C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks--final results of the I.M.P.A.C.T.2 study.

BACKGROUND: The placebo-controlled study International Multicentre Prospective Angioedema C1-INH Trial 1 (I.M.P.A.C.T.1) demonstrated that 20 U/kg C1 esterase inhibitor (C1-INH) concentrate (Berinert®; CSL Behring, Marburg, Germany) is effective in treating acute abdominal and facial Hereditary Angioedema (HAE) attacks. METHODS: I.M.P.A.C.T.2 was an open-label extension study of I.M.P.A.C.T.1 to evaluate the safety and efficacy of long-term treatment with 20 U/kg C1-INH for successive HAE attacks at any body location. Efficacy outcomes included patient-reported time to onset of symptom relief (primary) and time to complete resolution of all symptoms (secondary), analysed on a per-patient and per-attack basis. Safety assessments included adverse events, vital signs, viral safety and anti-C1-INH antibodies. RESULTS: During a median study duration of 24 months, 1085 attacks were treated in 57 patients (10-53 years of age). In the per-patient analysis, the median time to onset of symptom relief was 0.46 h and was similar for all types of attacks (0.39-0.48 h); the median time to complete resolution of symptoms was 15.5 h (shortest for laryngeal attacks: 5.8 h; 12.8-26.6 h for abdominal, peripheral and facial attacks). Demographic factors, type of HAE, intensity of attacks, time to treatment, use of androgens and presence of anti-C1-INH antibodies had no clinically relevant effect on the efficacy outcomes. There were no treatment-related safety concerns. No inhibitory anti-C1-INH antibodies were detected in any patient. CONCLUSIONS: A single dose of 20 U/kg C1-INH concentrate is safe and provides reliable efficacy in the long-term treatment of successive HAE attacks at any body location.

Influence of renal dysfunction on the pharmacokinetics of the selective Na+/H+ exchange inhibitor EMD 87 580 in patients with chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) is a potential indication for the administration of EMD 87 580, a selective Na+/H+ exchange inhibitor. CHF is often accompanied by renal dysfunction, which is known to affect the pharmacokinetics of compounds predominately cleared by the kidneys. We examined the influence of renal dysfunction on the pharmacokinetics of EMD 87 580 in patients with CHF. METHODS: 21 patients with CHF and normal renal function (Group 1) and 9 patients with CHF and renal dysfunction (Group 2) received EMD 87 580 orally over 8 days. The mean creatinine clearance (CrCl) in Group 1 was 99.7 ml/min. 12 patients in this group were randomized to receive two doses of EMD 87 580 (7 patients 2 x 50 mg and 5 patients 2 x 100 mg). The 9 patients in Group 2 with renal dysfunction (mean CrCl = 49.5 ml/min) received 50 mg EMD 87 580 once daily. Plasma and urine samples were collected for pharmacokinetic assessment. RESULTS: In CHF patients with renal dysfunction EMD 87 580 clearance was reduced to approximately 50% compared to Group 1, i.e. 6.80 ml/min (4.89-11.60) vs. 12.73 ml/min (8.93-22.21), p < 0.05, for the 50 mg dose and 14.08 ml/min (9.96-18.10), p < 0.05, for the 100 mg dose. Consequently, plasma concentrations were increased in patients with renal dysfunction; AUC0-infinity 7,354 ng/ml x h (4,311-10,232) vs. 3,928 ng/ml x h (2,251-5,596, 50 mg dose, p < 0.05). A significant correlation was observed between EMD 87 580 plasma clearance and CrCl (r2 = 0.8062). CONCLUSION: In CHF patients with renal dysfunction EMD 87 580, clearance is reduced and plasma concentrations increased. Therefore, dose adjustments for EMD 87 580 are indicated in patients with CHF and renal dysfunction.

The Na(+)/H(+) exchange inhibitor eniporide as an adjunct to early reperfusion therapy for acute myocardial infarction. Results of the evaluation of the safety and cardioprotective effects of eniporide in acute myocardial infarction (ESCAMI) trial.

