Feasibility and cost of FH cascade screening in Belgium (BEL-CASCADE) including a novel rapid rule-out strategy.

BACKGROUND: Familial hypercholesterolaemia (FH) is underdiagnosed in most countries. We report our first experience from a national pilot project of cascade screening in relatives of FH patients. METHODOLOGY: Participating specialists recruited consecutive index patients (IP) with Dutch Lipid Clinic Network (DLCN) score ≥6. After informed consent, the relatives were visited by the nurses to collect relevant clinical data and perform blood sampling for lipid profile measurement. FH diagnosis in the relatives was based on the DLCN and/or MEDPED FH (Make-Early-Diagnosis-to-Prevent-Early-Deaths-in-FH) criteria. RESULTS: In a period of 18 months, a total of 127 IP (90 with definite FH and 37 with probable FH) were enrolled in 15 centres. Out of the 270 relatives visited by the nurses, 105 were suspected of having FH: 31 with DCLN score >8, 33 with DLCN score 5-8 and 41 with MEDPED FH criteria. In a post-hoc analysis, another set of MEDPED FH criteria established in the Netherlands and adapted to Belgium allowed to detect FH in 51 additional relatives. CONCLUSION: In a country with no national FH screening program, our pilot project demonstrated that implementing a simple phenotypical FH cascade screening strategy using the collaboration of motivated specialists and two nurses, allowed to diagnose FH in 127 index patients and an additional 105 of their relatives over the two-year period. Newly developed MEDPED FH cut-offs, easily applicable by a nurse with a single blood sample, might further improve the sensitivity of detecting FH within families.

A Belgian consensus strategy to identify familial hypercholesterolaemia in the coronary care unit and its subsequent cascade screening and treatment: BEL-FaHST (The BELgium Familial Hypercholesterolaemia STrategy).

BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is an autosomal dominant lipoprotein disorder characterized by significant elevation of low-density lipoprotein cholesterol (LDL-C) and markedly increased risk of premature cardiovascular disease (CVD). Because of the very high coronary artery disease risk associated with this condition, the prevalence of FH among patients admitted for CVD outmatches many times the prevalence in the general population. Awareness of this disease is crucial for recognizing FH in the aftermath of a hospitalization of a patient with CVD, and also represents a unique opportunity to identify relatives of the index patient, who are unaware they have FH. This article aims to describe a feasible strategy to facilitate the detection and management of FH among patients hospitalized for CVD. METHODS: A multidisciplinary national panel of lipidologists, cardiologists, endocrinologists and cardio-geneticists developed a three-step diagnostic algorithm, each step including three key aspects of diagnosis, treatment and family care. RESULTS: A sequence of tasks was generated, starting with the process of suspecting FH amongst affected patients admitted for CVD, treating them to LDL-C target, finally culminating in extensive cascade-screening for FH in their family. Conceptually, the pathway is broken down into 3 phases to provide the treating physicians with a time-efficient chain of priorities. CONCLUSIONS: We emphasize the need for optimal collaboration between the various actors, starting with a "vigilant doctor" who actively develops the capability or framework to recognize potential FH patients, continuing with an "FH specialist", and finally involving the patient himself as "FH ambassador" to approach his/her family and facilitate cascade screening and subsequent treatment of relatives.

Lipophilic nalmefene prodrugs to achieve a one-month sustained release.

Nalmefene is an opioid antagonist which as a once-a-day tablet formulation has recently been approved for reducing ethanol intake in alcoholic subjects. In order to address the compliance issue in this patient population, a number of potential nalmefene prodrugs were synthesized with the aim of providing a formulation that could provide plasma drug concentrations in the region of 0.5-1.0ng/mL for a one-month period when dosed intramuscular to dogs or minipigs. In an initial series of studies, three different lipophilic nalmefene derivatives were evaluated: the palmitate (C16), the octadecyl glutarate diester (C18-C5) and the decyl carbamate (CB10). They were administered intramuscularly to dogs in a sesame oil solution at a dose of 1mg-eq. nalmefene/kg. The decyl carbamate was released relatively quickly from the oil depot and its carbamate bond was too stable to be used as a prodrug. The other two derivatives delivered a fairly constant level of 0.2-0.3ng nalmefene/mL plasma for one month and since there was no significant difference between these two, the less complex palmitate monoester was chosen to demonstrate that dog plasma nalmefene concentrations were dose-dependent at 1, 5 and 20mg-eq. nalmefene/kg. In a second set of experiments, the effect of the chain length of the fatty acid monoester promoieties was examined. The increasingly lipophilic octanoate (C8), decanoate (C10) and dodecanoate (C12) derivatives were evaluated in dogs and in minipigs, at a dose of 5mg-eq. nalmefene/kg and plasma nalmefene concentrations were measured over a four-week period. The pharmacokinetic profiles were very similar in both species with Cmax decreasing and Tmax increasing with increasing fatty acid chain length and the target plasma concentrations (0.5-1.0ng/mL over a month-long period) were achieved with the dodecanoate (C12) prodrug. These data therefore demonstrate that sustained plasma nalmefene concentrations can be achieved in both dog and minipig using nalmefene prodrugs and that the pharmacokinetic profile of nalmefene can be tuned by varying the length of the alkyl group.

