Necrolytic migratory erythema (glucagenoma)-like skin lesions induced by EGF-receptor inhibition.
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Carcinoma, Non-Small-Cell Lung↗
Biomedical subjects
F Follath
Publications and source records attributed to F Follath.
The EuroHeart Failure Survey programme--a survey on the quality of care among patients with heart failure in Europe. Part 2: treatment.
BACKGROUND: National surveys suggest that treatment of heart failure in daily practice differs from guidelines and is characterized by underuse of recommended medications. Accordingly, the Euro Heart Failure Survey was conducted to ascertain how patients hospitalized for heart failure are managed in Europe and if national variations occur in the treatment of this condition. METHODS: The survey screened discharge summaries of 11304 patients over a 6-week period in 115 hospitals from 24 countries belonging to the ESC to study their medical treatment. RESULTS: Diuretics (mainly loop diuretics) were prescribed in 86.9% followed by ACE inhibitors (61.8%), beta-blockers (36.9%), cardiac glycosides (35.7%), nitrates (32.1%), calcium channel blockers (21.2%) and spironolactone (20.5%). 44.6% of the population used four or more different drugs. Only 17.2% were under the combination of diuretic, ACE inhibitors and beta-blockers. Important local variations were found in the rate of prescription of ACE inhibitors and particularly beta-blockers. Daily dosage of ACE inhibitors and particularly of beta-blockers was on average below the recommended target dose. Modelling-analysis of the prescription of treatments indicated that the aetiology of heart failure, age, co-morbid factors and type of hospital ward influenced the rate of prescription. Age <70 years, male gender and ischaemic aetiology were associated with an increased odds ratio for receiving an ACE inhibitor. Prescription of ACE inhibitors was also greater in diabetic patients and in patients with low ejection fraction (<40%) and lower in patients with renal dysfunction. The odds ratio for receiving a beta-blocker was reduced in patients >70 years, in patients with respiratory disease and increased in cardiology wards, in ischaemic heart failure and in male subjects. Prescription of cardiac glycosides was significantly increased in patients with supraventricular tachycardia/atrial fibrillation. Finally, the rate of prescription of antithrombotic agents was increased in the presence of supraventricular arrhythmia, ischaemic heart disease, male subjects but was decreased in patients over 70. CONCLUSION: Our results suggest that the prescription of recommended medications including ACE inhibitors and beta-blockers remains limited and that the daily dosage remains low, particularly for beta-blockers. The survey also identifies several important factors including age, gender, type of hospital ward, co morbid factors which influence the prescription of heart failure medication at discharge.
Adrenergic beta-Antagonists↗
The EuroHeart Failure survey programme-- a survey on the quality of care among patients with heart failure in Europe. Part 1: patient characteristics and diagnosis.
BACKGROUND: The European Society of Cardiology (ESC) has published guidelines for the investigation of patients with suspected heart failure and, if the diagnosis is proven, their subsequent management. Hospitalisation provides a key point of care at which time diagnosis and treatment may be refined to improve outcome for a group of patients with a high morbidity and mortality. However, little international data exists to describe the features and management of such patients. Accordingly, the EuroHeart Failure survey was conducted to ascertain if appropriate tests were being performed with which to confirm or refute a diagnosis of heart failure and how this influenced subsequent management. METHODS: The survey screened consecutive deaths and discharges during 2000-2001 predominantly from medical wards over a 6-week period in 115 hospitals from 24 countries belonging to the ESC, to identify patients with known or suspected heart failure. RESULTS: A total of 46788 deaths and discharges were screened from which 11327 (24%) patients were enrolled with suspected or confirmed heart failure. Forty-seven percent of those enrolled were women. Fifty-one percent of women and 30% of men were aged >75 years. Eighty-three percent of patients had a diagnosis of heart failure made on or prior to the index admission. Heart failure was the principal reason for admission in 40%. The great majority of patients (>90%) had had an ECG, chest X-ray, haemoglobin and electrolytes measured as recommended in ESC guidelines, but only 66% had ever had an echocardiogram. Left ventricular ejection fraction had been measured in 57% of men and 41% of women, usually by echocardiography (84%) and was <40% in 51% of men but only in 28% of women. Forty-five percent of women and 22% of men were reported to have normal left ventricular systolic function by qualitative echocardiographic assessment. A substantial proportion of patients had alternative explanations for heart failure other than left ventricular systolic or diastolic dysfunction, including valve disease. Within 12 weeks of discharge, 24% of patients had been readmitted. A total of 1408 of 10434 (13.5%) patients died between admission and 12 weeks follow-up. CONCLUSIONS: Known or suspected heart failure comprises a large proportion of admissions to medical wards and such patients are at high risk of early readmission and death. Many of the basic investigations recommended by the ESC were usually carried out, although it is not clear whether this was by design or part of a general routine for all patients being admitted regardless of diagnosis. The investigation most specific for patients with suspected heart failure (echocardiography) was performed less frequently, suggesting that the diagnosis of heart failure is still relatively neglected. Most men but a minority of women who underwent investigation of cardiac function had evidence of moderate or severe left ventricular dysfunction, the main target of current advances in the treatment of heart failure. Considerable diagnostic uncertainty remains for many patients with suspected heart failure, even after echocardiography, which must be resolved in order to target existing and new therapies and services effectively.