OBJECTIVES: We conducted an international, prospective, randomized, double-blind, placebo-controlled phase 2 trial in patients undergoing thrombolytic therapy or primary angioplasty for acute ST-elevation myocardial infarction (MI) to investigate the effect of eniporide on infarct size and clinical outcome. BACKGROUND: Experimental studies suggest that the activity of the Na(+)/H(+) exchange (NHE) plays an important role in the unfavorable sequels of myocardial ischemia and reperfusion. Eniporide specifically inhibits the NHE-1 isoform and has been shown to limit infarct size in experimental models. METHODS: The primary efficacy end point was the infarct size measured by the cumulative release of alpha-hydroxybutyrate dehydrogenase (alpha-HDBH) (area under the curve [AUC] 0 to 72 h). In stage 1, 50, 100, 150 or 200 mg eniporide given as a 10-min infusion before start of reperfusion therapy were compared with placebo in 430 patients, and in stage 2, 100 and 150 mg eniporide were compared with placebo in 959 patients. RESULTS: In stage 1, the administration of 100 mg and 150 mg eniporide resulted in smaller infarct sizes (mean alpha-HBDH AUC in U/ml x h, placebo: 44.2, 100 mg eniporide: 40.2, 150 mg eniporide: 33.9), especially in the angioplasty group. In contrast, in stage 2 there was no difference in the enzymatic infarct size between the three groups (placebo: 41.2, 100 mg eniporide: 43.0, 150 mg eniporide: 41.5). Overall there was no effect of eniporide on clinical outcome (death, cardiogenic shock, heart failure, life-threatening arrhythmias). However, there was a significant reduction of the incidence of heart failure in patients reperfused late (>4 h). CONCLUSIONS: In this large study administration of the NHE-1 inhibitor eniporide, before reperfusion therapy in patients with acute ST elevation MI, did not limit infarct size or improve clinical outcome.

[Clinical safety using the thrombocyte aggregation inhibitor c7E3 in interventional cardiology in 520 patients]. / Klinische Sicherheit der Anwendung des Thrombozytenaggregationshemmers c7E3 in der Interventionellen Kardiologie bei 520 Patienten.

The monoclonal antibody c7E3 (ReoPro) is a highly selective inhibitor of platelet aggregation that binds to the fibrinogen receptor (GP IIb/IIIa) on the surface of platelets and leads to a dose-dependent, nearly complete inhibition of platelet aggregation. The clinical value of c7E3 to reduce ischemic events after PTCA in addition to heparin and aspirin has been demonstrated in the EPIC-, EPILOG-, and CAPTURE-trial. In these studies, c7E3 was associated with an increased bleeding risk after the coronary intervention. The DTREO-Trial (German trial with c7E3) was designed as a prospective study to investigate the clinical safety of c7E3 in the daily routine of a cath lab. From April 1995 through September 1996 520 patients were enrolled at 30 German sites. c7E3 was mainly used in patients with acute coronary syndromes (55% unstable angina Braunwald Class I-III and C; 28% in acute myocardial infarction) and in patients with complex coronary lesions (AHA/ACC classification type B and C lesion in 84% of the study group). In 51% of the interventions a stent was implanted (25% in bailout-situations and in 26% as an elective intervention) and c7E3 was used as an adjunctive to prevent sub-acute stent thrombosis. The incidence of "major" bleeding events (TIMI-classification) was less frequent in this study as in the EPIC-trial and comparable to the results of the EPILOG- and CAPTURE trial. In conclusion this study confirms the positive risk profile of c7E3 in patients undergoing high-risk percutaneous revascularization procedures.

On-line evaluation of systolic performance by densitometry in digital left ventriculography.