Where does the interplay between cholesterol absorption and synthesis in the context of statin and/or ezetimibe treatment stand today?

The evidence of the different concepts underlying the interplay between cholesterol absorption and synthesis in the context of statin and ezetimibe treatment were reviewed in the light of the eight major trials where cholesterol absorption and synthesis were analyzed on a large scale using the plasma levels of precursors of cholesterol and plant sterols. The only concept supported in all studies is a significant and consistent increase of cholesterol absorption with statin (correlated with the inhibition of synthesis) and of cholesterol synthesis with ezetimibe, whereas in combination, statin and ezetimibe reduce both cholesterol synthesis and absorption. In contrast, most of the other concepts failed to be clearly proven. At baseline, the inverse relationship between cholesterol absorption and synthesis (only examined in two studies) was found to be weak. On statin treatment, four studies showed that the changes in cholesterol synthesis and absorption, contributed less than 9% to the variability in cholesterol response to statin therapy. It has not been consistently demonstrated that good absorbers/bad synthesizers are bad responders to statin (6 studies) and good responders for ezetimibe (3 studies). There is also no clear inverse correlation between LDL reduction on statin treatment and that on ezetimibe treatment. Finally, the original idea from the first pioneer study of Miettinen et al. that, the higher the baseline intestinal ability to absorb cholesterol, the lower the benefit on the clinical cardiovascular outcomes was not reproduced in the PROSPER study. In conclusion, with the exception of a reverse effect of statin and ezetimibe on absorption and synthesis, most ideas supporting the interplay between cholesterol absorption and synthesis lacked consistency between studies. At present, the use of the plasma levels of plant sterols and cholesterol precursors as markers of cholesterol absorption and synthesis is far too limited to definitively solve these questions.

Effects of raloxifene treatment on the phenotype of blood monocytes.

Raloxifene (RLX), a selective oestrogen receptor modulator, has oestrogen-agonist effects on bone, lipoproteins, and homocysteine and oestrogen-antagonist activity in the breast and uterus, positioning it as a potential drug for long-term prevention of coronary heart disease in postmenopausal women. To further evaluate its influence on cardiovascular risk factors, we studied the effects of 60 mg/day RLX on serum lipid levels, inflammatory (high-sensitivity C-reactive protein, and coagulation (fibrinogen) markers, monocytes, and fibrinolysis in 15 healthy postmenopausal women. Markers were measured at baseline, after 1 month without treatment, and after 3 months of treatment. Fibrinolysis was evaluated using the euglobulin clot lysis time (ECLT) determined with a new semiautomatic optical method. Monocyte phenotype was determined by measurement of the expression of the antigens CD14, HLA-DR, and CD62-L using flow cytometry. After 3 months of RLX treatment, we observed a decrease in total cholesterol (p = 0.002), in low-density lipoprotein cholesterol (p <0.001), and in lipoprotein A (p = 0.01). Fibrinogen (p = 0.002) decreased significantly, and high-sensitivity C-reactive protein had a tendency to decrease, but this did not reach statistical significance (p = 0.06). RLX treatment had no effect on ECLT (p = 0.223) or on white blood cell, lymphocyte, and total monocyte counts (p = 0.313). Monocyte expression of HLA-DR, CD14, and CD62-L was not modified by the treatment. In conclusion, we confirm that RLX has beneficial short-term effects on levels of lipids and inflammatory markers, with no effect on fibrinolysis or monocyte phenotype.

