Interstitial nephritis and nephrogenic diabetes insipidus in a patient treated with pemetrexed.

We present a case of interstitial nephritis and nephrogenic diabetes insipidus (NDI) in a patient treated with pemetrexed (500 mg/m(2)) for non-small cell lung cancer. Renal impairment and diabetes insipidus appeared after the first treatment cycle while he totally received four cycles of chemotherapy. There was not any significant myelosuppression and the patient was on regular supplementation with folic acid and vitamin B(12). He was not on any other medications and he did not receive any nephrotoxic agents. Kidney biopsy showed acute tubular necrosis together with interstitial inflammatory infiltrate of mononuclear cells and interstitial fibrosis occupying 25% of the cortex. There was not any improvement of renal function after a 2-week trial of oral prednisone. In the present case report, we review the literature for pemetrexed-induced renal toxicity and the possible mechanisms involved.

Effectiveness and tolerability of adding ezetimibe to niacin-based regimens for treatment of primary hyperlipidemia.

OBJECTIVE: To determine the effectiveness and tolerability of adding ezetimibe, 10 mg daily, to niacin-based regimens for dyslipidemia. METHODS: We conducted a retrospective review of medical records of 53 patients in 2 lipid clinics who received ezetimibe as add-on therapy to stable doses of niacin and other lipid medications. Mean percentage changes of lipoprotein cholesterol and triglyceride levels were determined. Safety and tolerability measures included adverse events, serum hepatic transaminases, and hemoglobin A1c (in patients with diabetes). RESULTS: Most study subjects (81%) had established atherosclerotic disease. The niacin formulation was extended-release in 31 patients (58%), immediate-release in 17 (32%), and slow-release in 5 (9%). Most patients (75%) were also taking a statin. Add-on ezetimibe therapy yielded mean reductions of 18% for total cholesterol (P<0.001), 25% for low-density lipoprotein (LDL) cholesterol (P<0.001), and 17% for triglycerides (P<0.001). High-density lipoprotein (HDL) cholesterol did not change significantly (+2%). Only 7 patients (13%) met Adult Treatment Panel III (ATP III) LDL cholesterol goals before the addition of ezetimibe, but 24 (45%; P<0.001 compared with baseline) attained these goals after addition of ezetimibe to the therapeutic regimen. Ezetimibe effectiveness did not correlate with the baseline dose of niacin or the dose/efficacy of the statin used. The addition of ezetimibe to niacin-based therapy for dyslipidemia was well tolerated. No patient had clinically significant elevations in hepatic enzyme or hemoglobin A1c levels or discontinued the ezetimibe therapy permanently. CONCLUSION: In our study, the addition of ezetimibe to niacin-based regimens lowered the LDL cholesterol level by 25% and did not change the level of HDL cholesterol. This combination can be useful in multidrug regimens for high-risk patients with dyslipidemia who are not achieving ATP III treatment goals.

Eotaxin and obesity.

CONTEXT: Asthma and obesity incidence is increasing worldwide, and asthma is often more severe in the obese. Eotaxin, a CC chemokine, is important in extrinsic asthma, an inflammatory disorder. OBJECTIVE: Our objective was to examine the relation between eotaxin and obesity. DESIGN: We conducted a comparison study of eotaxin in mice fed high-fat vs. standard chow diet for 26 wk, in obese vs. lean humans, in obese humans before and after 4-6 wk of weight loss, and in sc vs. visceral adipose tissue from patients undergoing bariatric surgery. SETTING: Our clinical study occurred in an outpatient weight loss program. PATIENTS: Patients were obese adults with metabolic syndrome (n = 40) and nine morbidly obese bariatric surgery patients. INTERVENTION: Intervention was a very-low-calorie diet. MAIN OUTCOME MEASURES: We assessed circulating eotaxin and eotaxin mRNA levels in adipose tissue. RESULTS: Serum eotaxin levels were significantly higher in obese mice, and adipose mRNA levels correlated positively with serum eotaxin levels. Adipose tissue explants from obese mice showed increased secretion of eotaxin compared with explants from lean mice. In obese patients, plasma eotaxin levels were significantly higher than in lean controls and significantly reduced after weight loss, and eotaxin mRNA levels were 4.7-fold higher in visceral than sc adipose tissue. CONCLUSIONS: Circulating eotaxin and eotaxin mRNA levels in visceral adipose tissue were increased in obesity in mice and humans. Adipose tissue explants secrete eotaxin, and the stromal/vascular component of adipose tissue seems to be the predominant source of eotaxin. Diet-induced weight loss in humans led to reduction in plasma eotaxin levels, demonstrating that clinical interventions that target obesity can modulate systemic eotaxin levels.

