Unwanted Hormonal and Metabolic Effects of Postoperative Adjuvant Mitotane Treatment for Adrenocortical Cancer

Mitotane is widely used for the treatment of adrenocortical cancer (ACC), although the drug-related toxicity complicates its use. The aim of this study is to assess comprehensively the different endocrine and metabolic unwanted effects of the drug, and to provide data on the supportive therapies. We retrospectively analyzed 74 ACC patients adjuvantly treated with mitotane for ≥12 months. During the treatment period (40 months, 12–195), 32.4% of patients needed replacement therapy for mineralocorticoid deficit, 36.2% for hypothyroidism and 34.3% for male hypogonadism. In fertile women, hypogonadism was uncommon, while 65.4% of women developed ovarian cysts. Although no significant change in low-density lipoprotein (LDL) was observed, statins were started in 50% of patients for a significant increase in total cholesterol and triglycerides. Dyslipidemia occurred early, after a median time of 6 months from mitotane start. Conversely, testosterone replacement was usually started after >2 years. In many cases, ranging from 29.4% to 50% according to the side effect, toxicity occurred well before the achievement of the target mitotane concentrations. Supportive therapies were able to revert the biochemical alterations induced by mitotane, although higher doses were needed for a likely pharmacokinetic interaction of exogenous steroids and statins with mitotane. In conclusion, adjuvant mitotane therapy is associated with a spectrum of unwanted effects encompassing the function of different endocrine glands and requires a careful clinical and biochemical assessment associated with the therapeutic drug monitoring.

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Antioxidant and Chemopreventive Effect of Aliophen® Formulation Based on Malts and Hops

Antioxidants ◽

10.3390/antiox10010029 ◽

2020 ◽

Vol 10 (1) ◽

pp. 29

Author(s):

Idolo Tedesco ◽

Carmela Spagnuolo ◽

Stefania Bilotto ◽

Angelo A. Izzo ◽

Francesca Borrelli ◽

...

Keyword(s):

Health Effects ◽

Low Density Lipoprotein ◽

Antioxidant Properties ◽

Density Lipoprotein ◽

Ldl Oxidation ◽

Preneoplastic Lesions ◽

Chemically Induced ◽

Chemopreventive Effect ◽

The One ◽

Higher Doses

Experimental and clinical studies evidenced the health effects of moderate consumption of beer, mainly due to the presence of bioactive compounds, such as polyphenols, vitamins, or fibers. To exploit the potential beneficial effect on health and in disease prevention of these compounds, a new beverage based on barley malts and hops named Aliophen® has been designed, through a patented production process, with a high total polyphenolic amount compared to alcohol-free beer and similar to the one present in light and dark beers. In the present study, the antioxidant activity of Aliophen® against low-density lipoprotein (LDL) oxidation and its ability to protect erythrocytes from hemolysis have been characterized. Moreover, the chemopreventive effect of Aliophen® against colon cancer has been assessed, employing a mouse model of chemically induced carcinogenesis using azoxymethane (AOM). Data obtained showed that Aliophen at a low dose (3 mg/kg) inhibited the formation of preneoplastic lesions, polyps, and tumors. At higher doses (300 mg/kg) the protective effect was measured in the first phase of the onset of cancer. The antioxidant properties of Aliophen® were also observed in AOM-treated mice where it increased the serum antioxidant capacity. Based on the data presented, Aliophen® can exert promising health effects, including an anticancer capacity presumably associated with its antioxidant properties.

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P01-249-Weight change and metabolic effects of asenapine in placebo- or olanzapine-controlled studies

European Psychiatry ◽

10.1016/s0924-9338(11)71960-5 ◽

2011 ◽

Vol 26 (S2) ◽

pp. 250-250

Author(s):

J. Zhao ◽

P. Cazorla ◽

J. Schoemaker ◽

M. Mackle ◽

J. Panagides ◽

...