The angiocardiographic evaluation of left ventricular end-diastolic (LVEDV) and end-systolic (LVESV) volumes and ejection fraction (EF) is routinely performed by the area-length method (ALM) but may lead to erroneous results. Digital imaging in real time allows densitometric procedures of determining left ventricular (LV) performance to be applied alternatively. In this study, we present densitometric algorithms for the analysis of LVEDV, LVESV, and EF from digital image data, establish accuracy and reproducibility, and determine value and limitations in comparison with ALM in single-plane 30 degrees right anterior oblique (RAO) projection. A linear relationship between iodine depth and measured densities is mainly burdened with scatter radiation and beam hardening which reduce primary radiation and suppress iodine depth. However, facilities such as deconvolution and correction algorithms are capable of reducing these sources of error. In the present study, computer-analyzed contrast images of iodine-filled wedges and spheres showed a near-linear relationship between iodine depth between 50-100 mg/cm2 and measured densities. Contrast images of heart casts and LV angio-grams of 54 patients were obtained with a digital image acquisition and processing system, and evaluated by two independent observers. The phantom study resulted in significantly (p < or = 0.01) better densitometric standard errors of estimate for volumes [3.3 ml densitometry (DENS) vs. 8.9 ml (ALM)] and simulated EF [4.3% (DENS) vs. 7.8% (ALM)] than ALM. The standard error of estimate for the comparison between both methods was 8.4 ml for volumes and 7.5% for EF. Densitometric volumes tended to underestimate volumes calculated by ALM. The angiographic study of patients demonstrated significant correlations between both methods (LVEDV r = 0.78, LVESV r = 0.83, total volumes: r = 0.89; EF r = 0.88). The standard errors of estimate can be ascribed to systematic, method-related errors of both DENS and ALM (LVEDV +/- 28.9 ml, LVESV +/- 23.4 ml, total volumes (EDV and ESV) +/- 27.1 ml; EF +/- 8.1%). The intra- and interobserver variability, respectively, exhibited significantly smaller (p < or = 0.01 and p < or = 0.05, respectively) standard errors of estimate for densitometric EF [4.6% (DENS) vs. 8.5% (ALM) and 7.1% (DENS) vs. 10.3% (ALM), respectively]. Inclined but not significant differences were found for LVEDV and LVESV. In conclusion, the data presented indicate that the calculation of LV volumes and EF in digital left ventriculography may be performed accurately by densitometric calculation in single-plane 30 degrees RAO projection. Minor underestimations in densitometric volume determination may be anticipated in the evaluation of LV geometry.

Ambulatory blood pressure monitoring: quantification of the early morning rise in blood pressure in normal case and in patients with symptoms of orthostatic dysregulation.

Though various parameters can be evaluated in ambulatory blood pressure monitoring, there is still a lack of reliable parameters for exact quantification of the early morning rise. Noninvasive ambulatory blood pressure monitoring (Space Labs 90207) was performed in 50 normotensive persons and in 52 patients with symptoms of orthostatic dysregulation. Twenty-two of the 52 patients showed normal and 19 showed sympathicotonic reactions in the orthostatic test by Thulesius. After smoothing the 24-h blood pressure profiles by Fourier analysis, the derivative was calculated from the profiles (differentiation) and the following parameters were determined: the beginning and the length of the early morning rise as well as time and point of the maximum rise. The maximum rise was compared to the difference between the nocturnal trough and the morning peak (absolute value) as well as to the percentage rise, where we found significant statistic correlations. Patients with sympathicotonic orthostatic dysregulation showed in comparison to the 50 normotensive persons a significantly lower (p < 0.05) maximum rise in blood pressure. Thus, Fourier analysis of 24-h blood pressure profiles allows determination of reliable parameters of the early morning rise in blood pressure and can be used for more precise differential diagnosis in patients with orthostatic dysregulation.

[Quantitative evaluation of myocardial perfusion with ultrafast magnetic resonance tomography]. / Quantitative Beurteilung der Myokardperfusion mit der ultraschnellen Magnetresonanztomographie.

