One-year safety and quality of life outcomes in patients with atrial fibrillation on dronedarone: prospective, non-interventional study in German ambulatory care.

BACKGROUND AND AIMS: The multichannel blocker dronedarone is currently indicated for the maintenance of sinus rhythm after successful cardioversion in adult clinically stable patients with paroxysmal or persistent atrial fibrillation (AF), with careful monitoring of cardiac, hepatic and renal function. We aimed to investigate patients' quality of life (QoL) and tolerability and effectiveness of dronedarone under real life conditions. METHODS: In the 1-year prospective, non-interventional IMPULS study, 161 office-based cardiologists, general practitioners and internists throughout Germany documented 549 patients with AF who were currently or newly prescribed dronedarone (safety set, SS). Of those, 342 patients (full analysis set, FAS) provided data on QoL at baseline, 6 months and 12 months). RESULTS: Mean age of patients was 67.6/66.3 years; 53.0 %/57.3 % were men (SS/FAS). AF type at inclusion in the SS/FAS was paroxysmal in 71.9 %/71.3 % and persistent in 26.0 %/26.6 % (missing in 2.0 %/2.0 %). The proportion of patients in sinus rhythm increased from 44.6 % at baseline to 70.2 % (SS). The mean value on the 100-point visual analogue scale (EuroQol EQ-5D) increased from 62.3 ± 17.1 at baseline by 11.4 ± 18.7 points (FAS, p<0.0001). The AF-QoL Psychological Domain improved from 44.6 ± 22.6 at baseline by 16.0 ± 23.5 points at 1 year (p<0.0001), the AF-QoL physical domain from 49.5 ± 22.1 by 10.9 ± 22.5 points (p<0.0001), and the AF-QoL sexual domain from 61.8 ± 27.1 by 6.6 ± 28.2 points (p<0.0001). In all, 136 patients (24.8 % of all patients in the safety set) had at least one adverse drug reaction (ADR) causally related to dronedarone. CONCLUSIONS: Various dimensions of quality of life of patients with AF were improved on dronedarone under clinical practice conditions. No previously unknown safety issues were noted.

A global perspective on blood pressure treatment and control in a referred cohort of hypertensive patients.

Hypertensive patients with cardiovascular (CV) comorbidities are at increased risk, and cardiologists' care should put particular emphasis on controlling blood pressure. Data on blood pressure treatment and control and drug utilization on a global scale, however, are scarce. Aiming to resolve this lack of information, the authors analyzed the data of International Survey Evaluating Microalbuminuria Routinely by Cardiologists in Patients With Hypertension (i-SEARCH) to gain further insights into national and regional blood pressure control and antihypertensive pharmacotherapy prescribed in cardiology practice. A total of 22,282 patients with hypertension from 26 countries were enrolled in 2005/2006. A total of 18,652 patients were treated (mean age, 63.0±11.4 years; 52.2% male; mean body mass index, 28.9 kg/m2). Mean systolic blood pressure was 148.2±19.8 mm Hg and diastolic blood pressure was 86.7±11.6 mm Hg. Blood pressure was controlled in 8.3% of diabetic and 25.3% of nondiabetic patients (21.2% overall), with particularly good control rates in North and Latin America (28.0% and 30.6%, respectively). A total of 31.2% of patients were treated with 1, 39.7% with 2, and 29.1% with ≥3 drugs. ß-blockers were being used most frequently (47.9%), in both monotherapy and combination therapy despite low numbers of patients with respective compelling indications for their use. The present data illustrate the potential for an improvement of blood pressure treatment and control in daily cardiology practice.

Determination of the newer quinolones levofloxacin and moxifloxacin in plasma by high-performance liquid chromatography with fluorescence detection.

