Effects of antiepileptic drugs on lipids, homocysteine, and C-reactive protein.

OBJECTIVE: The widely prescribed anticonvulsants phenytoin and carbamazepine are potent inducers of cytochrome P450 enzymes, which are involved in cholesterol synthesis. We sought to determine whether these drugs have an effect on cholesterol and other serological markers of vascular risk. METHODS: We recruited 34 epilepsy patients taking carbamazepine or phenytoin in monotherapy whose physicians had elected to change treatment to one of the noninducing anticonvulsants lamotrigine or levetiracetam. Fasting blood samples were obtained both before and 6 weeks after the switch to measure serum lipid fractions, lipoprotein(a), C-reactive protein, and homocysteine. A comparator group of 16 healthy subjects underwent the same serial studies. RESULTS: In the epilepsy patients, switch from either phenytoin or carbamazepine produced significant declines in total cholesterol (-24.8 mg/dl), atherogenic (non-high-density lipoprotein) cholesterol (-19.9 mg/dl), triglycerides (-47.1mg/dl) (all p < 0.0001), and C-reactive protein (-31.4%; p = 0.027). Patients who stopped taking carbamazepine also had a 31.2% decline in lipoprotein(a) level (p = 0.0004), whereas those taken off phenytoin had a decrease in homocysteine level (-1.7 micromol/L; p = 0.005). All of these changes were significant when compared with those seen in healthy subjects (p < 0.05). Results were similar whether patients were switched to lamotrigine or levetiracetam. INTERPRETATION: Switching epilepsy patients from the enzyme-inducers carbamazepine or phenytoin to the noninducing drugs levetiracetam or lamotrigine produces rapid and clinically significant amelioration in several serological markers of vascular risk. These findings suggest that phenytoin and carbamazepine may substantially increase the risk for cardiovascular and cerebrovascular disease.

Effect of Xuezhikang, an extract from red yeast Chinese rice, on coronary events in a Chinese population with previous myocardial infarction.

Results of well-controlled prospective clinical trials showed the efficacy of lipid-lowering therapies in the reduction of cardiovascular (CV) events in western populations, but they were not reported with a Chinese population. This multicenter study was conducted to determine the effects of Xuezhikang (XZK), a partially purified extract of red yeast rice, on lipoprotein and CV end points in Chinese patients who experienced a previous myocardial infarction. Nearly 5,000 of these patients with average low-density lipoprotein cholesterol levels at baseline were randomly assigned either to placebo or to XZK daily for an average of 4.5 years. The primary end point was a major coronary event that included nonfatal myocardial infarction and death from coronary heart disease. Frequencies of the primary end point were 10.4% in the placebo group and 5.7% in the XZK-treated group, with absolute and relative decreases of 4.7% and 45%, respectively. Treatment with XZK also significantly decreased CV and total mortality by 30% and 33%, the need for coronary revascularization by 1/3, and lowered total and low-density lipoprotein cholesterol and triglycerides, but raised high-density lipoprotein cholesterol levels. In conclusion, long-term therapy with XZK significantly decreased the recurrence of coronary events and the occurrence of new CV events and deaths, improved lipoprotein regulation, and was safe and well tolerated.

Scintigraphic imaging of body neuroendocrine tumors.

Radionuclide imaging is often used in the diagnosis and work-up of a wide range of neoplasms, on the basis of the biologic behavior of the tumor. Neuroendocrine tumors are a subgroup of neoplasms that are generally small and slow growing, and consequently their identification with conventional anatomic imaging can be difficult. Depending on the physiologic properties of the tumor, functional images obtained with radionuclides are often complementary to anatomic images, not only in the localization of the tumor and its metastases, but also in the assessment of prognosis and response to therapy. Familiarity with the choice of the appropriate radiopharmaceutical, proper imaging protocols, and the wide range of imaging patterns will enable the radiologist to guide the clinician in case management.

Changing concepts in the management of differentiated thyroid cancer.

The management of patients with differentiated thyroid cancer has changed significantly over the last few decades. Mortality has decreased as the result of earlier detection, refined surgical approaches, subsequent radioiodine ablation, and the development of more sensitive methods for detecting and monitoring disease recurrence. The latter has been facilitated by serum thyroglobulin measurements, the use of recombinant human thyrotropin, and the use of 18F-deoxyglucose/positron emission tomography in selected instances where radioiodine imaging fails to locate known or suspected recurrent or metastatic disease.

The role of nuclear medicine in the evaluation of complex regional pain syndrome type I.