Keyword(s):

Weight Gain ◽

Weight Change ◽

Serum Lipids ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Metabolic Effects ◽

Glucose Levels ◽

Baseline Weight ◽

Image Position ◽

Post Hoc

IntroductionWeight change and metabolic effects of atypical antipsychotics vary considerably.ObjectiveAssess weight and metabolic effects of asenapine in adults.AimDemonstrate that asenapine marketed doses are well tolerated compared with placebo or olanzapine.MethodsData were from pooled asenapine trials that used placebo (1748 patients; duration: 1−6 wk) and/or olanzapine (3430 patients; duration, 3−>100 wk) controls. Asenapine doses were 5 or 10 mg BID (2–20 mg BID in 2 studies); olanzapine doses were 5–20 mg QD. Post hoc inferential analyses based on ANOVA assessed change from baseline weight, body mass index, and fasting lipid and glucose levels.ResultsTable 1 summarizes the results.[Change From Baseline Weight and Metabolic Paramete]DiscussionThese post hoc pooled analyses support published reports and suggest asenapine was associated with moderate weight gain and increased fasting triglyceride and glucose levels vs placebo, but lower propensity for weight gain or increased serum lipids (ie, triglycerides, low-density lipoprotein, and cholesterol) vs olanzapine.

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Antioxidative and Metabolic Effects of Lactobacillus plantarum, Inulin, and Their Synbiotic on the Hypothalamus and Serum of Healthy Rats

Nutrition and Metabolic Insights ◽

10.1177/1178638820925092 ◽

2020 ◽

Vol 13 ◽

pp. 117863882092509

Author(s):

Elaheh-Sadat Hosseinifard ◽

Khadijeh Bavafa-Valenlia ◽

Maryam Saghafi-Asl ◽

Mohammad Morshedi

Keyword(s):

High Density Lipoprotein ◽

Lactobacillus Plantarum ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Serum Levels ◽

Lipoprotein Cholesterol ◽

Metabolic Effects ◽

Low Density ◽

Low Density Lipoprotein Cholesterol ◽

Oxidative Markers

Nowadays, much attention has been paid to the link between gut microbiota and brain. The beneficial metabolic effects of probiotics and prebiotics in several diseases such as diabetes and obesity have been reported. However, studies bridging the association of gut microbiome with brain function in healthy states are rare. Therefore, it was hypothesized that the administration of Lactobacillus plantarum ( L plantarum) and inulin may affect serum and hypothalamic metabolic parameters as well as oxidative markers in healthy male rats. Daily L plantarum (107 CFU/mL) and inulin (5% of daily food weight) or their combination (synbiotic) was given to healthy rats. Then, serum and hypothalamic levels of leptin, insulin, and oxidative markers were measured. Administration of synbiotic for 8 weeks led to significant changes in serum levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, low-density lipoprotein/high-density lipoprotein ratio, triglyceride, and total cholesterol. The intake of synbiotic also resulted in a significantly reduced hypothalamic level of malondialdehyde and increased hypothalamic superoxide dismutase (SOD). Also, L plantarum could significantly increase hypothalamic SOD level. Furthermore, synbiotic administration insignificantly increased the hypothalamic and serum levels of insulin and leptin. These findings suggest that the synbiotic could significantly improve oxidative markers and lipid profile in healthy rats. Therefore, simultaneous intake of L plantarum and inulin appears to be more effective in the amelioration of metabolic and oxidative parameters.

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Supratherapeutic Response to Ezetimibe Administered with Cyclosporine

Annals of Pharmacotherapy ◽

10.1345/aph.1g015 ◽

2005 ◽

Vol 39 (9) ◽

pp. 1561-1565 ◽

Cited By ~ 28

Author(s):

Sheri L Koshman ◽

Lucille D Lalonde ◽

Ilene Burton ◽

Wayne J Tymchak ◽

Glen J Pearson

Keyword(s):

Heart Transplant ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Pharmacokinetic Interaction ◽

Fold Increase ◽

Lipid Lowering ◽

National Guidelines ◽

Orthotopic Heart Transplant ◽

Lipid Panel ◽

Attractive Option

OBJECTIVE: To report the case of a patient who underwent orthotopic heart transplant (OHT) and demonstrated a supratherapeutic response to ezetimibe when administered with cyclosporine. CASE SUMMARY: Ezetimibe 10 mg/day was added to the lipid-lowering regimen (atorvastatin 40 mg/day) of a 64-year-old male patient after OHT to achieve a target low-density lipoprotein cholesterol (LDL-C) level ≤97 mg/dL, as recommended by national guidelines. After 2 months of ezetimibe, the patient's LDL-C level had decreased by 60% to 51 mg/dL. Subsequently, the dose of ezetimibe was reduced to 5 mg/day and, after another 2 months, a repeat lipid panel revealed LDL-C 57 mg/dL. DISCUSSION: Hyperlipidemia is a common problem among heart transplant recipients. Combination therapy using a statin plus ezetimibe appears to be an attractive option to achieve target lipid levels in this population. However, the manufacturer warns that ezetimibe should be administered cautiously in patients concomitantly receiving cyclosporine. Unpublished data suggest a pharmacokinetic interaction between ezetimibe and cyclosporine that results in a significant 2.3- to 12-fold increase in exposure to total ezetimibe. An objective causality assessment in this case revealed that this supratherapeutic LDL-C reduction was probably related to coadministration of ezetimibe and cyclosporine. A potential mechanism to explain this interaction might be an alteration in glucuronidation induced by cyclosporine. CONCLUSIONS: When ezetimibe is prescribed for patients concomitantly receiving cyclosporine, it should be initiated at a lower than recommended dose (≤5 mg/day) and titrated upward. Careful and consistent monitoring of patients on this combination is also advised.