With the advent of ultrafast Magnetic Resonance Imaging (MRI), it is now possible to produce images with high temporal resolution. This gives the opportunity to record the passage of the paramagnetic contrast material Gadolinium-DTPA through the tissue of the heart muscle, yielding information on regional myocardial perfusion. We assessed the accuracy of MRI to detect and quantify reductions in coronary flow secondary to stenosis in dogs and patients. Regional blood flow was measured in dogs by left atrial injection of microspheres labeled with different radioactive isotopes. Signal intensity (SI) curves were generated in regions of interest over the myocardium and the cavum of the left ventricle. A newly developed two-compartment model based on the indicator-dilution method was used for interpretation of the SI-curves. In an optimization process the free parameters of the model equation were fitted to the measured SI-curves. The following flow parameters were determined: model parameter Q*, time to peak intensity (T), maximum signal intensity (SImax) and mean transit time (MTT) as calculated from a gamma variate fit. Absolute blood flow values were calculated for the parameters MTT and Q* assuming that the intravascular volume represents 10% of the total myocardial tissue volume. Measurements were performed on a 1.5 T Magnetom SP (Siemens AG, Erlangen) using a Turbo Flash sequence (TR = 6.5 ms, TE = 3 ms, TI = 100 ms, Flip Winkel = 9 degrees). Endsystolic images (voxel size = 1.8, 2.7, 15 mm3) were taken with an 18-cm Helmholtz surface coil in the short-axis view. A Gd-DTPA bolus (0.05 mmol/kg) was injected into the left atrium of 3 anesthetized closed-chest dogs. From the myocardial SI-curves the different parameters of myocardial perfusion were compared with flow assessed by microsphere injection over a wide range of myocardial blood flows (from 0.04 ml/min/g to 7.6 ml/min/g). A third-order polynominal fit showed a good correlation for the parameter Q* and MTT, whereas T and SImax were found to have a poor correlation. The linear regression analysis for a limited range of < 2 ml/min/g showed a superior estimation of myocardial perfusion for the parameter Q* than MTT. Blood flow > 2 ml/min/g was significantly underestimated by the MRT-measurements, but the parameter Q* showed the smallest amount of the divergent changes.(ABSTRACT TRUNCATED AT 400 WORDS)

Nitrendipine vs. captopril in essential hypertension: effects on circadian blood pressure and left ventricular hypertrophy.

Both nitrendipine and captopril have been shown to reverse left ventricular hypertrophy in hypertensive patients. So far, no study allowed a true comparison of these drugs in this regard and with respect to their potential of reducing circadian blood pressure. Therefore, a total of 86 patients with newly diagnosed arterial hypertension and echocardiographic evidence of left ventricular hypertrophy underwent randomized treatment with captopril (n = 43) or nitrendipine (n = 43). Eighteen patients had to be put on a combination therapy of nitrendipine and captopril during the course of the study to control blood pressure effectively. Before and after the 6th and 38th weeks of treatment all patients underwent ambulatory 24-hour blood pressure monitoring, M-mode echo assessment of left ventricular mass and Doppler evaluation of left ventricular filling. The 24-hour blood pressure data were smoothed with a Fourier series and then compared with a normotensive reference profile with respect to blood pressure load and variability. The daytime and nighttime mean and the office blood pressure were also analyzed. Substance-specific profiles of action were obtained by subtracting the smoothed profiles after therapy from the profiles before therapy. After 38 weeks ambulatory blood pressure had decreased from 152 +/- 11/101 +/- 7 to 137 +/- 13/87 +/- 10 mm Hg on nitrendipine and from 147 +/- 11/99 +/- 6 to 134 +/- 13/89 +/- 9 mm Hg on captopril. The substance-specific profiles calculated for captopril and nitrendipine showed a balanced antihypertensive effect throughout the day and the night. The mean percentage decreases in left ventricular muscle mass under nitrendipine was 15% and did not differ significantly from the decrease of 21% under treatment with captopril (p < 0.001). There is no significant association between the reduction in blood pressure and the regression of left ventricular hypertrophy. In patients with disturbances of left ventricular diastolic function the early-to-late diastolic left ventricular flow ratio and the isovolumetric relaxation time were improved independent of the drug used. It is concluded that a long-term therapy with captopril and nitrendipine leads to a comparable degree of circadian blood pressure reduction and regression of hypertensive left ventricular hypertrophy.