Chronic pain resulting from complex regional pain syndrome type I (CRPS I), formerly referred to as the reflex sympathetic dystrophy syndrome (RSDS), is a diagnostic challenge to the clinician. It involves multiple organ systems, namely peripheral as well as central nervous, vascular, soft tissue, and skeletal. It usually develops as a consequence of trauma, without nerve injury. Signs and symptoms vary depending on the time since the initiating event, and there is no confirmatory histopathologic diagnosis. This article summarizes the current consensus on the classification, pathophysiology, and diagnostic approaches, emphasizing the role of scintigraphy in the management of this multisystem disorder.

Beneficial effects of rosuvastatin alone and in combination with extended-release niacin in patients with a combined hyperlipidemia and low high-density lipoprotein cholesterol levels.

Patients with combined hyperlipidemia and low high-density lipoprotein (HDL) cholesterol levels may benefit from combination therapy with a statin and niacin; therefore, we assessed the efficacy and safety of rosuvastatin and extended-release (ER) niacin alone and in combination in 270 patients with this atherogenic dyslipidemia. Men and women > or =18 years with fasting total cholesterol levels > or =200 mg/dl, triglycerides 200 to 800 mg/dl, apolipoprotein B > or cf=110 mg/dl, and HDL cholesterol <45 mg/dl were randomized to 1 of 4 treatments in this 24-week, open-label, multicenter trial: rosuvastatin 10 to 40 mg; ER niacin 0.5 to 2 g; rosuvastatin 40 mg/ER niacin 0.5 to 1 g; or rosuvastatin 10 mg/ER niacin 0.5 to 2 g. Percent changes from baseline in low-density lipoprotein (LDL) cholesterol, non-HDL cholesterol, and other lipid measurements at week 24 were determined by analysis of variance, with statistical testing performed separately between the rosuvastatin monotherapy group and each remaining treatment group. Daily doses of rosuvastatin 40 mg reduced LDL and non-HDL cholesterol significantly more than either ER niacin 2 g or rosuvastatin 10 mg/ER niacin 2 g (-48% vs -0.1% and -36% for LDL cholesterol and -49% vs -11% and -38% for non-HDL cholesterol, respectively; p <0.01 for all comparisons); no additional reduction in LDL or non-HDL cholesterol was observed with the combination of rosuvastatin 40 mg/ER niacin 1.0 g (-42% and -47%; p = NS). Triglyceride reductions ranged from -21% (ER niacin monotherapy) to -39% (rosuvastatin 40 mg/ER niacin 1 g), but no observed differences were statistically significant. Compared with rosuvastatin alone, rosuvastatin 10 mg/ER niacin 2 g produced significantly greater increases in HDL cholesterol (11% vs 24%, p <0.001) and apolipoprotein A-I (5% vs 11%, p <0.017). Similar increases in HDL cholesterol and apolipoprotein A-I were noted between the monotherapy groups. Over 24 weeks, rosuvastatin alone was better tolerated than either ER niacin alone or the combinations of rosuvastatin and ER niacin.

Effects of extended-release niacin on lipoprotein subclass distribution.

The efficacy of extended-release niacin (niacin ER) on lipoprotein subclasses was evaluated in patients with primary hypercholesterolemia using a proton nuclear magnetic resonance method. Paired plasma samples collected at baseline and after 12 weeks' treatment with niacin ER 1,000 (n = 21) or 2,000 (n = 20) mg/day or placebo (n = 19) were available for 60 eligible patients from a previous multicenter, randomized, controlled trial. Niacin ER increased high-density lipoprotein (HDL) cholesterol and decreased low-density lipoprotein (LDL) cholesterol and very low-density lipoprotein triglycerides in a dose-dependent manner relative to placebo. Niacin ER increased large HDL particles (H5 and H4, corresponding to the HDL(2ab) fraction) without having a net effect on small HDL particles (H3, H2, and H1, corresponding to the HDL(3abc) fraction). It also decreased smaller, denser LDL particles (L1 and L2) and increased the larger, more buoyant L3 subclass. The inhibitory effect of niacin ER on very low-density lipoprotein was evident on the larger particles (V6, V5, V4, and V3 subclasses) rather than the smaller ones (V2 and V1). The results show that niacin ER produces a beneficial effect on lipoprotein subclasses, specifically decreasing the more atherogenic small, dense LDL particles and enhancing the cardioprotective large HDL particles.

Pharmacokinetics and Pharmacodynamics of Recombinant Human Insulin-Like Growth Factor.

