The lipid-lowering effects of lomitapide are unaffected by adjunctive apheresis in patients with homozygous familial hypercholesterolaemia - a post-hoc analysis of a Phase 3, single-arm, open-label trial.

OBJECTIVE: Lomitapide (a microsomal triglyceride transfer protein inhibitor) is an adjunctive treatment for homozygous familial hypercholesterolaemia (HoFH), a rare genetic condition characterised by elevated low-density lipoprotein-cholesterol (LDL-C), and premature, severe, accelerated atherosclerosis. Standard of care for HoFH includes lipid-lowering drugs and lipoprotein apheresis. We conducted a post-hoc analysis using data from a Phase 3 study to assess whether concomitant apheresis affected the lipid-lowering efficacy of lomitapide. METHODS: Existing lipid-lowering therapy, including apheresis, was to remain stable from Week -6 to Week 26. Lomitapide dose was escalated on the basis of individual safety/tolerability from 5 mg to 60 mg a day (maximum). The primary endpoint was mean percent change in LDL-C from baseline to Week 26 (efficacy phase), after which patients remained on lomitapide through Week 78 for safety assessment and further evaluation of efficacy. During this latter period, apheresis could be adjusted. We analysed the impact of apheresis on LDL-C reductions in patients receiving lomitapide. RESULTS: Of the 29 patients that entered the efficacy phase, 18 (62%) were receiving apheresis at baseline. Twenty-three patients (13 receiving apheresis) completed the Week 26 evaluation. Of the six patients who discontinued in the first 26 weeks, five were receiving apheresis. There were no significant differences in percent change from baseline of LDL-C at Week 26 in patients treated (-48%) and not treated (-55%) with apheresis (p = 0.545). Changes in Lp(a) levels were modest and not different between groups (p = 0.436). CONCLUSION: The LDL-C lowering efficacy of lomitapide is unaffected by lipoprotein apheresis.

Treatment of atherosclerosis in the new millennium: is there a role for vitamin E?

Oxidative stress appears to be of fundamental relevance to diseases as diverse as atherosclerosis, cancer, and Alzheimer's disease. Observational data in humans have suggested that antioxidant vitamin intake is associated with reduced cardiovascular disease. Animal studies are largely consistent with the concept that dietary supplementation with antioxidant vitamins reduces the progression of atherosclerosis. However, recent prospective, controlled clinical trials of vitamin E, including the Cardiovascular Disease, Hypertension and Hyperlipidemia, Adult-Onset Diabetes, Obesity, and Stroke (CHAOS) study, the Heart Outcomes Prevention Evaluation (HOPE) trial, Gruppo Italiano per lo Studio della Sopravvivvenza nell'Infarto Miocardico (GISSI)-Prevenzione trial, the Secondary Prevention with Antioxidants of Cardiovascular Disease in End Stage Renal Disease (SPACE) trial, and the Heart Protection Study (HPS) present a confused picture. The various possibilities that have been advanced to explain this discrepancy are discussed in this review. A striking feature of these and other trials of antioxidants is the absence of a biochemical basis for patient inclusion or, indeed, dose selection. Patients with high levels of oxidant stress or depletion of natural antioxidant defense systems may be the most likely to benefit from antioxidant therapy. If this is the case, then reliable, quantitative indices of in vivo oxidant stress such as urinary isoprostane levels should be considered as an inclusion criterion for patient selection. Future trials of antioxidant therapy in cardiovascular disease should then be targeted toward such patients with high levels of oxidant stress or patients with depletion of natural antioxidant defense systems. Furthermore, the dose of antioxidant should be chosen based on a surrogate readout that is a reliable, reproducible, and easily obtainable in vivo measure of oxidant stress. In the interim, although the safety of vitamin E up to doses of 800 IU/day has been determined, the conflicting nature of the results published to date encourages us to avoid making premature recommendations with respect to vitamin E supplementation in the prevention and treatment of cardiovascular disease.

Antioxidant therapy and atherosclerosis: animal and human studies.

Oxidation of LDL cholesterol appears to play a central role in the pathogenesis of atherosclerosis. Animal models of atherosclerosis have elucidated this process and have demonstrated an antioxidant effect of vitamin administration that has been correlated with delayed progression or regression of atherosclerosis. However, clinical trials of antioxidants present a confused picture. Explanations proposed for the discrepancy in results include differences in patient characteristics, the antioxidant content of their diets and dose selection. However, a striking feature of these trials is the absence of a biochemical basis for patient inclusion or dose selection. Reliable, quantitative indices of free radical induced modification of lipids, such as F2-isoprostanes have emerged. Future trials of anti-oxidant therapy in cardiovascular disease should be targeted toward patients with high levels of oxidant stress or patients with depletion of endogenous antioxidants. The dose of anti-oxidant should be chosen based on a surrogate readout, such as F2 isoprostanes, that is a reliable, reproducible and easily obtainable in vivo measure of oxidant stress.

