Thomas Sudhop

Inhibition of Intestinal Cholesterol Absorption by Ezetimibe in Humans

Background—Ezetimibe has been shown to inhibit cholesterol absorption in animal models, but studies on cholesterol absorption in humans have not been performed thus far. Methods and Results—The effect of ezetimibe (10 mg/d) on cholesterol absorption and synthesis, sterol excretion, and plasma concentrations of cholesterol and noncholesterol sterols was investigated in a randomized, double-blind, placebo-controlled, crossover study in 18 patients with mild to moderate hypercholesterolemia. Treatment periods lasted 2 weeks with an intervening 2-week washout period. Fractional cholesterol absorption rates averaged 49.8±13.8% on placebo and 22.7±25.8% on ezetimibe, indicating a reduction of 54% (geometric mean ratio;P < 0.001). Cholesterol synthesis increased by 89% from 931±1027 mg/d on placebo to 1763±1098 mg/d on ezetimibe (P <0.001), while the ratio of lathosterol-to-cholesterol, an indirect marker of cholesterol synthesis, was increased by 72% (P <0.001). Bile acid synthesis was insignificantly increased (placebo: 264±209 mg/d, ezetimibe: 308±184 mg/d;P =0.068). Mean percent changes from baseline for LDL and total cholesterol after ezetimibe treatment were −20.4% and −15.1%, respectively (P <0.001 for both), whereas campesterol and sitosterol were decreased by −48% and − 41%, respectively. Conclusion—In humans, ezetimibe inhibits cholesterol absorption and promotes a compensatory increase of cholesterol synthesis, followed by clinically relevant reductions in LDL and total cholesterol concentrations. Ezetimibe also reduces plasma concentrations of the noncholesterol sterols sitosterol and campesterol, suggesting an effect on the absorption of these compounds as well.

Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors (statins)

Abstract. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)-reductase inhibitors (statins) are mainly considered for long-term use and often constitute part of a multiple-drug regime. Besides common adverse drug effects, such as nausea, abdominal discomfort and headaches, all statins harbour the risk of myopathy and fatal rhabdomyolysis. Usually, the frequency of myopathy is low but the incidence increases during concomitant drug therapy. Statins do not differ in their pharmacodynamic property. Therefore, the differences in their pharmacokinetic profiles, i.e. affinity for metabolising enzymes, constitute the rationale for choosing a specific statin especially for combination therapy. In order to point out harmful combinations of therapeutics, this review summarises the pharmacokinetic data of six clinically used statins (atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin and simvastatin) with special regard to metabolism and drug interactions. In summary, statins that lack a significant hepatic metabolism, i.e. pravastatin, or that are metabolised by more than one cytochrome P450 isoenzyme, i.e. fluvastatin, or whose metabolism is taken over by other cytochrome P450 isoenzymes in case of blockage of the main metabolising enzyme, i.e. cerivastatin, are the least prone to drug interactions. Nevertheless, in case of a specific concomitant drug therapy known to be associated with a higher risk of adverse events, i.e. cyclosporin A and statin, clinical symptoms of myopathy and biochemical data, such as increasing serum creatine phosphokinase, should be monitored carefully.