A simple, accurate, sensitive, and precise reversed-phase (RP) high-performance liquid chromatographic (HPLC) method with fluorescence detection allowing the sensitive and specific quantitation of the newer fluoroquinolones levofloxacin and moxifloxacin is described. Moxifloxacin is used as the internal standard for the determination of levofloxacin and vice versa. A single-step liquid-liquid extraction from human plasma is sufficient for both quinolones. The method is linear from 0.1 to 15 microg/mL and 0.2 to 7 microg/mL for levofloxacin and moxifloxacin, respectively, covering the clinically relevant plasma concentration range. The limits of quantitation are 0.05 microg/mL (levofloxacin) and 0.2 microg/mL (moxifloxacin). The method is successfully applied to plasma drug level monitoring in a volunteer receiving single therapeutic doses of levofloxacin or moxifloxacin at two different occasions.

Effect of three months' treatment with irbesartan on blood and pulse pressure of hypertensive type 2 diabetic patients: open, observational study in 31,793 patients.

OBJECTIVES: In hypertensive diabetics the cardiovascular risk is substantially increased. Therefore, an effective reduction of both blood pressure and pulse pressure is of particular importance for these patients. The aim of the prospective observational study in hypertensive type 2 diabetics was to assess the effect of a switch from the previous antihypertensive therapy to the angiotensin-II-receptor antagonist irbesartan (alone or in combination with HCTZ) on the reduction of blood pressure and pulse pressure, the reduction of diabetic nephropathy (microalbuminuria), and tolerability. METHODS: 8714 general practitioners included 31,793 type 2 diabetics aged at least 18 years in an open observational study. After inclusion in to the study the patients received irbesartan 300 mg as monotherapy or in combination with hydrochlorothiazide 12.5 mg (HCTZ). Main outcome measures for efficacy were the reduction of systolic (SBP) and diastolic (DBP) blood pressures, reduction of pulse pressure, and blood pressure responder (reduction in DBP > or = 10 mmHg or diastolic < 90 mmHg), diastolic normalization (DBP < 90 mmHg) and overall normalization rates (SBP < 140 mmHg and DBP < 90 mmHg) after 3 months. Further outcome measures included the reduction of microalbuminuria or proteinuria, and adverse events (AEs) as a measure of tolerability. RESULTS: Thirty-eight per cent of patients received irbesartan 300 mg and 61% irbesartan in combination with HCTZ. Mean systolic blood pressure was reduced by 22.5 mmHg, diastolic blood pressure by 10.7 mmHg (baseline values: 160.2 and 93.2 mmHg). Pulse pressure fell on average by 11.6 mmHg. 83.4% of the patients were responders, with an overall normalization rate of 42.7% (SBP < 140 mmHg and DBP < 90 mmHg), respectively 73.8% (DBP < 90 mmHg). The antihypertensive benefit was achieved irrespective of the previous medication. Mean albuminuria decreased by about 27.7 mg/L. Only 0.3% of patients experienced adverse events. CONCLUSIONS: In type 2 diabetics with hypertension and either uncontrolled or no previous antihypertensive therapy a change to treatment with irbesartan or irbesartan/HCTZ for 3 months resulted in a distinct reduction of systolic and diastolic blood pressures, with concomitant effective reductions of pulse pressure and microalbuminuria.

Diagnosis of impaired glucose tolerance in hypertensive patients in daily clinical practice.

Many patients with hypertension suffer from impaired glucose tolerance or type 2 diabetes mellitus. Although these diagnoses are generally simple and reliable, it is more difficult to diagnose impaired glucose tolerance. As the gold standard (oral glucose tolerance test (OGTT)) is complicated to perform, a simpler alternative would be useful. The aims of the Pre-Diabetes Score study are to correlate demographic and/or laboratory parameters that are clinically simple to determine with the results of the OGTT and to determine the diagnostic significance of the combinations of parameters with regard to impaired glucose tolerance. A total of 260 patients were included in the evaluation; 39% had impaired glucose tolerance and 12% had diabetes mellitus. A combination of HbA1c of > or =6%, a venous fasting glucose of > or =110 mg/dl, an age of > or =55 years, a systolic blood pressure of > or =140 mmHg and an enlarged waist size is highly predictive of impaired glucose tolerance.