Hemodynamic interaction between a daily dosed phosphodiesterase 5 inhibitor, tadalafil, and the alpha-adrenergic blockers, doxazosin and tamsulosin, in middle-aged healthy male subjects.

The hemodynamic interaction between tadalafil (5 mg/d) and doxazosin or tamsulosin was investigated in 2 randomized, double-blind, crossover phase 1 studies. Healthy men (n = 45) received tadalafil or placebo for 28 days and increasing doses of doxazosin (1, 2, and 4 mg/d) for the last 21 days of treatment. In the second study, participants (n = 39) received tadalafil or placebo for 14 days and tamsulosin (0.4 mg/d) for the last 7 days of treatment. Similar mean maximum postbaseline changes in standing systolic blood pressure were observed in subjects given tadalafil or placebo with 4 mg of doxazosin (-0.5 mm Hg; 95% confidence interval, -4 to 3.1 mm Hg) or with tamsulosin (0.9 mm Hg; 95% confidence interval, -1.4 to 3.2 mm Hg). Standing systolic blood pressure less than 85 mm Hg (blood pressure outlier) occurred in 1 subject treated with 4 mg of doxazosin plus tadalafil but was not reported in subjects treated with tamsulosin and tadalafil. Three subjects experienced moderate hypotensive events lasting less than 2 hours, 2 with syncope (after tadalafil alone or with 4 mg of doxazosin) and 1 without (after 4 mg of doxazosin with placebo). The incidence of hypotension was low in healthy men given increasing doses of doxazosin with chronically dosed tadalafil or placebo. Administration of tadalafil with tamsulosin was well tolerated in healthy men.

Sleep apnoea-hypopnoea index is an independent predictor of high-sensitivity C-reactive protein elevation.

BACKGROUND: Recent reports have identified the apnoea and hypopnoea index (AHI) as an additional independent risk factor for cardiovascular morbidity and mortality. However, several studies reported contradictory results about the association between the serum C-reactive protein (CRP) level and the severity of apnoea. OBJECTIVE: The purpose of this work is to study this association in patients referred to the sleep laboratory for clinical suspicion of sleep apnoea and presenting a wide range of AHI. METHODS: Forty-nine consecutive patients were included in the study. The SigmaStat software package (Jandle Scientific) was used. Multilinear regression analysis was tested using a stepwise backward selection of the explicative variables. The clinical characteristics (diabetes, hypertension, smoking habits, gender) were treated as dichotomous variables, while all other data (age, BMI, lipids, white blood cells) were continuous ones; high-sensitivity (hs)-CRP was the dependent variable. RESULTS: In univariate analysis, AHI was correlated to hs-CRP: R = 0.43, p = 0.002. In multivariate analyses, we found an independent association between the AHI, adjusted for classical cardiovascular risk factors, and hs-CRP. CONCLUSION: In a sample of 49 patients, referred to the sleep laboratory for suspicion of sleep apnoea in routine practice, we observed an independent association between the AHI and hs-CRP.

Fibrinolysis and cardiovascular risk factors: association with fibrinogen, lipids, and monocyte count.

BACKGROUND: Numerous risk factors for cardiovascular disease (CVD) have been determined by clinical epidemiological observations. The missing link could be related to endothelial dysfunction and the resulting hypofibrinolysis. METHODS: In this cross-sectional study, we evaluated 160 subjects (134 in primary prevention) characterized by their clinical cardiovascular risk factors (CVRF), i.e., age, gender, diabetes, hypertension, smoking habit, and history of coronary event or stroke, and by their blood parameters, i.e., C-reactive protein (CRP), fibrinogen, leukocyte count (WBC), monocyte count (MC), total cholesterol, HDL cholesterol (HDL-c), LDL cholesterol (LDL-c), and triglycerides. We assessed their fibrinolytic capacity with a new method, Euglobulin Clot Lysis Time (ECLT). The effects of these clinical and biological parameters were evaluated in multivariate analysis (backward stepwise regression). RESULTS: ECLT was correlated with the Framingham risk score and was significantly influenced by the number of clinical CVRF. MC was confirmed to be an important predictive factor influencing ECLT. In subjects without clinical CVRF (n=46), 67% of the variability of ECLT was explained by a combination of MC, LDL-c, and fibrinogen. CONCLUSION: ECLT is related to the number of epidemiologically defined clinical CVRF and to MC. Because it integrates many risk factors, we suggest that fibrinolytic function could be a biological test useful for physicians in the cardiovascular risk assessment of their patients.