Aged↗
Clinical applications of B-type natriuretic peptide (BNP) testing.
Many claims have been made in recent years regarding the utility of plasma B-type natriuretic peptide (BNP) concentration measurements in the diagnosis, risk stratification and monitoring of patients with heart failure. This paper summarizes the current evidence and provides guidance for practising clinicians. Overall, plasma BNP testing appears to be of most value in the diagnostic arena, where it is likely to improve the performance of non-specialist physicians in diagnosing heart failure. In clinical practice, BNP testing is best used as a 'rule out' test for suspected cases of new heart failure in breathless patients presenting to either the outpatient or emergency care settings; it is not a replacement for echocardiography and full cardiological assessment, which will be required for patients with an elevated BNP concentration. Although work is ongoing in establishing the 'normal' values of BNP, heart failure appears to be highly unlikely below a plasma concentration of 100 pg/ml. However, as BNP levels rise with age and are affected by gender, comorbidity and drug therapy, the plasma BNP measurement should not be used in isolation from the clinical context.
Ambulatory Care↗
[The brain, a cardiac risk factor?].
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Adult↗
[Depression, stress and coronary heart disease--epidemiology, prognosis and therapeutic sequelae].
Depression and coronary heart disease may be related in several ways: (1) There is epidemiological evidence that high levels of depressive symptoms in male and female patients are associated with an increased risk of myocardial infarction and a higher mortality following an acute cardiac event. Furthermore, patients developing depression after myocardial infarction have more complications, including cardiac arrhythmias. (2) In patients with a chronic coronary heart disease depression also results in a worse cardiac functional status with more frequent and severe chest pain, more physical limitation, less treatment satisfaction and a lower perceived quality of life. Non-compliance with drug therapy is also more prevalent in depressed cardiac patients. (3) The possible pathophysiological mechanisms leading to more frequent complications of coronary heart disease in patients with depression are not fully explained, but could partly be due to higher sympatho-adrenergic stimulation and increased platelet aggregation. Some anti-depressant medications, on the other hand, may also cause cardiac symptoms and increase the risk in patients with coronary heart disease. The use of tricyclic antidepressants has been shown to result in a higher relative risk of myocardial infarction even after adjustment for other cardiovascular risk factors. Tricyclic anti-depressants may have direct cardiac effects, such as QT-prolongation with ventricular arrhythmias, orthostatic hypotension and, less frequently, myocardial dysfunction. In contrast such associations were not found with the newer serotonin re-uptake inhibitors. What are the practical consequences of the observed association between coronary artery disease and depression? First of all depression should better and earlier be recognised also by non-psychiatrists and treatment indications be discussed with specialists. At present, however, there is no clear evidence that ant-depressant drugs or psychotherapy will reduce the risk of myocardial infarction and improve prognosis. Further data are urgently needed to clarify the role of therapeutic interventions. Therefore, a closer research co-operation between cardiologists and psychiatrists should be promoted in future.
Antidepressive Agents↗
Management of heart failure in primary care (the IMPROVEMENT of Heart Failure Programme): an international survey.