Influence of the angiotensin converting enzyme inhibitor ramipril on high-sensitivity C-reactive protein (hs-CRP) in patients with documented atherosclerosis.

UNLABELLED: Some medications have been shown to produce reductions in hs-CRP levels after initiating therapy. Whereas the role of the renin-angiotensin system in the inflammatory process has been documented in more detail during the last few years, the impact of an ACE-inhibitor therapy on this process has not been fully understood so far. The aim of this study was to investigate the effect of a therapy with the angiotensin-converting enzyme (ACE) inhibitor ramipril on hs-CRP plasma concentrations in patients with atherosclerosis. METHODS AND RESULTS: A total of 24 patients were enrolled in this prospective, uncontrolled, open-label multicenter study. Inclusion criteria were documented atherosclerosis, baseline high-sensitivity C-reactive protein between 3 and 12 mg/l, LDL-Cholesterol < or =150 mg/dl and no previous treatment with ACE inhibitors or angiotensin receptor blockers. Ten patients, pretreated with statins, and 10 patients not previously treated with statins were eligible for statistical analysis. Baseline high-sensitivity C-reactive protein was significantly decreased from 3.99+/-1.61 mg/l (mean+/-SD) to 2.72+/-1.19 mg/l (-32%) after 3 months treatment with 10 mg ramipril daily (p=0.0002). The decrease was more pronounced in patients who had not been treated with statins previously (-1.50 mg/l+/-1.44 mg/l) compared to those who were pretreated (-0.90 mg/l+/-0.93 mg/l). CONCLUSIONS: The ACE inhibitor ramipril administered in a daily dose of 10 mg to patients with atherosclerosis reduces the high-sensitivity C-reactive protein concentration. This effect may contribute to cardiovascular risk reduction mediated by ramipril aside from the blood pressure lowering effect.

[Malaria in the emergency room. Results of the emergency treatment of 137 patients with symptomatic malaria]. / Malaria in der Notaufnahme. Ergebnisse der Notfallbehandlung bei 137 Patienten mit symptomatischer Malaria.

OBJECTIVE: To assess characteristics and outcome of emergency patients with acute malaria. PATIENTS AND METHODS: We retrospectively assessed the clinical and laboratory parameters of 137 consecutive patients (87 males, 50 females; median age 37 years, range 17 - 67 years) presenting with acute malaria to our tertiary care center between 1992 and 2002. RESULTS: Falciparum malaria was diagnosed in 116/137 and tertian malaria in 19/137 patients; a single patient was infected with both parasites while in another case the type of parasite remained unclear. Infections were acquired in Africa (121), Asia , and in the Americas . One traveler visited multiple continents. Only 36 % (50/137) of patients had used malaria chemoprophylaxis. 128/137 patients were treated as in-patients; 22 of these had to be treated on an intensive care unit. According to the criteria of the German Society of Tropical Medicine, 44/137 (32 %; 95 % confidence interval (CI): 25 - 40 %) patients suffered from complicated malaria. The overall mortality rate was 2/137 (1.5 %; 95 % CI: 0,4 - 5.2 %); the mortality rate of complicated malaria tropica was 2/44 (4,5 %; 95 % CI 1,3 - 15 %). Patients with complicated malaria were significantly older than those with uncomplicated malaria. Median length of hospital stay was 4 days in uncomplicated and 9 days in complicated cases. Based on costs of EUR 2500 per case, an attack rate of > 3 % in East African travelers and a cost of EUR 55 for a chemoprophylaxis with mefloquine, chemoprophylaxis is cost-effective. CONCLUSION: In our retrospective analysis, complicated malaria tropica was associated with older age. Although malaria causes considerable morbidity, the overall mortality from severe malaria is low. Reinforcement of chemoprophylaxis especially in travelers to Africa could reduce malaria cases and is cost-effective.