Relationship between CRP and hypofibrinolysis: Is this a possible mechanism to explain the association between CRP and outcome in critically ill patients?

BACKGROUND-: Endothelial cell dysfunction may be implicated in the development of multiple organ failure (MOF) by a number of mechanisms. Among these, altered fibrinolysis promotes fibrin deposition, which may create microvascular alterations during inflammation. Elevated concentrations of C-reactive protein (CRP), especially when these persist over time, are correlated with an increased risk of MOF and death. CRP may inhibit fibrinolysis by inducing plasminogen activator inhibitor-1 (PAI-1) release from human aortic endothelial cells. Moreover, the administration of recombinant CRP in volunteers may increase circulating PAI-1 levels.In this study, we tested the hypothesis that CRP is associated with hypofibrinolysis in intensive care patients with and without sepsis. METHODS-: We studied the association of inflammation and abnormal fibrinolysis in intensive care unit (ICU) patients with (n = 11) and without (n = 21) sepsis. The inflammatory response was assessed by serum concentration of C-reactive protein (CRP), a marker of the acute phase reaction, which increase rapidly in the inflammatory response, and the plasma fibrinolytic capacity was evaluated by the Euglobulin Clot Lysis Time (ECLT), determined by a new semi-automatic method. RESULTS-: ECLT was significantly higher in septic than non-septic patients (1104 +/- 439 vs 665 +/- 275 min; p = 0.002) and was significantly correlated with CRP concentration (R2 = 0.45; p < 0.001). In a multivariate analysis, CRP was the strongest predictor of ECLT (R2 = 0.51, F = 25.6, p < 0.001). In addition, the overall ICU length of stay was significantly correlated with CRP (R2 = 0.264, p = 0.003) and ECLT (R2 = 0.259, p = 0.003). CONCLUSION-: In critically ill patients a significant correlation thus exists between plasma fibrinolytic capacity and serum CRP levels. Our data were obtained in the first 24 hours of ICU admission or of sepsis, thus, the relation between CRP and hypofibrinolysis appeared very quickly. This finding is compatible with a link between inflammation and abnormal fibrinolysis, and may explain the negative prognostic value of CRP in critically ill patients.

Pharmacodynamic and pharmacokinetic interaction between fenofibrate and ezetimibe.

OBJECTIVE: The cholesterol absorption inhibitor, ezetimibe, significantly decreases low-density lipoprotein-cholesterol (LDL-C) levels in patients with primary hypercholesterolemia. The pharmacodynamic, pharmacokinetic, and safety profiles of ezetimibe and fenofibrate were evaluated alone and after co-administration in 32 subjects with primary hypercholesterolemia. RESEARCH DESIGN AND METHODS: This was a randomized, evaluator (single)-blind, placebo-controlled, parallel-group study. Subjects with untreated LDL-C > or = 130 mg/dL (3.37 mmol/L) were randomized to receive one of four oral treatments each morning for 14 days: fenofibrate 200 mg + ezetimibe 10 mg, fenofibrate 200 mg, ezetimibe 10 mg, or placebo. Serum lipids were assessed before drug administration on day 1, day 7, and day 14. Pharmacokinetic parameters were assessed on day 14. MAIN OUTCOME MEASURES: The primary pharmacodynamic parameter was percentage change from baseline in LDL-C concentration following co-administration of ezetimibe and fenofibrate vs either drug alone, or placebo. A secondary outcome was the potential for a pharmacokinetic interaction between ezetimibe and fenofibrate. RESULTS: Ezetimibe and fenofibrate co-administration was well tolerated and produced statistically significant mean percentage reductions from baseline in LDL-C (p < or = 0.05 vs either drug alone or placebo), total cholesterol and triglycerides (p < or = 0.05 vs either fenofibrate or placebo), apolipoprotein C-III (p < or = 0.05 vs placebo), and LDL-III (p < or = 0.05 vs either drug alone or placebo). Ezetimibe did not significantly affect the pharmacokinetics of fenofibrate. Concomitant fenofibrate administration significantly increased the mean C(max) and AUC of total ezetimibe approximately 64% and 48%, respectively. However, based on the established safety profile and flat dose-response of ezetimibe, this effect is not considered to be clinically significant. CONCLUSION: Co-administration of ezetimibe and fenofibrate produced significantly greater reductions in LDL-C than either drug alone and greater reductions in triglycerides than fenofibrate. These effects were accompanied by improvements in the lipid/lipoprotein profile, suggesting that co-administration therapy with ezetimibe and fenofibrate may be an effective therapeutic option for patients with mixed dyslipidemia.