BACKGROUND: Heart failure is a prevalent condition that is generally treated in primary care. The aim of this study was to assess how primary-care physicians think that heart failure should be managed, how they implement their knowledge, and whether differences exist in practice between countries. METHODS: The survey was undertaken in 15 countries that had membership of the European Society of Cardiology (ESC) between Sept 1, 1999, and May 31, 2000. Primary-care physicians' knowledge and perceptions about the management of heart failure were assessed with a perception survey and how a representative sample of patients was managed with an actual practice survey. FINDINGS: 1363 physicians provided data for 11062 patients, of whom 54% were older than 70 years and 45% were women. 82% of patients had had an echocardiogram but only 51% of these showed left ventricular systolic dysfunction. Ischaemic heart disease, hypertension, diabetes mellitus, atrial fibrillation, and major valve disease were all common. Physicians gave roughly equal priority to improvement of symptoms and prognosis. Most were aware of the benefits of ACE inhibitors and beta blockers. 60% of patients were prescribed ACE inhibitors, 34% beta blockers but only 20% received these drugs in combination. Doses given were about 50% of targets suggested in the ESC guidelines. If systolic dysfunction was documented, ACE inhibitors were more likely and beta blockers less likely to be prescribed than when there was no evidence of systolic dysfunction. INTERPRETATION: Results from this survey suggest that most patients with heart failure are appropriately investigated, although this finding might be as a result of high rates of hospital admissions. However, treatment seems to be less than optimum, and there are substantial variations in practice between countries. The inconsistencies between physicians' knowledge and the treatment that they deliver suggests that improved organisation of care for heart failure is required.
Aged↗
[Long-term diuretic treatment in heart failure: are there differences between furosemide and torasemide?].
BACKGROUND: Treatment for congestive heart failure (CHF) is an important factor in rising health care costs especially in patients requiring repeated hospitalisations. Diuretics remain the most frequently utilized drugs in symptomatic patients. In this study the long-term outcome under furosemide and torasemide, two loop diuretics with different pharmacokinetic properties, were evaluated during one year in an ambulatory care setting. AIMS: Comparison of hospitalization rates and estimated costs under long-term treatment with furosemide and torasemide in patients with CHF. METHODS: Retrospective analysis of disease course and resource utilization in 222 ambulatory patients receiving long-term treatment with furosemide (n = 111) or torasemide (n = 111). Data were also compared to those of a similar study including 1000 patients in Germany. RESULTS: Patients receiving long-term treatment with torasemide had a lower hospitalisation rate (3.6%) compared to patients on furosemide (5.4%). Corresponding hospitalization rates in the German study were 1.4% under torasemide and 2% under furosemide. The higher hospitalisation rates in Swiss patients could be explained by a higher average age (75 years vs. 69 years) and a longer duration of symptomatic heart failure (4.1 yrs vs. 0.7 yrs). Cost estimates based on the average number of hospital days (0.54 under torasemide compared to 1.05 under furosemide) indicated that the financial burden could be halved by a long-term torasemide treatment. CONCLUSION: Torasemide with its more complete and less variable bioavailability offers potential clinical and economic advantages over furosemide in the long-term treatment in patients with CHF.
Adult↗
Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial.
BACKGROUND: Levosimendan, a novel calcium sensitiser, improves myocardial contractility without causing an increase in myocardial oxygen demand. We compared the effects of levosimendan and dobutamine on haemodynamic performance and clinical outcome in patients with low-output heart failure. METHODS: Patients were recruited into a multicentre, randomised, double-blind, double-dummy, parallel-group trial. Under continuous haemodynamic monitoring, an initial loading dose of levosimendan of 24 microg/kg was infused over 10 min, followed by a continuous infusion of 0.1 microg kg(-1) min(-1) for 24 h. Dobutamine was infused for 24 h at an initial dose of 5 microg kg(-1) min(-1) without a loading dose. The infusion rate was doubled if the response was inadequate at 2h. The primary endpoint was the proportion of patients with haemodynamic improvement (defined as an increase of 30% or more in cardiac output and a decrease of 25% or more in pulmonary-capillary wedge pressure) at 24 h. Analyses were by intention to treat. FINDINGS: 103 patients were assigned levosimendan and 100 dobutamine. The primary haemodynamic endpoint was achieved in 29 (28%) levosimendan-group patients and 15 (15%) in the dobutamine group (hazard ratio 1.9 [95% CI 1.1-3.3]; p=0.022). At 180 days, 27 (26%) levosimendan-group patients had died, compared with 38 (38%) in the dobutamine group (0.57 [0.34-0.95]; p=0.029). INTERPRETATION: In patients with severe, low-output heart failure, levosimendan improved haemodynamic performance more effectively than dobutamine. This benefit was accompanied by lower mortality in the levosimendan group than in the dobutamine group for up to 180 days.
Cardiac Output, Low↗
The problem of chronic refractory angina; report from the ESC Joint Study Group on the Treatment of Refractory Angina.