Vascular Effects of Diet Supplementation With Plant Sterols

OBJECTIVES The purpose of this study was to evaluate vascular effects of diet supplementation with plant sterol esters (PSE). BACKGROUND Plant sterol esters are used as food supplements to reduce cholesterol levels. Their effects on endothelial function, stroke, or atherogenesis are not known. METHODS In mice, plasma sterol concentrations were correlated with endothelial function, cerebral lesion size, and atherosclerosis. Plasma and tissue sterol concentrations were measured by gas-liquid chromatography-mass spectrometry in 82 consecutive patients with aortic stenosis. RESULTS Compared with those fed with normal chow (NC), wild-type mice fed with NC supplemented with 2% PSE showed increased plant sterol but equal cholesterol plasma concentrations. The PSE supplementation impaired endothelium-dependent vasorelaxation and increased cerebral lesion size after middle cerebral artery occlusion. To test the effects of cholesterol-lowering by PSE, apolipoprotein E (ApoE)-/- mice were randomized to Western-type diet (WTD) with the addition of PSE or ezetimibe (EZE). Compared with WTD, both interventions reduced plaque sizes; however, WTD + PSE showed larger plaques compared with WTD + EZE (20.4 +/- 2.1% vs. 10.0 +/- 1.5%). Plant sterol plasma concentration strongly correlated with increased atherosclerotic lesion formation (r = 0.50). Furthermore, we examined plasma and aortic valve concentrations of plant sterol in 82 consecutive patients with aortic stenosis. Patients eating PSE-supplemented margarine (n = 10) showed increased plasma concentrations and 5-fold higher sterol concentrations in aortic valve tissue. CONCLUSIONS Food supplementation with PSE impairs endothelial function, aggravates ischemic brain injury, effects atherogenesis in mice, and leads to increased tissue sterol concentrations in humans. Therefore, prospective studies are warranted that evaluate not only effects on cholesterol reduction, but also on clinical endpoints.

Comparison of MELD, Child-Pugh, and Emory model for the prediction of survival in patients undergoing transjugular intrahepatic portosystemic shunting

OBJECTIVES:Recently, new prognostic models (Model for End-Stage Liver Disease [MELD model] and Emory score) were proposed for the prediction of survival in transjugular intrahepatic portosystemic shunt (TIPS) patients. Although the MELD model is considered to be superior and has consecutively been applied to priority listing for liver transplantation, these models have never been directly compared in terms of long-term prognosis. We therefore compared the prognostic accuracy of the different models, including the Child-Pugh score, in an unselected cohort of TIPS patients followed long-term.METHODS:Baseline risk scores for 162 unselected consecutive TIPS patients followed until death (n = 81), liver transplantation, or end of observation (n = 81) (mean follow-up 30.7 ± 26.4 months) were calculated, and respective concordance- (c-)statistics for the predictive accuracy of 3-, 12-, and 36-month survival for the three models were compared statistically.RESULTS:All three models predicted short-term (3-month) survival with similar accuracy. The MELD model generated the best c-statistics for both 12-month (c-statistic 0.73, 95% CI = 0.64–0.82) and 36-month survival (c-statistic 0.74, 95% CI = 0.64–0.84). The predictive accuracy of the Emory score was significantly lower (c-statistic for 12-month survival: 0.60, 95% CI = 0.52–0.68, p = 0.012 vs MELD). In the statistical comparison of the MELD and the Child-Pugh model, only a trend favoring MELD for the prediction of 1-yr survival in patients with intestinal bleeding could be observed (MELD: c-statistic 0.78, 95% CI = 0.67–0.89; Child-Pugh: c-statistic 0.67, 95% CI = 0.55–0.80, p = 0.059).CONCLUSIONS:The MELD model is superior to the Emory score but only slightly superior to the Child-Pugh classification for the prediction of long-term survival in TIPS patients.

Inhibition of cholesterol absorption by the combination of dietary plant sterols and ezetimibe: effects on plasma lipid levels