[Orthotopic liver transplantation in a 33-year-old patient with fulminant hepatitis B and HIV infection]. / Orthotope Lebertransplantation bei einem 33-jährigen Patienten mit fulminanter Hepatitis-B- und HIV-Infektion.

HISTORY AND CLINICAL FINDINGS: A 33-year-old man with fulminant hepatitis B infection was to have an orthotopic liver transplantation (OLTX) because of the otherwise poor prognosis. During preparations for it he was found also to have an HIV-infection. INVESTIGATIONS: Preoperatively the Quick value was 9%, and he had a grade 2 encephalopathy. His immune status was impaired: 477 CD4-T-helper cells/microliter. Virus load, measured with a quantitative HIV-RNA test, was < 80 copies/ml (i.e. below demonstrable level). DIAGNOSIS, TREATMENT AND COURSE: After the first transplantation had ended in organ failure, a second one two days later was successful. But there were several complications postoperatively: ischaemic-toxic tubular renal failure requiring haemodialysis, underperfusion of the right lobe of the liver due to arterial stenosis, pleural effusion, cytomegalovirus infection and cyclosporin-induced hypertension. But all these were successfully managed. At the time of this report, 27 months later, the patient felt well and his immune state was stable. During these 2 years he had a practically normal T-helper count and HIV-RNA measured below 80 copies/ml with good liver function. There has been no indication for antiviral treatment and there have been no complications relating to immunosuppression. CONCLUSION: The low life expectancy before effective antiviral drugs are available explains the reluctance to perform OLTX in HIV-infected patients. The favourable course in this case, using highly efficacious combined antiretroviral treatment now being available, indicates that after careful consideration, OLTX can be performed in selected patients with HIV.

Indication, outcome and follow up of intensive care in patients with HIV-infection.

BACKGROUND/AIM: The admission to intensive care is controversially discussed in patients with HIV infection, since life expectancy is limited. Therefore, we analyzed indications, outcomes and follow up of all patients with confirmed HIV-infection and Aids defining symptoms who had been admitted to the intensive care unit (ICU) of our department between 1985-1996. RESULTS: 49 patients were admitted to the ICU, 42 of them with CDC stage C of HIV infection before admission. The leading indications were pneumonia (n = 15; PCP: 10, bacterial: 5), acute bleedings (n = 14), acute neurological diseases (n = 6), and gastrointestinal perforation (n = 5). Overall mortality was 39% (19/49) with a higher mortality seen in patients with respiratory disorders (53%) compared to non-respiratory disorders (22%, n.s.). The only significant predictor of mortality was the serum creatinine (p = 0.001), while differences in the APACHE II score between survivors and non-survivors did not reach statistical significance (22 +/- 7, 16 +/- 5; p = 0.14). During follow up no difference was seen in the life expectancy of HIV-infected survivors of intensive care as compared to those patients with AIDS who had never been admitted to ICU (8.4 months versus 9 months). DISCUSSION: The need for intensive care in HIV infected patients does not accelerate the progression of HIV infection to death, if the complications requiring ICU intervention can be managed successfully. Respiratory infections and impaired renal function are risk factors for a fatal outcome. Thus, HIV infected patients benefit from intensive care therapy.

Labelling studies for structure elucidation of a new hydroxymetabolite of tramadol.

Tramadol, racemic 1-(3-methoxyphenyl)-2-(dimethylaminomethyl)cyclohexane-1-ol, is an effective analgesic drug. Metabolites of tramadol described so far originate from O- and N-demethylation and are excreted in urine directly or after conjugation. A further metabolite was found in human liver microsome incubations and in the urine of volunteers after ingestion of tramadol. To elucidate the structure of the new metabolite, seven deuterated isotopomers of tramadol have been synthesized and ingested by volunteers. The mass spectra of the metabolites derived showed (i) that it was a hydroxy metabolite, (ii) that the hydroxy group was not located on the aromatic ring, the side chain, or the positions 2 and 6 of the cyclohexane ring, (iii) that the hydroxy-group was introduced to one of the the positions 3, 4 or 5 of the cyclohexane ring. The hydroxy metabolite was formed preferentially from the (-)-enantiomer, (1S,2S)-tramadol.

