Combination therapy with carvedilol and amiodarone in patients with severe heart failure

Nägele, Herbert; Bohlmann, Michael K.; Eck, Ulrich; Petersen, B.; Rödiger, W

doi:10.1016/s1388-9842(99)00071-9

Cited by 40 publications

(25 citation statements)

References 31 publications

(29 reference statements)

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“…19) The present finding that the metabolism of S-enantiomer was not changed in Caco-2 cells treated with VD 3 (Fig. 1B), suggested that CYP3A4 is not significantly responsible for the metabolism of carvedilol in the cells.…”

Section: Resultsmentioning

confidence: 69%

“…12,21) In the present study, we investigated the metabolism of R-and S-carvedilol in human intestinal epithelial Caco-2 cells. Treatment of Caco-2 cells with b-NF and VD 3 induces UGTs and CYP3A4, respectively. 11,14,15,19,20) We, therefore, also evaluated changes in the metabolic rate of Rand S-carvedilol in b-NF-and VD 3 -treated Caco-2 cells.…”

Section: Resultsmentioning

confidence: 99%

“…[1][2][3][4] Carvedilol is highly lipophilic and is absorbed rapidly from the gastrointestinal tract after oral administration. Orally administered carvedilol undergoes stereoselective first-pass metabolism, and the blood concentration of R-enantiomer with very low b-blocking activity is approximately 2-fold higher than that of S-enantiomer with high b-blocking activity.…”

mentioning

confidence: 99%

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Stereoselective Metabolism of Carvedilol by the .BETA.-Naphthoflavone-Inducible Enzyme in Human Intestinal Epithelial Caco-2 Cells

Ishida

Honda

Shimizu

et al. 2007

Biological & Pharmaceutical Bulletin

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Carvedilol is a b-adrenoceptor antagonist, and has been clinically used to treat chronic heart failure as well as hypertension, angina pectoris, and cardiac arrhythmias. [1][2][3][4] Carvedilol is highly lipophilic and is absorbed rapidly from the gastrointestinal tract after oral administration. Orally administered carvedilol undergoes stereoselective first-pass metabolism, and the blood concentration of R-enantiomer with very low b-blocking activity is approximately 2-fold higher than that of S-enantiomer with high b-blocking activity. 5,6) Both enantiomers are eliminated predominantly by hepatic metabolism, with renal excretion accounting for only 0.3% of the administered dose. 7) Carvedilol is metabolized extensively via aliphatic side-chain oxidation, aromatic ring oxidation, and conjugation pathways.8) Oldham and Clarke reported that oxidative activity for carvedilol is observed in cytochrome P450 (CYP) 2D6, 2C9, 3A4, and 1A2. 9) In addition, Ohno et al. reported that UDP-glucuronosyltransferase (UGT) 2B7, 2B4, and 1A1 are capable of catalyzing the glucuronidation of carvedilol. 10) However, it is still unclear which enzyme is responsible for the stereoselective presystemic clearance of carvedilol. Furthermore, although CYP3A4 and several UGTs are expressed in intestinal epithelial cells, it is also unknown whether the intestine as well as the liver is involved in the first-pass metabolism of carvedilol.The approach for investigating intestinal drug absorption and metabolism is to use human intestinal cell lines, such as the frequently used line Caco-2. This line spontaneously differentiates, after which it shows enterocyte-like morphology and forms polarized monolayers via tight junctions. It also expresses various transporters and efflux pumps such as P-glycoprotein.11,12) Therefore, it has been utilized to examine the mechanism responsible for the intestinal absorption of various compounds. 12,13) In addition, several UGTs, such as UGT1A1, 1A6, and 2B7, are expressed in Caco-2 cells, and the expression of some UGTs is induced by aromatic hydrocarbon receptor (AhR) ligands, such as b-naphthoflavone (b-NF).14,15) Therefore, glucuronidation of drugs in the intestine has been studied using Caco-2 cells. [16][17][18] In contrast, the Caco-2 cell line had not been employed to examine the intestinal metabolism of CYP3A4 substrates due to its lack of CYP3A4 expression. Recently, however, it has been reported that CYP3A4 in Caco-2 cells is induced by 1a,25-dihydroxyvitamin D 3 (VD 3 ). 11,19) The finding suggests that this cell line may also be utilized to investigate intestinal drug metabolism by CYP3A4. In the present study, we investigated whether carvedilol is metabolized stereoselectively in Caco-2 cells, and also evaluated the changes in the metabolic rate of carvedilol in b-NF-and VD 3 -treated Caco-2 cells. MATERIALS AND METHODS MaterialsCarvedilol was kindly supplied by Daiichi Pharmaceutical (Tokyo, Japan). b-NF was obtained from Nacalai Tesque (Kyoto, Japan). VD 3 and 3Ј-azido-3Ј-deoxythimidine (AZT...