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Initiation and progression of atherosclerosis – enzymatic or oxidative modification of low-density lipoprotein?

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm.2006.259 ◽

2006 ◽

Vol 44 (12) ◽

Cited By ~ 18

Author(s):

Michael Torzewski ◽

Karl J. Lackner

Keyword(s):

Low Density Lipoprotein ◽

Hydrolytic Enzymes ◽

Atherosclerotic Lesion ◽

Density Lipoprotein ◽

Chronic Inflammatory Disease ◽

Oxidative Modification ◽

Low Density ◽

Biochemical Alterations ◽

Diagnosis And Prognosis ◽

Arterial Intima

AbstractAtherosclerosis is widely regarded as a chronic inflammatory disease that develops as a consequence of entrapment of low-density lipoprotein (LDL) in the arterial intima. Native LDL lacks inflammatory properties, so the lipoprotein must undergo biochemical alterations to become atherogenic. Among several other candidates, two different concepts of lipoprotein modification are propagated, the widespread oxidation hypothesis and the less common E-LDL hypothesis, which proposes that modification of LDL occurs through the action of ubiquitous hydrolytic enzymes (enzymatically modified LDL or E-LDL) rather than oxidation. By clearly distinguishing between the initiation and progression of atherosclerotic lesion development, this article reviews comparative studies of both types of lipoprotein modification and submits a viewpoint for discussion proposing that these lipoprotein modifications do not really compete, but rather complement one another. According to this concept, E-LDL might be more important for the initiation of atherosclerosis, while oxidative modification of LDL might be more helpful for diagnosis and prognosis of the disease.Clin Chem Lab Med 2006;44:1389–94.

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Impact of Simvastatin on Adipose Tissue: Pleiotropic Effects in Vivo

Endocrinology ◽

10.1210/en.2009-0603 ◽

2009 ◽

Vol 150 (12) ◽

pp. 5262-5272 ◽

Cited By ~ 39

Author(s):

Tayeba Khan ◽

Mark P. Hamilton ◽

Dorothy I. Mundy ◽

Streamson C. Chua ◽

Philipp E. Scherer

Keyword(s):

Insulin Sensitivity ◽

Secretory Pathway ◽

Low Density Lipoprotein ◽

Antioxidant Properties ◽

Density Lipoprotein ◽

Metabolic Effects ◽

Whole Body ◽

Multiple Levels ◽

Circulating Levels

Abstract Statins belong to a class of drugs well known for their ability to reduce circulating low-density lipoprotein cholesterol. In addition to cholesterol lowering, they also exhibit potential antiinflammatory and antioxidant properties, suggesting that tissues other than liver may be targeted by statins to exert their beneficial metabolic effects. Adipocytes have received very little attention as a potential target of these drugs, possibly because adipocytes are not a major source of biosynthetic cholesterol. Here, we examine the effects of simvastatin on the secretory pathway, inflammation, and cellular metabolism of adipocytes as well as on whole-body insulin sensitivity. We find that statins have a selective effect on the secretion of the insulin-sensitizing adipokine adiponectin by reducing circulating levels of the high-molecular-weight form of adiponectin specifically with a concomitant increase in intracellular adiponectin levels. However, these effects on adiponectin do not translate into changes in metabolism or whole-body insulin sensitivity, potentially due to additional antiinflammatory properties of statins. In addition, ob/ob mice treated with statins have reduced adiposity and an altered ultrastructure of the plasma membrane with respect to caveolar histology. Our data demonstrate that statins have major effects on the cellular physiology of the adipocyte on multiple levels.