Pitfalls of the WHIs: Women's Health Initiative.

Recently, the use of hormone replacement therapy (HRT) at menopause has become a matter of debate. Its utility has been questioned after the publication of the results of the Women's Health Initiative (WHI) studies. This trial was divided in two arms of which the first examined the use of combined HRT (continuous estrogens plus progestins) and the second the use of estrogens alone in menopausal women. The first arm was terminated prematurely at 5.2 years because the number of cases of coronary heart disease (CHD), strokes, venous thromboembolic disease, and breast cancer were more in women receiving HRT than in women receiving placebo, if the nominal confidence intervals (CIs) were taken into account. However, in the same study the authors made clear that the adjusted CIs should be taken into account instead of the nominal ones. These latter ones caused the ending of the trial. Moreover, WHI was criticized for its conclusions as far as cardiovascular disease is concerned because of serious defects regarding design of the trial. If the adjusted CIs were taken into account then the increase in adverse events was significant only for deep vein thrombosis. The second arm demonstrated that the use of estrogens was not correlated to an increase of neither breast cancer incidence nor cardiovascular disease. A closer look at the results of the WHI trial reveals that the use of HRT for 5 years should not be considered deleterious for the appearance of breast cancer, cardiovascular diseases, strokes, and pulmonary embolisms. We suggest that HRT should be given early in menopause. The regimen should be individualized for each patient. More intense follow-up should be offered to women with a positive family history of breast cancer, diagnosed coronary disease, and to women with a predisposition to deep venous thrombosis.

Hormone replacement therapy in breast cancer survivors.

It is well known that women with breast cancer who undergo therapies beyond the surgical intervention (adjuvant chemotherapy, hormone therapy, or both) often suffer from the lack of estrogen, manifesting as climacteric symptoms in either treated premenopausal or postmenopausal women. Although HRT (hormone replacement therapy) is traditionally viewed as a contraindication in women with a history of breast cancer, more women are willing to receive HRT for symptom relief. No observational or retrospective study in breast cancer survivors (whether in pre- or postmenopausal women) has shown an increased risk of tumor recurrence or increased mortality associated with HRT use. Nevertheless, because these studies are retrospective and different in terms of lymph node status, estrogen receptor (ER) status, and type of HRT used, firm conclusions on potential HRT use cannot be safely drawn. The few prospective studies appear controversial possibly due to differences in the studies' design. A potential scheme for possible HRT use in selected breast cancer survivors with severe climacteric symptoms is suggested. The duration of HRT use is debatable because there is insufficient evidence at present. However, the available data suggest that 3-year and possibly 5-year HRT use may be safe. In summary, while HRT cannot currently be recommended as first-line therapy, it may still be of benefit in the management of selected early stage breast cancer survivors with refractory climacteric symptoms after a well-informed decision and an individualized risk benefit discussion.

Multiplexed analysis of biomarkers related to obesity and the metabolic syndrome in human plasma, using the Luminex-100 system.