Consumption of plant sterols and treatment with ezetimibe both reduce cholesterol absorption in the intestine. However, the mechanism of action differs between the two treatments, and the consequences of combination treatment are unknown. Therefore, we performed a double-blind, placebo-controlled, crossover study for the plant sterol component with open-label ezetimibe treatment. Forty mildly hypercholesterolemic subjects were randomized to the following treatments for 4 weeks each: 10 mg/day ezetimibe combined with 25 g/day control spread; 10 mg/day ezetimibe combined with 25 g/day spread containing 2.0 g of plant sterols; 25 g/day spread containing 2.0 g of plant sterols; and placebo treatment consisting of 25 g/day control spread. Combination treatment of plant sterols and ezetimibe reduced low density lipoprotein cholesterol (LDL-C) by 1.06 mmol/l (25.2%; P < 0.001) compared with 0.23 mmol/l (4.7%; P = 0.006) with plant sterols and 0.94 mmol/l (22.2%; P < 0.001) with ezetimibe monotherapy. LDL-C reduction conferred by the combination treatment did not differ significantly from ezetimibe monotherapy (−0.12 mmol/l or −3.5%; P = 0.13). Additionally, the plasma lathosterol-to-cholesterol ratio increased with all treatments. Sitosterol and campesterol ratios increased after plant sterol treatment and decreased upon ezetimibe and combination therapy. Our results indicate that the combination of plant sterols and ezetimibe has no therapeutic benefit over ezetimibe monotherapy in subjects with mild hypercholesterolemia.

Management of Drug-to-Drug Interactions Between Cyclosporine A and the Protease-Inhibitor Lopinavir/ Ritonavir in Liver-Transplanted HIV-Infected Patients

Highly active antiretroviral therapy (HAART) has improved the life expectancy of HIV‐infected patients, allowing orthotopic liver transplantation as a reasonable treatment option for selected patients with terminal liver disease. Both non‐nucleoside reverse transcriptase inhibitors and protease inhibitors, key elements of HAART, give rise to substantial drug‐to‐drug interactions with immunosuppressive drugs such as tacrolimus and cyclosporine A. After studying 12‐hour pharmacokinetic profiles in 3 HIV‐positive patients after liver transplantation, we describe how dosing of cyclosporine A can be adjusted to maintain effective immunosuppressive drug levels on a daily dosing schedule when ritonavir‐boosted indinavir or lopinavir‐based antiretroviral therapy is given. To avoid toxic drug levels, we used an orally available cyclosporine A formulation prepared from the commercial available intravenous solution, which enabled dose adjustments in 1‐mg increments. Under ritonavir‐boosted HAART, cyclosporine A levels showed markedly altered absorption/elimination characteristics with more or less constant blood‐levels throughout the dosing interval and prolonged elimination half‐lives up to 38 hours. To obtain equivalent areas under the curve of cyclosporine A, daily doses were reduced to 5–20% of the individual standard doses given before initiation of ritonavir‐boosted HAART. Because of the flat absorption/elimination profiles under ritonavir‐boosted HAART cyclosporine A, dosing could be reliably monitored long term by measuring cyclosporine A trough‐levels. (Liver Transpl 2004;10:939–944.)

INTERFERON/ANTIOXIDANT COMBINATION THERAPY FOR CHRONIC HEPATITIS C--A CONTROLLED PILOT TRIAL

The effects of two forms of antioxidative co-therapy were analyzed in 24 interferon-alpha (IFN)-naive patients with chronic hepatitis C who were randomized to either receive IFN monotherapy (3 x 4.5 million units IFN-alpha 2a per week), (group A), or IFN and N-acetylcysteine (N-acetylcysteine (NAC) 1.800 mg/day) plus sodium selenite (400 microg/day) supplementation (group B), or treatment as in group B plus vitamin E (544 IU/day) (group C), over 24 weeks. Changes in histology, normalization of ALT, reduction of viral RNA, serum levels of glutathione, selenium, vitamin E, erythrocyte glutathione peroxidase, trolox equivalent antioxidative capacity (TEAC), thiobarbituric acid reactive substances (TBARS) and protein carbonyl groups were measured. Low baseline TEAC and elevated TBARS indicated increased oxidative stress before therapy, which was not affected by antioxidant supplementation. At the end of treatment complete responses were found in 3/8, 2/8 and 6/8 patients in groups A, B and C, respectively, but liver histology had not significantly improved. Vitamin E treated patients had a 2.4 greater chance (95% CI: 1.05-5.5) of obtaining a complete response and had significantly greater reduction in viral load (P = 0.028) than patients without vitamin E. Relapses, i.e. re-appearance of detectable hepatitis C virus (HCV) RNA and/or re-elevation of ALT-activity occurred in 7 out of the 11 responders within 6 months after termination of therapy (group A: 2/3, group B: 1/2 and group C: 4/6). Thus, no overall beneficial effect of antioxidant/IFN therapy was detected. However, the apparent trend towards a more favorable outcome with vitamin E supplementation warrants to further study this substance as an adjuvant to IFN therapy in chronic hepatitis C.