Recombinant human insulin-like growth factor (rhIGF-I) was evaluated in 18 healthy males to determine its effects on serum glucose, its relationship of total IGF levels to serum glucose response and dose proportionality when administered intravenously (IV) and subcutaneously (SQ). One group of six subjects received 60, 120, and 180 &mgr;g kg(minus sign1) IV over 8 h, 1 week apart, and three groups of four subjects received 60, 120, and 180 &mgr;g kg(minus sign1) IV over 8 h, and then 1 week later received 60, 120, and 90 &mgr;g kg(minus sign1) SQ of rhIGF-I, respectively. During each dosing period, placebo and then rhIGF-I was administered on two consecutive days. Intravenous and subcutaneous does of rhIGF-I demonstrated significant decreases in glucose levels as compared to placebo that did not correspond to peak total IGF levels. Sequential repeat administration of IV infusions of rhIGF-I in a single group of subjects demonstrated significant dose-dependent increases, whereas single administration of the doses in three groups of subjects failed to demonstrate dose dependency for either the IV or subcutaneous routes of administration. These findings suggest that saturation of the binding proteins and sites occurred at the lowest dose (60 &mgr;g kg(minus sign1)) evaluated.

Scintigraphic manifestations of thyrotoxicosis.

The term thyrotoxicosis refers to the clinical syndrome of increased systemic metabolism that results when the serum concentrations of free thyroxine, free triiodothyronine, or both are elevated. The term hyperthyroidism refers to overactivity of the thyroid gland with a resultant increase in thyroid hormone synthesis and release into the systemic circulation. These terms are not interchangeable, since thyrotoxicosis can develop in thyroid conditions that are not associated with increased thyroid function, such as thyroiditis, or in so-called factitious hyperthyroidism. The clinical signs and symptoms of thyrotoxicosis are virtually identical regardless of the cause. However, in a given patient, every attempt should be made to determine the exact cause of the thyrotoxicosis, as this in turn determines the prognosis and treatment. Since thyroid scintigraphy demonstrates the functional state of the thyroid gland, it should be used, in conjunction with determination of radioactive iodine uptake, as the imaging modality of choice for diagnosis of thyrotoxicosis. Although the scintigraphic features of several of the thyroid disorders that cause thyrotoxicosis may overlap, their recognition helps narrow the differential diagnosis, thereby guiding the referring physician in the work-up and management of this disorder.

The effects of niacin on lipoprotein subclass distribution.

Dyslipidemia is a heterogeneous metabolic condition; high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very-low-density lipoprotein represent families of lipoprotein particles that differ in size and composition and vary in atherogenicity. Lipoprotein subclasses containing apolipoprotein B promote atherosclerosis, of which the most atherogenic appear to be the small, dense LDL and large very-low-density lipoprotein subclasses, while the large HDL2 subclass, which transports esterified cholesterol from the periphery to the liver, is considered the more cardioprotective. Niacin has long been known to improve concentrations of all major lipids and lipoproteins, but it also has consistently favorable effects on subclass distribution. A MEDLINE search was conducted for clinical studies reporting the effects of niacin on lipoprotein subclasses. The niacin-associated elevations in HDL cholesterol likely stem from differential drug effects on subclasses, producing favorable changes in levels of HDL2 and apolipoprotein A-I. Niacin has more moderate LDL cholesterol-lowering efficacy, but this change is associated with an increase in LDL particle size and a shift from small LDL to the less atherogenic, large LDL subclasses. In addition, it also tends to decrease concentrations of the larger very-low-density lipoprotein subclasses. Niacin confers diverse benefits with respect to both the quantity and quality of lipid and lipoprotein particles.

Rosuvastatin alone or with extended-release niacin: a new therapeutic option for patients with combined hyperlipidemia.