[Ergotamine-induced rectal stenosis in a patient with long-term migraine]. / Ergotamin-induzierte Rektumstenose bei einer Patientin mit langjähriger Migräne.

A 36 year old woman was admitted to our hospital for treatment of a high-grade rectal stenosis of unknown origin. She had a history of migraine going back 10 years. On intensive questioning she admitted using up to 5 ergotamine-containing suppositories a day. On the basis of history and clinical investigations the rectal stenosis must be connected with the abuse of ergotamine-containing suppositories. This case demonstrates that patients with an unexplained rectal syndrome should be asked for analgetics-containing suppositories specifically. Only discontinuation of treatment in time can preserve the patient from development of a rectal stenosis. In case of a rectal stenosis surgical treatment can be avoided by means of endoscopic controlled dilatation.

[Digital subtraction angiocardiography: reliability of densitometric determination of left ventricular volume and ejection fraction]. / Digitale Subtraktionsangiokardiographie: Zuverlässigkeit densitometrischer Bestimmung des linksventrikulären Volumens und der Ejektionsfraktion.

The angiographic assessment of left ventricular volume (LV) and ejection fraction (EF) by means of the area-length method (ALM) is based upon geometric assumptions, which might lead to erroneous results. With the development of digital subtraction angiocardiography in real-time, densitometric procedures of calculating left ventricular parameters can be used on-line. This study examines both reliability and accuracy of a densitometric technique for evaluating LV and EF in comparison to the single-plane ALM. Contrast images of heart casts and left ventricular angiograms of 54 patients suffering from different cardiac diseases were obtained by the image acquisition and processing system Polytron 1000 VR (Siemens AG, Erlangen, FRG). Digital images of both heart casts and patients were evaluated densitometrically and geometrically by two independent observers. In the phantom study the densitometric method exhibited a significantly (p < 0.01) better agreement with the true values than the ALM. The evaluation of left ventricular angiograms in patients comparing densitometry with the ALM demonstrated a relatively high residual deviation (enddiastolic volume Syx = +/- 27 ml, endsystolic volume Syx = +/- 19.4 ml). This is mainly due to systematic, method-related errors of densitometry and the morphometric technique. The intra- and interobserver variability in calculating EF showed a significantly (p < 0.05) smaller residual deviation for densitometry than for ALM; no significant differences were found for the calculation of LV. In conclusion, we demonstrated that the presented densitometric technique offers an objective and simple means of determining LV and EF with comparable reliability and validity to the area-length method.

A new approach for evaluating circadian blood pressure levels and variability from 24 h ambulatory blood pressure profiles.

In 24 h blood pressure monitoring the severity of arterial hypertension is generally classified on the basis of the arithmetic mean of the diastolic blood pressure between 6 AM and 10 PM. In the present study Fourier analysis was used for evaluation of circadian blood pressure level and variability. A common reference profile was calculated on the basis of a group of 50 normotensive profiles. This reference profile is characterized by the fact that the sum of the squares of the distances between the individual profiles and the reference profile is a minimum. The individual 24 h profiles of 103 patients with untreated arterial hypertension were also each described by a Fourier series and were then compared with the normotensive reference profile. The comparison was made not only with respect to the absolute pressure over 24 h but also with respect to the circadian fluctuations in blood pressure. Our results show that the Fourier analysis of 24 h blood pressure profiles presented here can be used for more precise evaluation of 24 h blood pressure profiles.

[Ambulatory blood pressure monitoring: significance of blood pressure variability for progression of heart hypertrophy]. / Ambulantes Blutdruckmonitoring: Bedeutung der Blutdruckvariabilität für die Progression einer Herzhypertrophie.