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Angina Pectoris↗
One-year mortality among unselected outpatients with heart failure.
OBJECTIVE: To estimate 1-year mortality and prognostic factors in unselected outpatients with heart failure, and to compare the observed mortality with the estimates of the primary care physicians. METHODS AND RESULTS: Four hundred and eleven consecutive patients with heart failure New York Heart Association (NYHA) class II-IV (mean population age 75 years, 56% males) were enrolled in 71 primary care offices throughout Switzerland. During a mean follow-up period of 1.4 years, 68 patients had died. One-year total mortality was 12.6% compared to 4.3% in the underlying Swiss population (standardized mortality ratio 3.0). Among patients with heart failure NYHA II, III and IV, mortality was 7.1%, 15.0% and 28.0%, respectively. In multivariate Cox regression, statistically significant (P<0.05) predictors of mortality were NYHA class (NYHA III: risk ratio [RR]=1.6; NYHA IV: RR=2.2), recent hospital stay for heart disease (RR=2.3), creatinine>120 micromol.l(-1) (RR=1.8) systolic blood pressure<100 mmHg (RR=2.4), heart rate>100 min(-1) (RR=2.7), age (per 10 years, RR=1.6) and female gender (RR=0.49). Among patients with reduced left ventricular ejection fraction, 1-year mortality was 14.3%, and predictors were similar except that female gender was no longer associated with reduced mortality. Primary care physicians significantly overestimated 1-year mortality (estimated mortality 25.9% vs observed mortality 12.6%,P =0.001). CONCLUSIONS: Unselected outpatients with heart failure have a poor prognosis, particularly those with advanced heart failure and a recent hospital stay for heart disease. Primary care physicians are aware of the high mortality of this growing patient population.
Aged↗
Metabolism of amiodarone. II. High-performance liquid chromatographic assay for mono-N-desethylamiodarone hydroxylation in liver microsomes.
Amiodarone (AMI) is a potent antiarrhythmic drug. In vivo and in vitro, AMI is biotransformed to mono-N-desethylamiodarone (MDEA). Recently, it was observed that MDEA was further hydroxylated to n-3'-hydroxybutyl-MDEA (3'OH-MDEA). The performance of a HPLC-UV assay being developed for the quantification of the new compound was investigated. Liver microsomes isolated from rabbit, rat and human biotransformed MDEA to 3'OH-MDEA. Their estimates of Michaelis-Menten parameters were Km=6.39, 25.2, 19.4 microM; Vmax=560, 54, 17.3 pmol/mg protein/min), respectively. Thus, hydroxylase activity in mammals may be the origin of the species dependence observed in the AMI metabolism.
Amiodarone↗
Post-prandial lipaemia and endothelial function among healthy men.
BACKGROUND: There is evidence that elevated post-prandial lipoproteins adversely affect progression and outcome of cardiovascular disease. Traditional risk factors are associated with impaired endothelium-mediated vasodilatation. However, studies regarding the relationship between post-prandial lipaemia and endothelial function are divergent. METHODS: Twelve healthy non-smokers were included in this study. Before and after intake of a lipid cocktail rich in dairy fat, we tested endothelial-dependent (acetylcholine 0.8-160 mg/min per 100 ml forearm tissue) and -independent (sodium nitroprussid 0.6 microgram/min) vascular function in the forearm vascular bed with plethysmography. Moreover, we tested the effect of 1-NMMA, a competitive inhibitor of the NO synthetase, on base-line flow. Extent of post-prandial lipaemia was assessed with the increases in triglycerides and retinyl-palmitate, a marker for intestinally derived lipoproteins. RESULTS: Baseline flow was higher after the test meal than during fasting (preprandial 6.5 +/- 0.5 ml/min* 100 ml tissue, post-prandial 8.0 +/- 0.5, p = 0.03), but similar after 1-NMMA (p = 0.85). Before and after intake of the test meal, there was no significant difference in acetylcholine-induced endothelium-dependent vasodilatation (repeated measurement ANOVA, p = 0.22). At the highest acetylcholine dose, forearm flow was very similar (fasting 18.4 +/- 1.9, post-prandial 17.9 +/- 1.9, p = 0.75). At maximum acetylcholine dose, there was a weak inverse but non-significant correlation between forearm flow and post-prandial triglyceridaemia (r = -0.38, p = 0.23) and intestinally derived lipoproteins (chylomicrons r = -0.29, p = 0.35, chylomicron remnants r = -0.15, p = 0.63). However, at the lowest acetylcholine dose there was a suggestion for a positive correlation between change in flow and post-prandial lipaemia (triglyceridaemia, r = 0.53, p = 0.07; chylomicrons, r = 0.41, p = 0.18 and remnants, r = 0.51, p = 0.09). Endothelium-independent vasodilatation in response to sodium nitroprusside did not significantly change (p = 0.23). CONCLUSION: Our results suggest that among healthy men post-prandial lipaemia is not associated with a notable impairment of endothelium-mediated vascular function in forearm resistance vessels.