Effects of vitamin E on lipid peroxidation in healthy persons.

CONTEXT: Oxidative stress may play a role in the development or exacerbation of many common diseases. However, results of prospective controlled trials of the effects of antioxidants such as vitamin E are contradictory. OBJECTIVE: To assess the effects of supplemental vitamin E on lipid peroxidation in vivo in healthy adults. DESIGN: Randomized, double-blind, placebo-controlled trial conducted March 1999 to June 2000. SETTING: A general clinical research center in a tertiary referral academic medical center. PARTICIPANTS: Thirty healthy men and women aged 18 to 60 years. INTERVENTIONS: Participants were randomly assigned to receive placebo or alpha-tocopherol dosages of 200, 400, 800, 1200, or 2000 IU/d for 8 weeks (n = 5 in each group), followed by an 8-week washout period. MAIN OUTCOME MEASURES: Three indices of lipid peroxidation, urinary 4-hydroxynonenal (4-HNE) and 2 isoprostanes, iPF(2alpha)-III and iPF(2alpha)-VI, measured by gas chromatography/mass spectrometry and compared among the 6 groups at baseline, 2, 4, 6, and 8 weeks, and 1, 3, and 8 weeks after discontinuation. RESULTS: Circulating vitamin E levels increased in a dose-dependent manner during the study. No significant effect of vitamin E on levels of urinary 4-HNE or either isoprostane was observed. Mean (SEM) baseline vs week 8 levels of iPF(2alpha)-III were 154 (20.1) vs 168 (22.3) pg/mg of creatinine for subjects taking placebo; 165 (19.6) vs 234 (30.1) pg/mg for those taking 200 IU/d of vitamin E; and 195 (26.7) vs 213 (40.6) pg/mg for subjects taking 2000 IU/d. Corresponding iPF(2alpha)-VI levels were 1.43 (0.6) vs 1.62 (0.4) ng/mg of creatinine for subjects taking placebo; 1.64 (0.3) vs 1.24 (0.8) ng/mg for those taking 200 IU/d of vitamin E; and 1.83 (0.3) vs 1.94 (0.9) ng/mg for those taking 2000 IU/d. Baseline vs week 8 levels of 4-HNE were 0.5 (0.04) vs 0.4 (0.05) ng/mg of creatinine for subjects taking placebo; 0.4 (0.06) vs 0.5 (0.02) ng/mg with 200 IU/d of vitamin E; and 0.2 (0.02) vs 0.2 (0.1) ng/mg with 2000 IU/d. CONCLUSIONS: Our results question the rationale for vitamin E supplementation in healthy individuals. Specific quantitative indices of oxidative stress in vivo should be considered as entry criteria and for dose selection in clinical trials of antioxidant drugs and vitamins in human disease.

Safety and effectiveness of Niaspan when added sequentially to a statin for treatment of dyslipidemia.

Niaspan, when added to a stable dose of a statin in 66 subjects, was found to be safe and highly effective in improving lipid parameters. Subgroup analyses demonstrated its effectiveness in lowering low-density lipoprotein cholesterol in persons not at the National Cholesterol and Education Program low-density lipoprotein cholesterol target and in raising high-density lipoprotein cholesterol in persons with levels < 40 mg/dl.

Indices of lipid peroxidation in vivo: strengths and limitations.

Oxidant stress has been widely implicated as a mechanism of disease, yet clinical trials of antioxidants have not included a biochemical basis for dose selection or patient inclusion. Many of the indices traditionally employed to assess lipid peroxidation have relied on measurements performed in ex vivo systems of questionable relevance to events in vivo. Commonly employed in vivo indices of lipid peroxidation are constrained by such issues as the nonspecificity or instability of the target anylate, contamination of the anylate by events ex vivo, and nonspecificity of analytical methodology. More recently, specific methodology based on mass spectrometry has been applied to both 4-hydroxynonenal and a variety of isoprostanes in human biological fluids. Measurement of these compounds in urine reflects lipid peroxidation in vivo and offers a noninvasive approach that may be readily applied to clinical trials.

Specific analysis in plasma and urine of 2,3-dinor-5, 6-dihydro-isoprostane F(2alpha)-III, a metabolite of isoprostane F(2alpha)-III and an oxidation product of gamma-linolenic acid.