Combination therapy with a statin and niacin may provide optimal therapy for patients with combined hyperlipidemia and low levels of high-density lipoprotein (HDL) cholesterol. The authors assessed the efficacy and safety of rosuvastatin monotherapy, extended-release (ER) niacin monotherapy, or rosuvastatin and ER niacin combined therapy in patients with atherogenic dyslipidemia. In a 24-week, open-label, multicenter trial, men and women aged > or =18 years with fasting levels of total cholesterol > or =200 mg/dL, HDL cholesterol > or =45 mg/dL, triglycerides 200-800 mg/dL, and apolipoprotein B > or =110 mg/dL were randomly assigned to one of four treatment groups: rosuvastatin 10-40 mg, ER niacin 0.5-2 g, rosuvastatin 40 mg plus ER niacin 0.5-1 g, or rosuvastatin 10 mg plus ER niacin 0.5-2 g. Daily doses of rosuvastatin 40 mg monotherapy reduced low-density lipoprotein (LDL) cholesterol and non-HDL cholesterol levels significantly more than did either ER niacin 2 g monotherapy or rosuvastatin 10 mg combined with ER niacin 2 g. Addition of ER niacin 1 g to rosuvastatin 40 mg did not further reduce total or non-HDL cholesterol. Triglyceride reductions were similar among the four treatment groups. ER niacin mono- and combined therapy produced significantly greater rises in HDL cholesterol and apolipoprotein A-1 than did rosuvastatin monotherapy. Rosuvastatin monotherapy was better tolerated than ER niacin taken either alone or with rosuvastatin. In this study, rosuvastatin very effectively improved the three major lipoprotein-lipid abnormalities of combined hyperlipidemia.

Hypercholesterolemia. The NCEP Adult Treatment Panel III Guidelines.

Coronary heart disease (CHD) is a significant cause of morbidity and mortality in older patients. Therefore, its treatment and prevention is vital to improving the length and quality of life for the geriatric population at large. Clinical trial data have demonstrated that patients age 65 and older derive the same benefit from blood cholesterol reduction as younger adults. As a result, the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) recommends appropriate therapeutic lifestyle changes and drug therapy for older individuals with established CHD or for those at high risk for CHD. Drug therapy in this population, while safe, requires careful monitoring and dose adjustment due to potentially altered drug metabolism and concomitant medications. These factors lead to use of lower starting doses of lipid-lowering medications in older patients. Prudent individualized evaluation and customized therapy provide optimal cardiovascular outcomes.

Effects of walnut consumption as part of a low-fat, low-cholesterol diet on serum cardiovascular risk factors.

Serum components, such as lipoproteins, coagulation factors (factor VII, tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), fibrinogen), and homocysteine have been associated with cardiovascular disease. Dietary intervention with a low-fat, low-cholesterol diet has favorably influenced cardiovascular disease and certain food, specifically the consumption of nuts, has been associated with reduced cardiovascular risks. The effects of walnuts, as part of a low-fat, low-cholesterol diet, on serum cardiovascular risk factors were determined. Sixty-seven (67) outpatients with borderline high total cholesterol following a low-fat, low-cholesterol diet for six weeks before being randomly assigned to continue the diet or have 64 grams/day of walnuts in conjunction with the diet. After six weeks, the patients' diets were switched. Therefore, all patients consumed 64 grams/day of walnuts for six weeks during part of the trial as part of a low-fat, low cholesterol diet. Serum lipids demonstrated a significant reduction in triacyglycerols and favorable trend with decreases in total cholesterol, low-density lipoprotein (LDL) cholesterol, and a slight increase in high-density lipoprotein (HDL) cholesterol. No statistical effects on homocysteine or the coagulation factors were observed. However, there was a slight favorable trend for tPA and PAI-1. This study demonstrated that walnuts, when consumed as part of a low fat, low-cholesterol diet, have a beneficial effect on serum cardiovascular risk factors. However, these changes may not explain all of the beneficial effects that walnut consumption has on cardiovascular disease.

Effects of Xuezhikang in patients with dyslipidemia: a multicenter, randomized, placebo-controlled study.

BACKGROUND: Xuezhikang (XZK) is an extract of fermented red yeast rice that has lipid-lowering properties. OBJECTIVE: To evaluate the effects of XZK on lipids in subjects with dyslipidemia but no coronary heart disease. METHODS: A total of 116 adults with baseline non-high-density lipoprotein cholesterol (non-HDL-C) levels of approximately 208 mg/dL and low-density lipoprotein cholesterol (LDL-C) levels of approximately 175 mg/dL were randomized to either placebo or XZK 1200 or 2400 mg daily and treated for 12 weeks. RESULTS: A majority of the patients were white (53.4%) or Asian (37.1%). Daily XZK 1200 mg and 2400 mg for 4 to 12 weeks resulted in statistically significant (P < .001) and clinically meaningful decreases in non-HDL-C (∼24% reduction) and LDL-C (∼27% reduction) compared with placebo. XZK treatment at either dose enabled approximately 50% of subjects to reduce their LDL-C levels by ≥ 30%. Doubling the XZK daily dose from 1200 to 2400 mg at treatment week 8 caused an additional 4.6% reduction in LDL-C. Significant benefits were also observed across secondary efficacy variables, including total cholesterol (TC), apolipoprotein B (Apo B), triglycerides, HDL-C, the TC/HDL-C ratio, and the Apo B/Apo A-I ratio, at treatment week 8 or 12. XZK was safe and well tolerated. Safety and tolerability profiles were similar across treatment groups. Most adverse events were gastrointestinal. No subject experienced myopathy or markedly elevated liver transaminases or creatine kinase. CONCLUSION: Xuezhikang significantly reduced non-HDL-C and LDL-C, and was well tolerated. Further, longer-term studies in more diverse patient populations are needed to corroborate these findings.