BACKGROUND: The complex pathology of disease has sparked the development of novel protein expression profiling techniques that require validation in clinical settings. This study focuses on multiplexed analyses of adipocytokines and biomarkers linked to the metabolic syndrome, diabetes, and cardiovascular disease. METHODS: Multiplexed immunoassays using fluorescent microspheres and the Luminex-100 system were performed on plasma from 80 obese patients (40 with the metabolic syndrome) before and after 6-8 weeks of diet-induced weight loss. Leptin, insulin, C-peptide, monocyte chemoattractant protein-1 (MCP-1), eotaxin, interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha), and IL-6 concentrations measured with multiplex panels from 3 different manufacturers were compared with results from commercial ELISAs. Detection limits and between- and within-run imprecision were determined for each analyte. Bland-Altman analysis was used to determine agreement between multiplexed immunoassays and ELISAs. RESULTS: Correlation between the Luminex multiplexed assays and ELISAs was good for leptin (Linco), insulin (Linco), MCP-1 (Biosource and Upstate), and eotaxin (Biosource) with correlation coefficients of 0.711-0.895; fair for eotaxin (Upstate) and C-peptide (Linco) with correlation coefficients of 0.496-0.582; and poor for TNF-alpha, IL-8, and IL-6 (Linco, Biosource, Upstate, and R&D) with correlation coefficients of -0.107 to 0.318. Within- and between-run imprecision values for the multiplex method were generally <15%. Relative changes in plasma leptin and insulin concentrations after diet-induced weight loss were similar whether assessed by multiplex assay or ELISA. CONCLUSION: Although this technology appears useful in clinical research studies, low assay sensitivity and poor correlations with conventional ELISA methods for some analytes with very low plasma concentrations should be considered when using the Luminex platform in clinical studies.

Effectiveness and tolerability of ezetimibe add-on therapy to a bile acid resin-based regimen for hypercholesterolemia.

Combination lipid-reducing therapy is increasingly used, particularly for the management of severe or combined dyslipidemia in patients at high risk for coronary heart disease. To assess the potential additive effects of combining the cholesterol absorption inhibitor ezetimibe with a bile acid resin (BAR), a prospective chart review was performed of 40 patients in whom ezetimibe 10 mg/day was added to a stable regimen that included a BAR. At an average follow-up of 107 +/- 57 days, ezetimibe coadministration significantly reduced total cholesterol by 18%, triglycerides by 14%, and low-density lipoprotein cholesterol by 19% (all p < or =0.03), without significantly changing high-density lipoprotein cholesterol, and the combination was well tolerated.

Management of metabolic syndrome: statins.

Individuals who have the metabolic syndrome are at increased risk for cardiovascular disease. Combined dyslipidemia is an important component of metabolic syndrome, contributing to excess cardiovascular risk. Lifestyle and pharmacologic interventions are warranted for effective management of this syndrome. This article discusses the current evidence supporting the use of statins and their beneficial impact on lipid and nonlipid aspects of metabolic syndrome-related pathology.

Adiponectin, inflammation, and the expression of the metabolic syndrome in obese individuals: the impact of rapid weight loss through caloric restriction.

Severe obesity increases the prevalence of the metabolic syndrome, and moderate acute weight loss with a very low-calorie diet in obese subjects with the metabolic syndrome leads to significant metabolic benefits. Adiponectin has been implicated in both the pathogenesis of obesity-related insulin resistance and increased inflammation. We analyzed the relationship of the adipocyte-derived hormone adiponectin with indices of inflammation, adiposity, and insulin resistance in obese subjects with (MS+, n = 40) and without (MS-, n = 40) the metabolic syndrome and examined the acute effects of rapid weight loss. MS+ subjects had significantly lower adiponectin (7.6 +/- 0.6 vs. 10.4 +/- 0.6 microg/ml; P = 0.003) and significantly higher TNF-alpha (3.3 +/- 0.2 vs. 2.8 +/- 0.3 pg/ml; P = 0.004) levels compared with MS- subjects matched for age and body mass index. Plasma adiponectin and TNF-alpha levels were inversely related to the number of metabolic syndrome factors in a stepwise manner. After 4-6 wk of weight loss, there was marked improvement in glucose, insulin, leptin, and triglycerides, whereas adiponectin and TNF-alpha concentrations did not change. Thus, increases in plasma levels of adiponectin or reductions in TNF-alpha are not required for marked improvements in glucose/insulin and lipid metabolism with acute weight loss.

Role of non-high-density lipoprotein cholesterol in prevention of cardiovascular disease: updated evidence from clinical trials.