It is known that ambulatory blood-pressure monitoring gives a better prediction of target organ damage and prognosis than clinical blood pressure. Many studies have found a closer correlation for ambulatory blood pressure with left ventricular hypertrophy than clinical blood pressure. One question that is discussed controversely is whether the variability of blood pressure is also a determinant of target organ damage independent of the average level. In 52 patients with elevated casual blood pressure a 24-h ambulatory blood-pressure measurement (Space Labs 90202) was performed and left ventricular hypertrophy was evaluated by M-mode echocardiography. The following parameters of blood pressure variability were calculated from the profiles: the standard deviation of the mean value, the variation coefficient and the parameter of variability as proposed by Schächinger et al. Furthermore a Fourier analysis of the blood pressure data was performed to quantify blood pressure variability. We found no statistically significant correlation between blood pressure variability and left ventricular mass. However, systolic and diastolic blood pressure level showed a significant correlation with left ventricular hypertrophy (r = 0.45 and r = 0.49, p < 0.05). Thus, blood pressure variability as calculated from the ambulatory, non-invasive blood pressure monitoring is a poor predictor for secondary damage of the heart.

[Analysis of circadian blood pressure profiles using Fourier analysis]. / Analyse von zirkadianen Blutdruckprofilen mit Hilfe der Fourieranalyse.

Blood pressure is subject to considerable circadian and situational fluctuation. In 24-h blood-pressure monitoring the severity of arterial hypertension is generally classified on the basis of the arithmetic mean of the diastolic blood pressure between 07.00 and 22.00 hours. In the present study Fourier analysis was used to generate continuous functions from the discrete blood-pressure values measured during 24-h blood-pressure monitoring in a sample of 50 normotensive persons aged from 25 to 80 years. A common reference profile was then constructed from these 50 profiles. This reference profile is characterized by the fact that the sum of the integrals over the squares of the distances between the individual profiles and the reference profile is the smallest possible. The reference profile is thus the best approximation of all normotensive profiles and practically ignores individual blood pressure fluctuations. The individual 24-h profiles of 80 patients with untreated arterial hypertension were classified on the basis of the daytime mean as mild, moderate or severe arterial hypertension and also each is described by a Fourier series. The pathological profiles were then compared with the normotensive reference profile. The comparison was made, not only with respect to the absolute pressure over 24 h, but also with respect to the circadian fluctuations in blood pressure. Comparison of the profiles shows that the Fourier analysis of 24-h blood-pressure profiles presented here permits reliable analysis and classification of arterial hypertension and can thus be used for more precise evaluation of the influence of antihypertensives on 24-h blood-pressure profiles.

[The determination of myocardial perfusion parameters from coronary angiograms by analysing the passage of contrast media through the myocardium]. / Bestimmung von Parametern der Myokard-perfusion aus Koronarangiogrammen durch Analyse der myokardialen Kontrastimittelpassage.

Digital subtraction angiography allows to record the passage of contrast material through the myocardium as a time-intensity curve, the so-called densogram. Temporal changes of contrast material in a region of interest are described by a differential equation. The free parameters of this model equation are determined by a curve-fitting procedure. Four parameters of the model equation are expected to be connected with myocardial perfusion. We intended to verify this assumption by comparing changes in coronary blood flow (CBF) with changes of the different parameters. The angiograms of 9 patients without coronary artery disease were studied before and after intravenous application of dipyridamole. Changes in CBF were assessed by a videodensitometric method. Linear regressions between changes of CBF and the parameters of the differential equation show the following results: one parameter of the model equation--the ratio of regional blood flow and regional volume--remarkably underestimated CBF changes. This can be explained by an increase of regional blood volume after increased CBF due to dipyridamole. However, a close correlation was found between CBF changes and the remaining parameters. This study suggests that digital measurements from coronary angiograms using the presented model equation provide a means of assessing myocardial perfusion.