Conversion from enzyme-inducing antiepileptic drugs to topiramate: effects on lipids and C-reactive protein.

PURPOSE: We previously demonstrated that converting patients from the enzyme-inducers phenytoin or carbamazepine to the non-inducers levetiracetam or lamotrigine reduces serum lipids and C-reactive protein (CRP). We sought to determine if the same changes would occur when patients were switched to topiramate, which has shown some evidence of enzyme induction at high doses. We also examined the effects of drug switch on low-density lipoprotein (LDL) particle concentration. METHODS: We converted 13 patients from phenytoin or carbamazepine monotherapy to topiramate monotherapy (most at doses of 100-150 mg/day). Fasting lipids, including LDL particle concentration, and CRP were obtained before and ≥6 weeks after the switch. A group of normal subjects had the same serial serologic measurements to serve as controls. RESULTS: Conversion from inducers to topiramate resulted in a -35 mg/dL decline in total cholesterol (p=0.033), with significant decreases in all cholesterol fractions, triglycerides, and LDL particle concentration (p≤0.03 for all), as well as a decrease of over 50% in serum CRP (p<0.001). Alterations in cholesterol fractions and CRP remained significant when compared to those seen in normal controls. CONCLUSIONS: Changes seen when inducer-treated patients are converted to TPM closely mimic those seen when inducer-treated patients are converted to lamotrigine or levetiracetam. These findings provide evidence that CYP450 induction elevates CRP and serum lipids, including LDL particles, and that these effects are reversible upon deinduction. Low-dose TPM appears not to induce the enzymes involved in cholesterol synthesis.

Subclinical hyperthyroidism: current concepts and scintigraphic imaging.

Subclinical hyperthyroidism is defined as normal serum free thyroxine and a free triiodothyronine level, with a thyroid-stimulating hormone level suppressed below the normal range and is usually undetectable. Although patients with this diagnosis have no or few signs and symptoms of overt thyrotoxicosis, there is sufficient evidence that it is associated with a relatively higher risk of supraventricular arrhythmias as well as the acceleration or the development of osteoporosis. Consequently, the approach to the patient with subclinical hyperthyroidism is controversial, that is, therapeutic intervention versus watchful waiting. Regardless, it is imperative for the referring physician to identify the causative thyroid disorder. This is optimally accomplished by a functional study, namely scintigraphy. Recognition of the scan findings of the various causes of subclinical hyperthyroidism enables the imaging specialist to help in diagnosing the underlying condition causing thyroid-stimulating hormone suppression thereby facilitating the workup and management of this thyroid disorder.

Effects of niacin and Niaspan on HDL lipoprotein cellular SR-BI-mediated cholesterol efflux.

BACKGROUND: Niacin, the lipid-regulating agent with the longest therapeutic experience, has been demonstrated to both raise high-density lipoprotein cholesterol (HDL-C) levels and to diminish the risk of atherosclerosis and its vascular complications. OBJECTIVE: The present study was carried out to explore niacin's effect on scavenger receptor class B type I (SR-BI)-mediated cholesterol efflux, a component of reverse cholesterol transport, using an in vitro model system. METHODS: Thirty frozen samples from a large randomized, multicenter trial comparing crystalline niacin, extended-release niacin (Niaspan), and placebo were analyzed for SR-BI efflux. RESULTS: Both the extended-release and crystalline niacin demonstrated significant increases in HDL-C (approximately 50%) over baseline values compared to the placebo group (14%). This was associated with a significant increase in SR-BI efflux of 2.7% and 3.4% for extended-release niacin and niacin, respectively, compared to placebo (0.4%). Although, there was no relationship between HDL-C and SR-BI efflux at baseline or at the end of treatment, there was a linear relation between the changes in HDL-C and SR-BI efflux (r = 0.58, P < 0.002). CONCLUSION: This study suggests that niacin has a beneficial effect on SR-BI efflux that is related to the change in level of HDL-C.