F(2)-isoprostanes (iPs) are free radical-catalyzed isomers of prostaglandin F(2alpha). Circulating and urinary iPs have been used as indices of lipid peroxidation in vivo. Utilizing an (18)O-labeled homologous internal standard, we developed a gas chromatography/mass spectrometry assay for the 2,3-dinor-5,6-dihydro (dinor-dihydro) metabolite of iPF(2alpha)-III. Although urinary excretion of iPF(2alpha)-III reflects systemic lipid peroxidation, the metabolite is more abundant (median of 877 (range of 351-1831) versus 174 (range of 56-321) pg/mg of creatinine; p < 0.01) than the parent iP in urine and can be measured in plasma. Metabolite analysis may be preferable in plasma due to the abundance of arachidonic acid as a source of ex vivo lipid peroxidation. Also, iPF(2alpha)-III may be formed in blood samples in a cyclooxygenase-dependent manner by platelets ex vivo. By contrast, the metabolite is not formed by aggregated platelets (0.71 +/- 0.08 versus 0.65 +/- 0.09 pg/ml). Although the metabolite/parent ratio is altered in cirrhosis, urinary dinor-dihydro-iPF(2alpha)-III is elevated and increases further during reperfusion following orthoptic liver transplantation. In addition to its formation as an iPF(2) metabolite, analysis of gamma-linolenic acid autooxidation products and the compound present in freeze-thawed plasma suggests that gamma-linolenic acid may also be an important source of dinor-dihydro-iPF(2alpha)-III.

Alcohol-induced generation of lipid peroxidation products in humans.

To address the hypothesis that elevated blood alcohol increases systemic oxidant stress, we measured urinary excretion of isoprostanes (iPs), free radical-catalyzed products of arachidonic acid. Ten healthy volunteers received acute doses of alcohol (Everclear-R) or placebo under randomized, controlled, double-blind conditions. Urinary iPF2a-III increased in a time- and dosage-dependent manner after dosing with alcohol, with the peak urinary iPF2a-III excretion correlating with the rise in blood alcohol. To determine whether oxidant stress was associated with alcohol-induced liver disease (ALD), we then studied the excretion of iP in individuals with a documented history of alcohol-induced hepatitis or alcohol-induced chronic liver disease (AC). Both urinary iPF2a-III and urinary iPF2a-VI were markedly increased in patients with acute alcoholic hepatitis. In general, urinary iPF2a-III was significantly elevated in cirrhotic patients, relative to controls, but excretion was more pronounced when cirrhosis was induced by alcohol than by hepatitis C. Excretion of iPF2a-VI, as well as 4-hydroxynonenal and the iPF2a-III metabolite, 2,3-dinor-5, 6-dihydro-iPF2a-III, was also increased in AC. Vitamin C, but not aspirin, reduced urinary iPs in AC. Thus, vasoactive iPs, which serve as indices of oxidant stress, are elevated in the urine in both acute and chronic ALD. Increased generation of iPs by alcohol in healthy volunteers is consistent with the hypothesis that oxidant stress precedes and contributes to the evolution of ALD.

A randomized, placebo-controlled, crossover study of E5510 and aspirin in healthy volunteers.

Platelet inhibition significantly reduces the risk of cardiovascular mortality and morbidity. However, current antiplatelet therapies have limitations, and more efficacious agents are needed. E5510 is a novel compound that has multiple platelet inhibitory effects in in vitro studies. We compared the in vivo, pharmacodynamic effects of maximal antiplatelet doses of E5510 (20 mg) with 300 mg aspirin in a placebo-controlled, triple crossover trial in nine healthy volunteers. Collagen-induced platelet aggregation and serum thromboxane B2 (TxB2) were similarly inhibited by both compounds in the first 12 h but showed recovery at 24 h in the E5510 group only (p < 0.05). Thrombin and U46619-induced platelet aggregation, as well as basal and prostaglandin E2 (PGE2)-stimulated platelet cyclic adenosine monophosphate (cAMP) levels were unchanged after ingestion of either agent. E5510 and aspirin reduced systemic thromboxane formation without affecting prostacyclin biosynthesis. Neither E5510 nor aspirin inhibited the excretion of 8-epi PGF2alpha and 5,6-DHET, two indices of cyclooxygenase-independent arachidonate metabolism. In conclusion, (a) E55 10 in vivo most likely induces a reversible inhibition of cyclooxygenase, without affecting thromboxane synthetase, phosphodiesterase, thrombin, or thromboxane receptor-mediated signaling; (b) single doses of aspirin or E5510 affect thromboxane/prostacyclin profiles favorably, supporting their use in acute coronary syndromes. This study outlines a comprehensive and minimally invasive approach for the assessment of the in vivo mechanism of action of novel antiplatelet agents.