Cholesterol absorption inhibitors for the treatment of hypercholesterolaemia.

The benefits of lipid lowering therapy on coronary heart disease have been clearly established in many clinical trials on primary and secondary prevention. Despite the availability of potent lipid lowering drugs, many patients do not reach the current treatment goals. This paper reviews new therapeutic approaches in lipid lowering drugs focusing on compounds which lower cholesterol absorption. The role of plant sterols and stanols, new acyl-CoA:cholesterol O-acyl transferase (ACAT) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, and ezetimibe are summarised.Although the lipid lowering effect of plant sterols and plant stanols is only moderate, their use as functional foods is beneficial for patients with mild hypercholesterolaemia and is able to enhance the lipid lowering effect of HMG-CoA reductase inhibitors (statins). The role of ACAT inhibitors that might also inhibit cholesterol absorption remains unclear. Avasimibe, the first oral bioavailable ACAT inhibitor, has entered phase III trials. However, the presently available data in humans do not indicate a clear clinical benefit. The role of MTP inhibitors, which exhibit remarkable effects on all plasma lipids, also remains unclear, as safety concerns must first be addressed. Ezetimibe, the first available 2-azetidinone, succeeded in phase III trials showing remarkable effects in inhibition of cholesterol absorption as well as cholesterol lowering. The synergistic effect of co-administration of ezetimibe with statins seemingly offers a new approach in reaching the therapeutic goals.

Pharmacology of 3‐Hydroxy‐3‐Methylglutaryl‐Coenzyme A Reductase Inhibitors (Statins), Including Rosuvastatin and Pitavastatin

Coronary heart disease (CHD) is the leading cause of morbidity and mortality in the Western world, with hypercholesterolemia as the major risk factor. The 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase inhibitors represent the most efficient drugs for the treatment of hypercholesterolemia. They lower plasma cholesterol due to the inhibition of endogenous cholesterol synthesis in the liver and subsequent increased expression of low‐density lipoprotein (LDL) receptors, resulting in an up‐regulated catabolic rate for plasma LDL. The beneficial effect of statins on the incidence of CHD was clearly demonstrated in several large‐scale clinical trials. Currently, five statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) are available, and two novel compounds (pitavastatin, rosuvastatin) are undergoing clinical investigation. To point out potential mechanisms leading to increased toxicity and to compare the novel statins with the established ones, this article summarizes their pharmacological data since the prevalence of adverse events can be explained at least in part by their pharmacokinetic differences.

Intestinal expression of P‐glycoprotein (ABCB1), multidrug resistance associated protein 2 (ABCC2), and uridine diphosphate–glucuronosyltransferase 1A1 predicts the disposition and modulates the effects of the cholesterol absorption inhibitor ezetimibe in humans

Ezetimibe is an inhibitor of the cholesterol uptake transporter Niemann‐Pick C1‐like protein (NPC1L1). Target concentrations can be influenced by intestinal uridine diphosphate–glucuronosyltransferases (UGTs) and the efflux transporters P‐glycoprotein (P‐gp) (ABCB1) and multidrug resistance associated protein 2 (MRP2) (ABCC2). This study evaluates the contribution of these factors to the disposition and cholesterol‐lowering effect of ezetimibe before and after induction of UGT1A1, P‐gp, and MRP2 with rifampin (INN, rifampicin).