[Progress of acute liver failure and indications for liver transplantation]. / Verlauf des akuten Leberversagens und Indikationsstellung zur Lebertransplantation.

OBJECTIVE: To analyse the course of acute liver failure and the indications for liver transplantation. PATIENTS AND METHODS: In 16 patients who developed acute liver failure between July 1992 and July 1997 the indications for liver transplantation and total survival time were analysed retrospectively. RESULTS: Intensive medical care (ventilation, dialysis) was necessary in 60% of the patients to bridge organ failure until liver transplantation. In 14 patients liver transplantation was indicated. Eleven of the patients, with a minimal Quick value of less than 10%, presented with the prognostically poorest London criteria. In two patients the combination of three additional criteria of the London classification led to liver transplantation being indicated. In one patient with Wilson's disease the transplantation was undertaken despite good clotting factor synthesis, because an encephalopathy occurred. In two patients liver transplantation was not undertaken even though indicated, in one because liver functions improved, in the other because necrotizing pancreatitis had occurred. In another patient, who had been poisoned by eating the mushroom Amanita phalloides, the attempted transplantation was cut short, because intestinal necrosis had developed, and the patient died during the operation. Nine of the eleven patients who had a transplantation and three of the four treated conservatively survived. CONCLUSION: The 60-day survival rate in this series, achieved in a recently established transplantation programme, is high (12 of 16; 75%), being comparable to those in larger transplantation centres.

[Nosocomial ventilator-associated pneumonias caused by Aspergillus fumigatus in non-immunosuppressed, non-neutropenic patients]. / Nosokomiale Beatmungspneumonien durch Aspergillus fumigatus bei nicht-immunsupprimierten, nicht-neutropenischen Patienten.

We observed three cases of severe ventilator-associated pneumonia due to Aspergillus fumigatus in non-immunosuppressed, non-neutropenic patients. Autopsy confirmed an angioinvasive pattern of spreading with septic foci. In all cases conditions associated with temporary immunodysfunction like underlying diseases, antecedent sepsis or pneumonia, coinfections or steroid therapy were present. Although Aspergillus fumigatus was isolated in all cases in cultures of tracheobronchial secretions, the correct diagnosis was not obtained during lifetime. Our cases demonstrate that pneumonia due to Aspergillus fumigatus must be taken into account also in this patient population.

[The Churg-Strauss syndrome with cerebral seizures and terminal kidney failure]. / Churg-Strauss-Syndrom mit zerebralen Krampfanfällen und terminaler Niereninsuffizienz.

HISTORY AND CLINICAL FINDINGS: A 67-year-old man with known bronchial asthma was admitted to hospital because of deteriorating general state of health, fever, progressive renal failure and confusional states. INVESTIGATIONS: Erythrocyte sedimentation rate was 70/95 mm and the concentration of C-reactive protein raised to 30 mg/dl. WBC count was 19,000/microliter with 39% eosinophilia. Anticytoplasmatic antibodies (cANCA) had a high titre (1:160). On admission the creatinine level was 5.6 mg/dl. Renal biopsy indicated marked glomerular and tubulo-interstitial scarring. Chest radiograms showed transient pulmonary infiltrates. Churg-Strauss syndrome (CSS) was diagnosed on the basis of the clinical and biochemical findings. TREATMENT AND COURSE: Haemodialysis was instituted to counteract the renal failure with water retention. Inflammatory parameters and clinical symptoms rapidly responded to administration of corticosteroids (prednisolone, initially 250 mg/d for 3 days, then 150 mg/d for 5 days followed by slowly decreasing doses). Two weeks after starting prednisolone he had secondary generalised seizures. Magnetic resonance imaging (MRI) of the skull demonstrated marked hyperintense focal changes which in their pattern were characteristic of cerebral vasculitis. As a steroid-refractory condition had to be assumed, cyclophosphamide was also given (100 mg/d). Within 6 weeks the clinical symptoms gradually regressed and the MRI changes became practically normal. CONCLUSION: Early combined immunotherapy should be given if CSS runs a complicated course, rather than the usually recommended corticosteroid monotherapy.