Antiplatelet drugs.

The evidence in support of the safety and efficacy of aspirin in the secondary prevention of platelet dependent vascular occlusion is compelling. The utility of this drug has stalled the development of potential competitors, such as thromboxane antagonists. The emergence of glycoprotein IIb/IIIa antagonists as the most promising competitors for aspirin has focused attention on the possibility of delivering these drugs at an effective dose safely.

Are CT infarcts a separate risk factor in patients with transient cerebral ischaemic episodes?

CT cerebral infarcts have been reported in a number of studies of patients with transient ischaemic episodes. The hypothesis that these asignomatic infarcts, i.e. without associated clinical neurological deficit reflect the ability of the brain to limit the extent of neuronal damage through its collateral circulation was tested in 50 patients undergoing both CT scanning and cerebral angiography. Out of 50 patients there were 15 patients with a total of 17 infarcts on CT scan. Fourteen of 50 patients had evidence of diminished collateral reserve capacity on cerebral angiography. Ten of these 14 patients (71%) had CT evidence of infarction, in contrast to an incidence of five out of 36 patients (14%) without evidence of diminished collateral reserve. These results indicate that CT infarcts and collateral cerebral circulation must be evaluated as prognostic factors in patients with T.I.A.s.

Heparin kinetics in vascular surgery.

Currently there is little information available about the efficacy of heparin during vascular surgery or of the effects of surgical trauma on heparin kinetics. This study was undertaken to evaluate the kinetics of heparin therapy during vascular surgery. Nine patients undergoing major vascular surgery (one carotid, one common iliac and seven aortic operations) were studied both preoperatively and intra-operatively, each patient acting as his own control. Following determination of control activated partial thromboplastin time (APTT) and plasma heparin levels, heparin (100 u/kg body weight) was administered intravenously. Heparin dosage ranged form 4500 units to 8600 units with a mean dose of 6500 units. Plasma heparin and APTT levels were then measured at 10 minute intervals for 1 hour and 20 minute intervals for a second hour. The mean pre-operative and intra-operative APTT levels at ten minutes attained maximal values of 6.6 +/- 3.7 and 8.8 +/- 1.7 times the control respectively. At the end of 2 hours the mean APTT remained greater than 2.5 times the control in both groups. Mean plasma heparin level was 0.83 +/- 0.04 units at 10 minutes and was almost identical in both groups. Heparin level was not a reliable indicator of anticoagulant effect as most patients achieved the same levels but had markedly differing APTT results. The results of this study suggest that excessive doses of heparin may be used in vascular surgery and that surgical trauma does not significantly alter sensitivity to heparin.(ABSTRACT TRUNCATED AT 250 WORDS)

Labetalol, beta blockers, and acute deterioration of chronic airway obstruction.

The effects on lung function of labetalol (a combined alpha and beta adrenergic receptor blocker) and three beta adrenergic receptor blockers (propranolol, atenolol, metoprolol) have been assessed in patients with chronic airflow obstruction using a double-blind trial. With the dosages used, all drugs produced an equivalent fall of blood pressure. Propranolol was the only drug that significantly increased airways obstruction (FEV1, specific airways resistance). Following salbutamol, labetalol was associated with a significantly greater improvement of airflow than either propranolol or metoprolol. On these acute studies, the order of preference for beta blocking drugs in management of hypertension in patients with obstructive airways disease, would be labetalol, (atenolol) or (metoprolol) and then propranolol.

Hydrothorax with peritoneal dialysis: radionuclide detection of a pleuro-peritoneal connection.

Unilateral hydrothorax occurring during peritoneal dialysis is well described and has been presumed to be secondary to a pleuroperitoneal communication. Diagnosis of these communications usually requires invasive procedures. A non-invasive method of confirmation of abnormal pleuro-peritoneal communication using radionuclide scanning is outlined. The occurrence of this complication has usually meant cessation of this type of dialysis. However, this patient illustrates that continuation of peritoneal dialysis is possible.

Unusual calcium oxalate crystals in ethylene glycol poisoning.

A patient poisoned with ethylene glycol exhibited the symptoms of (1) hysteria, (2) metabolic acidosis with both a large anion gap and osmolal gap, and (3) crystalluria. However, the shape of the urinary crystals was prismatic and resembled hippurate rather than the expected dipyramidal calcium oxalate dihydrate. X-ray crystallography positively identified them as calcium oxalate monohydrate.