levels as having primary hypoalphalipoproteinaemia (n=44). Hypercholesterolaemic patients exhibited the highest serum Lp(a) levels, while hypertriglyceridaemic patients exhibited the lowest. Patients with mixed hyperlipidaemia had intermediate serum Lp(a) concentration, which was significantly higher than that of hypertriglyceridaemic patients but significantly lower than that of hypercholesterolaemic patients. Interestingly, patients with low serum HDL-cholesterol levels presented with low serum Lp(a) concentration similar to that of hypertriglyceridaemic patients. In hypercholesterolaemic patients no correlation was found between serum total and low-density lipoprotein (LDL) cholesterol nor apolipoprotein B (apoB) levels and Lp(a) concentration. On the contrary, in hypertriglyceridaemic patients an inverse correlation was observed between serum triglycerides and Lp(a) concentration. After dividing the hypertriglyceridaemic patients into one group with elevated (>1.3 g/L) serum apoB levels (n=32) and another group with normal apoB levels (n=19), we found that the median serum Lp(a) concentration was three times higher in hyperapoB patients compared to patients with normal apoB levels. We conclude that serum Lp(a) levels are different in various types of primary hyperlipidaemia and are modulated according to the type of lipid elevation.

Increased activity of platelet-activating factor acetylhydrolase in low-density lipoprotein subfractions induces enhanced lysophosphatidylcholine production during oxidation in patients with heterozygous familial hypercholesterolaemia.

Patients with heterozygous familial hypercholesterolaemia (FH) have elevated plasma concentrations of low-density lipoprotein (LDL) and develop premature atherosclerosis. There is increasing evidence that oxidative modification of LDL is important for the pathogenesis of atherosclerosis, and the LDL-associated platelet-activating factor acetylhydrolase (PAF-AH) seems to play a key role in LDL oxidation by hydrolysing the oxidized phospholipids of phosphatidylcholine (PC) and producing lysophosphatidylcholine (lyso-PC). We measured the total serum and high-density lipoprotein (HDL) levels of PAF-AH activity and studied the distribution of PAF-AH activity among three LDL subfractions isolated by gradient ultracentrifugation in 15 patients with heterozygous FH and 13 normolipidaemic control subjects. We also determined the lyso-PC production in each LDL subfraction during Cu2(+)-induced oxidation in vitro. The total serum PAF-AH activity in heterozygous FH patients was significantly higher than in control subjects, whereas the HDL-associated PAF-AH activity, expressed as a percentage of total serum PAF-AH activity, was significantly lower in the FH patients than in control subjects (13.9 +/- 6.6% vs. 30.6 +/- 4.4%, P < 0.001). Among the LDL subfractions, the PAF-AH activity in both normolipidaemic control subjects and FH patients, expressed as nmol mg-1 protein min-1, was significantly higher in the LDL3 subfraction (33.1 +/- 4.8 and 53.4 +/- 11.5 respectively) than in the LDL2 (18.6 +/- 5.3 and 26.8 +/- 10.4 respectively, P < 0.0001 for both comparisons) and LDL1 subfractions (5.1 +/- 1.5 and 7.8 +/- 2.6, respectively, P < 0.0001 for both comparisons). Additionally, the enzyme activity in each LDL subfraction of the heterozygous FH patients was significantly higher than in control subjects (P < 0.02 for LDL1, P < 0.03 for LDL2 and P < 0.0001 for LDL3). No difference was observed in the susceptibility to oxidation of each LDL subfraction among the heterozygous FH patients and the normolipidaemic control subjects. During oxidation, the PAF-AH activity decreased, whereas the lyso-PC levels significantly increased in all subfractions of both groups. The lyso-PC/sphingomyelin molar ratio in each LDL subfraction of the FH patients 3 h after the onset of the oxidation was significantly higher than in control subjects [0.38 +/- 0.05 and 0.27 +/- 0.04, respectively, for LDL1 (P < 0.006), 0.47 +/- 0.08 and 0.39 +/- 0.03, respectively, for LDL2 (P < 0.04), 0.55 +/- 0.11 and 0.42 +/- 0.06, respectively, for LDL3 (P < 0.02)]. Our results show that heterozygous FH patients exhibit higher PAF-AH activity than control subjects in all LDL subfractions, resulting in higher lyso-PC production during oxidation, which confers on these subfractions higher biological potency. This phenomenon, in combination with the diminished anti-atherogenic and antioxidant capability of HDL in these patients due to the relatively low HDL-cholesterol levels compared with LDL-cholesterol levels and, consequently, the relatively low HDL-associated PAF-AH activity, could contribute to the higher atherogenicity and incidence of coronary artery disease observed in FH patients.