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Abstract MP49: Subgroup Analysis of Icosapent Ethyl for Hypertriglyceridemia in Prevention of Non-Fatal Stroke and Overall Mortality

Stroke ◽

10.1161/str.52.suppl_1.mp49 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Salman Assad ◽

Mehar Zahid ◽

Shuja Assad Malik

Keyword(s):

Subgroup Analysis ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Metabolic Effects ◽

Controlled Study ◽

High Dose ◽

Low Density ◽

Icosapent Ethyl ◽

Secondary Outcomes ◽

Overall Mortality

Background and Purpose: Often in clinical practice, stroke patients with elevated triglycerides more than 150 mg/dl are seen despite being treated with moderate to high-intensity statins and with even in settings of low-density lipoprotein (LDL) <70 mg per deciliter (mg/dl). This analysis aims to understand the role of icosapent ethyl (IPE) for controlling the elevated triglycerides in cardiovascular and cerebrovascular high-risk populations. Methods: We performed the subgroup analysis of the REDUCE-IT double-blinded controlled study. The patient population included had either established cardiovascular disease or diabetes and other risk factors, who had been receiving statin therapy and who had a fasting triglyceride level of 135 to 499 mg/dl and a low-density lipoprotein cholesterol level of 41 to 100 mg/dl. The patients were randomly assigned to receive 2 g of IPE twice daily (total daily dose, 4 g) or placebo. The primary outcomes assessed as nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. The secondary outcomes were death from any cause, cardiovascular, or cerebrovascular related mortality. Results: Almost 8179 patients were studied (70.7%) for secondary prevention of cardiovascular and cerebrovascular events and were followed for a median of 4.9 years. The rate of death from any cause was 6.7% in the IPE group and 7.6% in the placebo group (hazard ratio [HR], 0.87; 95% confidence interval [CI] 0.74 to 1.02). The time to event analysis over 4.5 years follow up showed better primary outcomes by 17.2% in the IPE group than 22% in placebo, HR 0.75; 95% CI, 0.68 to 0.83; p<0.001). The secondary outcomes in terms of overall mortality from cerebrovascular or cardiovascular accidents were reduced by 25% in IPE compared to placebo (HR: 0.74; 95% CI 0.65-0.83; p<0.001). Conclusion: The combination therapy of IPE with moderate to high dose statins reduces the overall risk of cardiovascular and cerebrovascular accidents and mortality. The better primary and secondary outcomes were achieved irrespective of triglyceride levels at one year and it does explain the other metabolic effects of IPE.

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Beyond cholesterol: the enigma of atherosclerosis revisited

Thrombosis and Haemostasis ◽

10.1160/th03-12-0733 ◽

2004 ◽

Vol 91 (04) ◽

pp. 639-645 ◽

Cited By ~ 43

Author(s):

Karl Lackner ◽

Shan-Rui Han ◽

Michael Torzewski ◽

Matthias Husmann ◽

Sucharit Bhakdi

Keyword(s):

Immune System ◽

Low Density Lipoprotein ◽

Hydrolytic Enzymes ◽

Density Lipoprotein ◽

Chronic Inflammatory Disease ◽

C Reactive Protein ◽

Transport Pathway ◽

Biochemical Alterations ◽

Reactive Protein ◽

Sequence Of Events

SummaryAtherosclerosis is widely regarded as a chronic inflammatory disease that develops as a consequence of entrapment of low density lipoprotein (LDL) in the arterial intima. Native LDL lacks inflammatory properties, so the lipoprotein must undergo biochemical alterations in order to become atherogenic. Modification is commonly regarded as being dangerous because it bestows inflammatory properties onto the lipoprotein. Most current models consider oxidation to be the decisive modifying event. Here, we submit a different concept for discussion. We propose that modification of tissue-entrapped LDL is required because it enables the lipoprotein to signal to the immune system and effect its own removal. Oxidation would be too haphazard to fulfill this function. We summarize the evidence indicating that modification occurs through the action of ubiquitous hydrolytic enzymes. Enzymatically remodeled LDL binds C-reactive protein. C-reactive protein bound to remodeled LDL not only activates complement but also regulates it by inhibiting activation of the terminal complement cascade. Simultaneously, epitopes are exposed to enable the lipoprotein to be recognized and taken up by macrophages. The high density lipoprotein-dependent reverse transport pathway concludes the sequence of events that clear tissues of cholesterol in a non-inflammatory manner very similar to what has been described for the removal of apoptotic cells. It is proposed that these physiological processes occur throughout life without harm, pathology evolving only when the machinery suffers overload. Detrimental effects are then evoked primarily by the unreigned activation of complement, macrophages, and other effectors of the immune system in the lesions.