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Section: Resultsmentioning

confidence: 69%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Stereoselective Metabolism of Carvedilol by the .BETA.-Naphthoflavone-Inducible Enzyme in Human Intestinal Epithelial Caco-2 Cells

Ishida

Honda

Shimizu

et al. 2007

Biological & Pharmaceutical Bulletin

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“…52 A prospective clinical trial was subsequently reported, in which patients with severe HF treated for 1 year with carvedilol plus amiodarone experienced significant clinical benefits. 53 Compared with entry, 26% more patients were in sinus rhythm at the end of 1 year, the average heart rate was reduced from 90 to 59 beats/ min, and the number of PVCs and episodes of tachycardia was significantly suppressed. Left ventricular EF increased from 26 to 39% and the average NYHA clinical class improved from 3.17 to 1.8.…”

Section: Ventricular Arrhythmiasmentioning

confidence: 95%

“…9). 53 However, the possibility of severe bradycardia must be anticipated with this combination of two negatively chronotropic drugs. In this population, approximately 6% of patients became pacemaker dependent within 1 year.…”

Section: Ventricular Arrhythmiasmentioning

confidence: 99%

Carvedilol's antiarrhythmic properties: Therapeutic implications in patients with left ventricular dysfunction

Naccarelli

Lukas

2005

Clinical Cardiology

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Summary:Carvedilol is a beta-and alpha-adrenergic-blocking drug with clinically important antiarrhythmic properties. It possesses anti-ischemic and antioxidant activity and inhibits a number of cationic channels in the cardiomyocyte, including the HERG-associated potassium channel, the L-type calcium channel, and the rapid-depolarizing sodium channel. The electrophysiologic properties of carvedilol include moderate prolongation of action potential duration and effective refractory period; slowing of atrioventricular conduction; and reducing the dispersion of refractoriness. Experimentally, carvedilol reduces complex and repetitive ventricular ectopy induced by ischemia and reperfusion.In patients, carvedilol is effective in controlling the ventricular rate response in atrial fibrillation (AF), with and without digitalis, and is useful in maintaining sinus rhythm after cardioversion, with and without amiodarone. In patients with AF and heart failure (HF), carvedilol reduces mortality risk and improves left ventricular (LV) function. Large-scale clinical trials have demonstrated that combined carvedilol and angiotensin-converting enzyme inhibitor therapy significantly reduces sudden cardiac death, mortality, and ventricular arrhythmia in patients with LV dysfunction (LVD) due to chronic HF or following myocardial infarction (MI).Despite intensive neurohormonal blockade, mortality rates remain relatively high in patients with post-MI and nonischemic LVD. Recent trials of implantable cardioverter-defibrillators added to pharmacologic therapy, especially beta blockers, have shown a further reduction in arrhythmic deaths in these patients.

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Pacemaker Therapy for Advanced Ischemic Heart Disease

Boehmer

2008

Interventional Treatment of Advanced Ischemic Heart Disease

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Combination therapy with carvedilol and amiodarone in patients with severe heart failure

Cited by 40 publications

References 31 publications

Stereoselective Metabolism of Carvedilol by the .BETA.-Naphthoflavone-Inducible Enzyme in Human Intestinal Epithelial Caco-2 Cells

Stereoselective Metabolism of Carvedilol by the .BETA.-Naphthoflavone-Inducible Enzyme in Human Intestinal Epithelial Caco-2 Cells

Carvedilol's antiarrhythmic properties: Therapeutic implications in patients with left ventricular dysfunction

Pacemaker Therapy for Advanced Ischemic Heart Disease

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