Adult↗
Lethal autoimmune myocarditis in interferon-gamma receptor-deficient mice: enhanced disease severity by impaired inducible nitric oxide synthase induction.
BACKGROUND: Interferon-gamma (IFN-gamma) is an essential cytokine in the regulation of inflammatory responses in autoimmune diseases. Little is known about its role in inflammatory heart disease. METHODS AND RESULTS: We showed that IFN-gamma receptor-deficient mice (IFN-gammaR(-/-)) on a BALB/c background immunized with a peptide derived from cardiac alpha-myosin heavy chain develop severe myocarditis with high mortality. Although myocarditis subsided in wild-type mice after 3 weeks, IFN-gammaR(-/-) mice showed persistent disease. The persistent inflammation was accompanied by vigorous in vitro CD4 T-cell responses and impaired inducible nitric oxide synthase expression, together with evidence of impaired nitric oxide production in IFN-gammaR(-/-) hearts. Treatment of wild-type mice with the nitric oxide synthetase inhibitor N:-nitro-l-arginine-methyl-ester enhanced in vitro CD4 T-cell proliferation and prevented healing of myocarditis. CONCLUSIONS: Our data provide evidence that IFN-gamma protects mice from lethal autoimmune myocarditis by inducing the expression of inducible nitric oxide synthase followed by the downregulation of T-cell responses.
Adjuvants, Immunologic↗
Toxicity of amiodarone and amiodarone analogues on isolated rat liver mitochondria.
BACKGROUND: Amiodarone is a well-known mitochondrial toxin consisting of a benzofuran ring (ring A) coupled to a p-OH-benzene structure substituted with 2 iodines and a diethyl-ethanolamine side chain (ring B). AIM: To find out which part of amiodarone is responsible for mitochondrial toxicity. METHODS: Amiodarone, ring A and B without the ethanolamine side-chain and iodines (B0), ring A and B with iodines but no ethanolamine (B2), ring B with 1 iodine and no ethanolamine (C1) and ring B with ethanolamine and 2 iodines (D2) were studied. RESULTS: In freshly isolated rat liver mitochondria, amiodarone inhibited state 3 glutamate and palmitoyl-CoA oxidation and decreased the respiratory control ratios. B0 and B2 were more potent inhibitors than amiodarone and B2 more potent than B0. C1 and D2 showed no significant mitochondrial toxicity. After disruption, mitochondrial oxidases and complexes of the electron transport chain were inhibited by amiodarone, B0 and B2, whereas C1 and D2 revealed no inhibition. Beta-oxidation showed a strong inhibition by amiodarone, B0 and B2 but not by C1 or D2. Ketogenesis was almost unaffected. CONCLUSIONS: Amiodarone, B0 and B2 are uncouplers of oxidative phosphorylation, and inhibit complexes I, II and III, and beta-oxidation. The benzofuran structure is responsible for mitochondrial toxicity of amiodarone and the presence of iodine is not essential.
Amiodarone↗
Anthracycline-induced acute cardiotoxicity in adults treated for leukaemia. Analysis of the clinico-pathological aspects of documented acute anthracycline-induced cardiotoxicity in patients treated for acute leukaemia at the University Hospital of Zürich, Switzerland, between 1990 and 1996.