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Influence of the d3GH receptor polymorphism on the metabolic and biochemical phenotype of GH-deficient adults at baseline and during short- and long-term recombinant human GH replacement therapy

Acta Endocrinologica ◽

10.1530/eje-10-0317 ◽

2010 ◽

Vol 163 (3) ◽

pp. 361-368 ◽

Cited By ~ 19

Author(s):

Claudia Giavoli ◽

Emanuele Ferrante ◽

Eriselda Profka ◽

Luca Olgiati ◽

Silvia Bergamaschi ◽

...

Keyword(s):

Insulin Sensitivity ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Metabolic Effects ◽

Functional Difference ◽

Fat Percentage ◽

Rhgh Therapy ◽

The Impact

ObjectiveA common polymorphic variant of GH receptor (exon 3 deletion, d3GHR) has been linked with increased response to recombinant human GH (rhGH) in some patients with or without GH deficiency (GHD). The aim of the study was to investigate the impact of the GHR genotype on the phenotype of GHD adults and on the metabolic effect of rhGH therapy.DesignProspective study of GHD patients evaluated before and during short- (1 year,n=100) and long-term (5 years,n=50) rhGH therapy.MethodsEffects of rhGH on IGF1 levels, body composition (body fat percentage, BF%), body mass index, lipid profile, and glucose homeostasis (fasting insulin and glucose, insulin sensitivity indexes) were evaluated according to the presence or the absence of the d3GHR variant.ResultsThe different genotype did not influence basal phenotype of GHD. Short-term rhGH determined normalization of IGF1 levels, decrease in BF%, and worsening of insulin sensitivity, independently from the presence of the d3GHR allele. A significant increase in high-density lipoprotein cholesterol occurred in the d3GHR group. Normalization of IGF1 levels and decrease in BF% were maintained after 5 years. Insulin sensitivity restored to basal values, though in d3GHR patients fasting glucose remained significantly higher than at baseline. After both 1 and 5 years, percentage of subjects with impaired glucose tolerance, similar in the two groups at baseline, decreased in fl/fl while doubled in d3GHR patients. In this last group, a long-term significant reduction in total and low-density lipoprotein cholesterol was also observed.ConclusionThe functional difference of d3GHR may influence some metabolic effects of rhGH on GHD adults.

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Low-dose dexamethasone administration for 3 weeks favorably affects plasma HDL concentration and composition but does not affect very low-density lipoprotein kinetics

Acta Endocrinologica ◽

10.1530/eje-12-0180 ◽

2012 ◽

Vol 167 (2) ◽

pp. 217-223 ◽

Cited By ~ 7

Author(s):

Xuewen Wang ◽

Faidon Magkos ◽

Bruce W Patterson ◽

Dominic N Reeds ◽

Janine Kampelman ◽

...

Keyword(s):

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Plasma Lipoprotein ◽

Metabolic Effects ◽

Very Low Density Lipoprotein ◽

Low Density ◽

Particle Sizes ◽

Lipoprotein Subclass ◽

The Metabolic Syndrome

ObjectiveSubclinical hypercortisolemia often occurs in subjects with features of the metabolic syndrome, and it has been suggested that it may be, at least in part, responsible for the development of these metabolic abnormalities. However, the metabolic effects of glucocorticoid administration to mimic subclinical glucocorticoid excess have not been evaluated.MethodsWe used stable isotope-labeled tracer methods in conjunction with magnetic resonance techniques to measure the effect of glucocorticoid excess within the physiological range (∼0.7 mg dexamethasone/day for 3 weeks) on glucose and free fatty acid (FFA) rates of appearance (Ra) into plasma, intrahepatic triglyceride (TG) content, very low-density lipoprotein (VLDL)-TG and VLDL-apolipoprotein B-100 (apoB-100) kinetics and plasma lipoprotein subclass concentrations, and particle sizes in nine overweight and obese individuals.ResultsDexamethasone treatment led to a very small but significant increase in body weight (from 87.4±7.1 to 88.6±7.2 kg; P=0.003) and increased HDL-cholesterol (from 45.9±2.8 to 55.1±4.6 mg/dl; P=0.037) and HDL particle (from 33.7±2.2 to 41.4±4.2 nmol/l; P=0.023) concentrations in plasma but had no effect on intrahepatic TG content, glucose and FFA Ra in plasma, hepatic VLDL-TG and VLDL-apoB-100 secretion rates and mean residence times in the circulation, plasma TG and LDL-cholesterol concentrations, and plasma lipoprotein particle sizes.ConclusionSubclinical hypercortisolemia does not have significant adverse metabolic consequences.

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