PURPOSE OF REVIEW: Although current clinical practice and treatment guidelines focus on low-density lipoprotein cholesterol as the basis for diagnosing and treating atherogenic dyslipidemias, many persons who develop cardiovascular disease do not have substantially elevated low-density lipoprotein cholesterol levels but may have low levels of high-density lipoprotein cholesterol and elevated triglycerides. Assessment of non-high-density lipoprotein cholesterol level provides a measure of cholesterol contained in all atherogenic particles, including low-density lipoprotein, lipoprotein(a), and triglyceride-rich particles such as very low density lipoprotein, very low density lipoprotein remnants, and intermediate-density lipoprotein. In the third Adult Treatment Panel guidelines of the US National Cholesterol Education Program, non-high-density lipoprotein cholesterol was introduced as a secondary target of therapy in persons with high triglyceride levels. RECENT FINDINGS: A growing number of epidemiological studies and clinical trials have examined the relation between non-high-density lipoprotein cholesterol level and cardiovascular disease events. Non-high-density lipoprotein cholesterol has been shown to be a better predictor for cardiovascular events than low-density lipoprotein cholesterol, and trials of statin therapy have demonstrated reductions in non-high-density lipoprotein cholesterol as well as low-density lipoprotein cholesterol. SUMMARY: Clinical trial evidence indicates the importance of incorporating all atherogenic lipoprotein particles in risk stratification. Non-high-density lipoprotein cholesterol is the most readily available surrogate marker for assessment of these particles and may also be a potential target of lipid-altering therapy. Statin therapy, which has already been demonstrated to decrease cardiovascular morbidity and mortality, provides significant reductions in non-high-density lipoprotein cholesterol.

Use of Statins for Secondary Prevention.

The causal role of hyperlipidemia in the pathogenesis of atherosclerosis is beyond dispute. The principal lipid abnormality responsible for coronary heart disease (CHD) is considered to be the elevation of the low-density lipoprotein cholesterol (LDL-C), although reduced levels of high-density lipoprotein cholesterol, and most recently elevated triglyceride levels, have also been associated with increased risk for CHD. The risk with these lipid abnormalities exists both in the asymptomatic population as well as in individuals with clinical evidence of atherosclerosis. Most patients with established CHD, and noncoronary atherosclerosis, will need drug therapy to achieve their National Cholesterol Education Program Adult Treatment Panel LDL-C goal of less than 100 mg/dL; the most efficacious, safe, and well-tolerated drugs for this purpose are the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or statins. The role of statins for secondary cardiovascular disease prevention has been well established in several large randomized clinical trials. New data now suggest that statins offer significant benefits to a broad range of patients at high global CHD risk, and should be regarded as an integral part of the management of acute coronary syndromes.

Combination therapy for combined dyslipidemia.

Patients with combined dyslipidemia are at high risk for coronary artery disease and often require combination drug therapy to achieve lipid levels recommended by the US National Cholesterol Education Program's third Adult Treatment Panel (ATP III). In addition to recommendations for low-density lipoprotein (LDL) cholesterol and triglyceride levels, ATP III established non-high-density lipoprotein (HDL) cholesterol goals for individuals with triglycerides >or=2.26 mmol/L (>or=200 mg/dL). It also introduced certain criteria for the diagnosis of the metabolic syndrome, a clustering of risk factors (abdominal obesity, elevated triglycerides, low HDL cholesterol, elevated blood pressure, impaired fasting glucose) that increases cardiovascular risk and is common in patients with combined dyslipidemia. Statin monotherapy has been shown to benefit these patients, and additional benefit may be obtained by combination therapy that provides greater reductions in both LDL cholesterol and triglycerides as well as greater increases in HDL cholesterol. However, combining a statin with either niacin or a fibrate may increase the risk for myopathy and therefore requires careful monitoring and evaluation of the risk-benefit ratio for each patient. Moreover, combination therapy may be associated with increased drug costs and decreased patient compliance. Recently developed agents that may improve the effectiveness of combination therapy include ezetimibe-a cholesterol absorption inhibitor-and a formulation that combines extended-release niacin and lovastatin in a single pill. Clinical trials are needed to determine the optimal treatment in patients with combined dyslipidemia.