Polymorphic CYP2D6 mediates O-demethylation of the opioid analgesic tramadol.

OBJECTIVE: This study was designed to investigate whether the in vivo metabolism of tramadol was influenced by CYP2D6 polymorphism. METHODS: The extent of tramadol O- and N-demethylation was calculated by determining the amounts of tramadol and O- and N-desmethyltramadol in 24 h urine after ingestion of a test dose of tramadol. The O- and N-demethylation rates were calculated by dividing the 24-h urinary excretion amount of tramadol by that of O- and N-desmethyltramadol. Volunteers were phenotyped for CYP2D6 polymorphism using sparteine as an in vivo probe. RESULTS AND CONCLUSION: High correlation was found between tramadol-O-demethylation and sparteine oxidation in 71 extensive metabolizers of sparteine (rs = 0.544). The mean metabolic ratio of tramadol O-demethylation was significantly higher in poor metabolizers of sparteine than in extensive metabolizers (4.4 vs 0.8). These in vivo results confirm that tramadol O-demethylation is carried out to a large extent by the polymorphic CYP2D6.

Labelling studies for structure elucidation of a new hydroxymetabolite of tramadol.

Abstract Tramadol, racemic 1-(3-methoxyphenyl)-2-(dimethylaminomethyl)cyclohexane-1-ol, is an effective analgesic drug. Metabolites of tramadol described so far originate from O- and N-demethylation and are excreted in urine directly or after conjugation. A further metabolite was found in human liver microsome incubations and in the urine of volunteers after ingestion of tramadol. To elucidate the structure of the new metabolite, seven deuterated isotopomers of tramadol have been synthesized and ingested by volunteers. The mass spectra of the metabolites derived showed (i) that it was a hydroxy metabolite, (ii) that the hydroxy group was not located on the aromatic ring, the side chain, or the positions 2 and 6 of the cyclohexane ring, (iii) that the hydroxy-group was introduced to one of the the positions 3, 4 or 5 of the cyclohexane ring. The hydroxy metabolite was formed preferentially from the (-)-enantiomer, (1S,2S)-tramadol.

High-performance liquid chromatographic assay for the simultaneous determination of tramadol and its metabolites in microsomal fractions of human liver.

A high-performance liquid chromatographic assay for the quantitative determination of the opioid analgesic tramadol and its metabolites is described. A homologue of tramadol [1-(m-hydroxyphenyl)-2-(N-ethyl-N-methylaminomethyl)cycloheptane-1 -ol hydrochloride] is used as internal standard. The assay allows the determination of tramadol O- and N-demethylation activity in vitro in microsomal fractions of human liver. Tramadol and its in vitro generated Phase I metabolites are extracted by a one-step extraction procedure from microsomal incubation mixtures using methylene chloride. Extraction efficiencies of tramadol, O-demethyltramadol and mono-N-demethyltramadol were 70, 91 and 94% respectively. The isocratic high-performance liquid chromatographic system employs a C18 reversed-phase column. The mobile phase is a mixture of methanol, ammonium hydrogencarbonate solution and ammonium hydroxide solution. Sensitivity of the assay was 0.5, 0.2 and 0.2 microgram/ml for tramadol, O-demethyltramadol and mono-N-demethyltramadol, respectively. Within-run precision of the overall assay was 13, 3.1 and 7.6% for tramadol, O-demethyltramadol and mono-N-demethyltramadol, respectively. Accuracy of the assay was determined as mean differences of concentrations added and found in microsomal fractions. It was -2.4% for tramadol, -0.85% for O-demethyltramadol and 0.32% for mono-N-demethyltramadol.