Elevated interleukin-1 beta in the circulation of patients with essential hypertension before any drug therapy: a pilot study.

Immune system disturbances have been implicated in the pathogenesis of essential hypertension. The aim of this study was to determine the levels of the interleukin-1 beta and soluble interleukin-2 receptors in serum samples from 114 hypertensive patients before any drug therapy because there are no well-established data regarding these immunologic mediators in essential hypertension. We found increased levels of interleukin-1 beta in 59.6% of patients, while soluble interleukin-2 receptors were not detected. The interleukin-1 beta levels were significantly higher in patients than in healthy controls (P = 0.0001). We conclude that patients with essential hypertension have high levels of interleukin-1 beta but not indicators of cellular immune activation in their sera. Further studies are in progress in order to confirm, explain and assess the clinical utility of the above findings.

The beneficial effect of tamoxifen on serum lipoprotein-A levels: an additional anti-atherogenic property.

It has recently been suggested that increased lipoprotein (a) levels are an independent risk factor for coronary heart disease. It has also been reported that tamoxifen can induce changes in blood lipid values. In this prospective study we investigated the long term effects tamoxifen on the lipid profile, focusing on lipoprotein (a) levels. Thirty-eight postmenopausal women with breast cancer treated with tamoxifen at a dose of 20 mg daily were studied. The mean age was 61 years. Serum lipoprotein (a) levels and lipid parameters (total cholesterol, high and low density lipoprotein cholesterol, triglycerides, apolipoprotein A-I and B) were measured after an overnight fast on the 1, 3, 6 and 9 month of tamoxifen treatment. A progressive fall in median lipoprotein(a) levels from 8 mg/dl to 3 mg/dl (p < 0.001) was observed. In addition, a significant decrease in the total and low density lipoprotein cholesterol and in apolipoprotein B, as well as an increase in apolipoprotein A-l were also noticed. It is concluded that our data on serum lipoprotein(a) levels agree with the beneficial anti-atherogenic effects of tamoxifen administration on lipoproteins.

Lipid parameters including Lp(a) in hemodialysis patients.

Chronic hemodialysis (CHD) patients have a high incidence and prevalence of atherosclerotic disease which may be related to numerous atherosclerotic risk factors. Among them dyslipidemia plays a significant role. Elevated Lp(a) levels, which are strongly associated with atherosclerosis, have been reported recently in uremic patients. The aim of our study was the determination of the levels of lipid parameters including Lp(a) in 151 CHD patients (76 male) aged 57 (12-81) years, who were on hemodialysis for a mean of 44.3 (range 1 to 189) months. Eighty-four normal individuals age and sex matched were used as controls. The median serum Lp(a) concentration in hemodialysis patients was 13 mg/dL compared with 6.5 mg/dL in healthy controls, p < 0.001 by distribution-free Mann-Whitney test. The prevalence of subjects with Lp(a) levels above 25 mg/dL was significantly higher in CHD patients compared to normal subjects (30% vs. 8%, p < 0.001). Even if CHD patients were matched for fasting lipid levels, they showed Lp(a) levels significantly higher than controls. No significant correlation was found between Lp(a) levels and either the age of the patients or the duration of hemodialysis. The etiology of primary renal disease did not influence the Lp(a) levels.