Tolerability, safety, pharmacodynamics, and pharmacokinetics of rasagiline: a potent, selective, and irreversible monoamine oxidase type B inhibitor.

STUDY OBJECTIVE: To investigate the tolerability, safety, pharmacodynamics, and pharmacokinetics of rasagiline after once-daily oral administration of single or repeated doses. DESIGN: A randomized, double-blind, placebo-controlled, three-way, single-dose study and a randomized, double-blind, placebo-controlled, repeated-dose study. SETTING: Clinical research center in France. SUBJECTS: Healthy male volunteers aged 18-40 years (12 in the single-dose study, 24 in the repeated-dose study). INTERVENTION: In the single-dose study, subjects received, in a randomized sequence, single doses of placebo, rasagiline 1 mg, and rasagiline 5 mg; or placebo, rasagiline 2 mg, and rasagiline 10 mg. Six subjects received an additional single dose of rasagiline 20 mg. There was a 2-week washout period between each dose. In the repeated-dose study, subjects were randomized to receive rasagiline 2 mg, 5 mg, or 10 mg, or placebo once/day for 10 days. MEASUREMENTS AND MAIN RESULTS: To assess tolerability and safety, patients underwent physical examinations, vital sign measurements, 12-lead electrocardiograms, clinical laboratory testing, and bleeding time studies. To determine platelet monoamine oxidase type B (MAO-B) activity and rasagiline pharmacokinetics, blood and urine samples were taken. In the single-dose study, rasagiline 1-20 mg was well tolerated. Each dose significantly inhibited platelet MAO-B activity. In the repeated-dose study, all doses of rasagiline were well tolerated; almost full inhibition of platelet MAO-B activity was achieved with each rasagiline dose. CONCLUSION: Rasagiline is well tolerated at doses up to 20 mg once/day and is a potent inhibitor of platelet MAO-B in humans.

Oral bioavailability of gatifloxacin in healthy volunteers under fasting and fed conditions.

The effect of food on the pharmacokinetics of gatifloxacin given as a single oral dose of 400 mg under fasting and fed conditions was determined in 18 healthy male volunteers in an open, two-way, randomised cross-over study. Concomitant food intake did not significantly alter the peak plasma concentrations (C(max)) or the area under the plasma concentration-time curve (AUC) of gatifloxacin. The mean C(max) levels under fasting and fed conditions were 3.5 and 3.2 mg/l, respectively, after the 400-mg single dose of gatifloxacin. The corresponding mean AUC data were 32.8 mg x h/l (fasted) and 30.5 mg x h/l (fed). Moreover, the rate of absorption was not affected by food intake. The median T(max) value was 2 h in both treatment periods. No clinically relevant adverse effects or changes in clinical laboratory test results, ECGs or physical examinations were observed. The results of this study indicate that gatifloxacin given as a single 400-mg oral dose was well tolerated in the presence or absence of food. Concomitant administration of a continental breakfast with a caloric content of 1,050 kcal had no effect on the bioavailability of gatifloxacin. It is suggested that gatifloxacin can be given without regard to meals.

Multiple-dose pharmacokinetics and excretion balance of gatifloxacin, a new fluoroquinolone antibiotic, following oral administration to healthy Caucasian volunteers.

The multiple-dose pharmacokinetics and excretion balance of gatifloxacin were evaluated in 42 healthy Caucasian volunteers. Following multiple oral doses of 400 and 600 mg, the pharmacokinetics of gatifloxacin were similar on days 1 and 15, suggesting no therapeutically relevant time-dependent changes in the pharmacokinetics of gatifloxacin at the doses and duration of dosing studied. Gatifloxacin was rapidly absorbed and a favourable elimination half-life of 7-8 h was evaluated. Saliva concentrations were similar to plasma concentrations. The main route of excretion is the urine. After a single dose of 400 mg of gatifloxacin, the recovery in urine was 83% and 5.2% in faeces. Following multiple doses of 400 or 600 mg, the renal excretion was 80 and 77%, respectively. The drug was well tolerated.