BACKGROUND: Acute cardiotoxicity due to anthracyclines is a rare, but life-threatening event. Interindividual sensitivity to anthracyclines is highly variable and cannot be predicted for the individual patient. PATIENTS AND METHODS: This is a retrospective study. Medical charts and autopsy reports of patients treated for acute leukemia between 1990 and 1996 at the University Hospital of Zürich, Switzerland were reviewed and searched for anthracycline-associated acute cardiotoxicity. Patients with pre-existing heart disease known to be associated with cardiotoxicity were excluded. RESULTS: Seven patients treated for leukemia with proven anthracycline-associated acute cardiotoxicity were included. In six patients the direct cause of death was acute cardiotoxicity due to the treatment. One patient recovered from cardiac failure but died a few months later from refractory leukemia. Clinical symptoms were those of a heart failure. Pathological findings were dilatative cardiac hypertrophy and pericardial effusion. Microscopically the typical findings of myocardial fibrosis and perinuclear vacuolisated myocytes were seen. CONCLUSIONS: The awareness of acute adverse effects on cardiac performance by anthracyclines faciliates early recognition and prevention of heart failure. Reliable tests are needed for the early diagnosis of subclinical myocardial damage in order to identify patients at risk.
Acute Disease↗
Metabolism of amiodarone (Part III): identification of rabbit cytochrome P450 isoforms involved in the hydroxylation of mono-N-desethylamiodarone.
1. Amiodarone (AMI) is a potent anti-arrhythmic drug and mono-N-desethylamiodarone (MDEA) is its only known metabolite. It was found recently that in rabbit liver microsomes MDEA was biotransformed to n-3-hydroxybutyl-MDEA (3OH-MDEA). 2. In liver microsomes isolated from the untreated rabbit, the formation of 3OH-MDEA obeyed Michaelis-Menten enzyme kinetics with Km = 6.39 +/- 1.07 microM and Vmax = 0.56 +/- 0.21 nmolmin(-1) mg(-1) protein. 3. Furthermore, (1) among chemicals usually used as inhibitors of cytochrome P450, only midazolam (MDZ), cyclosporin A and ketoconazole inhibited the MDEA hydroxylase activity significantly (>60% inhibition), (2) MDZ, a substrate of CYP3A, inhibited the 30OH-MDEA formation competitively (Ki = 10 +/- 5 microM), (3) the formation rates of 3OH-MDEA correlated positively with those of 1'OH-MDZ (r = 0.81; n = 6), and (4) MDEA hydroxylase activity of microsomes isolated from rabbit rifampicin-induced cultured hepatocytes was 4-fold more active than the control. 4. Since CYP3A6 is mainly induced by rifampicin in rabbit-cultured hepatocytes, the data suggest that this isoform is involved in the biotransformation of MDEA to 3OH-MDEA. 5. Since alpha-naphthoflavone, cimetidine and quinidine also partially inhibited the MDEA hydroxylase activity, it is possible that other CYPs, such as 1A, 2C and 2D, may also be active in the metabolism of amiodarone.
Amiodarone↗
Metabolism of amiodarone (part I): identification of a new hydroxylated metabolite of amiodarone.
UNLABELLED: Amiodarone (AMI) is a potent antiarrhythmic drug, but its metabolism has not yet been fully documented. Mono-N-desethylamiodarone (MDEA) is its only known metabolite. Our preliminary investigations using rabbit liver microsomes had shown that in vitro AMI was biotransformed to MDEA, and the latter was rapidly further biodegraded to other unknown products. The aim of the present study was to investigate the chemical structure of the biotransformed compound of MDEA. Upon incubation of MDEA with rabbit liver microsomes and NADPH as cofactor, MDEA was biotransformed into three unknown products: X1, X2, and X3. The products were purified using chromatography. The chemical structure of the major product, X1, was investigated in detail. HPLC-ESI-MS revealed that MDEA had been oxygenated. Hydrogen-deuterium exchange experiments showed that the X1 molecule contained one exchangeable hydrogen atom more than its precursor MDEA, indicating that MDEA had been hydroxylated. Further results from ESI-MS/MS analysis indicated that the site of hydroxylation was the n-butyl side chain. NMR analysis (1H NMR, one-dimensional-total correlation spectroscopy, and heteronuclear multiple-bond correlation spectroscopy) established the 3-position (omega-1) of the butyl moiety as the specific carbon atom that is hydroxylated. Rat liver microsomes were also able to catalyze MDEA hydroxylation. Compound X1, as analyzed by HPLC-ESI-MS and ESI-MS/MS, was detected in the liver, heart, lung, and kidney tissue of four rats receiving AMI, suggesting that the hydroxylated MDEA was a secondary metabolite of AMI. CONCLUSION: in mammals, MDEA is hydroxylated to the secondary metabolite of AMI [2-(3-hydroxybutyl)-3-[4-(3-ethylamino-1-oxapropyl)-3,5-diiodobenzoyl]-benzofuran].
Amiodarone↗